Functional Integrity Research Articles

Allogeneic bone marrow mesenchymal stem cell-derived exosomes alleviate human hypoxic AKI-on-a-Chip within a tight treatment window

BackgroundAcute hypoxic proximal tubule (PT) injury and subsequent maladaptive repair present high mortality and increased risk of acute kidney injury (AKI) - chronic kidney disease (CKD) transition. Human bone marrow mesenchymal stem cell-derived exosomes (hBMMSC-Exos) as potential cell therapeutics can be translated into clinics if drawbacks on safety and efficacy are clarified. Here, we determined the real-time effective dose and treatment window of allogeneic hBMMSC-Exos, evaluated their performance on the structural and functional integrity of 3D microfluidic acute hypoxic PT injury platform.MethodshBMMSC-Exos were isolated and characterized. Real-time impedance-based cell proliferation analysis (RTCA) determined the effective dose and treatment window for acute hypoxic PT injury. A 2-lane 3D gravity-driven microfluidic platform was set to mimic PT in vitro. ZO-1, acetylated α-tubulin immunolabelling, and permeability index assessed structural; cell proliferation by WST-1 measured functional integrity of PT.ResultshBMMSC-Exos induced PT proliferation with ED50 of 172,582 µg/ml at the 26th hour. Hypoxia significantly decreased ZO-1, increased permeability index, and decreased cell proliferation rate on 24–48 h in the microfluidic platform. hBMMSC-Exos reinforced polarity by a 1.72-fold increase in ZO-1, restored permeability by 20/45-fold against 20/155 kDa dextran and increased epithelial proliferation 3-fold compared to control.ConclusionsThe real-time potency assay and 3D gravity-driven microfluidic acute hypoxic PT injury platform precisely demonstrated the therapeutic performance window of allogeneic hBMMSC-Exos on ischemic AKI based on structural and functional cellular data. The novel standardized, non-invasive two-step system validates the cell-based personalized theragnostic tool in a real-time physiological microenvironment prior to safe and efficient clinical usage in nephrology.

Proton magnetic resonance spectroscopy in children with some neurological and mental disorders accompanied by mental and speech development delay: a prospective study

Proton magnetic resonance spectroscopy in children with some neurological and mental disorders accompanied by mental and speech development delay: a prospective study

Blocking proteinase-activated receptor 2 signaling relieves pain, suppresses nerve sprouting, improves tissue repair, and enhances analgesic effect of B vitamins in rats with Achilles tendon injury.

Tendon injury produces intractable pain and disability in movement, but the medications for analgesia and restoring functional integrity of tendon are still limited. In this study, we report that proteinase-activated receptor 2 (PAR2) activation in dorsal root ganglion (DRG) neurons contributes to chronic pain and tendon histopathological changes produced by Achilles tendon partial transection injury (TTI). Tendon partial transection injury increases the expression of PAR2 protein in both somata of DRG neurons and their peripheral terminals within the injured Achilles tendon. Activation of PAR2 promotes the primary sensory neuron plasticity by activating downstream cAMP-PKA pathway, phosphorylation of PKC, CaMKII, and CREB. Blocking PAR2 signaling by PAR2 small-interference RNA or antagonistic peptide PIP delays the onset of TTI-induced pain, reverses the ongoing pain, as well as inhibits sensory nerve sprouting, and promotes structural remodeling of the injured tendon. Vitamin B complex (VBC), containing thiamine (B1), pyridoxine (B6), and cyanocobalamin (B12), is effective to ameliorate TTI-induced pain, inhibit ectopic nerve sprouting, and accelerate tendon repair, through suppressing PAR2 activation. These findings reveal a critical role of PAR2 signaling in the development of chronic pain and histopathological alterations of injured tendon following Achilles tendon injury. This study suggests that the pharmaceuticals targeting PAR2, such as VBC, may be an effective approach for the treatment of tendon injury-induced pain and promoting tendon repair.

Low Functional network integrity in cognitively unimpaired and MCI subjects with depressive symptoms: results from a multi-center fMRI study

Evidence suggests that depressive symptomatology is a consequence of network dysfunction rather than lesion pathology. We studied whole-brain functional connectivity using a Minimum Spanning Tree as a graph-theoretical approach. Furthermore, we examined functional connectivity in the Default Mode Network, the Frontolimbic Network (FLN), the Salience Network, and the Cognitive Control Network. All 183 elderly subjects underwent a comprehensive neuropsychological evaluation and a 3 Tesla brain MRI scan. To assess the potential presence of depressive symptoms, the 13-item version of the Beck Depression Inventory (BDI) or the Geriatric Depression Scale (GDS) was utilized. Participants were assigned into three groups based on their cognitive status: amnestic mild cognitive impairment (MCI), non-amnestic MCI, and healthy controls. Regarding affective symptoms, subjects were categorized into depressed and non-depressed groups. An increased mean eccentricity and network diameter were found in patients with depressive symptoms relative to non-depressed ones, and both measures showed correlations with depressive symptom severity. In patients with depressive symptoms, a functional hypoconnectivity was detected between the Anterior Cingulate Cortex (ACC) and the right amygdala in the FLN, which impairment correlated with depressive symptom severity. While no structural difference was found in subjects with depressive symptoms, the volume of the hippocampus and the thickness of the precuneus and the entorhinal cortex were decreased in subjects with MCI, especially in amnestic MCI. The increase in eccentricity and diameter indicates a more path-like functional network configuration that may lead to an impaired functional integration in depression, a possible cause of depressive symptomatology in the elderly.

Wound healing activity of hydromethanolic Dioscorea bulbifera extract on male wistar rat excision wound models

IntroductionWound healing is a complex physiological process that involves a series of coordinated events that recover structural and functional tissue integrity. The desire to promote nature-based solutions has led to the screening of various plants and herbs for their wound healing potentials with results showing the enhancement of various aspects of the wound healing process. Dioscorea bulbifera possesses a wide range of applications in folk remedies. In traditional Chinese medicine, it is used in the treatment of mumps, goitre, sore throat, gastric cancer and carcinoma of the rectum alone or in combination with other plants. The present study evaluated the effect of hydromethanolic extract of Dioscorea bulbifera (HEDB) on wound size, percentage of wound contraction and tissue hydroxyproline in male Wistar rat excision wound models. MethodsTwenty-five (25) male Wistar rats (180–200 g) were used for the study. They were divided into five (5) groups comprising five (5) animals per group. A circular excision wound (1.5–2 cm) was experimentally induced in each animal following ketamine anaesthesia. Groups I and II served as negative and positive controls and were treated with topical administration of distilled water and petroleum jelly respectively. Groups III, IV and V served as the experimental groups and were treated with 200, 400 and 800 mg/kg of HEDB topically. The diameter of the wound was measured and the wound area and percentage of wound contraction were calculated. Tissue hydroxyproline was determined using tissue excised from the healed portion of the dorsal surface of the animals via coulometric standard procedures. ResultsData from the study indicates that animals in the experimental groups (III, IV and V) had an earlier wound closure compared to the control. Animals treated with 200 mg/kg HEDB (Group III) showed complete wound closure by day 17, whereas animals treated with 400 mg/kg (Group IV) and 800 mg/kg HEDB (Group V) groups achieved complete wound closure by the 18th and 20th day of the experiment respectively. Similarly, all the animals in the experimental groups had significantly increased percentage of wound contraction compared to negative control (P < 0.05). Tissue hydroxyproline was significantly raised amongst the animals treated with 200 and 800 mg/kgHEDB compared to the negative control (p < 0.05). DiscussionEvidence from the study has shown that HEDB possesses potent wound healing activity as the present study has demonstrated that it reduced wound area, and increased wound contraction and tissue hydroxyproline on experimentally induced excision wound male Wistar rat models. These findings provide scientific evidence that validates the traditional medicinal application of Dioscorea bulbifera in promoting wound healing.

Heterogenous effect of early adulthood stress on cognitive aging and synaptic function in the dentate gyrus.

Cognitive aging widely varies among individuals due to different stress experiences throughout the lifespan and vulnerability of neurocognitive mechanisms. To understand the heterogeneity of cognitive aging, we investigated the effect of early adulthood stress (EAS) on three different hippocampus-dependent memory tasks: the novel object recognition test (assessing recognition memory: RM), the paired association test (assessing episodic-like memory: EM), and trace fear conditioning (assessing trace memory: TM). Two-month-old rats were exposed to chronic mild stress for 6 weeks and underwent behavioral testing either 2 weeks or 20 months later. The results show that stress and aging impaired different types of memory tasks to varying degrees. RM is affected by combined effect of stress and aging. EM became less precise in EAS animals. TM, especially the contextual memory, showed impairment in aging although EAS attenuated the aging effect, perhaps due to its engagement in emotional memory systems. To further explore the neural underpinnings of these multi-faceted effects, we measured long-term potentiation (LTP), neural density, and synaptic density in the dentate gyrus (DG). Both stress and aging reduced LTP. Additionally, the synaptic density per neuron showed a further reduction in the stress aged group. In summary, EAS modulates different forms of memory functions perhaps due to their substantial or partial dependence on the functional integrity of the hippocampus. The current results suggest that lasting alterations in hippocampal circuits following EAS could potentially generate remote effects on individual variability in cognitive aging, as demonstrated by performance in multiple types of memory.

Antenatal Ureaplasma Infection Causes Colonic Mucus Barrier Defects: Implications for Intestinal Pathologies.

Chorioamnionitis is a risk factor for necrotizing enterocolitis (NEC). Ureaplasma parvum (UP) is clinically the most isolated microorganism in chorioamnionitis, but its pathogenicity remains debated. Chorioamnionitis is associated with ileal barrier changes, but colonic barrier alterations, including those of the mucus barrier, remain under-investigated, despite their importance in NEC pathophysiology. Therefore, in this study, the hypothesis that antenatal UP exposure disturbs colonic mucus barrier integrity, thereby potentially contributing to NEC pathogenesis, was investigated. In an established ovine chorioamnionitis model, lambs were intra-amniotically exposed to UP or saline for 7 d from 122 to 129 d gestational age. Thereafter, colonic mucus layer thickness and functional integrity, underlying mechanisms, including endoplasmic reticulum (ER) stress and redox status, and cellular morphology by transmission electron microscopy were studied. The clinical significance of the experimental findings was verified by examining colon samples from NEC patients and controls. UP-exposed lambs have a thicker but dysfunctional colonic mucus layer in which bacteria-sized beads reach the intestinal epithelium, indicating undesired bacterial contact with the epithelium. This is paralleled by disturbed goblet cell MUC2 folding, pro-apoptotic ER stress and signs of mitochondrial dysfunction in the colonic epithelium. Importantly, the colonic epithelium from human NEC patients showed comparable mitochondrial aberrations, indicating that NEC-associated intestinal barrier injury already occurs during chorioamnionitis. This study underlines the pathogenic potential of UP during pregnancy; it demonstrates that antenatal UP infection leads to severe colonic mucus barrier deficits, providing a mechanistic link between antenatal infections and postnatal NEC development.

Comparative evaluation of stress generation in primary teeth restored with zirconia and BioFlx crowns: A finite element analysis

Background: Maintaining the functional integrity of primary teeth is important, as these teeth are integral in vital functions such as mastication, speech development, and space maintenance for permanent teeth; hence, premature loss of primary teeth can affect a child’s quality of life. Various restorative materials are available to restore the function of grossly decayed teeth. Stainless steel crowns and zirconia crowns are widely used in pediatric dentistry; however, there are certain disadvantages associated with these materials. Recently introduced BioFlx crowns provide acceptable esthetics with a conservative approach. Nevertheless, there is a lack of evidence regarding their strength and clinical acceptability. Finite element analysis measures the physical response of teeth and assesses the stress generation, which is important to estimate the integrity of the restorations and crowns. Purpose: The aim of this in vitro study was to evaluate and compare stress generation in primary teeth restored with zirconia and BioFlx crowns using finite element analysis. Methods: Models of extracted teeth restored with zirconia and BioFlx crowns were used for the study. The finite element analysis of these models was carried out through Analysis of Systems (ANSYS) software. The models were subjected to a simulated occlusal loading force of 245 N. Results: Von Mises stress generated in BioFlx crowns along with underlying dentin was much less compared to that which was generated in zirconia crowns. Conclusion: Restoring the functional integrity of carious teeth is essential. BioFlx crowns can be used as full coverage restorations and can be a suitable alternative to zirconia crowns and traditional stainless steel crowns.

“Pelvic Neuro-Visualization: An Anatomical Illustration of the Autonomic Pelvic Nervous Network in Gynecologic Surgery”

ObjectiveDuring radical pelvic surgeries fibers of the autonomic pelvic nervous network can be accidentally damaged leading to significant visceral sequelae, which dramatically affect women's quality of life because of urinary, anorectal, and sexual postoperative dysfunctions.1,2 Direct visualization is one way to preserve hypogastric nerves (HNs), pelvic splanchnic nerves (PSNs), and the bladder branches from the inferior hypogastric plexus (IHP). However, the literature lacks critical photos and/or illustrations that are necessary to understand the precise anatomy needed to preserve the pelvic autonomic fibers. DesignNarrated laparoscopic video footage for identifying, dissecting, and preserving the autonomic nerve bundles during pelvic surgery. SettingTertiary level hospital—“IRCCS Istituto Nazionale dei Tumori”, Milano, Italy. InterventionsVisceral pelvic innervation is established by the superior hypogastric plexus(SHP) located anteriorly to the aortic bifurcation and the median sacral vessels and carries mostly sympathetic fibers. SHP divides in front of the sacrum into the right and left HN. At the level of the paracervix, the HNs join the parasympathetic PSNs coming out from sacral root S2, S3, S4 to form the IHP.2–5 Here, we performed laparoscopic surgery, before “Laparoscopic Approach to Cervical Cancer” trial (LACC) era, identifying key anatomic landmarks useful to highlight the path of the most commonly encountered autonomic pelvic nerves in gynecologic radical surgery: during the narration we describe and illustrate the procedure to identify all autonomic pelvic nerves, the sympathetic fibers, the PSNs, and the bladder branch emerging from the IHP in order to preserve their anatomic and functional integrity. This technique is anatomically and surgically indicated for adequate removal of the parametrical issues and vagina while preserving the total pelvic nervous system. ConclusionNerve-sparing surgery reduces bowel-, bladder- and sexual­ dysfunction without decreasing surgical efficacy.1,2 To accomplish safe and effective surgery, comprehension of the 3 dimensional structure of the vascular and nerve anatomy in the pelvis is essential. This video provides a great resource to educate surgeons, especially the youngest ones, about the retroperitoneal nervous networking: we identified the autonomic nerve pathway from adjacent tissues along the pathway consisting of cardinal, sacro-uterine, rectouterine/vaginal, and vesico-uterine ligaments.

Blocking cGAS-STING pathway promotes post-stroke functional recovery in an extended treatment window via facilitating remyelination.

Ischemic stroke is a major cause of worldwide death and disability, with recombinant tissue plasminogen activator being the sole effective treatment, albeit with a limited treatment window. The cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) pathway is emerging as the major DNA-sensing pathway to invoke immune responses in neuroinflammatory disorders. By performing a series of neurobehavioral assessments, electrophysiological analysis, high-throughput sequencing, and cell-based assays based on the transient middle cerebral artery occlusion (tMCAO) mouse stroke model, we examined the effects and underlying mechanisms of genetic and pharmacological inhibition of the cGAS-STING pathway on long-term post-stroke neurological functional outcomes. Blocking the cGAS-STING pathway, even 3days after tMCAO, significantly promoted functional recovery in terms of white matter structural and functional integrity as well as sensorimotor and cognitive functions. Mechanistically, the neuroprotective effects via inhibiting the cGAS-STING pathway were contributed not only by inflammation repression at the early stage of tMCAO but also by modifying the cell state of phagocytes to facilitate remyelination at the sub-acute phase. The activation of the cGAS-STING pathway significantly impeded post-stroke remyelination through restraining myelin debris uptake and degradation and hindering oligodendrocyte differentiation and maturation. Manipulating the cGAS-STING pathway has an extended treatment window in promoting long-term post-stroke functional recovery via facilitating remyelination in a mouse stroke model. Our results highlight the roles of the cGAS-STING pathway in aggregating stroke pathology and propose a new way for improving functional recovery after ischemic stroke. This work was primarily funded by the National Key R&D Program of China.

Eriocitrin prevents Sepsis-induced acute kidney injury through anti-inflammation and anti-oxidation via modulating Nrf2/DRP1/OPA1 signaling pathway

BackgroundSevere inflammation and oxidative stress are characteristics of sepsis-associated kidney injury with high morbidity and mortality. Eriocitrin (ERI) has shown promise in suppressing sepsis-associated kidney injury and LPS-induced periodontal disease, however, its efficacy in alleviating SAKI remains unexplored. This study aimed to investigate the therapeutic potential of ERI on SAKI through in vivo and in vitro experiments, elucidating its underlying mechanism. MethodsThe therapeutic effects of ERI against SAKI were evaluated by survival rate, changes of serum creatinine (Scr) and blood urea nitrogen (BUN) and statistic of renal histological score in a Cecal ligation and puncture (CLP)-induced septic mice. Impactions about anti-coagulation, anti-inflammation, anti-oxidative stress and improvement of mitochondrial damage and mitochondrial morphology were further assayed. In vitro, HUVECs upon stimulation of LPS with or without different dosage of ERI, followed by evaluating changes in inflammation, mitochondrial dynamic equilibrium and signaling pathways. ResultsERI demonstrated ameliorative effects on SAKI by attenuating inflammation, oxidative stress and coagulation evidenced by the improved survival rate, alleviated kidney histological injury, declined BUN and Scr in serum and diminished levels of inflammation cytokines, and coagulation factors. Mechanistically, ERI suppressed DRP1-regulated mitochondrial fission and promoted OPA1-modulated mitochondrial fusion by activating Nrf2 in septic mice and LPS-stimulated HUVECs, which maintained mitochondrial dynamic equilibrium, improved mitochondrial morphology, assured integrity of mitochondrial function, decreased oxidative stress, impeded overwhelming inflammation, and thus, played a pivotal role in ERI's protection against SAKI. ConclusionOur data confirmed the therapeutic potential of ERI in mitigating SAKI，suggesting its viability as a pharmacological agent in clinic settings.

The impact of egg consumption on indices of gastrointestinal health: a systematic literature review

Eggs are highly digestible, nutrient-rich and are a valuable source of protein and choline, thereby promoting a range of health benefits. Several studies have found an association between protein intake and gastrointestinal microbial diversity(1), while bacterial fermentation of undigested protein in the large bowel can produce short-chain fatty acids, such as butyrate, positively influencing host metabolic health, gut integrity and immune function(2). On the other hand, dietary choline stimulates gastrointestinal bacterial production of trimethylamine and the prothrombotic compound trimethylamine-N-oxide (TMAO)(3). Despite these established links, limited studies have explored the effects of whole egg intake on indices of gastrointestinal health. This systematic literature review aimed to synthesise research that has investigated the impact of egg-supplemented diets or egg consumption on markers of gastrointestinal health including microbiome, function and symptoms. This review was conducted in accordance with PRISMA guidelines. Five databases (Ovid Medline, Embase, CINAHL Plus, SCOPUS, and PsychInfo), and reference lists of relevant papers, were searched from inception until April 2023. Studies were included if they examined the link between whole chicken egg consumption and gastrointestinal health in healthy adults (aged&gt;16). Indices of gastrointestinal health were defined as any outcomes related to gastrointestinal factors, including symptoms, microbiome, inflammation, colonic fermentation and TMAO. Reviews and case studies were excluded. All studies underwent risk of bias assessment. Overall, 548 studies were identified and 19 studies were included after screening. Eight of these were randomised controlled trials (RCTs), 8 cross-sectional and 3 prospective cohort studies. Participants ranged in number between 20-32,166 and in age between 18–84 years. Study periods varied between 3–14 weeks for RCTs and 6 months–12.5 years for prospective cohort studies. RCTs examined intakes between 1–4 eggs/day, with the majority examining 3 eggs/day (n = 6). The primary outcome across 15 articles was TMAO levels, with most reporting no significant associations (n = 13). Five studies examined inflammation with inconsistent findings ranging from no alterations (in TNF-α, IL-8, CRP), increases (in anti-inflammatory marker LTB5, TNF-α), and decreases (in IL-6, CRP). Lastly, 7 studies explored alterations in microbiome. Two RCTs and 2 cross-sectional trials reported no alterations in microbial diversity in response to eggs. Meanwhile, 2 cross-sectional and 1 prospective study linked specific bacteria to consistent egg intake. Eggs were associated with species that produce butyrate (E.rectale, F.prausnitzii, M.smithii, and R.bromii), and protect against metabolic syndrome (A.muciniphila). This systematic review found that egg consumption did not increase levels of the undesirable biomarker TMAO and were associated with butyrate-producing bacteria. Evidence regarding the effect of egg intake on inflammation was inconsistent. This review revealed the general lack of available research investigating whole eggs and gastrointestinal health. Future carefully designed RCTs are required to improve understanding of how eggs may influence the gastrointestinal microbiome and colonic fermentation.

The Functional Integrity of the Anterior Cruciate Ligament Can Be Objectively Assessed With the Use of Stress Radiographs: A Systematic Review.

Stress radiography is a viable imaging modality that can also be used to assess the integrity of the anterior cruciate ligament (ACL) after primary or secondary injury. Because conventional radiography is relatively easy, affordable, and available worldwide, the diagnostic efficacy of ACL standing, lateral decubitus, and supine stress radiography should be evaluated. To examine the existing literature regarding the application of stress radiography in evaluating the integrity of the ACL. Systematic review; Level of evidence, 3. Using the PubMed and MEDLINE databases for relevant articles published between 1980 and the present, a systematic review was conducted to identify evidence related to the radiographic diagnosis or assessment of ACL tears. The literature search was conducted in September 2022. Of 495 studies, 16 (1823 patients) were included. Four studies examined standing stress radiography, and 12 investigated lateral decubitus or supine stress radiography. Significant heterogeneity in imaging technique and recorded anterior tibial translation was identified. Anterior tibial translation for ACL-injured knees ranged from 1.2 to 10.6 mm for standing stress radiographs and 2.7 to 11.2 mm for supine stress radiographs, with high sensitivities and specificities for both. Stress radiography was a dependable diagnostic method for identifying ACL rupture. Further research is necessary to determine the ideal anatomic landmarks, optimal patient positioning, and appropriate applied stresses to establish a standardized protocol for both assessing ACL tears and evaluating the postoperative integrity of ACL reconstruction using stress radiography.

Low-level photodynamic therapy in chronic wounds

BackgroundChronic wounds refer to those that can't reconstruct anatomical and physical functional integrity, and are usually associated with signs of microbial infection. Current therapies include debridement and dressing change, local or systemic application of antibiotics, and medical dressing care, which are not ideal for the healing of chronic wounds. ObjectiveTo explore the efficacy and safety of photodynamic therapy (ALA-PDT) for the treatment of chronic infectious wounds. Materials and methodsALA-PDT was used in ten patients with persistent wound infections and systemic complications who did not respond to conventional treatment. 5 % ALA solution was applied to the wound surface after debridement, incubated for 3 h with light protection, and then irradiated with red light for 20 min. This procedure was repeated every two weeks, and any adverse reactions were recorded. After the end of three treatments, the patients were followed up for 3 months. ResultsPatients who exhibit resistance to traditional therapies demonstrate a favorable therapeutic outcome with ALA-PDT, although complications may impede wound healing. All participants successfully underwent ALA-PDT treatment and subsequent monitoring, with 90 % achieving complete healing. Common adverse reactions to ALA-PDT encompass treatment-related pain, temporary erythema, and swelling, all of which are well-tolerated by patients without enduring severe consequences. ConclusionsALA-PDT proves to be an efficacious intervention for managing chronic wounds, irrespective of the presence of localized infections or systemic complications.

Determinants and predictive model of failure of surgical repair of obstetric vesico-vaginal fistula in the Democratic Republic of the Congo

IntroductionSurgical repair of obstetric fistula aims to restore the anatomical and functional integrity of the urinary tract, enabling affected women to regain their dignity and quality of life. However, such repairs can end in a failure. The aim of this study is to develop a predictive score to identify factors influencing failure of surgical repair of obstetric vesico-vaginal fistula (FSROVVF) in the Democratic Republic of the Congo.MethodsThis was an analytical cross-sectional study of 318 women with obstetric vesico-vaginal fistula (OVVF) who had undergone surgical management. A bivariate and then a multivariate analysis were performed. Score discrimination was assessed using the ROC curve and C-index, and score calibration using the Hosmer–Lemeshow test.ResultsSurgical repair of OVVF was unsuccessful in 16.98% of cases (54/318). After logistic modeling, six criteria emerged as predictive factors for FSROVVF: the presence of fibrosis (AOR = 5.01; 95% CI:1.73–14.49), the presence of 2 or more fistulas (AOR = 9.04; 95% CI:3.01–27.13), the association of OVVF with another anatomoclinical entity of fistula (AOR = 3.16; 95% CI:1.09–9.13), the fistula size > 3 cm (AOR = 3.65; 95% CI:1.36–9.76), the peri-operative hemorrhage (AOR = 7.01; 95% CI:2.33–21.03), and the post-operative infection (AOR = 178.89; 95% CI:26.09–1226.64). A score ranging from 0 to 13 points was obtained, of which a value ≤ 5 points defines a low risk of FSROVVF, a value between 6 and 8 points defines a moderate risk and value ≥ 9 points corresponds to a high risk of FSROVVF. The area under the ROC curve of the score is 0.925 with a sensitivity of 61.11%, a specificity of 96.59%, a positive predictive value of 78.57% and a negative predictive value of 92.39%.ConclusionThis study demonstrated that the number of fistulas ≥ 2, fistula size > 3 cm, fibrosis, association of OVVF with other types of fistulas, peri-operative hemorrhage, and post-operative infection are factors predictive of FSROVVF. These six factors are key contributors to the score used to predict FSROVVF. Once validated, this score will inform and enable preoperative counseling regarding the prognosis and the chances of a successful outcome of surgical repair of OVVF.

Applying a semi-quantitative risk assessment on petroleum production unit

Applying safety means in the industry, especially in the petroleum industry is very important to maintain the industrial facility. A semi-quantitative risk assessment as Layers of Protection Analysis (LOPA) is used widely to quantify data after qualitative risk analysis as HAZOP using a simpler way than quantitative risk analysis ‘QRA’ as fault tree analysis ‘FTA’. This determines if a new safety integrity function ‘SIF’ is needed. This paper introduces a novel fuzzy logic system to solve the failure of crude oil shipping pumps. Several models are studied to select the most appropriate fuzzy membership functions. Results are compared with results from the LOPA model, which shows the advantages of using the proposed model to reduce the RRF for the potential hazard and achieve a simple and reliable control method.

Focused ultrasound-mediated blood–brain barrier opening is safe and feasible with moderately hypofractionated radiotherapy for brainstem diffuse midline glioma

BackgroundDiffuse midline glioma (DMG) is a pediatric tumor with dismal prognosis. Systemic strategies have been unsuccessful and radiotherapy (RT) remains the standard-of-care. A central impediment to treatment is the blood–brain barrier (BBB), which precludes drug delivery to the central nervous system (CNS). Focused ultrasound (FUS) with microbubbles can transiently and non-invasively disrupt the BBB to enhance drug delivery. This study aimed to determine the feasibility of brainstem FUS in combination with clinical doses of RT. We hypothesized that FUS-mediated BBB-opening (BBBO) is safe and feasible with 39 Gy RT.MethodsTo establish a safety timeline, we administered FUS to the brainstem of non-tumor bearing mice concurrent with or adjuvant to RT; our findings were validated in a syngeneic brainstem murine model of DMG receiving repeated sonication concurrent with RT. The brainstems of male B6 (Cg)-Tyrc-2J/J albino mice were intracranially injected with mouse DMG cells (PDGFB+, H3.3K27M, p53−/−). A clinical RT dose of 39 Gy in 13 fractions (39 Gy/13fx) was delivered using the Small Animal Radiation Research Platform (SARRP) or XRAD-320 irradiator. FUS was administered via a 0.5 MHz transducer, with BBBO and tumor volume monitored by magnetic resonance imaging (MRI).ResultsFUS-mediated BBBO did not affect cardiorespiratory rate, motor function, or tissue integrity in non-tumor bearing mice receiving RT. Tumor-bearing mice tolerated repeated brainstem BBBO concurrent with RT. 39 Gy/13fx offered local control, though disease progression occurred 3–4 weeks post-RT.ConclusionRepeated FUS-mediated BBBO is safe and feasible concurrent with RT. In our syngeneic DMG murine model, progression occurs, serving as an ideal model for future combination testing with RT and FUS-mediated drug delivery.

The establishment of diseased human whole organ model by normothermic machine perfusion technique: Principle of concept.

The global incidence of liver diseases is rising, yet there remains a dearth of precise research models to mimic these diseases. The use of normothermic machine perfusion (NMP) to study diseased livers recovered from liver transplantation (LT) recipients presents a promising avenue. Accordingly, we have developed a machine perfusion system tailored specifically for the human whole diseased livers and present our experience from the NMP of diseased livers. Six diseased livers recovered from LT recipients with different diagnoses were collected. The diseased livers were connected to the machine perfusion system that circulated tailored perfusate, providing oxygen and nutrients. The pressure and flow of the system were recorded, and blood gas analysis and laboratory tests of perfusate and bile were examined to analyze the function of the diseased livers. Liver tissues before and after NMP were collected for histological analysis. Experiments showed that the system maintained the diseased livers in a physiological state, ensuring stable hemodynamics and a suitable partial pressure of oxygen and carbon dioxide. The results of blood gas analysis and laboratory tests demonstrated a restoration and sustenance of metabolism with minimal damage. Notably, a majority of the diseased livers exhibited bile production continuously, signifying their vivid functional integrity. The pathological characteristics remained stable before and after NMP. We successfully established the machine perfusion system tailored specifically for diseased human whole livers. Through the application of this system, we have developed a novel invitro model that faithfully recapitulates the main features of human liver disease. This model holds immense promise as an advanced disease modeling platform, offering profound insights into liver diseases and potential implications for research and therapeutic development.

Zinc alleviates thermal stress-induced damage to the integrity and barrier function of cultured chicken embryonic primary jejunal epithelial cells via the MAPK and PI3K/AKT/mTOR signaling pathways

Zinc (Zn) could alleviate the adverse effect of high temperature (HT) on intestinal integrity and barrier function of broilers, but the underlying mechanisms remain unclear. We aimed to investigate the possible protective mechanisms of Zn on primary cultured broiler jejunal epithelial cells exposed to thermal stress (TS). In Exp.1, jejunal epithelial cells were exposed to 40℃ (normal temperature, NT) and 44℃ (HT) for 1, 2, 4, 6, or 8 h. Cells incubated for 8 h had the lowest transepithelial resistance (TEER) and the highest phenol red permeability under HT. In Exp.2, the cells were preincubated with different Zn sources (Zn sulfate as iZn and Zn proteinate with the moderate chelation strength as oZn) and Zn supplemental levels (50 and 100 µmol/L) under NT for 24 h, and then continuously incubated under HT for another 8 h. TS increased phenol red permeability, lactate dehydrogenase (LDH) activity and p-PKC/PKC level, and decreased TEER, cell proliferation, mRNA levels of claudin-1, occludin, zona occludens-1 (ZO-1), PI3K, AKT and mTOR, protein levels of claudin-1, ZO-1 and junctional adhesion molecule-A (JAM-A), and the levels of p-ERK/ERK, p-PI3K/PI3K and p-AKT/AKT. Under HT, oZn was more effective than iZn in increasing TEER, occludin, ZO-1, PI3K, and AKT mRNA levels, ZO-1 protein level, and p-AKT/AKT level; supplementation with 50 μmol Zn/L was more effective than 100 μmol Zn/L in increasing cell proliferation, JAM-A, PI3K, AKT, and PKC mRNA levels, JAM-A protein level, and the levels of p-ERK/ERK and p-PI3K/PI3K; furthermore, supplementation with 50 μmol Zn/L as oZn had the lowest LDH activity, and the highest ERK, JNK-1, and mTOR mRNA levels. Therefore, supplemental Zn, especially 50 μmol Zn/L as oZn, could alleviate the TS-induced integrity and barrier function damage of broiler jejunal epithelial cells possibly by promoting cell proliferation and tight junction protein expression via the MAPK and PI3K/AKT/mTOR signaling pathways.

Mechanical pain sensitivity is associated with hippocampal structural integrity.

Rodents and human studies indicate that the hippocampus, a brain region necessary for memory processing, responds to noxious stimuli. However, the hippocampus has yet to be considered a key brain region directly involved in the human pain experience. One approach to answer this question is to perform quantitative sensory testing on patients with hippocampal damage-ie, medial temporal lobe epilepsy. Some case studies and case series have performed such tests in a handful of patients with various types of epilepsy and have reported mixed results. Here, we aimed to determine whether mechanical pain sensitivity was altered in patients diagnosed with temporal lobe epilepsy. We first investigated whether mechanical pain sensitivity in patients with temporal lobe epilepsy differs from that of healthy individuals. Next, in patients with temporal lobe epilepsy, we evaluated whether the degree of pain sensitivity is associated with the degree of hippocampal integrity. Structural integrity was based on hippocampal volume, and functional integrity was based on verbal and visuospatial memory scores. Our findings show that patients with temporal lobe epilepsy have lower mechanical pain sensitivity than healthy individuals. Only left hippocampal volume was positively associated with mechanical pain sensitivity-the greater the hippocampal damage, the lower the sensitivity to mechanical pain. Hippocampal measures of functional integrity were not significantly associated with mechanical pain sensitivity, suggesting that the mechanisms of hippocampal pain processing may be different than its memory functions. Future studies are necessary to determine the mechanisms of pain processing in the hippocampus.