Silent Changes Research Articles

The Effects of Pediatric Acute Lymphoblastic Leukemia Treatment on Cardiac Repolarization.

Background: In recent years, cardiac dysfunction in childhood cancer survivors has become an important issue. Studies are focusing on identifying means for the early identification of patients at risk. Considering this, our study aims to investigate 24-hour Holter electrocardiogram (ECG) repolarization changes throughout doxorubicin (DOX) and cyclophosphamide (CPM) administration in pediatric patients treated for acute lymphoblastic leukemia (ALL). Methods: This was an investigator-driven, single-center, prospective, observational study. Enrolled children had a baseline bedside ECG examination performed before starting chemotherapy (T0). Serial Holter ECG examinations were conducted at three moments during their treatment protocol: day 8 (T1), day 29 (T2), and day 36 (T3). This study evaluated several ECG repolarization parameters, such as the QT interval, corrected QT interval (QTc), and QTc dispersion, as well as ST segment variations. Results: We evaluated 37 children diagnosed with ALL. The T0 examination revealed that over a third of patients had a resting heart rate (HR) outside the normal range for their age and sex. During chemotherapy, statistically significant increases in both HR as well as QT and QTc dispersion values were noticed, especially during the first DOX administration. What is more, a significant increase in the percentage of patients with ST segment depression from T1 to T2 and T3 was noticed. Rhythm disturbances were rare in the study population, with only a few patients presenting ventricular or supraventricular extrasystoles. Conclusions: This study reveals silent repolarization changes occurring early during anticancer treatment in children treated for ALL. These findings could aid in a better understanding of the cardiac toxicity mechanism, and they could potentially improve cardiac risk stratification for oncologic patients. Because of the small number of patients, our results need to be validated by larger studies.

Contrasting Effects of an Atherogenic Diet and High-Protein/Unsaturated Fatty Acids Diet on the Accelerated Aging Mouse Model SAMP8 Phenotype.

Background/Objectives: Aging has been extensively studied, with a growing interest in memory impairment by a neurobiological approach. Mitochondrial dysfunction is a hallmark of aging, contributing to the aging phenotype; therefore, mitochondrial interventions seem fundamental. The diet is a physiological approximation for modifying mitochondria, which could impact the age-related phenotype. Methods: We studied two diets with low-carbohydrate and high-fat compositions, differing in the amount of protein and the fat type disposable-the atherogenic diet Cocoa (high protein/high saturated fat/high cholesterol) and the South Beach diet (very high-protein/high-unsaturated fat)-on oxidative stress, mitochondrial state, and hippocampus-dependent memory in 3-month-old Senescence-Accelerated Mouse Model (SAMP8) seed over 3 months to determine their pro- or anti-aging effects. Results: Despite its bad reputation, the Cocoa diet reduces the reactive oxygen species (ROS) content without impacting the energy state and hippocampus-dependent spatial acuity. In contrast to the beneficial impact proposed for the South Beach diet, it induced a pro-aging phenotype, increasing oxidative damage and the levels of NR2B subunit of the NMDA, impairing energy and spatial acuity. Surprisingly, despite the negative changes observed with both diets, this led to subtle memory impairment, suggesting the activation of compensatory mechanisms preventing more severe cognitive decline. Conclusions: Our results demonstrated that diets usually considered good could be detrimental to the onset of aging. Also, probably due to the brain plasticity of non-aged animals, they compensate for the damage, preventing a more aggravated phenotype. Nevertheless, these silent changes could predispose or increase the risk of suffering pathologies at advanced age.

Mapping the molecular motions of 5-HT3 serotonin-gated channel by voltage-clamp fluorometry.

The serotonin-gated ion channel (5-HT3R) mediates excitatory neuronal communication in the gut and the brain. It is the target for setrons, a class of competitive antagonists widely used as antiemetics, and is involved in several neurological diseases. Cryo-electron microscopy (cryo-EM) of the 5-HT3R in complex with serotonin or setrons revealed that the protein has access to a wide conformational landscape. However, assigning known high-resolution structures to actual states contributing to the physiological response remains a challenge. In the present study, we used voltage-clamp fluorometry (VCF) to measure simultaneously, for 5-HT3R expressed at a cell membrane, conformational changes by fluorescence and channel opening by electrophysiology. Four positions identified by mutational screening report motions around and outside the serotonin-binding site through incorporation of cysteine-tethered rhodamine dyes with or without a nearby quenching tryptophan. VCF recordings show that the 5-HT3R has access to four families of conformations endowed with distinct fluorescence signatures: 'resting-like' without ligand, 'inhibited-like' with setrons, 'pre-active-like' with partial agonists, and 'active-like' (open channel) with partial and strong agonists. Data are remarkably consistent with cryo-EM structures, the fluorescence partners matching respectively apo, setron-bound, 5-HT bound-closed, and 5-HT-bound-open conformations. Data show that strong agonists promote a concerted motion of all fluorescently labeled sensors during activation, while partial agonists, especially when loss-of-function mutations are engineered, stabilize both active and pre-active conformations. In conclusion, VCF, though the monitoring of electrophysiologically silent conformational changes, illuminates allosteric mechanisms contributing to signal transduction and their differential regulation by important classes of physiological and clinical effectors.

Mapping the molecular motions of 5-HT3 serotonin-gated channel by voltage-clamp fluorometry

The serotonin-gated ion channel (5-HT3R) mediates excitatory neuronal communication in the gut and the brain. It is the target for setrons, a class of competitive antagonists widely used as antiemetics, and is involved in several neurological diseases. Cryo-electron microscopy (cryo-EM) of the 5-HT3R in complex with serotonin or setrons revealed that the protein has access to a wide conformational landscape. However, assigning known high-resolution structures to actual states contributing to the physiological response remains a challenge. In the present study, we used voltage-clamp fluorometry (VCF) to measure simultaneously, for 5-HT3R expressed at a cell membrane, conformational changes by fluorescence and channel opening by electrophysiology. Four positions identified by mutational screening report motions around and outside the serotonin-binding site through incorporation of cysteine-tethered rhodamine dyes with or without a nearby quenching tryptophan. VCF recordings show that the 5-HT3R has access to four families of conformations endowed with distinct fluorescence signatures: ‘resting-like’ without ligand, ‘inhibited-like’ with setrons, ‘pre-active-like’ with partial agonists, and ‘active-like’ (open channel) with partial and strong agonists. Data are remarkably consistent with cryo-EM structures, the fluorescence partners matching respectively apo, setron-bound, 5-HT bound-closed, and 5-HT-bound-open conformations. Data show that strong agonists promote a concerted motion of all fluorescently labeled sensors during activation, while partial agonists, especially when loss-of-function mutations are engineered, stabilize both active and pre-active conformations. In conclusion, VCF, though the monitoring of electrophysiologically silent conformational changes, illuminates allosteric mechanisms contributing to signal transduction and their differential regulation by important classes of physiological and clinical effectors.

Spectral degradation and carrier sentences increase age-related temporal processing deficits in a cue-specific manner.

Advancing age is associated with decreased sensitivity to temporal cues in word segments, particularly when target words follow non-informative carrier sentences or are spectrally degraded (e.g., vocoded to simulate cochlear-implant stimulation). This study investigated whether age, carrier sentences, and spectral degradation interacted to cause undue difficulty in processing speech temporal cues. Younger and older adults with normal hearing performed phonemic categorization tasks on two continua: a Buy/Pie contrast with voice onset time changes for the word-initial stop and a Dish/Ditch contrast with silent interval changes preceding the word-final fricative. Target words were presented in isolation or after non-informative carrier sentences, and were unprocessed or degraded via sinewave vocoding (2, 4, and 8 channels). Older listeners exhibited reduced sensitivity to both temporal cues compared to younger listeners. For the Buy/Pie contrast, age, carrier sentence, and spectral degradation interacted such that the largest age effects were seen for unprocessed words in the carrier sentence condition. This pattern differed from the Dish/Ditch contrast, where reducing spectral resolution exaggerated age effects, but introducing carrier sentences largely left the patterns unchanged. These results suggest that certain temporal cues are particularly susceptible to aging when placed in sentences, likely contributing to the difficulties of older cochlear-implant users in everyday environments.

Compounding Effects of Aging and Sex on Cerebrovascular Endothelial Mitochondria

Despite the increasing burden of age-related neurological diseases such as vascular cognitive impairment and dementia or Alzheimer’s disease, the underlying mechanisms of these pathologies are not clear. Nonetheless, structural and functional changes in the microvasculature represent probable pathological aspects of these age-associated diseases. The silent and cumulative changes in endothelial mitochondria with subsequently compromised cerebral vascular function are thought to play a central role in neurological disease development. We tested the hypothesis that mitochondrial morphological changes in endothelial cells facilitate the distinct aging- and sex-related differences in the cerebral microvascular proteome and energetics. Mito-dendra2 (mt-D2) labeled endothelial mitochondria were imaged in vivo via a cranial window using two-photon microscopy at 875 nm in young and old, male and female, mito-Dendra2 mice (YM, YF, OM, and OF, respectively). Mt-D2 associated signal was analyzed in 3D stacks using the Huygens Pro CE 23.04.0p3 object analyzer (160 images, originated from 4-5 mt-D2 mice/groups). We also measured mRNA copy numbers of mitochondrial fission and fusion genes in isolated, cortical microvessels (<70 μm) from YM, YF, OM, and OF C57Bl/6J mice (n=7-11/age/sex) using ddPCR. Kruskal-Wallis test with Dwass-Steel-Critchlow-Fligner post-hoc comparisons were used to compare mt-D2 signal among YM, YF, OM, and OF, whereas Mann-Whitney U test determined changes across age and sex strata. p<0.05 was considered statistically significant. mRNA copy numbers were normalized to housekeeping genes (GAPDH, β-actin, and HPRT-1) and compared with one-way ANOVA based on data distribution. Analysis of four object parameters revealed that object surface was smaller in old vs. young that was significant in YM vs. OM. We found significantly greater corrected lateral width in OM vs. YM, OF vs. YF, and in YF vs. YM. The lateral aspect ratio was significantly greater in YM vs. OM, in YF vs. OF, as well as in YM vs. YF. Accordingly, the axial sphericity of the principal box was significantly greater in OM vs. YM, in OF vs. YF, and in YF vs. YM. Normalized mRNA copy numbers of mitochondrial fission and fusion genes were not statistically different in our samples for DRP-1, Fis-1 or Mfn-1/2, Opa-1, respectively. These results suggest that aging driven morphological differences, such as the shortening of endothelial mt-D2 signal are, at least in part, facilitated by altered fission/fusion protein abundances and/or activity rather than transcriptional changes in our samples. Although we are still analyzing other morphological parameters, by assessing the effect sizes and their physiological relevance, we postulate that these morphological differences contribute to the vulnerability of the aged cerebral microvasculature to injury. AG083567, 3P30GM145498-01, U54GM104940, HL148836. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Internet of Things (IoT): An Educational Need

Education around the world is experiencing major paradigm shifts in educational practices of teaching and learning under the umbrella of ICT enable learning environment. The world is witnessing spontaneous growth in communication technology computer network and information technology. Development of new broadband communication services and convergence of telecommunication with computers which can be set to be the internet of things have created numerous possibilities to use a variety of new technology tools for teaching and learning systems. The Internet of things is so much into everything these days that it has started to be called as Internet of everything. It is not very surprising that internet of things, as it is now called has made its way into the education industry as well. Keeping in the mind the intervention of computers and smart phones into our lives and its effect on the educational system today, it. Sounds a bit farfetched at first for the internet of things to do anything with the education industry. While some of the effect that internet of things can bring into the education sector are apparent but some will be implicit and are likely to make a silent change from the inside. The internet of things can begin disrupting the education on procedure as early as kindergarten and can continue to do so through 12th standard but perhaps most profound effects occur in higher education. We will discuss the change that the internet of things can bring into the field of education and the challenges and impact of the internet of things in the 21st century education sector.

Screening of silent inflammatory bowel disease in seronegative spondyloarthritis patients: Fecal calprotectin, ileo-colonoscopy and histopathology assessment

IntroductionSeronegative spondyloarthritis (SpA) patients are at an increased risk of developing silent inflammatory bowel disease (IBD). Early diagnosis may help avoid future complications and choose the most effective treatment. Aimof the workto screen for silent IBD in SpA patients. Patients and methodsThis study included 41 SpA patients subjected to clinical assessment regarding gastrointestinal symptoms, laboratory data and ileo-colonoscopy with tissue histopathology.Fecal calprotectin levels were measured by enzyme linked-immunosorbant assay (ELISA). The Bath ankylosing spondylitis disease activity index (BASDAI) and psoriatic arthritis disease activity score (PASDAS) were assessed. ResultsThe median age of patients was 40 years (23–58 years) with 27 males and 14 females (M: F 1.9:1); 28 had axial SpA and 13 psoriatic arthritis (PsA); 25 (61%) patients were active. Only 19.5% received non-steroidal anti-inflammatory drugs (NSAIDs) while 61% received biologics. Median fecal calprotectin was 88 mcg/g and was elevated in 71% of patients. Patients receiving biologics had significantly lower median levels of fecal calprotectin than those who did not (72.7 vs 436.7mcg/g; p = 0.012). Abnormal colonoscopy was seen in 14.6% of patients (three Crohn’s disease and three ulcerative colitis). 17 (41.5%) showed abnormal histopathology; 9 had moderate colitis and activity while five patients had moderate colitis with minimal activity. There was a significant relation between platelet count and abnormal colonoscopy findings (p = 0.01). ConclusionSpA patients can have macroscopic or microscopic silent IBD changes. Fecal calprotectin may be used for screening of silent IBD among those patients, however, it should be supported by ileo-colonoscopic examination and histopathological assessment.

Plasma phosphorylated tau 181 and modifiable risk factors for dementia in a large scale cohort of Australian older adults

AbstractBackgroundUp to 40% of dementia cases could be prevented by addressing modifiable risk factors. Alzheimer’s disease (AD), the most common form of dementia, is preceded by up to decades of silent pathological change providing an ideal window for early detection and intervention. In this study, our objective was to examine the associations between modifiable risk factors and plasma phosphorylated p‐tau 181, a hallmark biomarker of early AD.MethodParticipants were recruited from the Island Study Linking Ageing and Neurodegenerative Disease (ISLAND), a prospective public health initiative in Tasmania, Australia’s southernmost island state. ISLAND participants were invited to complete a set of surveys online: a questionnaire on dementia risk factor adherence, demographic surveys and cognitive tests via the Cambridge Neuropsychological Test Automated Battery (CANTAB); Paired Associates Learning (PAL) and Spatial Working Memory (SWM). At four clinics across the state, participants also provided blood samples for measurement of plasma phosphorylated p‐tau 181 and genotyping for APOE.ResultA total of 738 participants (mean age 65.41 years, mean education 17.36 years, 71.8% female, 26.4% ε4+) took part in the study. We found gender‐specific effects on cognition, whereby identifying as male was associated with significantly lower learning ability (PAL) whilst identifying as female was associated with significantly lower executive function (SWM). In multivariate linear models, increasing alcohol consumption (measured in standard drinks per week) was significantly associated with lower plasma p‐tau 181. In adjusted models, no other modifiable risk factors examined were associated with p‐tau 181. Increasing age, identifying as male and possessing at least one APOE ε4 allele were all associated with higher plasma concentrations of p‐tau 181ConclusionHigher alcohol consumption, higher age, identifying as male and having an APOE ε4 allele were all associated with lower plasma phosphorylated tau 181. This contributes to evidence that both modifiable and non‐modifiable dementia risk factors are related to the biological precedents of AD. These associations were related to gender and genetics, therefore a panel of modifiable and non‐modifiable variables should be included in screening or diagnostic testing for pre‐clinical AD. More research is needed regarding specific alcohol types and biomarkers of AD.

Depression among older adults in an urban slum of Raipur city – a community based cross-sectional study

BackgroundOlder adults are at risk of chronic, silent depressive changes and the vulnerability of older adults in urban slums of India is rarely exposed. The objective of this study was to estimate the prevalence of depression among the older adults in the urban slums of India and to study the factors associated with it.MethodsThis was a community based analytical cross-sectional study conducted in Urban Field Practice Area of a tertiary care teaching hospital in Chhattisgarh, India among older adults more than or equal to 60 years of age selected using two stage, simple random sampling. The data was collected in a sample of 400 older adults by face-to-face interview using self-designed, semi-structured and pretested proforma that included validated Hindi version of Geriatric Depression Scale (GDS-15) and analyzed using SPSS v23.ResultsThe prevalence of depression among older adults was 51.5% in the present study; with 27%, 12.8% and 11.8% having mild, moderate and severe depression respectively. Number of family members, living status of spouse, emotional attachment to family members, conflict in family, loneliness, social isolation, marginal friendship ties, functional status, physical exercise, active complains and diastolic BP were independent predictors of depression in older adults.ConclusionEarly identification of depression in older adults using GDS-15 and incorporation of social isolation and functionality assessment routinely by healthcare providers for all older adults attending the outpatient departments is the need of the hour. A holistic approach to care of older adults is vital as healthcare providers seek to understand the impact of multiple, complex, interconnected factors on overall health and well-being of older adults.

Increasing green footprints: Indications of transformations in the socio‐economic spaces of Bangladesh

AbstractIn recent decades, Bangladesh has seen significant environmental degradation and the loss of its GDP, which has had a detrimental effect on public health, agriculture, forestry, fisheries, industrial development, and environmental services. The unusually high temperatures, humidity, and unpredicted rainfall gave rise to disease like dengue and affecting peoples mental health. However, the government, as well as public and private groups, are undertaking some phenomenal efforts to help reduce environmental degradation and raise the number of green footprints. The objective of this article is to examine the green initiatives, strategies, and policies of Bangladeshi organizations in enhancing green footprints in the socio‐economic spaces, through comprehensive content analysis of various newspapers, journal articles, government reports, and company annual reports. The aim of this article is to trace out the evidences of change in the socio‐economic fabric of the society. The primary focus of the article on the environment friendly business activities, which eventually bring social changes. The article found that green HRM, green business, MFS, green corporate culture is increasingly been seen in the society, which indicate silent changes. Bangladesh has put regulations and programs into place to lessen carbon emissions and safeguard sensitive coastal areas. It is noteworthy for demonstrating a strong dedication to improving sustainable development and environmental preservation. Many organizations in Bangladesh have also received the prestigious Asia's Corporate Excellence and Sustainability Awards for their outstanding zeal to ensure positive environmental changes in the society. Moreover, large proportion of Bangladesh's energy mix comes from renewable energy sources, leading to the installed renewable energy capacity of 579 MW. Additionally, the government has announced plans on replacing traditional transport methods with electric or hybrid vehicles. Bangladesh has further solidified its position as the global leader in green garments factories, as the country has 176 such facilities that have received the USGBC's LEED accreditation. The article placed a strong emphasis on particular policy proposals, including the adoption of the circular economy, the digital economy, sustainable finance, car‐sharing systems, renewable energy sources in manufacturing and workplaces, and environmentally friendly practices in both public and private organizations.

Presence of Preoperative Neurodegeneration Biofluid Markers in Patients with Postoperative Delirium.

The pathophysiology of delirium is incompletely understood, including what molecular pathways are involved in brain vulnerability to delirium. This study examined whether preoperative plasma neurodegeneration markers were elevated in patients who subsequently developed postoperative delirium through a retrospective case-control study. Inclusion criteria were patients of 65 yr of age or older, undergoing elective noncardiac surgery with a hospital stay of 2 days or more. Concentrations of preoperative plasma P-Tau181, neurofilament light chain, amyloid β1-42 (Aβ42), and glial fibrillary acidic protein were measured with a digital immunoassay platform. The primary outcome was postoperative delirium measured by the Confusion Assessment Method. The study included propensity score matching by age and sex with nearest neighbor, such that each patient in the delirium group was matched by age and sex with a patient in the no-delirium group. The initial cohort consists of 189 patients with no delirium and 102 patients who developed postoperative delirium. Of 291 patients aged 72.5 ± 5.8 yr, 50.5% were women, and 102 (35%) developed postoperative delirium. The final cohort in the analysis consisted of a no-delirium group (n = 102) and a delirium group (n = 102) matched by age and sex using the propensity score method. Of the four biomarkers assayed, the median value for neurofilament light chain was 32.05 pg/ml for the delirium group versus 23.7 pg/ml in the no-delirium group. The distribution of biomarker values significantly differed between the delirium and no-delirium groups (P = 0.02 by the Kolmogorov-Smirnov test) with the largest cumulative probability difference appearing at the biomarker value of 32.05 pg/ml. These results suggest that patients who subsequently developed delirium are more likely to be experiencing clinically silent neurodegenerative changes before surgery, reflected by changes in plasma neurofilament light chain biomarker concentrations, which may identify individuals with a preoperative vulnerability to subsequent cognitive decline.

Ascaridia galli infection in chicken: Pathobiology and immunological orchestra.

Ascaridia galli is the largest gut-dwelling helminth of chickens, which confers adverse effects on meat and egg production; thus, on the animal protein supply and the economy. Both adult and immature parasites affect gut health, but larval stages play a major role in pathology. Here, we present immunology and pathology of A. galli in chickens. Literatures were surveyed through online platforms such as PubMed, Google Scholar and Researchgate. The larvae cause excessive mucus production, damage to the intestinal gland, hemorrhage, anemia, diarrhea, and malnutrition. The adult worms can cause death by intestinal obstruction and intussusception. Although both cellular and humoral immunity are involved in fighting against ascariasis, the role of naturally acquired immunity is poorly defined. In cellular immunity, Th-2 cytokines (IL-4, IL-5, IL-9, and IL-13), goblet cells (mucin), gut-associated lymphoid tissues, CD8α+ intraepithelial cells, TCRγδ + T cells, and TGF-β4 form a protective band. Type 2 immunity provides protection by forming a network of endogenous damage-associated molecular patterns, chitin, and parasitic antigens. Among antibodies, IgY is the most prominent in chickens and provides temporary humoral protection. During parasitic infection, infiltration of various immune cells is evident, especially in the intestinal epithelium, lamina propria, and crypts of the duodenum and jejunum. In chickens older than 12 weeks, gradual reduction of worm burden is more successful than the younger birds. Female chickens exert a short-lived but higher level of protection by passing IgY to chicks in the form of egg yolk antibodies. In laying conditions, immunity differs between breeds. This review provides an overview of the silent but inevitable pathological changes induced by A. galli and the interaction of host immunity with the parasite.

Aortic valve Replacement compared to Transcatheter Implant and its relationship with COgnitive Impairment (ARTICO) evaluated with neuropsychological and advanced neuroimaging: a longitudinal cohort study

Background Aortic stenosis is the most common valvulopathy in Western countries. The treatment of choice had been surgery aortic valve replacement (SAVR), but the improvement in endovascular approaches as transcatheter aortic valve implantation (TAVI), initially reserved for patients with very high surgical risk, has been extended to high and intermediate, and recently also to low-risk patients. Stroke and vascular cognitive impairment are the most important complications. It is not entirely clear which technique is best to avoid these complications as well as their impact. Our goal is to evaluate changes in cognitive performance in the early (1-month) and late (1-year) postoperative period in patients undergoing SAVR or TAVI, by extensive neuropsychological study (NRP) and advanced Magnetic Resonance Imaging (MRI).Specifically, to compare early and late cognitive changes after the intervention between both groups, the occurrence of stroke during follow-up and to compare the appearance of silent vascular lesions and changes in brain activity and functional connectivity with functional MRI during follow-up between both groups.Methods/designProspective longitudinal cohort study. A non-selected representative sample of 80 subjects, 40 SAVR and 40 TAVI to obtain a final sample of 36 eligible subjects in each group, ranging from 70 to 85 years old, with indication for aortic replacement and intermediate or high surgical risk will be studied. At baseline, within one month before the treatment, all individuals will undergo an extensive NRP and advanced MRI study. These studies will also be performed 1-month and 1-year after treatment, to assess the appearance of new vascular lesions, as well as changes in cognitive performance with respect to baseline.DiscussionThis study aims to evaluate changes in cognitive performance as well as both clinical and silent vascular events occurring in the early (1-month) and late (1-year) periods after SAVR and TAVI. We will also analyze the correlation between neuropsychological and neuroimaging approaches in order to evaluate cognition. Therefore, it may provide high-quality data of cognitive changes and vascular events for both techniques, and be useful to tailor interventions to individual characteristics and ultimately aiding in decision-making.Trial registrationThis study is register in Clinicaltrials.gov (NCT05235529) on 11th February 2022.

Non-Invasive Assessment of the Intraventricular Pressure Using Novel Color M-Mode Echocardiography in Animal Studies: Current Status and Future Perspectives in Veterinary Medicine.

The assessment of diastolic function has received great interest in order to comprehend its crucial role in the pathophysiology of heart failure and for the early identification of cardiac events. Silent changes in the intraventricular flow (IVF) dynamics occur before the deterioration of the cardiac wall, although they cannot be detected using conventional echocardiography. Collective information on left ventricular (LV) pressures throughout the cardiac cycle has great value when dealing with patients with altered hemodynamics. Accurate pressure measurement inside the ventricle can be obtained by invasive methods to determine the LV diastolic pressures, which reflect the myocardial relaxation and compliance. However, catheterization is only feasible in the laboratory setting and is not suitable for clinical use due to its disadvantages. In contrast, echocardiography is simple, safe, and accessible. Color M-mode echocardiography (CMME) is an advanced cardiac evaluation technique that can measure the intraventricular pressure differences (IVPDs) and intraventricular pressure gradients (IVPGs) based on the Doppler shift of the IVF. Recently, the assessment of IVPD and IVPG has gained growing interest in the cardiovascular literature in both animal and human studies as a non-invasive method for the early diagnosis of cardiac dysfunctions, especially diastolic ones. The usability of IVPD and IVPG has been reported in various surgically induced heart failure or pharmacologically altered cardiac functions in rats, dogs, cats, and goats. This report aims to give an overview of the current studies of CMME-derived IVPD and IVPG in animal studies and its feasibility for clinical application in veterinary practice and to provide the prospects of the technique's ability to improve our understanding.

Modifiable risk factors for dementia, cognition, and plasma phosphorylated tau 181 in a large-scale cohort of Australian older adults

Alzheimer’s disease (AD), the most common form of dementia, is preceded by years of silent pathological change. Our objective was to examine the associations between modifiable dementia risk factors, cognition, and plasma phosphorylated p-tau 181, a hallmark biomarker of AD in a large-scale community cohort. Participants (n = 738, mean age 65.41 years) from the Island Study Linking Ageing and Neurodegenerative Disease responded to online assessments collecting demographics, adherence to dementia risk factors and cognitive function, and provided a blood sample for analysis. We found less education was significantly associated with lower cognitive scores. Modifiable dementia risk factors were not associated with plasma p-tau 181. Further, we did not observe any significant relationships between plasma p-tau 181 and cognition. Nonmodifiable factors such as age, education, sex, and apolipoprotein E epsilon 4 displayed significant associations with cognition and plasma p-tau 181. In a cognitively healthy community cohort of Tasmanian Australians, we did not observe any associations between modifiable risk factors for dementia and plasma p-tau 181. Nonmodifiable risk factors were associated with both cognition and plasma p-tau. This contributes to a growing body of evidence investigating confounding factors in the interpretation of blood-based biomarkers for dementia.

Physiological biomarkers of silent brain damage leading to cognitive impairment and Dementia – direct and accessible clinical evidence

AbstractBackgroundCognitive assessment is the best clinical tool to detect cognitive impairments, yet it is evident only at late stages of disease progression. In contrast, silent brain network changes occur at early stages of the disease and it is estimated that a large proportion of dementias may be prevented or at‐least delayed if detected during early pathophysiology stages. Neuroimaging studies have shown that silent brain network findings, including white matter hyperintensities, lacunar infarctions and temporal atrophy are evident before objective cognitive impairment is detected and even more in ‘at risk’ population with risk factors for dementia. We aimed to evaluate direct physiological biomarkers that provide accessible clinical evidence of silent brain network damage that precede clinical cognitive findings and provide early clinical biomarkers that can facilitate early interventions.MethodBrain network performance was evaluated in 168 subjects ‘at risk’ for developing dementia (Table 1). Direct electrophysiological imaging (“Delphi”) was used to measure magnetically induced brain network electrophysiological response. MRI scans included T1, T2, FLAIR, Diffusion Weighted Imaging (DWI) and (SWI). They were analysed according to Fazekas scale for white matter Hyperintensities (WMH), lacunar Infarctions and medial temporal lobe atrophy (MTA). Objective cognitive evaluations were performed by a neuropsychologist interview and a computerized cognitive battery (NeurotraxTM).ResultDirect electrophysiological imaging (“Delphi”) was able to distinguish between severities of different MRI detected silent brain network damage findings. Magnetically induced direct electrophysiological response wave form adherence (WFA) significantly decreased with increase in WMH (Fig.1A; p<0.0001) and increase in MTA levels (Fig.1B; p<0.0001). Furthermore, WFA significantly decreased in subjects with lacunar infarctions (Fig.1C; p<0.0001).ConclusionSilent brain network deficits preceding dementia and cognitive decline are widely under detected due to lack of accessible tools. Data presented in this study demonstrates “Delphi” technology’s ability to detect silent brain network damage findings and severity levels that are identified in MRI scans. “Delphi” is a clinically accessible, direct, and objective technology that can facilitate early detection, prevention, delayed progression and management of mild cognitive impairment and dementia.

Identification and in silico characterization of CSRP3 synonymous variants in dilated cardiomyopathy

Synonymous variations have always been ignored while studying the underlying genetic mechanisms for most of the human diseases. However, recent studies have suggested that these silent changes in the genome can alter the protein expression and folding. CSRP3, which is a well-known candidate gene associated with dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM), was screened for 100 idiopathic DCM cases and 100 controls. Three synonymous variations were identified viz., c.96G > A, p.K32=; c.336G > A, p.A112=; c.354G > A, p.E118=. A comprehensive in silico analysis was performed using various web based widely accepted tools, Mfold, Codon Usage, HSF3.1 and RNA22. Mfold predicted structural changes in all the variants except c.96 G > A (p.K32=), however it predicted changes in the stability of mRNA due to all the synonymous variants. Codon bias was observed as evident by the Relative Synonymous Codon Usage and Log Ratio of Codon Usage Frequencies. The Human Splicing Finder also predicted remarkable changes in the regulatory elements in the variants c.336G > A and c.354 G > A. The miRNA target prediction using varied modes available in RNA22 revealed that 70.6% of the target sites of miRNAs in CSRP3 were altered due to variant c.336G > A while 29.41% sites were completely lost. Findings of the present study suggest that synonymous variants revealed striking deviations in the structural conformation of mRNA, stability of mRNA, relative synonymous codon usage, splicing and miRNA binding sites from the wild type suggesting their possible role in the pathogenesis of DCM, either by destabilizing the mRNA structure, or codon usage bias or else altering the cis-acting regulatory elements during splicing.

Silent Brain Changes in Children with Sickle Cell Disease

Silent Brain Changes in Children with Sickle Cell Disease

Ventricular and atrial function assessment with transthoracic echocardiography in patients with rheumatic inflammatory disease

BackgroundInflammatory rheumatic diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and systemic sclerosis (SSc), can cause cardiovascular complications in many cases. This study aimed to compare the ventricular and atrial functions of the heart between rheumatic patients and healthy controls using transthoracic echocardiography (TTE).ResultsThe study was performed between 64 patients with mentioned rheumatic diseases and 64 age- and sex-matched healthy controls who all underwent detailed history-taking and TTE. Echocardiographic parameters were measured and compared between the two groups. TTE showed significant differences in many echocardiographic parameters. Left ventricular end-diastolic diameter, left ventricular end-systolic diameter, right atrium area, inferior vena cava diameter, and systolic pulmonary artery pressure were significantly higher in patients compared to the controls (P < 0.001). Left ventricular ejection fraction and right ventricular end-diastolic diameter were not statistically different between the groups (P > 0.05). Right ventricular septal strain, right ventricular free wall strain, average longitudinal right ventricular strain, tricuspid annular plane systolic excursion, right ventricular systolic myocardial velocity, and right ventricular fractional area change were lower in inflammatory rheumatic patients (P < 0.001). The subgroup analysis showed the same results’ trend for each disease and its own control group comparison.ConclusionsCardiac involvement in rheumatologic diseases, especially SLE, RA, and SSc, should always be taken into consideration as there may be silent changes affecting the overall prognosis of patients. Using TTE helps diagnose and make a treatment plan for cardiovascular complications in rheumatic disease patients.