Pathophysiological Parameters Research Articles

A dissociated glucocorticoid receptor modulator mitigates glucolipotoxicity in the endocrine pancreas and peripheral tissues: Preclinical data from a mouse model of diet-induced type 2 diabetes.

Type 2 diabetes (T2D) is a prevalent metabolic disease linked to obesity and metabolic syndrome (MS). The glucolipotoxic environment (GLT) impacts tissues causing low-grade inflammation, insulin resistance and the gradual loss of pancreatic β-cell function, leading to hyperglycemia. We have previously shown that Compound A (CpdA), a plant-derived dissociative glucocorticoid receptor-modulator with inflammation-suppressive activity, displays protective effects on β-cells in type 1 diabetes murine models. This study aimed to evaluate whether the administration of CpdA can attenuate GLT effects and improve pathophysiological parameters in a murine model of T2D/MS. Eight-week-old male C57BL/6NCrl mice were fed either a standard chow diet or a high-fat/high-sucrose diet (HFHS) for 15weeks. From week 5 of feeding, each group received i.p. injections of CpdA (2.5μg/g) or vehicle three times a week. We also examined CpdA in vitro effect against GLT using the insulinoma cell line INS-1E and naïve isolated mouse islets. CpdA administration in HFHS fed mice improved glucose homeostasis and insulin sensitivity with no apparent side effects. CpdA treatment also preserved pancreatic islet architecture and insulin expression, while reducing hepatic steatosis and visceral adipose tissue inflammation induced by HFHS diet. In vitro assays in INS-1E cells and naïve isolated mouse islets demonstrated that CpdA counteracted GLT-induced inhibition of glucose-stimulated insulin secretion and supported the expression of key β-cell identity genes under GLT conditions. These findings highlight the potential protective effect of CpdA in preserving β-cell functionality and peripheral tissue physiology in the context of T2D/MS.

Transoral Incisionless Fundoplication Leads to Esophageal Mucosa Healing in Responder Patients Followed up to 2 Years, as Documented by Esophageal Mean Nocturnal Baseline Impedance.

Decrease of esophageal mean nocturnal baseline impedance reflects loss of mucosal integrity. It can predict response to anti-reflux therapy. Mean nocturnal baseline impedance after transoral incisionless fundoplication for gastroesophageal reflux disease has never been assessed. The aim of the study is to investigate mean nocturnal baseline impedance and conventional pathophysiological parameters following transoral incisionless fundoplication. Patients prospectively treated by transoral incisionless fundoplication in a single center were retrospectively reviewed regarding 1- and 2-year 24-hour pH-metry and multichannel intraluminal impedance with calculation of mean nocturnal baseline impedance, gastroesophageal reflux disease-health related quality of life and reflux symptom index scores. Thirty-eight and 17/38 patients with 1- and 2-year 24-hour pH-multichannel intraluminal impedance assessment and mean nocturnal baseline impedance's calculation after transoral incisionless fundoplication, respectively, were identified. Mean nocturnal baseline impedance significantly increased up to 2-year follow-up (P = 0.033), along with significant decrease in % of acid exposure time (P = 0.003), gastroesophageal reflux disease-health related quality of life score (P < 0.001), and reflux symptom index (P = 0.008), compared with baseline. The longest orthostatic reflux decreased too, approaching statistical significance (P = 0.054). These significant changes occurred in patients experiencing ≥ 50% reduction of symptom questionnaires' scores ("responders"). Conversely, mean nocturnal baseline impedance worsened and no significant changes of 24-hour pH-multichannel intraluminal impedance metrics were observed in "non-responder" patients (symptom questionnaires' scores decrease < 50%).ConclusionIn patients who responded a significant improvement of mean nocturnal baseline impedance and % acid exposure time was observed up to 2-year follow-up, suggesting that transoral incisionless fundoplication achieves an effective esophageal mucosa healing besides symptom improvement.

Objective functional improvement and vital prognosis after TAVR in patients with low-gradient aortic stenosis. Development of a predictive score

Abstract Introduction Patients with low-gradient aortic stenosis (mean gradient &amp;lt; 40 mmHg) (LGAS) supose a clinical challenge because in these patients the degree of functional recovery after TAVR could be lower and their prognostic evolution more adverse. This is relevant for the optimal indication of TAVR, especially with the growing number of patients with a borderline indication due to comorbidities or advanced age with certain degree of frailty. Purpose To develop a clinical model to predict the response to TAVR in LGAS patients based in non invasive physiological parameters at baseline. Methods In a cohort of patients undergoing TAVR a prospective evaluation of multiple pathophysiological parameters was performed derived from pre- and post-TAVR assessment with echocardiography, computed tomography, and non-invasive arterial pulse wave analysis with the Sphygmocor XCEL system. Objective functional improvement 6 months after TAVR was assessed by the 6-minute walk test and NT-proBNP levels. Clinical follow-up was performed at 1 year. Results Of the 450 patients included, 310 showed high aortic gradient and 140 (31%) low gradient, with an objective functional improvement in 90% and 64% (p&amp;lt;0.001) respectively, and with 1-year mortality of 4% and 12% (p=0.001). In the LGAS group, 1-year mortality was 20% in the subgroup without functional improvement and 8% (p=0.001) in the subgroup showing functional improvement. In the LGAS group, the pathophysiological parameters predictive of functional improvement were the augmentation index75 ≥ 45% (OR 4, CI 95% 1.9–11.3; p=0.006), posterior wall thickness ≤ 12 mm (OR 3.2, CI 95% 1.4–8; p=0.01) and absence of atrial fibrillation (OR 2.7, CI 95% 1.5–8.4; p=0.01). To generate a simple integer-based point score for each predictive variable, each beta coefficient was divided by the absolute value of the smallest coefficient, multiplied by 5, and rounded to the nearest integer. The values were 7, 6 and 5 respectively. Among the low-gradient population, in 55 patients with 0-6 score points the functional improvement was only 29%, while in the remaining 85 patients with 7-18 score points the functional improvement was 86% (p&amp;lt;0.001). Conclusions LGAS patients account for a relatively high proportion of patients undergoing TAVR. They show less objective functional recovery, which is associated with a significantly higher mortality at follow-up. We have developed a score based on 3 variables (augmentation index75, posterior wall thickness and atrial fibrillation) that can help predict the functional and prognostic response to TAVR in these patients.

Model order reduction and sensitivity analysis for complex heat transfer simulations inside the human eyeball.

Heat transfer in the human eyeball, a complex organ, is significantly influenced by various pathophysiological and external parameters. Particularly, heat transfer critically affects fluid behavior within the eye and ocular drug delivery processes. Overcoming the challenges of experimental analysis, this study introduces a comprehensive three-dimensional mathematical and computational model to simulate the heat transfer in a realistic geometry. Our work includes an extensive sensitivity analysis to address uncertainties and delineate the impact of different variables on heat distribution in ocular tissues. To manage the model's complexity, we employed a very fast model reduction technique with certified sharp error bounds, ensuring computational efficiency without compromising accuracy. Our results demonstrate remarkable consistency with experimental observations and align closely with existing numerical findings in the literature. Crucially, our findings underscore the significant role of blood flow and environmental conditions, particularly in the eye's internal tissues. Clinically, this model offers a promising tool for examining the temperature-related effects of various therapeutic interventions on the eye. Such insights are invaluable for optimizing treatment strategies in ophthalmology.

Analysis of Electrooculogram in Detecting Eye Movements Associated with Brain Injury

Electrooculogram (EOG) has been a valuable clinical neurophysiology tool in the past five decades of the twentieth century. It facilitated understanding more about eye movement, which is clinically useful in identifying the neural substrate disrupted due to brain injuries. This is vital since accurate measurement of neural injuries has a direct bearing on a patient’s life. A number of neurological investigations, including neurological assessment and diagnosis, are done based on measuring eye movements. This essay focuses on using EOG technology and its benefits in identifying limitations of using physiological indices in individuals because of measurable ocular pathophysiological parameters. In the current essay, the major objective will be to discuss the EOG features, the EOG record in healthy individuals, and the relationship of EOG recordings to affected individuals following a neurological event. The eye-integrated EOG recorded from the front part of the face measures eye position change and shows an exponential decay of voltage due to its design, eye physiology, and the removal of corneal function slowly from the corneal electrode. This makes it the best choice to provide an eye position record with high accuracy that can be made available easily for clinicians. The rapid recordings obtained using transcranial electromagnetic stimulation could demonstrate that EOG has the potential to provide high pre-surgical planning utilities for brain tumor removal. This technology is also best for identifying physiological variability within an individual; the same concept can be extended to study brain injuries that trigger physiological changes in eye muscles. In effect, it potentially becomes a tool for personalized care wherein severity estimation for brain injuries would be based on measuring ocular function rather than the nature of the injury. Given its clinical potential, the present essay will review EOG technologies to assess eye pixel movement, its potential for clinical evaluation, physiological basis, and the research evidence regarding changes in EOG in affected individuals with brain injury. In this essay, the long-lasting and short-lasting EOG changes are presented as case studies of individuals diagnosed with PTA, hence demonstrating its clinical utility.

Premature thymic functional senescence is a hallmark of childhood acute lymphoblastic leukemia survivorship

Childhood acute lymphoblastic leukemia (cALL) survivors suffer early-onset chronic diseases classically associated with aging. Normal aging is accompanied by organ dysfunctions, including immunological ones. We hypothesize that thymic immunosenescence occurs in cALL survivors and that its severity may correlate with early-onset chronic diseases. The PETALE study is a cALL survivor cohort with an extensive cardiovascular and metabolic evaluation. The thymic immunosenescence biomarker, signal joint T-cell receptor excision circles (TREC), was evaluated and was highly correlated with age in healthy participants (n = 281) and cALL survivors (n = 248). We observed a systematic thymic immunoage accentuation in each cALL survivor compared to controls ranging from 5.9 to 88.3 years. The immunoage gain was independent of age at diagnosis and treatment modalities and was more severe for females. Thymic aging was associated with several pathophysiological parameters, was greater in survivors suffering from metabolic syndrome, but there was no significant association with global physical condition. The decrease in TREC was independent from blood cell counts, which were normal, suggesting a segmental aging of the thymic compartment. Indeed, increased plasmatic T cell regulatory cytokines IL-6, IL-7 and GM-CSF accompanied high immunoage gain. Our data reveal that cALL or its treatment trigger a rapid immunoage gain followed by further gradual thymic immunosenescence, similar to normal aging. This leads to an enduring shift in accentuated immunoage compared to chronological age. Thus, accentuated thymic immunosenescence is a hallmark of cALL survivorship and TREC levels could be useful immunosenescence biomarkers to help monitoring the health of cancer survivors.

Assessment of Safe Early Fixation Strategies in a Cohort Polytraumatized Patients – How is the Surgical Treatment Influenced by the Injury Pattern?

Abstract Background While the inital assessment and the intial treatment of potentially life-threatening injuries is well-described, the surgical treatment strategy following initial resuscitation remains controversial. Timepoint of surgery and type of surgery still reamin topic of discussions. Various, different strategies for optimal timing of fracture fixation in polytrauma patients exist. Aims This study tests the hypothesis that a concept of clearing patients for early definitive surgery that relies on anatomical and physiologic parameters is influenced by the injury distribution. Methods Polytrauma patients treated at a Level 1 trauma center (01.01.2016 - 31.12.2018). Inclusion: primary admission, injury severity score (ISS) ≥16points, requirement of surgical fixation of major extremity or a truncal injury. Exclusion: death &amp;lt;72h after admission, severe traumatic brain injury (TBI). Stratification according to surgical fixation concept: Early total care (ETC, all surgeries &amp;lt;24 h), safe definitive surgery (SDS, staged surgeries &amp;lt;72h), and damage control orthopaedics (DCO, definitive care after stabilization). Endpoints: mortality, complication rates. Parameters of interest: Injury severity and distribution (ISS/AIS), pathophysiologic parameters of hemorrhagic shock, coagulopathy, hypothermia, soft tissue trauma. Results 527 patients, mean age 54.8 SD19.9 years, mean ISS 26.9 SD9.0 points, mortality 20.5%. Group ETC (n=21, 3.9%), Group SDS (n = 284, 53.9%), Group DCO (n = 222, 42.1%). Abdominal and spinal injuries associated with ETC (AIS Abdomen; OR 2.1, 95%CI 1.1 to 4.0, p = 0.026: AIS Spine OR 2.0, 95%CI 1.2 to 3.4, p = 0.007). Extremity and pelvic injuries associated with SDS (OR 1.8, 95%CI 1.1 to 2.8, p = 0.012 and OR 1.3, 95%CI 1.0 to 1.7, p = 0.036), head injuries associated with DCO (OR1.5, 95%CI 1.3 to 1.8, p &amp;lt;0.001). Head injuries were most relevant for mortality and were associated with patients undergoing DCO (29.7%) (ETC; 23.8%, SDS; 13.0%). Conclusion The concept of staged early fixation for major extremity and axial injuries (SDS) was successfully applied in the majority of patients. Predominant head and abdominal injuries were associated with ETC or DCO. The injury distribution influences decision making towards surgical management that is associated with a low complication rate.

Endotyping in ARDS: one step forward in precision medicine

BackgroundThe Berlin definition of acute respiratory distress syndrome (ARDS) includes only clinical characteristics. Understanding unique patient pathobiology may allow personalized treatment. We aimed to define and describe ARDS phenotypes/endotypes combining clinical and pathophysiologic parameters from a Canadian ARDS cohort.MethodsA cohort of adult ARDS patients from multiple sites in Calgary, Canada, had plasma cytokine levels and clinical parameters measured in the first 24 h of ICU admission. We used a latent class model (LCM) to group the patients into several ARDS subgroups and identified the features differentiating those subgroups. We then discuss the subgroup effect on 30 day mortality.ResultsThe LCM suggested three subgroups (n1 = 64, n2 = 86, and n3 = 30), and 23 out of 69 features made these subgroups distinct. The top five discriminating features were IL-8, IL-6, IL-10, TNF-a, and serum lactate. Mortality distinctively varied between subgroups. Individual clinical characteristics within the subgroup associated with mortality included mean PaO2/FiO2 ratio, pneumonia, platelet count, and bicarbonate negatively associated with mortality, while lactate, creatinine, shock, chronic kidney disease, vasopressor/ionotropic use, low GCS at admission, and sepsis were positively associated. IL-8 and Apache II were individual markers strongly associated with mortality (Area Under the Curve = 0.84).PerspectiveARDS subgrouping using biomarkers and clinical characteristics is useful for categorizing a heterogeneous condition into several homogenous patient groups. This study found three ARDS subgroups using LCM; each subgroup has a different level of mortality. This model may also apply to developing further trial design, prognostication, and treatment selection.

Does the injury pattern drive the surgical treatment strategy in multiply injured patients with major fractures?

The timing of definitive surgery in multiple injured patients remains a topic of debate, and multiple concepts have been described. Although these included injury severity as a criterion to decide on the indications for surgery, none of them considered the influence of injury distributions. We analyzed whether injury distribution is associated with certain surgical strategies and related outcomes in a cohort of patients treated according to principles of early and safe fixation strategies. In this retrospective cohort study, multiple injured patients were included if they were primarily admitted to a Level I trauma center, had an Injury Severity Score of ≥16 points, and required surgical intervention for major injuries and fractures. The primary outcome measure was treatment strategy. The treatment strategy was classified according to the timing of definitive surgery after injury: early total care (ETC, <24 hours), safe definitive surgery (SDS, <48 hours), and damage control (DC, >48 hours). Statistics included univariate and multivariate analyses of mortality and the association of injury distributions and surgical tactics. Between January 1, 2016, and December 31, 2022, 1,471 patients were included (mean ± SD age, 55.6 ± 20.4 years; mean Injury Severity Score, 23.1 ± 11.4). The group distribution was as follows: ETC, n = 85 (5.8%); SDS, n = 665 (45.2%); and DC, n = 721 (49.0%); mortality was 22.4% in ETC, 16.1% in SDS, and 39.7% in DC. Severe nonlethal abdominal injuries (odds ratio [OR], 2.2; 95% confidence interval [CI], 1.4-3.5) and spinal injuries (OR, 1.6; 95% CI, 1.2-2.2) were associated with ETC, while multiple extremity injuries were associated with SDS (OR, 1.7; 95% CI, 1.4-2.2). Severe traumatic brain injury was associated with DC (OR, 1.3; 95% CI, 1.1-1.4). When a correction for the severity of head, abdominal, spinal, and extremity injuries, as well as differences in the values of admission pathophysiologic parameters were undertaken, the mortality was 30% lower in the SDS group when compared with the DC group (OR, 0.3; 95% CI, 0.2-0.4). Major spinal injuries and certain abdominal injuries, if identified as nonlethal, trigger definitive surgeries in the initial setting. In contrast, severe TBI was associated with delayed fracture care. Patients with major fractures and other injuries were treated by SDS (definitive care, <48 hours) when the pathophysiological response was adequate. The choice of a favorable surgical treatment appears to depend on injury patterns and physiological patient responses. Therapeutic/Care Management; Level IV.

Cerebrovascular and cardiovascular autonomic regulation in sickle cell patients with white matter lesions.

White matter lesions (WMLs) are frequent in sickle cell disease (SCD), with a prevalence described to be as high as 53% by age 30. Cerebrovascular regulation and cardiovascular autonomic regulation, more specifically the sympatho-vagal balance, can be altered in SCD. In this study the association between WMLs, cerebrovascular regulation and sympatho-vagal balance was assessed in SCD patients. Sickle cell disease patients with no history of stroke were prospectively evaluated for cerebrovascular reactivity using the breath-holding test (BHT), the sympatho-vagal balance (ratio low frequency/high frequency [HF]) using heart rate variability parameters and cerebral autoregulation in the time domain using correlation index Mx, and arterial cerebral compliance based on continuous assessment of cerebral blood flow velocities using transcranial Doppler ultrasound and arterial blood pressure with photo-plethysmography. WMLs were assessed with magnetic resonance imaging using Fazekas score grading and the presence of lacunes. Forty-one patients (F/M 25/16) were included. Median age was 37.5 years (19-65). Twenty-nine (70.7%) patients had SS genotype. Eleven patients had WMLs (26.8%). Patients with WMLs were significantly older (p < 0.001), had a lower HF (p < 0.005) and an impaired cerebral arterial compliance (p < 0.014). The receiver operating curve for the regression model including age and HF showed a higher area under the curve compared to age alone (0.946 vs. 0.876). BHT and Mx did not significantly differ between the two groups. Lower parasympathetic activity and impaired cerebral arterial compliance were associated with WMLs in adults with SCD. This could potentially yield to a better understanding of pathophysiological parameters leading to premature cerebrovascular ageing in SCD.

Microfluidics-Based Blood Typing Devices: An In-Depth Overview.

Identification of correct blood types holds paramount importance in understanding the pathophysiological parameters of patients, therapeutic interventions, and blood transfusion. Considering the wide applications of blood typing, the requirement of centralized laboratory facilities is not well suited on many occasions. In this context, there has been a significant development of such blood typing devices on different microfluidic platforms. The advantages of these microfluidic devices offer easy, rapid test protocols, which could potentially be adapted in resource-limited settings and thereby can truly lead to the decentralization of testing facilities. The advantages of pump-free liquid transport (i.e., low power consumption) and biodegradability of paper substrates (e.g., reduction in medical wastes) make it a more preferred platform in comparison to other microfluidic devices. However, these devices are often coupled with some inherent challenges, which limit their potential to be used on a mass commercial scale. In this context, our Review offers a succinct summary of the recent development, especially to understand the importance of underlying facets for long-term sustainability. Our Review also delineates the role of integration with digital technologies to minimize errors in interpreting the readouts.

Prediction of acute lung injury assessed by chest computed tomography, oxygen saturation/fraction of inspired oxygen ratio, and serum lactate dehydrogenase in patients with COVID-19

IntroductionIn treating acute hypoxemic respiratory failure (AHRF) caused by coronavirus disease 2019 (COVID-19), clinicians choose respiratory therapies such as low-flow nasal cannula oxygenation, high-flow nasal cannula oxygenation, or mechanical ventilation after assessment of the patient's condition. Chest computed tomography (CT) imaging contributes significantly to diagnosing COVID-19 pneumonia. However, the costs and potential harm to patients from radiation exposure need to be considered. This study was performed to predict the quantitative extent of COVID-19 acute lung injury using clinical indicators such as an oxygenation index and blood test results. MethodsWe analyzed data from 192 patients with COVID-19 AHRF. Multiple logistic regression was used to determine correlations between the lung infiltration volume (LIV) and other pathophysiological or biochemical laboratory parameters. ResultsAmong 13 clinical parameters, we identified the oxygen saturation/fraction of inspired oxygen ratio (SF ratio) and serum lactate dehydrogenase (LD) concentration as factors associated with the LIV. In the binary classification of an LIV of ≥20 % or not and with the borderline LD = 2.2 × [SF ratio]−182.4, the accuracy, precision, diagnostic odds ratio, and area under the summary receiver operating characteristic curve were 0.828, 0.818, 23.400, and 0.870, respectively. ConclusionsThese data suggest that acute lung injury due to COVID-19 pneumonia can be estimated using the SF ratio and LD concentration without a CT scan. These findings may provide significant clinical benefit by allowing clinicians to predict acute lung injury levels using simple, minimally invasive assessment of oxygenation capacity and biochemical blood tests.

Current status and applications of photovoltaic technology in wearable sensors: a review

The rapid development of wearable sensor technology can be attributed to developments in materials, microelectronics, fabrication, communication systems, and Artificial Intelligence (AI). The use of wearable sensors enables continuous acquisition and monitoring of the pathophysiological parameters of a person in real time. The global market for health-related wearables has experienced significant growth, particularly in response to the COVID-19 pandemic. A wearable sensor module is comprised of various components, including a powering unit, sensor(s), acquisition unit, communication unit, and processing unit. The non-fluctuating power source with a long life is of utmost significance to the continuous and real-time operation of a wearable sensor. A wearable device can be powered by a rechargeable battery, such as a lithium-ion battery, which can be charged from a standard power source but requires regular recharging after depletion and has a negative environmental impact. This necessitates using green renewable energy sources like photovoltaic cells, piezoelectric generators, wind energy converters, and thermoelectric generators for powering wearable sensor modules. The photovoltaic cell that converts photonics into electrical energy is deemed a viable green energy source for wearable sensor modules. This article reviews the progress and application of photovoltaic technology in wearable sensor modules.

Therapeutic Approaches in Pulmonary Arterial Hypertension with Beneficial Effects on Right Ventricular Function—Preclinical Studies

Pulmonary hypertension (PH) is a progressive condition that affects the pulmonary vessels, but its main prognostic factor is the right ventricle (RV) function. Many mice/rat models are used for research in PAH, but results fail to translate to clinical trials. This study reviews studies that test interventions on pulmonary artery banding (PAB), a model of isolated RV disfunction, and PH models. Multiple tested drugs both improved pulmonary vascular hemodynamics in PH models and improved RV structure and function in PAB animals. PH models and PAB animals frequently exhibited similar results (73.1% concordance). Macitentan, sildenafil, and tadalafil improved most tested pathophysiological parameters in PH models, but almost none in PAB animals. Results are frequently not consistent with other studies, possibly due to the methodology, which greatly varied. Some research groups start treating the animals immediately, and others wait up to 4 weeks from model induction. Treatment duration and choice of anaesthetic are other important differences. This review shows that many drugs currently under research for PAH have a cardioprotective effect on animals that may translate to humans. However, a uniformization of methods may increase comparability between studies and, thus, improve translation to clinical trials.

THU312 The Type 1 Diabetes Susceptible LEW.1WR1 Rat Develops Insulin Resistance And Severe Non-alcoholic Fatty Liver Disease

Abstract Disclosure: S.T. Love-Rutledge: None. M. Wimalarathne: None. L.D. Mercado: None. A. Smiley: None. C. Apperson: None. Q.C. Vidal: None. A subpopulation of type 1 diabetes patients develop the pathophysiological parameters to be termed double diabetes. This patient population often develops obesity, non-alcoholic fatty liver disease, and other hallmarks of insulin resistance. The LEW.1WR1 rat is a type 1 diabetes susceptible rodent with hyperinsulinemia that has shown signs of fatty liver infiltration1,2. We hypothesized that LEW.1WR1 rats would develop insulin resistance and severe nonalcoholic fatty liver disease due to its increased circulating insulin and predisposition to autoimmune disease. LEW.1WR1 rats and Wistar Furth rats were used for the 18-week long experiment. Peripheral insulin sensitivity was evaluated using insulin tolerance tests at weeks 11 and 17 showing worsening insulin sensitivity as evidenced by the gradual slope compared to the steep slope of the Wistar Furth rats. HOMA-IR values support LEW.1WR1 rats develop worsening insulin sensitivity and are insulin resistant at week 23 of the experiment (2.613± 0.796, p &amp;lt; 0.0001). Terminal liver mass confirmed increased liver mass normalized to body mass and liver triglyceride levels suggested increased ectopic lid accumulation in the liver (Liver Mass 2.65% ±0.32 p = 0.0005 and triglyceride levels 192.8 ± 21.85 mg/dL, p = 0.034). The H&amp;E-stained digital liver slides were scored for liver ballooning, steatosis, and markers of inflammation. Fibrosis and terminal circulating cytokines were also measured to assess severity of condition. While both groups showed increased steatosis and injury ballooning, trichrome blue staining and inflammatory cytokines verify the severity of disease in the LEW.1WR1 rats. LEW rats have increased fibrosis area and high serum TNF-α, IFN-, MCP-1 levels. As hypothesized, we observed that LEW.1WR1 rats show characteristics of insulin resistance and malignant nonalcoholic fatty liver disease development.

Effect of Orofacial Myofunctional Therapy along with BiPAP on Pathophysiological Parameters of Obstructive Sleep Apnea: A Case Study

Background: Obstructive Sleep Apnea (OSA) is an increasingly common form of sleep-disordered breathing (SDB), with an incidence of 15% in men and 5% in women in adults. Itis characterized by repetitive collapse or obstruction of the pharyngeal airway during sleep. OSA is a multi-factorial disorder, where anatomical and non-anatomical factors can contribute to determine different pathophysiological traits. Obstructive sleep apnea (OSA) is the periodic transitory decline (hypopnea) or complete interruption (apnea) of breathing due to reduction or blocking of the upper airway during sleep. Aim: This study aims to investigate the Effect of Orofacial myofunctional therapy along with BiPAP on pathophysiological parameters of Obstructive sleep apnea. Case description: A 75 year old male presented with the history of Asthma and Hypertension &amp;amp; Diabetes Mellitus-II. He was diagnosed with Type 2 Respiratory Failure with Obstructive Sleep Apnea with Obesity. Orofacial Myofunctional Therapy (OMT) has been recently introduced as an OSA treatment option for patients with Obstructive Sleep Apnea. An One week exercise programme containing OMT with the routine physiotherapy (Breathing exercises, Active ROM for bilateral upper and lower extremities and functional activities) was given. The Epworth Sleepiness Scale assessing for patient’s sleepiness, Pittsburgh Sleep Quality Index (PSQI) used for assessing sleep quality of patient and SPO2 assessing for oxygen saturation levels in the blood. An One week exercise programme effectively improves changes in weak and dysfunctional upper airway muscles. Conclusion: Our present study concluded that Orofacial Myofunctional Therapy had proven to be effective in patient with OSA with BiPAP. Keywords: Obstructive Sleep apnea, Orofacial Myofunctional Therapy, BiPAP

Development of a quantitative systems pharmacology (QSP) model to support dose optimization of DS-1103a (anti SIRPa antibody) in combination with trastuzumab deruxtecan in patients with cancer.

e14509 Background: DS-1103a, an anti-human signal regulatory protein α (SIRPα) monoclonal antibody (mAb), is designed to block the SIRPα-CD47 axis “Don’t Eat Me” signal and trigger phagocytosis of tumor cells when combined with an Fc-active antitumor mAb. DS-1103a is being developed as a combination therapy with trastuzumab deruxtecan (T-DXd; DS-8201a) as the antibody-dependent cellular phagocytosis (ADCP) enabling antibody. We developed a QSP model to support the first in human (FIH) intravenous dosing (IV) based on predicted intratumoral receptor occupancy (RO) within immunological synapses (the intercellular contact zone between macrophages and cancer cells) and corresponding ADCP activity. Methods: The QSP model mechanistically integrated DS-1103a plasma pharmacokinetics (PK), tumor distribution and binding of receptors to both antibodies and their ligands to simulate RO in the tumor microenvironment (TME). A proximal pharmacodynamics pathway model was first developed to estimate the intratumoral RO required to induce desired levels of ADCP for DS-1103a+T-DXd combination therapy. A human model was then developed to integrate DS-1103a PK with derived intratumormal RO in patients considering key human pathophysiological parameters, including SIRPα expression, tumor lesion permeability, SIRPα+ cell fractions in TME, tumor capillary radius, SIRPα internalization, CD47 expression and tumor lesion size. Virtual patient simulations were conducted in various cancer types to facilitate FIH dose selection. Results: The proximal pharmacodynamics pathway model quantitatively recapitulated the dose dependent in vitro ADCP activities for DS-1103a+T-DXd combination therapy. The intratumoral RO (within synapses) required to induce desired levels of ADCP activity were also derived. The human model predicted similar dose dependent intratumoral RO in various cancer types. Virtual patient simulations indicated that a flat dose of 100 mg Q3W IV DS-1103a could achieve steady-state intratumoral RO sufficient to reach half of the maximal ADCP activity and would be a suitable FIH starting dose. The predicted steady-state intratumoral RO after a flat dose of ≥1000 mg Q3W IV DS-1103a is well above the predicted intratumoral RO threshold to achieve maximum ADCP activity. Conclusions: The QSP model mechanistically characterized DS-1103a mechanism of action and linked PK to intratumoral RO and corresponding ADCP activity in both in vitro and in vivo setting. The model was used to derive the FIH starting dose and potentially clinically effective doses for DS-1103a in combination with T-DXd. This QSP model will be integrated into a large-scale disease platform to support dose expansion and further dose optimization as new clinical data emerge.

R-(+)-Limoneno e seu derivado (–)-Carveol: uma revisão de seus efeitos sobre o diabetes

Diabetes is a metabolic disorder of multiple etiologies, which is mainly characterized by persistently high levels of glucose in the blood. Estimates from the World Health Organization (WHO) indicate that approximately 422 million people have diabetes and 1.6 million deaths are directly attributed to the disease each year. Faced with such relevant numbers, natural therapies are sought that are effective, efficient and low-cost for the referred pathology. Several natural products are already being used as adjuvants in the treatment of diabetes because they have hypoglycemic action, such as monoterpenes. However, there is a strong intention to expand the portfolio of natural products with hypoglycemic compounds. Thus, the objective of this study was to list information from the literature on diabetes and the applicability of natural products, emphasizing the antidiabetic action of the monoterpenes R-(+)-Limonene and (-)-Carveol. A narrative review was performed. The selected articles were directed to the pathophysiological parameters of diabetes and its complications, aspects of the use of natural products, monoterpenes and their therapeutic effects as antidiabetic agents. The research was carried out in the following databases: PubMed, Scielo, Portal Periódicos Capes, Scopus, Web of Science and Science Direct. Studies show that diabetes is a complex disease that causes a series of complications and can be treated with oral hypoglycemic agents, insulin, diet and physical activity. Researches related to R-(+)-Limonene and (-)-Carveol, in rats, showed positive results with antidiabetic action, acting in the reduction of the plasmatic levels of glucose, triglycerides and cholesterol and of the expression of inflammatory markers, as well as in the increased effect of antioxidant enzymes. However, studies involving these monoterpenes are still incipient, making this research timely. Thus, R-(+)-Limonene and (-)-Carveol are promising candidates for further research to elucidate their therapeutic effects alone or in combination with other antidiabetic monoterpenes.

Male reproductive system and simulated high-altitude environment: preliminary results in rats.

This study assessed the effects of a simulated high-altitude environment on the reproductive system of prepubertal male rats and the reversibility of these effects upon return to a normal environment. Three-week-old male Wistar rats were randomly allocated to 4 groups that were exposed to different conditions: a normal environment for 6 weeks and 12 weeks, respectively, hypobaric hypoxia for 6 weeks, and hypobaric hypoxia for 6 weeks followed by a normal environment for 6 weeks. Multiple pathophysiological parameters were evaluated at the histological, endocrine, and molecular levels. Hypobaric hypoxia exposure for 6 weeks during the prepubertal phase significantly altered physiological parameters, body functions, blood indices, and reproductive potential. Six weeks after returning to a normal environment, the damaged reproductive functions partially recovered due to compensatory mechanisms. However, several changes were not reversed after returning to a normal environment for 6 weeks, including disorders of body development and metabolism, increased red blood cells, increased fasting blood glucose, abnormal blood lipid metabolism, decreased testicular and epididymis weights, abnormal reproductive hormone levels, excessive apoptosis of reproductive cells, and decreased sperm concentration. In summary, a hypobaric hypoxic environment significantly impaired the reproductive function of prepubertal male rats, and a return to normal conditions during the postpubertal phase did not fully recover these impairments.

Changes in pathophysiology of tumor growth and functional activity of the hypothalamic-pituitary-thyroid axis in rats of both sexes with the development of Guerin's carcinoma on the background of hypothyroidism

Purpose of the study. Was to analyze changes in pathophysiological parameters of transplantable tumor growth and functional activity of the hypothalamic-pituitary-thyroid axis (HPT) in rats of both sexes with Guerin's carcinoma in presence of induced hypothyroidism.Materials and methods. The dynamics of tumor growth and average life span were assessed in white alley rats of both sexes with Guerins carcinoma transplanted subcutaneously on the background of thyreostatic induced hypothyroidism. RIA (radioimmune assay) and ELISA (enzyme-linked immunosorbent assay) methods were used to determine levels of thyroid hormones in the blood and thyroid and tumor samples, and thyrotropin-releasing hormone (TRH) in the hypothalamus, as well as TSH in the pituitary gland. The experiment included 2 control groups: animals of both sexes with hypothyroidism (control group 1, number of rodents = 15) and animals with subcutaneously transplanted Guerin's carcinoma without hypothyroidism (control group 2, number of rodents = 15).Results. Hypothyroidism in female rats inhibited the tumor growth and improved median survival by 1.8 times (p &lt; 0.05). No such effect was observed in males of the main group. Levels of regulatory peptides of the hypothalamus and pituitary gland declined in females of the main group, while levels of TSH in the pituitary gland in males increased, despite a decrease in TRH by 3.5 times. TSH levels decreased in the thyroid and blood of animals of both sexes; however, a decrease in levels of total and free circulating thyroxine (T4 and FT4) by 1.6 times and by 2.8 times was found in the tumor, respectively; samples of Guerin's carcinoma in males of the main group remained saturated with T4 and FT4 as well as and in control group rodents without induced hypothyroidism.Conclusions. The gender differences in the pathophysiology of the tumor development in presence of hypothyroidism, as well as changes in the functional activity of the HPT axis in experimental animals revealed in this study can probably be associated with sex hormones, which requires further study of the hypothalamic-pituitary-gonadal (HPG) axis and steroid hormones in peripheral organs and tumor samples.