Abnormal Function Research Articles

Application of genetic testing for the diagnosis of von Willebrand disease.

von Willebrand disease (VWD) is the most frequent inherited bleeding disorder with an estimated symptomatic prevalence of 1 per 1,000 in the general population. VWD is characterized by defects in the quantity, quality, or multimeric structure of von Willebrand factor (VWF), a glycoprotein being hemostatically essential in circulation. It is classified into three principal types; Low VWF/type 1 with partial quantitative deficiency of VWF, type 3 with virtual absence of VWF, and type 2 with functional abnormalities of VWF, being classified as 2A, 2B, 2M and 2N. A new VWD type has been recently discussed by the joint ASH/ISTH/NHF/WFH 2021 guidelines (i.e., type 1C) indicating patients with quantitative deficiency due to an enhanced VWF clearance. With the advent of next-generation sequencing technologies, the process of genetic diagnosis has substantially changed and improved accuracy. Therefore, nowadays patients with type 3 and severe type 1 VWD can benefit from genetic testing as much as type 2. Specifically, genetic testing can be used to confirm or differentiate a VWD diagnosis, as well as to provide genetic counseling. The focus of this manuscript is to discuss the current knowledge on VWD molecular pathophysiology and the application of genetic testing for VWD diagnosis.

RUFY4 deletion prevents pathological bone loss by blocking endo-lysosomal trafficking of osteoclasts

Mature osteoclasts degrade bone matrix by exocytosis of active proteases from secretory lysosomes through a ruffled border. However, the molecular mechanisms underlying lysosomal trafficking and secretion in osteoclasts remain largely unknown. Here, we show with GeneChip analysis that RUN and FYVE domain-containing protein 4 (RUFY4) is strongly upregulated during osteoclastogenesis. Mice lacking Rufy4 exhibited a high trabecular bone mass phenotype with abnormalities in osteoclast function in vivo. Furthermore, deleting Rufy4 did not affect osteoclast differentiation, but inhibited bone-resorbing activity due to disruption in the acidic maturation of secondary lysosomes, their trafficking to the membrane, and their secretion of cathepsin K into the extracellular space. Mechanistically, RUFY4 promotes late endosome-lysosome fusion by acting as an adaptor protein between Rab7 on late endosomes and LAMP2 on primary lysosomes. Consequently, Rufy4-deficient mice were highly protected from lipopolysaccharide- and ovariectomy-induced bone loss. Thus, RUFY4 plays as a new regulator in osteoclast activity by mediating endo-lysosomal trafficking and have a potential to be specific target for therapies against bone-loss diseases such as osteoporosis.

Cold-evoked potentials in Fabry disease and polyneuropathy

BackgroundFabry disease (FD) causes cold-evoked pain and impaired cold perception through small fiber damage, which also occurs in polyneuropathies (PNP) of other origins. The integrity of thinly myelinated fibers and the spinothalamic tract is assessable by cold-evoked potentials (CEPs). In this study, we aimed to assess the clinical value of CEP by investigating its associations with pain, autonomic measures, sensory loss, and neuropathic signs.MethodsCEPs were examined at the hand and foot dorsum of patients with FD (n = 16) and PNP (n = 21) and healthy controls (n = 23). Sensory phenotyping was performed using quantitative sensory testing (QST). The painDETECT questionnaire (PDQ), FabryScan, and measures for the autonomic nervous system were applied. Group comparisons and correlation analyses were performed.ResultsCEPs of 87.5% of the FD and 85.7% of the PNP patients were eligible for statistical analysis. In all patients combined, CEP data correlated significantly with cold detection loss, PDQ items, pain, and autonomic measures. Abnormal CEP latency in FD patients was associated with an abnormal heart frequency variability item (r = −0.684; adjusted p = 0.04). In PNP patients, CEP latency correlated significantly with PDQ items, and CEP amplitude correlated with autonomic measures (r = 0.688, adjusted p = 0.008; r = 0.619, adjusted p = 0.024). Furthermore, mechanical pain thresholds differed significantly between FD (gain range) and PNP patients (loss range) (p = 0.01).ConclusionsAbnormal CEPs were associated with current pain, neuropathic signs and symptoms, and an abnormal function of the autonomic nervous system. The latter has not been mirrored by QST parameters. Therefore, CEPs appear to deliver a wider spectrum of information on the sensory nervous system than QST alone.

Coronary microvascular dysfunction and atrial reservoir function

BackgroundCoronary microvascular dysfunction (CMD) refers to structural and functional abnormalities of the coronary microcirculation, which may be diagnosed using invasive coronary physiology. CMD is responsible for impaired diastolic cardiac function. It has recently been suggested that left atrial strain (LASr) represents a highly sensitive tool for detecting cardiac diastolic function abnormalities. Accordingly, the aim of this study was to investigate the relationship between CMD and LASr.MethodsConsecutively enrolled patients with non-obstructed coronary arteries (NOCA) underwent CMD and LASr evaluation by invasive thermodilution and noninvasive echocardiography, respectively.ResultsForty-two (42) patients were included, out of which 26 presented with CMD. There were no significant differences between CMD-positive and negative patients in terms of clinical and echocardiographic characteristics. LASr was significantly reduced in patients with CMD (24.6% ± 6.1 vs. 30.3 ± 7.8%, p = 0.01). A moderate correlation was observed between coronary flow reserve and LAsr (r = 0.47, p = 0.002). A multivariate logistic regression analysis demonstrated that CMD was independently associated with LASr (OR = 0.88, 95%CI 0.78–0.99.135, p = 0.04). A LASr cut-off of 25.5% enabled an optimal classification of patients with or without CMD.ConclusionPatients with NOCA and CMD had a significantly reduced LASr compared with patients without CMD, suggesting the early impairment of diastolic function in these patients.

Advancements and Future Directions in Prevention Based on Evaluation for Individuals With Clinical High Risk of Psychosis: Insights From the SHARP Study.

This review examines the evolution and future prospects of prevention based on evaluation (PBE) for individuals at clinical high risk (CHR) of psychosis, drawing insights from the SHARP (Shanghai At Risk for Psychosis) study. It aims to assess the effectiveness of non-pharmacological interventions in preventing psychosis onset among CHR individuals. The review provides an overview of the developmental history of the SHARP study and its contributions to understanding the needs of CHR individuals. It explores the limitations of traditional antipsychotic approaches and introduces PBE as a promising framework for intervention. Three key interventions implemented by the SHARP team are discussed: nutritional supplementation based on niacin skin response blunting, precision transcranial magnetic stimulation targeting cognitive and brain functional abnormalities, and cognitive behavioral therapy for psychotic symptoms addressing symptomatology and impaired insight characteristics. Each intervention is evaluated within the context of PBE, emphasizing the potential for tailored approaches to CHR individuals. The review highlights the strengths and clinical applications of the discussed interventions, underscoring their potential to revolutionize preventive care for CHR individuals. It also provides insights into future directions for PBE in CHR populations, including efforts to expand evaluation techniques and enhance precision in interventions.

Considerations on the Evolutionary Biology and Functions of Eosinophils: What the 'Haeckel'?

The origins and evolution of the eosinophilic leukocyte has received only scattered attention since Paul Ehrlich first named this granulocyte. Studies suggest that myeloperoxidase, expressed by granulocytes, and eosinophil peroxidase diverged some 60-70 million years ago, but invertebrate to vertebrate evolution of the eosinophil lineage is unknown. Vertebrate eosinophils have been characterized extensively in representative species at light microscopic, ultrastructural, genetic, and biochemical levels. Understanding of eosinophil function continues to expand and includes to date regulation of "Local Immunity And/Or Remodeling/Repair" (the so-called LIAR hypothesis), modulation of innate and adaptive immune responses, maintenance of tissue and metabolic homeostasis, and under pathologic conditions, inducers of tissue damage, repair, remodeling, and fibrosis. This contrasts with their classically considered primary roles in host defense against parasites and other pathogens, and involvement in T-helper 2 inflammatory and immune responses. The eosinophils' early appearance during evolution and continued retention within the innate immune system across taxa illustrate their importance during evolutionary biology. However, successful pregnancies in eosinophil-depleted humans/primates treated with biologics, host immune responses to parasites in eosinophil-deficient mice, and the absence of significant developmental or functional abnormalities in eosinophil-deficient mouse strains under laboratory conditions, raise questions of the continuing selective advantages of the eosinophil lineage in mammals and humans. The objectives of this review are to provide an overview on evolutionary origins of eosinophils across the animal kingdom, discuss some of their main functions in the context of potential evolutionary relevance, and highlight the need for further research on eosinophil functions and functional evolution.

Indian Thyroid society expert consensus on salt Iodisation

ABSTRACT Iodine, an essential micronutrient, is crucial for the production of thyroid hormones - triiodothyronine(T3) and thyroxine(T4). Thyroid hormones regulate the optimum mental development, physical growth and development, regulation of body metabolism, heat generation, and maintenance of body temperaturein an individual. Geological processes like flooding, soil erosion, deforestation, and rivers changing course, deplete the surface soil of iodine, as it is present in the top layers of soil and easily soluble in water. As a result, the population residing in the area with iodinedeficient soil, becomes susceptible to a spectrum of functional and developmental abnormalities due to dietary deficiency of iodine. Universal Salt Iodization (USI) for prevention of IDDs in India is a public health success story. The adoption of the salt iodization strategy serves as a textbook example of the journey of an intervention through the iterative loop of research to policy to programme. Salt iodization has proved to be a safe, accessible, available, affordable, and cost-effective strategy to address the burden of IDDs in India. India has been at the forefront of the efforts to control IDDs globally. India is on its way to achieving the target of > 90 percent household coverage of adequately iodized salt. Revised Food Safety and Standards (Fortification of Foods) Regulations released in 2019 introduced an upper limit for iodine concentration in salt, the adequate iodine level required at the production and consumer level, including the distribution channel at 15 – 30 ppm. Universal Salt Iodisation (USI) is India's public health success story. There is a need to consolidate progress so far and focus on strategy to reach the “last mile”. Sustainable elimination of Iodine Deficiency Disorders (IDDs) with Universal Salt Iodisation (USI) being the primary strategy needs to also factor in harmonisation with salt reduction strategy for control of non-communicable diseases.

Exploring the Link Between Autophagy-Lysosomal Dysfunction and Early Heterotopic Ossification in Tendons.

Heterotopic ossification (HO), the pathological formation of bone within soft tissues such as tendon and muscle, is a notable complication resulting from severe injury. While soft tissue injury is necessary for HO development, the specific molecular pathology responsible for trauma-induced HO remains a mystery. The previous study detected abnormal autophagy function in the early stages of tendon HO. Nevertheless, it remains to be determined whether autophagy governs the process of HO generation. Here, trauma-induced tendon HO model is used to investigate the relationship between autophagy and tendon calcification. In the early stages of tenotomy, it is observed that autophagic flux is significantly impaired and that blocking autophagic flux promoted the development of more rampant calcification. Moreover, Gt(ROSA)26sor transgenic mouse model experiments disclosed lysosomal acid dysfunction as chief reason behind impaired autophagic flux. Stimulating V-ATPase activity reinstated both lysosomal acid functioning and autophagic flux, thereby reversing tendon HO. This present study demonstrates that autophagy-lysosomal dysfunction triggers HO in the stages of tendon injury, with potential therapeutic targeting implications for HO.

A mandibular advancement device attenuates the abnormal morphology and function of mitochondria from the genioglossus in obstructive sleep apnea-hypopnea syndrome rabbits.

Obstructive sleep apnea hypopnea syndrome (OSAHS) is a serious and potentially life-threatening disease. Mandibular advancement device (MAD) has the characteristics of non-invasive, comfortable, portable and low-cost, making it the preferred treatment for mild-to-moderate OSAHS. Our previous studies found that abnormal contractility and fibre type distribution of the genioglossus could be caused by OSAHS. However, whether the mitochondria participate in these tissue changes is unclear. The effect of MAD treatment on the mitochondria of the genioglossus in OSAHS is also uncertain. To examine the morphology and function of mitochondria from the genioglossus in a rabbit model of obstructive sleep apnea-hypopnea syndrome (OSAHS), as well as these factors after insertion of a mandibular advancement device (MAD). Thirty male New Zealand white rabbits were randomised into three groups: control, OSAHS and MAD, with 10 rabbits in each group. Animals in Group OSAHS and Group MAD were induced to develop OSAHS by injection of gel into the submucosal muscular layer of the soft palate. The rabbits in Group MAD were fitted with a MAD. The animals in the control group were not treated. Further, polysomnography (PSG) and cone-beam computed tomography (CBCT) scan were used to measure MAD effectiveness. CBCT of the upper airway and PSG suggested that MAD was effective. Rabbits in the three groups were induced to sleep for 4-6 h per day for eight consecutive weeks. The genioglossus was harvested and detected by optical microscopy and transmission electron microscopy. The mitochondrial membrane potential was determined by laser confocal microscopy and flow cytometry. Mitochondrial complex I and IV activities were detected by mitochondrial complex assay kits. OSAHS-like symptoms were induced successfully in Group OSAHS and rescued by MAD treatment. The relative values of the mitochondrial membrane potential, mitochondrial complex I activity and complex IV activity were significantly lower in Group OSAHS than in the control group; however, there was no significant difference between Group MAD and the control group. The OSAHS-induced injury and the dysfunctional mitochondria of the genioglossus muscle were reduced by MAD treatment. Damaged mitochondrial structure and function were induced by OSAHS and could be attenuated by MAD treatment.

Coronary Microvascular Disease in Women: Epidemiology, Mechanisms, Evaluation, and Treatment.

Coronary microvascular dysfunction (CMD) involves functional or structural abnormalities of the coronary microvasculature resulting in dysregulation of coronary blood flow (CBF) in response to myocardial oxygen demand. This perfusion mismatch causes myocardial ischemia, which manifests in patients as microvascular angina (MVA). CMD can be diagnosed non-invasively via multiple imaging techniques or invasively using coronary function testing (CFT), which assists in determining the specific mechanisms involving endothelium-independent and dependent epicardial and microcirculation domains. Unlike traditional coronary artery disease (CAD), CMD can often occur in patients without obstructive atherosclerotic epicardial disease, which can make the diagnosis of CMD difficult. Moreover, MVA due to CMD is more prevalent in women and carries increased risk of future cardiovascular events. Successful treatment of symptomatic CMD is often patient-specific risk factor and endotype targeted. This article aims to review newly identified mechanisms and novel treatment strategies for managing CMD, and outline sex-specific differences in the presentation and pathophysiology of the disease.

Identification of Iodotyrosines as Novel Substrates for the Thyroid Hormone Transporter MCT8.

Background: Monocarboxylate transporter 8 (MCT8) is the most specific thyroid hormone transporter identified to date, deficiency of which has been associated with severe intellectual and motor disability and abnormal serum thyroid function tests. However, it is presently unknown if MCT8, similar to other thyroid hormone transporters, also accepts additional substrates, and if disruption of their transport may contribute to the observed phenotype. Methods: In this study, we aimed to identify such substrates by applying liquid chromatography-mass spectrometry-based metabolome analysis in lysates of control and MCT8-overexpressing Xenopus oocytes. A subset of identified candidate substrates were validated by direct transport studies in transiently transfected COS-1 cells and human fibroblasts, which endogenously express MCT8. Moreover, transport characteristics were determined, including transport saturation and cis-inhibition potency of thyroid hormone transport. Results: Metabolome analysis identified 21 m/z ratios, corresponding to 87 candidate metabolites, with a 2.0-times differential abundance in MCT8-injected oocytes compared with controls. These metabolites included 3,5-diiodotyrosine (DIT) and several amino acids, including glutamate and glutamine. In accordance, MCT8-expressing COS-1 cells had 2.2-times lower intracellular accumulation of [125I]-DIT compared with control cells. This effect was largely blocked in the presence of 3,3',5-triiodothyronine (T3) (IC50: 2.5 ± 1.5 µM) or thyroxine (T4) (IC50: 5.8 ± 1.3 µM). Conversely, increasing concentrations of DIT enhanced the accumulation of T3 and T4. The MCT8-specific inhibitor silychristin increased the intracellular accumulation of DIT in human fibroblasts. COS-1 cells expressing MCT8 also exhibited a 50% reduction in intracellular accumulation of [125I]-3-monoiodotyrosine (MIT). In contrast, COS-1 cells expressing MCT8 did not alter the intracellular accumulation of [3H]-glutamate or [3H]-glutamine. However, studies in human fibroblasts showed a 1.5-1.9 times higher glutamate uptake in control fibroblasts compared with fibroblasts derived from patients with MCT8 deficiency, which was not affected in the presence of silychristin. Conclusions: Taken together, our results suggest that the iodotyrosines DIT and MIT can be exported by MCT8. MIT and DIT interfere with MCT8-mediated transport of thyroid hormone in vitro and vice versa. Future studies should elucidate if MCT8, being highly expressed in thyroidal follicular cells, also transports iodotyrosines invivo.

Analysis of Risk Factors for Death in the Coronavirus Disease 2019 (COVID-19) Population: Data Analysis from a Large General Hospital in Anhui, China.

During the coronavirus disease 2019 (COVID-19) pandemic, clinical prevention, early diagnosis, and hematological monitoring were challenging areas.This study aims to comparerisk factors and hematological and biochemical data in non-survivor group patientswith COVID-19 versus survivor group patients.A total of 204 patients with COVID-19 were selected as research subjects from December 2022 to January 2023. We analyzed the age, sex, time from onset to admission, and laboratory test indicators upon admission. The differences between surviving and deceased patients and mortality-related risk factors were examined. Among the 204 patients, 168 survived, whereas 36 died during hospitalization. Significant differences were observed between the two groups with COVID-19 across various factors, including age (p < 0.0001), WBC count (p < 0.0001), RBC count (p < 0.05), neutrophils (p < 0.0001), lymphocytes (p < 0.05), mean corpuscular hemoglobin concentration (MCHC) (p < 0.0001), RBC distribution width-standard deviation (RDW-SD) (p < 0.0001), RBC distribution width coefficient of variation (RDW-CV) (p < 0.0001), aspartate aminotransferase (AST) (p < 0.05), albumin (ALB) (p < 0.0001), creatinine (CR) (p < 0.0001), uric acid (UA) (p < 0.0001), blood urea nitrogen (BUN) (p < 0.0001), plasma thrombin time (TT) (p < 0.05), prothrombin time (PT) (p < 0.0001), and D-dimer (p < 0.0001). Multivariate logistic analysis revealed that older age, CR, UA, and ALB were independent factors associated with death (p < 0.05).Elderly patients with underlying diseases, abnormal routine blood test indices, and abnormal renal function and coagulation indices are at an increased worse prognosisand should be identified early. Age, UA, CR, and ALB can be used as predictors to assess the worse prognosisin the hospital.

Basic and Informative Photographic Standards for Cleft Lip Patients

Background: Standardized and reliable medical photographs are crucial for preoperative and postoperative comparisons and academic communication in the medical field. There is limited research on photographic techniques in patients with cleft lip. Deformities of the lip and nose in patients with cleft lip are not only associated with morphological abnormalities but also with abnormalities of muscle function. Methods: Considering the morphology and function of the lips and nose in cleft lip patients, the study captured the deformity of cleft lip patients in 6 positions: frontal view, 45 degrees left-right tilted side view, 90 degrees left-right tilted side view, and basal view, and in 5 facial expressions: tightly closed lips, slightly open mouth, smiling, teeth bared, and pout. Results: In 6 different positions and 5 different expressions, we took pictures of lip and nasal deformities covering most of the common deformities in patients with cleft lip, such as white lip scarring, interruption of continuity of vermillion border, lip prolapse, asymmetric corners of the mouth, collapsed ala nasi, loss of the nasal base and deviated nasal septum. Conclusions: This paper suggests a set of effective, easy-to-follow, and precise photographic protocols to assist cleft lip surgeons in capturing suitable and informative, high-quality 2D digital photographs. Level of Evidence: Level—V.

Clinical thinking and instrumental diagnostics in the late stage of hypersensitive pneumonitis

The existing inertia of clinical thinking in establishing a diagnosis, even in the presence of instrumental and valid diagnostic criteria, does not always allow for a reconsideration of the diagnosis given to the patient, especially several years ago. Existing clinical recommendations for certain nosological forms, which currently play a decisive role in diagnostics, treatment, and quality assessment of medical services, may not be fully applicable to all patients with a specifi c disease. As an illustration of the above, a clinical example of a patient diagnosed with “bronchial asthma” about 15 years ago without diagnostic criteria for this condition is provided. Three years ago, on a hospitalization described in the article, a chest computed tomography scan revealed typical signs of diff use pulmonary pneumonia. However, this did not allow for a change in the stereotypical diagnostic view and the correct diagnosis and appropriate treatment, including in a specialized pulmonology department. As a result, the disease progressed with the development of complications in the form of severe respiratory and heart failure. Only a reassessment of clinical symptoms, including inspiratory crackles, chest CT scan (diffuse opacity reduction resembling ground glass), and restrictive abnormalities in external respiration function without obstructive components, allowed for a reevaluation of the diagnosis and the prescription of pathogenetic therapy with glucocorticoids in combination with treatment for respiratory and heart failure, leading to rapid clinical improvement.

Characteristics and Neural Mechanisms of Sleep-Wake Disturbances After Traumatic Brain Injury.

Sleep-wake disturbances (SWDs) are one of the most common complaints following traumatic brain injury (TBI). The high prevalence and socioeconomic burden of SWDs post-TBI have only been recognized in the past decade. Common SWDs induced by TBI include excessive daytime sleepiness (EDS), hypersomnia, insomnia, obstructive sleep apnea (OSA), and circadian rhythm sleep disorders. Sleep disturbances can significantly compromise quality of life, strain interpersonal relationships, diminish work productivity, exacerbate other clinical conditions, and impede the rehabilitation process of TBI patients. Consequently, the prompt regulation and enhancement of sleep homeostasis in TBI patients is of paramount importance. Although studies have shown that abnormal neural network function, neuroendocrine changes, disturbance of sleep-wake regulators, and immune inflammatory responses related to brain structural damage induced by TBI are involved in the development of SWDs, the exact neuropathological mechanisms are still poorly understood. Therefore, we systematically review the current clinical and experimental studies on the characteristics and possible neural mechanisms of post-TBI SWDs. Elucidating the neural underpinnings of post-TBI SWDs holds the potential to diversify and enhance therapeutic approaches for these conditions. Such advancements could hasten the recuperation of TBI patients and ameliorate their overall quality of life. It is our aspiration that departments specializing in neurosurgery, rehabilitation, and neuropsychiatry will be able to recognize and address these conditions promptly, thereby facilitating the healing journey of affected individuals.

Aminotransferase trends in propionic acidemia

AbstractPropionic acidemia is a metabolic condition with multiple serious acute and chronic presentations that require strict monitoring. Literature on liver function abnormalities in propionic acidemia is scarce, and the mechanism of liver impairment in this condition remains unclear. Currently, there is no indication for liver‐function tests during follow‐up and their clinical or prognostic utility is unknown. This study aimed to determine aminotransferase trends in individuals with propionic acidemia at a single institution. We retrospectively evaluated and classified the aminotransferases of 12 patients with propionic acidemia during hospital admissions and routine office visits. The present findings suggest that aminotransferase elevations are very common in this population and can persist beyond acute illness. During hospitalization events, aminotransferases were not a predictor of severity, duration of stay, and readmission within 1 month. Understanding aminotransferase trends in these patients will help clinicians make decisions in the acute setting and potentially in the follow‐up of new therapies.

Assessment of cerebral venous sinus: Anatomical and functional diagnostic performance of three-dimensional reconstruction models based on venous sinus MRI and CT images

Venous sinus stenosis is commonly observed in patients presenting with pulsatile tinnitus (PT). While magnetic resonance imaging (MRI) and computed tomography (CT) are commonly used for assessing venous sinus geometries, the preferred modality remains unclear. In this study, we reconstructed the three-dimensional (3D) geometries of the venous sinus using MRI and CT imaging data from 20 PT patients. We conducted comparisons of the anatomical features of the venous sinus through case-wise analysis and anatomic geometrical parameter-wise analysis. Our findings indicate that by taking the geometries from CT as a reference, MRI could provide a better illustration of venous structure, primarily due to a stronger flow signal concentrated in the vascular tree. We observed high agreements in anatomic parameters measured from 3D geometries reconstructed based on CT and MRI in 19 out of 20 cases. Notably, the cross-sectional area of the sinus and segment length displayed the highest consistency, with a mean difference of -5.01% and 6.5% between modalities, respectively. In addition, we noticed that 55% of cases exhibited consistency in analyzing the confluence of the sinus, while variants of connectivity and collateral branching were observed between CT and MRI. Importantly, CT-based geometric reconstruction provided better detail of inflow side branches in the straight sinus, whereas MRI preserved more side branches of outflow in the downstream sinus. It is important to note that CT-based evaluation may be affected by the bone structures surrounding the venous sinus, whereas MRI-based evaluation focuses on blood flow to the segments, potentially indicating both anatomical and functional abnormalities.

Mitochondrial dysfunction in brain tissues and Extracellular Vesicles Fragile X-associated tremor/ataxia syndrome.

Mitochondrial impairments have been implicated in the pathogenesis of Fragile X-associated tremor/ataxia syndrome (FXTAS) based on analysis of mitochondria in peripheral tissues and cultured cells. We sought to assess whether mitochondrial abnormalities present in postmortem brain tissues of patients with FXTAS are also present in plasma neuron-derived extracellular vesicles (NDEVs) from living carriers of fragile X messenger ribonucleoprotein1 (FMR1) gene premutations at an early asymptomatic stage of the disease continuum. We utilized postmortem frozen cerebellar and frontal cortex samples from a cohort of eight patients with FXTAS and nine controls and measured the quantity and activity of the mitochondrial proteins complex IV and complex V. In addition, we evaluated the same measures in isolated plasma NDEVs by selective immunoaffinity capture targeting L1CAM from a separate cohort of eight FMR1 premutation carriers and four age-matched controls. Lower complex IV and V quantity and activity were observed in the cerebellum of FXTAS patients compared to controls, without any differences in total mitochondrial content. No patient-control differences were observed in the frontal cortex. In NDEVs, FMR1 premutation carriers compared to controls had lower activity of Complex IV and Complex V, but higher Complex V quantity. Quantitative and functional abnormalities in mitochondrial electron transport chain complexes IV and V seen in the cerebellum of patients with FXTAS are also manifest in plasma NDEVs of FMR1 premutation carriers. Plasma NDEVs may provide further insights into mitochondrial pathologies in this syndrome and could potentially lead to the development of biomarkers for predicting symptomatic FXTAS among premutation carriers and disease monitoring.

Normative Values of Echocardiographic Chamber Size and Function in Older Healthy Adults: The Multi-Ethnic Study of Atherosclerosis.

Echocardiographic (2-dimensional echocardiography) thresholds indicating disease or impaired functional status compared with normal physiological aging in individuals aged ≥65 years are not clearly defined. In the present study, we sought to establish standard values for 2-dimensional echocardiography parameters related to chamber size and function in older adults without cardiopulmonary or cardiometabolic conditions. In this cross-sectional study of 3032 individuals who underwent 2-dimensional echocardiography at exam 6 in the MESA (Multi-Ethnic Study of Atherosclerosis), 608 participants fulfilled our inclusion criteria of healthy aging, with normative values defined as the mean ± 1.96 standard deviation and compared across sex and race and ethnicity. Functional status measures included NT-proBNP (N-terminal pro-B-type natriuretic peptide), 6-minute walk distance, and Kansas City Cardiomyopathy Questionnaire. Prognostic performance using MESA cutoffs was compared with established guideline cutoffs using time-to-event analysis. The normative aging cohort (69.5±7.0 years, 46.2% male, 47.5% White) had lower NT-proBNP, higher 6-minute walk distance, and higher (better) Kansas City Cardiomyopathy Questionnaire summary values. Women had significantly smaller chamber sizes and better biventricular systolic function. White participants had the largest chamber dimensions, whereas Chinese participants had the smallest, even after adjustment for body size. Current guidelines identified 81.6% of healthy older adults in MESA as having cardiac abnormalities. Among a large, diverse group of healthy older adults, we found significant differences in cardiac structure and function by sex and race/ethnicity, which may signal sex-specific cardiac remodeling with advancing age. It is crucial for existing guidelines to consider the observed and clinically significant differences in cardiac structure and function associated with healthy aging. Our study highlights that existing guidelines, which grade abnormalities in echocardiographic cardiac chamber size and function based on younger individuals, may not adequately address the anticipated changes associated with normal aging.

Nebulized inhalation of nintedanib-loaded biomimetic nano-liposomes attenuated bleomycin-induced interstitial lung fibrosis in mice

Idiopathic pulmonary fibrosis (IPF) is an irreversible interstitial lung disease with a poor prognosis. However, there are currently few drugs available for its treatment. Nintedanib is clinically effective but is associated with gastrointestinal adverse effects and weight loss. Due to drug intolerance, the overall outcomes of nintedanib therapy are substantially compromised in quite a few patients. In the present study, we synthesized nintedanib-loaded biomimetic liposomes (Nin-lipo) to improve the antifibrotic efficacy and drug tolerance of nintedanib. It was observed that nebulized inhalation of small doses of Nin-lipo (2 mg/kg) resulted in greater delivery efficiency and higher drug concentrations in lung tissue than conventional oral doses of nintedanib (60 mg/kg). Furthermore, Nin-lipo significantly inhibited bleomycin (BLM)-induced pulmonary fibrosis and improved lung function in mice. The possible molecular mechanism of anti-fibrosis by Nin-lipo was investigated. Nin-lipo was found to act mechanistically on alveolar macrophages via alveolar surfactant proteins A and D (SP-A/D) by simulating pulmonary surfactants and inhibiting the polarization of M2 macrophages. These effects thereby reduced the secretion of transforming growth factor 1 (TGF-β1) in macrophages. Moreover, Nin-lipo demonstrated significant efficacy against weight loss and liver function abnormalities in a mouse model caused by nintedanib. Therefore, nebulized Nin-lipo could greatly improve the antifibrotic efficacy of nintedanib while maintaining an excellent safety profile. Nin-lipo could potentially be developed as a new therapy for IPF.