Third Space Research Articles

Imidazo[2,1-b][1,3]thiazine Derivatives as Potential Modulators of Alpha-Synuclein Amyloid Aggregation.

Insoluble amyloid fibrils accumulate in the intercellular spaces of organs and tissues, leading to various amyloidosis-related disorders in the human body. Specifically, Parkinson's disease is associated with the aggregation of alpha-synuclein. However, current treatments for Parkinson's primarily focus on managing motor symptoms and slowing disease progression. Efforts to prevent and halt the progression of these diseases involve the search for small molecular compounds. In this work, we synthesized imidazo[2,1-b][1,3]thiazines in an atom-economic way by cyclization of 2-alkynylthioimidazoles using 10% AuCl as the catalyst. We identified several compounds with specific functional groups capable of both inhibiting the aggregation of alpha-synuclein and redirecting the fibril formation pathway. The investigation into how these substances function revealed that imidazo[2,1-b][1,3]thiazine derivatives can influence alpha-synuclein aggregation in several ways. They not only inhibit the primary nucleation process and maintain a balance toward nonaggregated protein states but also stabilize smaller oligomeric species of alpha-synuclein and cause the formation of fibrils with unique structures and forms. These imidazo[2,1-b][1,3]thiazines could potentially be used in developing highly efficient, small molecular weight protein aggregation inhibitors.

Anesthetic Challenges in A Heart Failure Patient for Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy: A Case Report

CRS-HIPEC is a procedure for the treatment of peritoneal malignancies. It is a multi-step procedure consisting of initial tumor debulking, followed by heated application of chemotherapy. Throughout the procedure multiple physiologic changes occur: large fluid losses and shifts, hemodynamic derangements, extremes of temperatures. Knowledge of the physiologic changes during each phase is essential in forming an anesthetic plan for this case. For this particular case, the patient has an ejection fraction of 35%. The reduced ejection fraction requires careful attention and modification in management. Thus, a tailored anesthetic plan is of particular importance. There is a scarcity of studies regarding anesthetic management in a heart failure patient for CRS-HIPEC, hence it is important to explore the implications of this disease process on anesthetic management.

SPathDB: a comprehensive database of spatial pathway activity atlas.

Spatial transcriptomics sequencing technology deepens our understanding of the diversity of cell behaviors, fates and states within complex tissue, which is often determined by the fine-tuning of regulatory network functional activities. Therefore, characterizing the functional activity within tissue space is helpful for revealing the functional features that drive spatial heterogeneity, and understanding complex biological processes. Here, we describe a database, SPathDB (http://bio-bigdata.hrbmu.edu.cn/SPathDB/), which aims to dissect the pathway-mediated multidimensional spatial heterogeneity in the context of functional activity. We manually curated spatial transcriptomics datasets and biological pathways from public data resources. SPathDB consists of 1689868 spatial spots of 695 slices from 84 spatial transcriptome datasets of human and mouse, which involves 36 tissues, and also diseases such as cancer, and provides interactive analysis and visualization of the functional activities of 114998 pathways across these spatial spots. SPathDB provides five flexible interfaces to retrieve and analyze pathways with highly variable functional activity across spatial spots, the distribution of pathway functional activities along pseudo-space axis, pathway-mediated spatial intercellular communications and the associations between spatial pathway functional activity and the occurrence of cell types. SPathDB will serve as a foundational resource for identifying functional features and elucidating underlying mechanisms of spatial heterogeneity.

Differential Lipid Signatures of Lumbar and Cisternal Cerebrospinal Fluid.

The molecular composition of cerebrospinal fluid (CSF) is often used as a key indicator of biochemical alterations within distinct brain and spinal cord fluid compartments. The CSF protein content in lumbar CSF samples is widely employed as a biomarker matrix for diagnosing brain-related pathological conditions. CSF lipid profiles may serve as promising complementary diagnostics, but it remains unresolved if the lipid distribution is consistent along the neuroaxis. The lipid composition was determined with liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) in cisternal CSF obtained from healthy subjects undergoing preventive surgery of an unruptured aneurism (n = 11) and lumbar CSF obtained from individuals referred for the clinical evaluation of cognitive dysfunction but subsequently cleared and deemed healthy (n = 19). We reveal discernible variations in lipid composition along the neuroaxis, with a higher overall lipid concentration in cisternal CSF, although with different relative distributions of the various lipid classes in the two compartments. The cisternal CSF contained elevated levels of most lipid classes, e.g., sphingomyelins, lysophosphatidylcholines, plasmenylphosphatidylcholines, phosphatidic acids, and triacylglycerols, whereas a few select lipids from the classes of fatty acids, phosphatidylcholines, amides and plasmenylphosphatidylethanolamines were, oppositely, elevated in the lumbar CSF pool. The distinct lipid distribution along the neuroaxis illustrates that the molecular constituents in these two CSF compartments are not uniform. These findings emphasize the necessity of establishing a lumbar lipid index for the accurate interpretation of the cranial CSF lipid profile.

First-year real-world experience of intravitreal brolucizumab injection for refractory neovascular age-related macular degeneration.

To investigate the first-year real-world anatomical and functional outcomes of intravitreal brolucizumab injection in eyes with refractory neovascular age-related macular degeneration (nAMD). Retrospective observational study. nAMD patients who showed poor response to previous anti-vascular endothelial growth factor (VEGF) agents were switched to brolucizumab. Functional and anatomical outcomes were evaluated at initial treatment of nAMD, after treatment with other anti-VEGF agents and after switching and treating with brolucizumab for 1 year. Safety profile was also evaluated after brolucizumab injection. Best-corrected visual acuity (BCVA), central foveal thickness (CFT), subfoveal choroidal thickness (SFCT), and the presence of fluid in different compartments (intraretinal fluid [IRF], subretinal fluid [SRF], pigment epithelial detachment [PED]) were assessed at each time point. A total of 40 eyes of 40 patients were included in the study. BCVA remained unchanged throughout treatment (p > 0.05). CFT did not change after treatment with other anti-VEGF agents (p = 0.588) but decreased after switching to brolucizumab (p < 0.001). SFCT decreased after treatment with other anti-VEGF agents (p = 0.025) but not after switching to brolucizumab (p = 0.236). Presence of SRF (p = 0.001) and PED (p = 0.001) decreased significantly after switching to brolucizumab, despite their persistence with prior treatments using other anti-VEGF agents. However, IRF persisted even after switching to brolucizumab (p = 0.745). Intraocular inflammation (IOI)-related adverse events were reported in 3 eyes (7.14%). Analysis of first-year real-world outcomes after switching to brolucizumab in nAMD patients refractory to other anti-VEGF agents showed improved anatomic outcomes, limited functional improvement and low incidence of IOI-related adverse events.

Artificial gravity: an effective countermeasure for microgravity-induced headward fluid shift?

Long-duration spaceflight is associated with pathophysiological changes in the intracranial compartment hypothetically linked to microgravity-induced headward fluid shift. This study aimed to determine whether daily artificial gravity (AG) sessions can mitigate these effects, supporting its application as a countermeasure to spaceflight. Twenty-four healthy adult volunteers (16 men) were exposed to 60 days of 6° head-down tilt bed rest (HDTBR) as a ground-based analog of chronic headward fluid shift. Subjects were divided equally into three groups: no AG (control), daily 30-min intermittent AG (iAG), and daily 30-min continuous (cAG). Internal carotid artery (ICA) stroke volume (ICASV), ICA resistive index (ICARI), ICA flow rate (ICAFR), aqueductal cerebral spinal fluid flow velocity (CSFV), and intracranial volumetrics were quantified at 3 T. MRI was performed at baseline, 14 and 52 days into HDTBR, and 3 days after HDTBR (recovery). A mixed model approach was used with intervention and time as the fixed effect factors and the subject as the random effect factor. Compared with baseline, HDTBR was characterized by expansion of lateral ventricular, white matter, gray matter, and brain + total intracranial cerebral spinal fluid volumes, increased CSFv, decreased ICASV, and decreased ICAFR by 52 days into HBTBR (All Ps < 0.05). ICARI was only increased 14 days into HDTBR (P < 0.05). Neither iAG nor cAG significantly affected measurements compared with HDTBR alone, indicating that 30 min of daily exposure was insufficient to mitigate the intracranial effects of headward fluid shift. Greater AG session exposure time, gravitational force, or both are suggested for future countermeasure research.NEW & NOTEWORTHY Brief exposure to continuous or intermittent artificial gravity via short-arm centrifugation was insufficient in mitigating the intracranial pathophysiological effects of the headward fluid shift simulated during head-down tilt bed rest (HDTBR). Our results suggest that greater centrifugation session duration, gravitational force, or both may be required to prevent the development of spaceflight-associated neuro-ocular syndrome and should be considered in future ground-based countermeasure studies.

Uncovering the Impact of COVID-19 Mediated Bidirectional Dysregulation of CYP3A4 on Systemic and Pulmonary Drug Concentrations Using Physiologically Based Pharmacokinetic Modeling.

Several clinical studies have shown that COVID-19 increases the systemic concentration of drugs in hospitalized COVID-19 patients. However, it is unclear how COVID-19-mediated bidirectional dysregulation of hepatic and pulmonary CYP3A4 impacts drug concentrations, especially in the lung tissue which is most affected by the disease. Herein, PBPK modeling was used to demonstrate the differences in systemic and pulmonary concentrations of four respiratory infectious disease drugs when CYP3A4 is concurrently downregulated in the liver and upregulated in the lung based on existing clinical data on COVID-19 - CYP3A4 interactions at varying severity levels including outpatients, non-ICU, and ICU patients. The study showed that hepatic metabolism is the primary determinant of both systemic and pulmonary drug concentrations despite the concurrent bidirectional dysregulation of liver and lung CYP3A4. ICU patients had the most systemic and pulmonary drug exposure with a percentage increase in AUCplasma of approximately 44%, 56%, 114%, and 196% for clarithromycin, nirmatrelvir, dexamethasone, and itraconazole, respectively, relative to the healthy group. Within the ICU cohort, clarithromycin exhibited its highest exposure in lung tissue mass with a fold change of 1189, while nirmatrelvir and dexamethasone showed their highest exposure in the plasma compartment, with fold changes of about 126 and 5, respectively, compared to the maximum therapeutic concentrations for their target pathogens. Itraconazole was significantly under-exposed in the lung fluid compartment potentially explaining its limited efficacy for the treatment of COVID-19. These findings underscore the importance of optimizing dosing regimens in at risk ICU patients to enhance both efficacy and safety profiles. Significance Statement This study investigated whether COVID-19-mediated concurrent hepatic downregulation and pulmonary upregulation of CYP3A4 leads to differences in the systemic and pulmonary concentrations of four respiratory medicines. The study demonstrated that intercompartmental differences in drug concentrations were driven by only hepatic CYP3A4 expression. This work suggests that ICU patients with significant COVID-19 - CYP3A4 interactions may be at risk of clinically relevant COVID-19-drug interactions, highlighting the need for optimizing dosing regimens in this patient group to improve safety and efficacy.

Biopsychosocial Health Considerations for Astronauts in Long-Duration Spaceflight: A Narrative Review.

Long-duration spaceflights beyond low-Earth orbit, including missions to the Moon and Mars, pose significant health risks. Although biomedical approaches commonly appear in the literature, considering psychological and social factors alongside physiologic health offers a more holistic approach to astronaut care. Integrating the biopsychosocial (BPS) framework into medical planning addresses complex spaceflight challenges and aids in developing mitigation strategies. This review examined health risks associated with long-duration spaceflight within a BPS framework. Sources included governmental space agencies, academic textbooks, and relevant publications from multiple databases. Considering the National Aeronautics and Space Administration's Human Research Program's 5 main hazards, a conceptual model was developed to highlight the multifactorial BPS effects of spaceflight. In space, astronauts face unique environments and biological adaptations, including fluid shift, plasma volume loss, bone density loss, and muscle atrophy. Noise and the absence of natural light disrupt circadian rhythms, causing sleep disturbances and fatigue, which affect physical and mental health. Studies on crews in isolated and confined extreme environments reveal psychosocial challenges, including impaired mood and cognition, interpersonal tension, and miscommunication. International collaboration in spaceflight introduces differences in communication, problem solving, and social customs due to diverse cultural backgrounds. Upcoming long-distance missions likely will amplify these challenges. This review emphasizes BPS health considerations in long-duration spaceflight. It highlights the interplay among psychological, social, and biological factors, advocating for multidisciplinary teams and a holistic approach to astronaut health and mission planning and the potential added value of BPS perspectives in considering countermeasures.

Optimizing Subretinal Bleb Formation for Visual Streak Involvement in a Porcine Model for Retinal Gene Therapy.

Subretinal (SR) injection in porcine models is a promising avenue for preclinical evaluation of cell and gene therapies. Targeting of the subretinal fluid compartment (bleb) is critical to the procedure, especially if treatment of the cone-rich area centralis is required (i.e., visual streak [VS] in pigs). To our knowledge, this study is the first to investigate the influence of injection site placement on VS involvement in the pig eye. We performed 23-gauge pars plana vitrectomy followed by SR injection in 41 eyes of 21 animals (Sus scrofa domesticus). In 27 eyes (65.9%), the injection site was placed superior to the VS, and in 14 eyes (34.1%) it was placed inferior to it. Using intraoperative imaging, blebs were classified based on their propagation behavior relative to the VS. In 79% of cases, blebs from inferior injection sites developed away from the VS, exhibiting a mean ± SEM vertical anisotropy (AP) of 0.67 ± 0.11. In contrast, blebs from superior injection sites tended to develop toward the VS with an AP of 1.27 ± 0.18 (P = 0.0070). Blebs developed away from the VS in only 41% of injections (P = 0.0212). Inferior blebs were orientated close to 0° (horizontal), whereas superior blebs displayed varied orientations with a mean angle of 56° (P = 0.0008). Bleb propagation was anisotropic (i.e., directionally biased) and dependent on injection site placement. Superior injection sites led to superior VS detachment. Morphological analysis suggested increased adhesion forces at the VS and superior vascular arcades. This study will aid the planning of surgeries for targeted subretinal delivery in pig models.

Papilla Access Tunnel Combined With the Laterally Closed Tunnel: A Technique for Treatment of Deep Gingival Recession in the Anterior Mandible.

Treatment of gingival recession in the anterior mandible is more complex due to unique anatomic features including excessive tension due to frenal and muscle attachments, thin tissue, shallow vestibule, and narrow interdental space. These features are particularly limiting in the presence of deep recession and negatively impact the success most routine soft tissue grafting procedures. The recently proposed laterally closed tunnel combined the benefit of tension management from tunneling rather than incising papillae with lateral closure of deep recession to minimize the need for coronal advancement. This is an effective, although technically demanding procedure. This report presents a method of facilitating tunnel preparation by utilizing superficial papillary access incisions bilaterally in the papilla between the lateral incisor and canine. This papilla has the least tension and most robust interdental volume and blood supply. This incision creates a mini flap that facilitates tunnel dissection and graft placement. Because the mini flap is used for graft insertion, the suturing for lateral closure can be performed before graft insertion. The result is reduced technical difficulty.

Adding Highly Variable Genes to Spatially Variable Genes Can Improve Cell Type Clustering Performance in Spatial Transcriptomics Data.

Spatial transcriptomics has allowed researchers to analyze transcriptome data in its tissue sample's spatial context. Various methods have been developed for detecting spatially variable genes (SV genes), whose gene expression over the tissue space shows strong spatial autocorrelation. Such genes are often used to define clusters in cells or spots downstream. However, highly variable (HV) genes, whose quantitative gene expressions show significant variation from cell to cell, are conventionally used in clustering analyses. In this report, we investigate whether adding highly variable genes to spatially variable genes can improve the cell type clustering performance in spatial transcriptomics data. We tested the clustering performance of HV genes, SV genes, and the union of both gene sets (concatenation) on over 50 real spatial transcriptomics datasets across multiple platforms, using a variety of spatial and non-spatial metrics. Our results show that combining HV genes and SV genes can improve overall cell-type clustering performance.

A microphysiological assay for studying T-cell chemotaxis, trafficking and tumor killing

Tumors in patients non-responsive to immunotherapy harbor a series of barriers that impede the efficacy of effector T-cells. Consequently, therapeutically modulating the chemotaxis machinery to enable effector T cell infiltration and function in the tumor could result in more successful therapeutic outcomes. Complexin-vitromodels allow re-creation ofin-vivotumor complexities in anin-vitrosetting, allowing improved translatability to patient biology at the laboratory scale. We identified a gap in available industrial scale microphysiological (MPS) assays for faster validation of targets and strategies that enable T-cell chemotaxis and effector function within tumor microenvironments. Using a commercially available, 96-chip 2-lane microfluidic assay system, we present a novel, scalable, complexin vitroMPS assay to study 3D T-cell chemotaxis and function within native, extracellular matrix (ECM)-rich multicellular tumor environments. Activated or naïve CD3+ T-cells stained with far-red nuclear stain responded to the chemokine gradients generated within the matrigel-collagen ECM by migrating into the microfluidic channel (∼5 mm horizontal window), in a concentration- and cell type-dependent manner. Furthermore, we observed and tracked chemotaxis and cancer cell killing function of antigen-specific CD4.CD8. chimeric antigen receptor (CAR)-T cells that responded to CXCR3 agonist gradient built through the expansive 5 mm of cancer cell colony containing stroma. The 2-lane assay system yielded useful information regarding donor and dose-dependent differences in CAR-T cell chemotaxis and tumor killing. The scalable assay system allows a granular window into immune cell migration and function in tissue spaces beyond endothelium, addressing a missing gap in studying tissue-specific immune cell chemotaxis and function to bring forward advancements in cancer immunotherapy.

Ventilatory response to head-down-tilt in healthy human subjects.

Postural fluid shifts may directly affect respiratory control via a complex interaction of baro- and chemo-reflexes, and cerebral blood flow. Few data exist concerning the steady state ventilatory responses during head-down tilt. We examined the cardiorespiratory responses during acute 50° head-down tilt (HDT) in 18 healthy subjects (mean [SD] age 27 [10] years). Protocol 1 (n=8, two female) was 50° HDT from 60° head-up posture sustained for 10min, while exposed to normoxia, normoxic hypercapnia (5% CO2), hypoxia (12% inspired O2) or hyperoxic hypercapnia (95% O2, 5% CO2). Protocol 2 (n=10, four female) was 50° HDT from supine, sustained for 10min, while breathing either medical air or normoxic hypercapnic (5% CO2) gas. Ventilation ( , pneumotachograph), end-tidal O2 and CO2 concentration and blood pressure (Finapres) were measured continuously throughout each protocol. Middle cerebral artery blood flow velocity (MCAv; transcranial Doppler) was also measured during protocol 2. Ventilation increased significantly (P<0.05) compared to baseline during HDT in both hyperoxic hypercapnia (protocol 1 by mean [SD] 139 [26]%) and normoxic hypercapnia (protocol 1 by mean [SD] 131 [21]% and protocol 2 by 129 [23]%), despite no change in or from baseline. No change in was observed during HDT with medical air or hypoxia, and there was no significant change in MCAv during HDT compared to baseline. The absence of change in cerebral blood flow leads us to postulate that the augmented ventilatory response during steep HDT may involve mechanisms related to cerebral venous pressure and venous outflow.

9332 Breathless Struggle: Unraveling The Interplay Between DKA And Acute Respiratory Distress Syndrome

Abstract Disclosure: S. Zahra: None. R. Subramani: None. M. Abbas: None. K.Y. Hasan: None. F. Manas: None. C. Bajracharya: None. Introduction: Diabetic Ketoacidosis (DKA) is a life threatening emergency with mortality rate of 0.15%-0.30%. Acute Respiratory Distress Syndrome (ARDS) is a rare complication of DKA which presents as a sudden onset of dyspnea and progressive hypoxia. It is an inflammatory process that damages the alveolar-capillary membrane leading to the fluid leakage into the alveolar space. The incidence of ARDS in DKA remains unknown. It is more commonly seen in adolescents and young adults. The exact pathogenesis of ARDS in DKA is currently unknown. Some proposed mechanisms are that a severe metabolic acidosis in DKA along with increased cytokines production due to long standing hyperglycemia leads to increased capillary membrane permeability allowing fluid to accumulate in the alveolar space. TNF-a and IL-6 along with other pro-inflammatory cytokines are known to cause endothelial damage and increase pulmonary permeability leading to pulmonary edema. However most DKA patients with severe metabolic acidosis do not develop ARDS. Case Presentation:Case 1: A 19 year old male with uncontrolled type I diabetes mellitus presented with altered mental status. On examination, he was tachycardic and tachypneic with dry mucous membranes. Lab workup revealed leukocytosis, severe hyperglycemia, and severe anion gap metabolic acidosis with beta hydroxybutyrate level of 14.20 mmol/L (normal: 0.02-0.27 mmol/L). He was diagnosed with DKA and started on intravenous fluids, and insulin as per institutional DKA protocol. Approximately 12 hours post-admission, the patient experienced sudden-onset dyspnea with deteriorating hypoxia, necessitating emergent intubation and mechanical ventilation. Chest radiography displayed bilateral patchy ground-glass opacifications consistent with acute respiratory distress syndrome (ARDS). Despite the administration of 8 liters of intravenous fluids, the patient exhibited a negative net fluid balance of 2.3 liters, implicating fluid shift. Further investigations, including bronchoscopy and bronchoalveolar lavage, revealed an unobstructed airway, minimal secretions, and no evidence of hemorrhage or infection. Comprehensive infectious work-ups yielded negative results as well, reinforcing the diagnosis of DKA as the underlying cause of ARDS. Conclusion: Acute Respiratory Distress Syndrome is a rare but potentially fatal complication of Diabetic Ketoacidosis. Early recognition of this serious pulmonary complication of DKA and its prompt management is essential to prevent respiratory failure and mortality. Presentation: 6/1/2024

Using noninvasive imaging to assess manual lymphatic drainage on lymphatic/venous responses in a spaceflight analog

This retrospective case series (clinicaltrials.gov NCT06405282) used noninvasive imaging devices (NIID) to assess the effect of manual lymphatic drainage (MLD) on dermal/venous fluid distribution, perfusion, and temperature alterations of the head, neck, upper torso, and legs while in the 6-degree head-down tilt validated spaceflight analog. A lymphatic fluid scanner measured tissue dielectric constant levels. Near-infrared spectroscopy assessed perfusion, by measuring tissue oxygenation saturation. Long-wave infrared thermography measured tissue temperature gradients. Fifteen healthy, university students participated. NIID assessments were taken 1 minute after assuming the HDT position and then every 30 minutes, with MLD administered from 180 to 195 minutes. Subjects returned to the sitting position and were assessed at post-225 min NIID demonstrated significant changes from baseline (p < 0.01), although these changes at areas of interest varied. MLD had a reverse effect on all variables. NIID assessment supported the potential use of MLD to mitigate fluid shifts during a spaceflight analog.

Could prayer’s info-energy restore the distorted informational field in the extracellular space of cancerous tissue?

This article explains for the first time how stress (negative emotions or just negative thinking) causes cancer or chronic disease of the genetically inherited weak organ. For the first time, it is explained why for some individuals stress leads to chronic disease of the genetically inherited weak organ, while for other individuals it leads to cancer of the genetically inherited weak organ. It is believed to be with genetic predisposition, but for the first time this article explains what this means. 1/ Stress causes chronic disease of genetically inherited weak organ when the integrating energy within the cell is weak. This makes the cellular biorhythms of the genetically-inherited weak organ weakly integrated and easily disintegrated by stress, which by causing delays disorders the biorhythms, and results in chronic disease. 2/ Stress causes cancer of the genetically inherited weak organ, when the integrating energy between the cells is weak. When the weak extracellular energy is farther weakened by stress, at critically low energy stacked-coin formations appear between the cells, which disconnect the cells. The disconnected cells start to multiply fast as they would do in the case of cut wound, to heal the wound fast. However, in the case of wound the cells are ruled where to go by the current of regrowth. In the case of cancer, they multiply senselessly, which is called malignancy. Since both energies - within the cells and in the extracellular space - are informational nonlinear electromagnetic fields (NEMFs) and prayer is information, prayer should be able to influence the cellular organization in the case of chronic diseases, and the extracellular formations in the case of cancer.

The conceptus and its parts: ontogenetic recapitulation in early human development.

Our understanding of the processes of human development that occur during and just after implantation is still incomplete. The anatomical studies by Erich Blechschmidt (1904-1992) at the University of Göttingen demonstrate the uniqueness and beauty of the early stages of individual human development or ontogeny. The interpretations of human embryology by Blechschmidt offer a simple unifying hypothesis: metabolic and biomechanical events are repeated, and this can be described as an ontogenetic recapitulation. This commentary provides a rationale for using some older terms and introducing new ones in the description of early human development. The product of conception is a conceptus; the outer part of the conceptus is the ectoblast and everything inside is the endoblast; the endocyst arises in the endoblast when the future amniotic fluid is forming. The human embryo arises from the innermost part of the endocyst. Terms such as morula, gastrula, and cyema, which are imported from zoology and ignore the role of the zona pellucida and constrained fluid compartments in the conceptus, can be avoided.

Plasma volume response patterns and a physiologic model of ultrafiltration in hemodialysis.

Ultrafiltration (UF) is an essential process of restoring fluid homeostasis during hemodialysis (HD). Fluid shifts across the extracellular compartments during UF, predominantly across the capillary interface and between the macro- and microcirculation. A mismatch between UF and transcapillary fluid transport can lead to hemodynamic instability leading to cardiac morbidity. We wished to study intradialytic fluid transport characteristics and their variation during UF to identify factors that govern variability in transcapillary fluid movement in HD. Twenty-two patients undergoing stable HD sessions were studied to measure and monitor absolute blood and plasma volume throughout UF. A computational mathematical model of predicted plasma volume decay during UF was analyzed with respect to the intradialytic real-time data profile. Pre- and post-dialysis fluid status was assessed using multifrequency bioimpedance spectroscopy. Serum electrolytes, osmolality, and total protein concentration were measured pre- and post-dialysis and during the intradialytic phase. Two distinct profiles of PV responses were detected. 60% of the patients presented plasma volume decline, characterized by a high percentage of volume decrease during the first hour, and a subsequent slower decrease with early rebound. The model was modified to achieve a proper fit of these volume profiles, assuming time-dependent changes in selected parameters governing the refilling flow. Although the modified model could more accurately fit the data, the new parameter values often fell outside of a physiologically acceptable range, suggesting that other factors not included in the classic description of transcapillary fluid transport might be the cause of the observed patterns.

Effects of 90-Minute Football Match on Red Blood Indices in Sedentary Young Males

While exercise-induced haemorheological alterations are well-documented in various sports, the specific impact of a football match on red blood cell (RBC) parameters remains unknown. This study investigates the acute effects of a 90-minute football match on RBC indices in sedentary young males. After inclusion and exclusion criteria, twenty (20) moderately active, non-smoking male volunteers (mean age: 20.00 ± 0.4 years) participated in the study. Venous blood samples were collected pre- and post- football match to assess RBC count, haematocrit (HCT), and plasma volume (PV). Data generated were subjected to paired student's t-tests using SPSS, to compare values between pre- and post-match measurements. A p-value of less than 0.05 was considered indicative of statistical significance. The results showed a statistically significant decrease in haematocrit (HCT) and red blood cell count (RBC) after the match (p &lt; 0.05) when compared to pre-match values. This was accompanied by a significant increase in plasma volume (PV) (p &lt; 0.05), which was higher than pre-match values. These changes suggest that the physiological demands of the football match influenced blood parameters, likely due to fluid shifts and haemodilution during intense physical activity. These findings suggest potential implications for exercise physiology, diagnosis, and therapy in sports medicine.

PBPK modeling of recombinant factor IX Fc fusion protein (rFIXFc) and rFIX to characterize the binding to type 4 collagen in the extravascular space.

Patients with severe and sometimes moderate hemophilia B are prophylactically treated with factor IX concentrates to prevent bleeding. For some time now, various extended terminal half-life (EHL) recombinant factor IX concentrates are available allowing less frequent administration during prophylaxis in comparison to standard half-life recombinant FIX (rFIX). Especially, recombinant FIX-Fc fusion protein (rFIXFc; Alprolix®) exhibits a rapid distribution phase, potentially due to binding to type IV collagen (Col4) in the extravascular space. Studies suggest that the presence of extravascular rFIXFc is protective against bleeding as without measurable FIX activity in plasma, and no extra bleeding seems to occur. The physiologically based pharmacokinetic (PBPK) model for rFIXFc which we describe in this study, is able to accurately predict the observed concentration-time profiles of rFIXFc in plasma and is able to quantify the binding of rFIXFc to Col4 in the extravascular space after an intravenous dose of 50 IU/kg rFIXFc in a male population. Our model predicts that the total AUC of rFIXFc bound to Col4 in the extravascular space is approximately 19 times higher compared to the AUC of rFIXFc in plasma. This suggests that rFIXFc present in the extravascular compartment may play an important role in achieving hemostasis after rFIXFc administration. Further studies on extravascular distribution of rFIXFc and the distribution profile of other EHL-FIX concentrates are needed to evaluate the predictions of our PBPK model and to investigate its clinical relevance.