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World Journal of Transplantation Jun 2024The number of solid organ transplantations performed annually is increasing and are increasing in the following order: Kidney, liver, heart, lung, pancreas, small bowel,...
The number of solid organ transplantations performed annually is increasing and are increasing in the following order: Kidney, liver, heart, lung, pancreas, small bowel, and uterine transplants. However, the outcomes of transplants are improving (organ survival > 90% after the 1 year). Therefore, there is a high probability that a general surgeon will be faced with the management of a transplant patient with acute abdomen. Surgical problems in immunocompromised patients may not only include graft-related problems but also nongraft-related problems. The perioperative regulation of immunosuppression, the treatment of accompanying problems of immunosuppression, the administration of cortisol and, above all, the realization of a rapidly deteriorating situation and the accurate evaluation and interpretation of clinical manifestations are particularly important in these patients. The perioperative assessment and preparation includes evaluation of the patient's cardiovascular system and determining if the patient has hypertension or suppression of the hypothalamic-pituitary-adrenal axis, or if the patient has had any coagulation mechanism abnormalities or thromboembolic episodes. Immunosuppression in transplant patients is associated with the use of calcineurin inhibitors, corticosteroids, and antiproliferation agents. Many times, the clinical picture is atypical, resulting in delays in diagnosis and treatment and leading to increased morbidity and mortality. Multidetector computed tomography is of utmost importance for early diagnosis and management. Transplant recipients are prone to infections, especially specific infections caused by cytomegalovirus and , and they are predisposed to intraoperative or postoperative complications that require great care and vigilance. It is necessary to follow evidence-based therapeutic protocols. Thus, it is required that the clinician choose the correct therapeutic plan for the patient (conservative, emergency open surgery or minimally invasive surgery, including laparoscopic or even robotic surgery).
PubMed: 38947966
DOI: 10.5500/wjt.v14.i2.93944 -
ACS Omega Jun 2024Increased deposition of amyloid-β (Aβ) plaques in the brain is a frequent pathological feature observed in human immunodeficiency virus (HIV)-positive patients....
Increased deposition of amyloid-β (Aβ) plaques in the brain is a frequent pathological feature observed in human immunodeficiency virus (HIV)-positive patients. Emerging evidence indicates that HIV regulatory proteins, particularly the transactivator of transcription (TAT) protein, could interact with Aβ peptide, accelerating the formation of Aβ plaques in the brain and potentially contributing to the onset of Alzheimer's disease in individuals with HIV infection. Nevertheless, the molecular mechanisms underlying these processes remain unclear. In the present study, we have used long all-atom molecular dynamics simulations to probe the direct interactions between the TAT protein and Aβ peptide at the molecular level. Sampling over 28.0 μs, our simulations show that TAT protein induces a shift in the Aβ monomer ensemble toward elongated conformations, exposing aggregation-prone regions on the surface and thereby inducing subsequent aggregation. TAT protein also appears to enhance the stability of preformed Aβ fibrils, while increasing the β-sheet content within these fibrils. Our atomistically detailed simulations qualitatively agree with previous in vitro and in vivo studies. Importantly, our simulations identify key interactions between Aβ and the TAT protein that drive the Aβ aggregation process and stabilize the preformed Aβ aggregates, which are particularly challenging to obtain through current experimental techniques.
PubMed: 38947850
DOI: 10.1021/acsomega.4c02643 -
ACS Omega Jun 2024The fuel in a scramjet combustor must be injected into a high-speed crossflow and mixed with supersonic air in a very short period of time in order for the scramjet jet...
The fuel in a scramjet combustor must be injected into a high-speed crossflow and mixed with supersonic air in a very short period of time in order for the scramjet jet to operate reliably. More generally, the supersonic air is produced by the lower cover, similar to a Laval type nozzle, of the scramjet combustor. However, significant variation in lower cover geometry is prone to produce unstable vortexes. The unstable vortexes are accompanied by nonuniform stress and strain and are detrimental to the lower cover, even to the combustor. Inspired by mechanical design, this study proposes to change lower cover geometry by decreasing its sizes and then evaluates effects of these changes on kerosene fuel-air interaction in the combustor. The evaluation is based on three-dimensional computational fluid dynamics with couple level set and volume of fluids, which characterizes the penetration height, span expansion area, shock wave angle, and Sauter mean diameter of kerosene jets for three different injection diameters (0.5, 1.0, and 1.5 mm). The simulated air-kerosene interactions reasonably agree with the past numerical findings at identical working conditions. This result demonstrates the effectiveness of the changed lower cover geometry for the scramjet combustor.
PubMed: 38947818
DOI: 10.1021/acsomega.4c03500 -
Infection and Drug Resistance 2024Fungal infections represent a worldwide concern for public health, due to their prevalence and significant increase in cases each year. Among the most frequent mycoses... (Review)
Review
Fungal infections represent a worldwide concern for public health, due to their prevalence and significant increase in cases each year. Among the most frequent mycoses are those caused by members of the genera , and , which have been treated for years with conventional antifungal drugs, such as flucytosine, azoles, polyenes, and echinocandins. However, these microorganisms have acquired the ability to evade the mechanisms of action of these drugs, thus hindering their treatment. Among the most common evasion mechanisms are alterations in sterol biosynthesis, modifications of drug transport through the cell wall and membrane, alterations of drug targets, phenotypic plasticity, horizontal gene transfer, and chromosomal aneuploidies. Taking into account these problems, some research groups have sought new therapeutic alternatives based on drug repositioning. Through repositioning, it is possible to use existing pharmacological compounds for which their mechanism of action is already established for other diseases, and thus exploit their potential antifungal activity. The advantage offered by these drugs is that they may be less prone to resistance. In this article, a comprehensive review was carried out to highlight the most relevant repositioning drugs to treat fungal infections. These include antibiotics, antivirals, anthelmintics, statins, and anti-inflammatory drugs.
PubMed: 38947372
DOI: 10.2147/IDR.S466336 -
Annals of Global Health 2024Minimum meal frequency is the number of times children eat in a day. Without adequate meal frequency, infants and young children are prone to malnutrition. There is...
Spatial Variation and Determinants of Inadequate Minimum Meal Frequency among Children Aged 6-23 Months in Ethiopia: Spatial and multilevel analysis using Ethiopian Mini Demographic and Health Survey (EMDHS) 2019.
Minimum meal frequency is the number of times children eat in a day. Without adequate meal frequency, infants and young children are prone to malnutrition. There is little information on the spatial distribution and determinants of inadequate meal frequency at the national level. Therefore, we aimed to investigate the spatial distribution and determinants of inadequate meal frequency among young children in Ethiopia. The most recent Ethiopian demographic and health survey data was used. The analysis was conducted using a weighted sample of 1,610 children aged 6-23 months old. The Global Moran's I was estimated to assess the regional variation in minimum meal frequency. Further, a multivariable multilevel logistic regression model was fitted to identify factors associated with inadequate meal frequency. The AOR (adjusted odds ratio) at 95% CI (confidence interval) was computed to assess the strength and significance of the relationship between explanatory variables and the outcome variable. Factors with a p-value of <0.05 are declared statistically significant This study revealed that the prevalence of inadequate meal frequency was found to be 30.56% (95% CI: 28.33-32.88). We identified statistically significant clusters of high inadequate meal frequency, notably observed in Somalia, northern Amhara, the eastern part of southern nations and nationalities, and the southwestern Oromia regions. Child age, antenatal care (ANC) visit, marital status, and community level illiteracy were significant factors that were associated with inadequate meal frequency. According to the study findings, the proportion of inadequate meal frequency among young children in Ethiopia was higher and also distributed non-randomly across Ethiopian regions. As a result, policymakers and other concerned bodies should prioritize risky areas in designing intervention. Thus, special attention should be given to the Somalia region, the northern part of Amhara, the eastern part of Southern nations and nationalities, and southwestern Oromia.
Topics: Humans; Ethiopia; Infant; Female; Male; Multilevel Analysis; Health Surveys; Meals; Spatial Analysis; Feeding Behavior; Logistic Models; Educational Status; Adult; Young Adult; Socioeconomic Factors
PubMed: 38947310
DOI: 10.5334/aogh.4448 -
MedRxiv : the Preprint Server For... Jun 2024Inclusion body myositis (IBM) is the most prevalent muscle disease in adults for which no current treatment exists. The pathogenesis of IBM remains poorly defined....
BACKGROUND
Inclusion body myositis (IBM) is the most prevalent muscle disease in adults for which no current treatment exists. The pathogenesis of IBM remains poorly defined. Inflammation and mitochondrial dysfunction are the most common histopathological findings. In this study, we aimed to explore the interplay between inflammation and mitochondrial dysfunction in IBM patients, highlighting sex differences.
METHODS
We included 38 IBM patients and 22 age- and sex-matched controls without myopathy. Bulk RNA sequencing, Meso Scale Discovery ELISA, western blotting, histochemistry and immunohistochemistry were performed on frozen muscle samples from the study participants.
RESULTS
We demonstrated activation of the NLRP3 inflammasome in IBM muscle samples, with the NLRP3 inflammasome pathway being the most upregulated. On muscle histopathology, there is increased NRLP3 immunoreactivity in both inflammatory cells and muscle fibers. Mitophagy is critical for removing damaged mitochondria and preventing the formation of a vicious cycle of mitochondrial dysfunction-NLRP3 activation. In the IBM muscle samples, we showed altered mitophagy, most significantly in males, with elevated levels of p-S65-Ubiquitin, a mitophagy marker. Furthermore, p-S65-Ubiquitin aggregates accumulated in muscle fibers that were mostly type 2 and devoid of cytochrome-c-oxidase reactivity. Type 2 muscle fibers are known to be more prone to mitochondrial dysfunction. levels correlated with p-S65-Ubiquitin levels in both sexes but with loss of in muscle strength only in males. Finally, we identified sex-specific molecular pathways in IBM, with females having activation of pathways that could offset some of the pathomechanisms of IBM.
CONCLUSIONS
NLRP3 inflammasome is activated in IBM, along with altered mitophagy particularly in males, which is of potential therapeutic significance. These findings suggest sex-specific mechanisms in IBM that warrant further investigation.
PubMed: 38947067
DOI: 10.1101/2024.06.15.24308845 -
The Lancet Regional Health. Europe Aug 2024Hepatocellular carcinoma (HCC) prognosis remains dismal due to late-stage diagnosis; surveillance has been demonstrated to increase early diagnosis rates and receipt of... (Review)
Review
Hepatocellular carcinoma (HCC) prognosis remains dismal due to late-stage diagnosis; surveillance has been demonstrated to increase early diagnosis rates and receipt of curative treatment. Acknowledging limitations in the evidence base for HCC surveillance, international professional bodies reiterate the recommendation for biannual HCC surveillance and NHS England supports measures aimed to increase surveillance uptake. The current ad hoc provision of HCC surveillance is prone to failures, evident by low surveillance uptake and high numbers of patients being diagnosed outside of surveillance. We discuss challenges related to HCC surveillance in the UK and potential solutions to addressing them. We highlight the requirements of a consistent and effective national surveillance process, and suggest pathways on how this can be achieved.
PubMed: 38946891
DOI: 10.1016/j.lanepe.2024.100963 -
Journal of Experimental Zoology. Part... Jul 2024Salinity can be an environmental stressor for anurans, as their highly permeable skin makes them prone to osmotic stress when exposed to saline conditions. However,...
Salinity can be an environmental stressor for anurans, as their highly permeable skin makes them prone to osmotic stress when exposed to saline conditions. However, certain anuran species have colonized areas near saltwater habitats, suggesting an ability to acclimate to saline conditions. Here, we evaluated physiological and behavioral responses to saline conditions in adult Cuban treefrogs (Osteopilus septentrionalis), an invasive anuran found throughout Florida. To examine their response to salinity, adult frogs were maintained in two treatments simulating a freshwater (0.5 ppt) or brackish (8.0 ppt) environment for 6 weeks. To assess their physiological response to this potential stressor, all frogs were submerged in a brackish solution to quantify individual weight change every 2 weeks. We found that frogs maintained in brackish solution lost more weight at Weeks 2 and 6 when compared to Week 0, suggesting that salinity may be an environmental stressor for Cuban treefrogs. Yet, the weight change at Week 4 was similar to the pre-exposure period, which may indicate that constant exposure to salinity may alter their physiological response to saline conditions. To supplement the physiological analyses, we investigated avoidance behavior toward saline conditions by offering individuals a choice between freshwater or brackish environments. Our results showed that Cuban treefrogs chose freshwater environments more frequently and may thus avoid saline ones. This study reveals that salinity may induce plastic and avoidance responses in Cuban treefrogs, potentially allowing them to expand their range into areas typically stressful for most anurans.
PubMed: 38946593
DOI: 10.1002/jez.2841 -
Amyloid : the International Journal of... Jul 2024Genotyping and amyloid fibril detection in tissues are generally considered the diagnostic gold standard in transthyretin-related amyloidosis. Patients carry less stable...
BACKGROUND
Genotyping and amyloid fibril detection in tissues are generally considered the diagnostic gold standard in transthyretin-related amyloidosis. Patients carry less stable TTR homotetramers prone to dissociation into non-native monomers, which rapidly self-assemble into oligomers and, ultimately, amyloid fibrils. Thus, the initial event of the amyloid cascade produces the smallest transthyretin species: the monomers. This creates engineering opportunities for diagnosis that remain unexplored.
METHODS
We hypothesise that molecular sieving represents a promising method for isolating and concentrating trace TTR monomers from the tetramers present in plasma samples. Subsequently, immunodetection can be utilised to distinguish monomeric TTR from other low molecular weight proteins within the adsorbed fraction. A two-step assay was devised (ImmunoSieve assay), combining molecular sieving and immunodetection for sensing monomeric transthyretin. This assay was employed to analyse plasma microsamples from 10 individuals, including 5 pre-symptomatic carriers of TTR-V30M, the most prevalent amyloidosis-associated TTR variant worldwide, and 5 healthy controls.
RESULTS
The ImmunoSieve assay enable sensitive detection of monomeric transthyretin in plasma microsamples. Moreover, the circulating monomeric TTR levels were significantly higher in carriers of amyloidogenic TTR mutation.
CONCLUSIONS
Monomeric TTR can function as a biomarker for evaluating disease progression and assessing responses to therapies targeted at stabilising native TTR.
PubMed: 38946492
DOI: 10.1080/13506129.2024.2368860 -
Genome Biology and Evolution Jul 2024Recent years have seen a dramatic increase in the number of canine genome assemblies available. Duplications are an important source of evolutionary novelty and are also...
Recent years have seen a dramatic increase in the number of canine genome assemblies available. Duplications are an important source of evolutionary novelty and are also prone to misassembly. We explored the duplication content of nine canine genome assemblies using both genome self-alignment and read-depth approaches. We find that 8.58% of the genome is duplicated in the canFam4 assembly, derived from the German Shepherd Dog Mischka, including 90.15% of unplaced contigs. Highlighting the continued difficulty in properly assembling duplications, less than half of read-depth and assembly alignment duplications overlap, but the mCanLor1.2 Greenland wolf assembly shows greater concordance. Further study shows the presence of multiple segments that have alignments to four or more duplicate copies. These high-recurrence duplications correspond to gene retrocopies. We identified 3,892 candidate retrocopies from 1,316 parental genes in the canFam4 assembly and find that approximately 8.82% of duplicated base pairs involve a retrocopy, confirming this mechanism as a major driver of gene duplication in canines. Similar patterns are found across eight other recent canine genome assemblies, with metrics supporting a greater quality of the PacBio HiFi mCanLor1.2 assembly. Comparison between the wolf and other canine assemblies found that 92% of retrocopy insertions are shared between assemblies. By calculating the number of generations since genome divergence, we estimate that new retrocopy insertions appear, on average, in 1 out of 3,514 births. Our analyses illustrate the impact of retrogene formation on canine genomes and highlight the variable representation of duplicated sequences among recently completed canine assemblies.
PubMed: 38946312
DOI: 10.1093/gbe/evae142