Secretome of Hypoxia-Preconditioned Mesenchymal Stem Cells Promotes Liver Regeneration and Anti-Fibrotic Effect in Liver Fibrosis Animal Model.

<b>Background and Objective:</b> Liver fibrosis (LF) is a most common pathological process characterized by the activation of hepatocytes leading to the accumulation of extracellular matrix (ECM). Hypoxia precondition treated in MSCs (H-MSCs) could enhance their immunomodulatory and regeneration capability, through expressing robust anti-inflammatory cytokines and growth factors, known as H-MSCs secretome (SH-MSCs) that are critical for the improvement of liver fibrosis. However, the study regarding the efficacy and mechanism of action of SH-MSCs in ameliorating liver fibrosis is still inconclusive. In this study, the therapeutic potential and underlying mechanism for SH-MSCs in the treatment of liver fibrosis were investigated. <b>Materials and Methods:</b> A rat model with liver fibrosis induced by CCl₄ was created and maintained for 8 weeks. The rats received intravenous doses of SH-MSCs and secretome derived from normoxia MSCs (SN-MSCs), filtered using a tangential flow filtration (TFF) system with different molecular weight cut-off categories, both at a dosage of 0.5 mL. The ELISA assay was employed to examine the cytokines and growth factors present in both SH-MSCs and SN-MSCs. On the ninth day, the rats were euthanized and liver tissues were collected for subsequent histological examination and analysis of mRNA expression. <b>Results:</b> The ELISA test revealed that SH-MSCs exhibited higher levels of VEGF, PDGF, bFGF, IL-10, TGF-ß and IL-6 compared to SN-MSCs. <i>In vivo</i>, administration of SH-MSCs notably decreased mortality rates. It also demonstrated a reduction in liver fibrosis, collagen fiber areas, α-SMA positive staining and relative mRNA expression of TGF-ß. Conversely, SN-MSCs also contributed to liver fibrosis improvement, although SH-MSCs demonstrated more favorable outcomes. <b>Conclusion:</b> Current findings suggested that SH-MSCs could improve CCl₄-induced liver fibrosis and decrease α-SMA and TGF-ß expression.

The application of Near-Infrared Spatially Resolved Spectroscopy in scope of achieving continuous real-time quality monitoring and control of tablets with challenging dimensions.

In scope of achieving real-time release of tablets, quality attributes need to be monitored and controlled through Process Analytical Technology tools such as near-infrared spectroscopy (NIRS). The authors evaluated the suitability of NIR-Spatially Resolved Spectroscopy (NIR-SRS) for continuous real-time monitoring and control of content uniformity, hardness and homogeneity of tablets with challenging dimensions. A novel user-friendly research and development inspection unit was used as standalone equipment for the analysis of small oblong tablets with deep-cut break lines. A total of 66 tablets varying in hardness and Active Pharmaceutical Ingredient (API) content were inspected, with each tablet being analysed five times and measurements repeated on three different days. Partial Least Squares (PLS) models were developed to assess content uniformity and hardness, of which the former showed higher accuracy. The authors attempted to visualize tablet homogeneity through NIR-SRS spectra by regressing all spectra obtained during a single measurement using a content uniformity PLS model. The NIR-SRS probe demonstrated its potential towards real-time release testing through its ability to quickly monitor content uniformity, hardness and visualize homogeneity, even for tablets with challenging dimensions.

Penta-Helix Model of E-Government in Combating Corruption in Indonesia and Malaysia: The Moderating Effect of Religiosity.

Background: E-government is an initiative taken by governments worldwide to align the administration of their countries. Governments have utilized the internet as part of a transition into a globalized economy. This helps reduce red tape and procedures in dealing with people in government agencies. This study aims to develop an e-government model as an anti-corruption strategy by applying the Penta-helix model and religiosity as the moderating variable. Methods: The data was gathered from government officials, representatives in business, media, academia, and NGOs, in Indonesia and Malaysia in 2021. Online questionnaires were distributed to 240 respondents from Indonesia and Malaysia. In addition, SPSS v.25 and SEM AMOS v.25 were used to analyze the data. Results: The findings indicate that the Penta-helix elements and religiosity could help to reduce corruption in Indonesia. Meanwhile, Malaysia must increase its human resource competency and embed the religiosity element as a tool to reduce corruption. Conclusion: Penta-helix and religious factors should be incorporated by organizations in Malaysia and Indonesia as part of their strategy in combating corruption.

Family with Peutz-Jeghers syndrome in Indonesia.

Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant disorder characterised by mucocutaneous pigmentation, gastrointestinal polyps and an increased risk of gastrointestinal and other cancers. We report an Indonesian woman, aged 28, with black spots on her lips who had multiple polyps extending from the stomach to the rectum. Her father and a son also had mucocutaneous lesions but they did not undergo gastrointestinal investigations. All three had mutations in the serine/threonine kinase 11 gene (STK11).

TPLS as predictive platform for twin-screw wet granulation process and formulation development.

In recent years, the interest in continuous manufacturing techniques, such as twin-screw wet granulation, has increased. However, the understanding of the influence of the combination of raw material properties and process settings upon the granule quality attributes is still limited. In this study, a T-shaped partial least squares (TPLS) model was developed to link raw material properties, the ratios in which these raw materials were combined and the applied process parameters for the twin-screw wet granulation process with the granule quality attributes. In addition, the predictive ability of the TPLS model was used to find a suitable combination of formulation composition and twin-screw granulation process settings for a new API leading to desired granule quality attributes. Overall, this study helped to better understand the link between raw material properties, formulation composition and process settings on granule quality attributes. Moreover, as TPLS can provide a reasonable starting point for formulation and process development for new APIs, it can reduce the experimental development efforts and consequently the consumption of expensive (and often limited available) new API.

Study of Fe3O4-PPy Core-Shell Nanocomposite in the Diagnosis of Tumor Markers in the Tissues of Early Gastric Cancer Patients.

In order to study Fe3O4-Polypyrrole (Fe3O4-PPy) core-shell nanocomposite in the diagnosis of tumor markers in the diseased gastric tissues of early cancer patients, a total of 160 cases of patients, who were confirmed as early gastric cancer by gastroscopy or postoperative pathology at a designated hospital of the study from December 2014 to December 2018, were selected as research objects and were divided into two groups of observation and control group with 80 cases in each group. For each patient in the two groups, two pieces of diseased gastric tissue were firstly taken through gastroscopy; then the observation group applied Fe3O4-PPy with the particle diameter of 150-350 nm as carrier to detect the contents of carbohydrate antigen 19-9 (CA19-9), alpha-fetoprotein (AFP), carbohydrate antigen 242 (CA242), carcinoembryonic antigen (CEA) and carbohydrate antigen 72-4 (CA72-4) in the diseased gastric tissue, while the control group directly detected the contents of corresponding tumor markers; after the detections, the sensitivity, specificity and diagnostic efficiency of each marker in the two groups of patients were calculated, and receiver operating characteristics (ROC) curves with the areas under the curves (AUC) were drawn to analyze the correlation between the level of Fe3O4-PPy and the detection efficiency of gastric cancer markers. The results show that the detection sensitivity (82.17%, 80.32%, 79.48%, 84.63%, and 85.66%) and specificity (76.75%, 79.66%, 81.07%, 83.47%, and 85.24%) of CA19-9, AFP, CA242, CEA, and CA72-4 in the tumor tissue of patients in observation group for the diagnosis of early gastric cancer are higherthan the sensitivity (78.66%, 79.25%, 76.18%, 82.11%, and 83.45%) and specificity (74.37%, 76.94%, 77.24%, 81.22%, and 81.59%) of that in control group with statistically significant differences (P < 0.05). Therefore, it is believed that the Fe3O4-PPy is of great significance for the detection of early gastric tumor markers in the tissues of patients with early gastric cancer, and has certain value for the auxiliary diagnosis of early gastric cancer and the observation of therapeutic effects. This study results provide a reference for the further researches of Fe3O4-PPy in the diagnosis of tumor markers in patients with early gastric cancer.

Scientific evidence on natural disasters and health emergency and disaster risk management in Asian rural-based area.

INTRODUCTION: Disaster epidemiological studies indicate that Asia has the highest frequency of natural disasters. Rural communities are heavily impacted by natural disasters and have different healthcare needs to urban ones. Referencing Asian countries, this paper's objective is to provide an overview of health impacts and the current evidence for designing programmes and policies related to rural health emergency and disaster risk management (health-EDRM). SOURCES OF DATA: This paper uses published English-only reports and papers retrieved from PubMed, Google Scholar, Embase, Medline and PsycINFO on rural disaster and emergency responses and relief, health impact and disease patterns in Asia (January 2000-January 2018). AREAS OF AGREEMENT: Earthquakes are the most studied natural disasters in rural communities. The medical burden and health needs of rural communities were most commonly reported among populations of extreme age. Most of the existing research evidence for rural interventions was reported in China. There lacks published peer-reviewed reports of programme impacts on personal and community preparedness. AREAS OF CONTROVERSY: There is a lack of evidence-based health-EDRM interventions to evaluate implementation effectiveness in rural areas despite vast volumes of health-related disaster literature. GROWING POINTS: Climate change-related disasters are increasing in frequency and severity. Evidence is needed for disaster risk reduction interventions to address the health risks specific to rural populations. AREAS TIMELY FOR DEVELOPING RESEARCH: To support global policy development, urgent evidence is needed on the intervention effectiveness, long-term health outcomes, local and cultural relevance as well as sustainability of health relief produced by Health-EDRM programmes in rural areas.

Prevalence and predictors of delayed clinical diagnosis of Type 2 diabetes: a longitudinal cohort study.

AIMS: To examine the prevalence and person-level predictors of undiagnosed Type 2 diabetes among adults with elevated HbA1c values. METHODS: We identified adults without diabetes who had a first elevated HbA1c (index HbA1c ≥ 48 mmol/mol; ≥ 6.5%) between January 2014 and December 2015, and classified them by Type 2 diabetes diagnosis status at 1 year following this result. Multilevel modelling techniques were used to examine the association of individual demographic, clinical, and utilization characteristics with remaining undiagnosed. We quantified differences in early Type 2 diabetes care between diagnosed and undiagnosed individuals. RESULTS: Of the 18 356 adults with a first elevated index HbA1c , 30.2% remained undiagnosed with Type 2 diabetes 1 year later. Individuals with lower index HbA1c values [adjusted odds ratio (aOR) 5.95, 95% confidence interval (CI) 5.21-6.78 for 48 to <53 mmol/mol (6.5% to 7.0%); referent 53 to <64 mmol/mol (7.0% to <8.0%)], who were ≥ 70 years old (aOR 1.40, 95% CI 1.24-1.59; referent 50-59 years), and who had a prior prediabetes diagnosis (aOR 1.35, 95% CI 1.24-1.47; referent no prediabetes) had increased odds of remaining undiagnosed. After adjusting for age, race, and index HbA1c , remaining undiagnosed was associated with lower odds of initiating metformin (aOR 0.06, 95% CI 0.05-0.07). CONCLUSIONS: Almost one-third of adults with an elevated HbA1c value were not diagnosed with Type 2 diabetes within 1 year. Undiagnosed Type 2 diabetes, in turn, was associated with differences in early care. Strategies that leverage the electronic health record to facilitate earlier diagnosis may help reduce delays and allow for early intervention towards the goal of improved outcomes.

Comparing volume-clamp method and intra-arterial blood pressure measurements in patients with atrial fibrillation admitted to the intensive or medium care unit.

International guidelines highlight the importance of blood pressure (BP) in patients with atrial fibrillation (AF). However, BP measurement in AF is complicated by beat-to-beat fluctuation. Automated BP measurement devices are not validated for patients with AF and no consensus exists on how to measure BP in AF manually. Beat-to-beat BP measurement using the volume-clamp method (VCM) could represent a non-invasive method to accurately assess BP, but has not been validated in AF. 31 admitted patients with sustained AF and 10 control patients with sinus rhythm underwent simultaneous intra-arterial and non-invasive BP measurement using a VCM monitor (Nexfin®, BMEYE, Amsterdam, The Netherlands). Patients with compromised peripheral perfusion, high doses of vasopressor drugs or peripheral edema were excluded. Differences in systolic, diastolic and mean BP of 5 (standard deviation; SD 8) mmHg (accuracy and precision) between both methods were considered acceptable. Additionally, the magnitude of beat-to-beat fluctuations in systolic BP of both methods was compared. In AF, the differences between noninvasive and invasive BP were -4 (SD 12), +1 (SD 7) and 0 (SD 8) mmHg for systolic, diastolic and mean BP respectively. Absolute differences in beat-to-beat BP fluctuations were 1.5 (IQR 0.8-3.8) mmHg. Accuracy of VCM in AF was similar to sinus rhythm. In conclusion, in patients with AF, accurate and precise measurement of non-invasive beat-to-beat BP measurement using the VCM is possible, the one exception being the precision of systolic BP. Beat-to-beat variability can be accurately reproduced.

Hyperoxia does not directly affect vascular tone in isolated arteries from mice.

Hospitalized patients often receive oxygen supplementation, which can lead to a supraphysiological oxygen tension (hyperoxia). Hyperoxia can have hemodynamic effects, including an increase in systemic vascular resistance. This increase suggests hyperoxia-induced vasoconstriction, yet reported direct effects of hyperoxia on vessel tone have been inconsistent. Furthermore, hyperoxia-induced changes in vessel diameter have not been studied in mice, currently the most used mammal model of disease. In this study we set out to develop a pressure-myograph model using isolated vessels from mice for investigation of pathways involved in hyperoxic vasoconstriction. Isolated conduit and resistance arteries (femoral artery and gracilis arteriole, respectively) from C57BL/6 mice were exposed to normoxia (PO2 of 80 mmHg) and three levels of hyperoxia (PO2 of 215, 375 and 665 mmHg) in a no-flow pressure myograph setup. Under the different PO2 levels, dose-response agonist induced endothelium-dependent vasodilation (acetylcholine, arachidonic acid), endothelium-independent vasodilation (s-nitroprusside), as well as vasoconstriction (norepinephrine, prostaglandin F2α) were examined. The investigated arteries did not respond to oxygen by a change in vascular tone. In the dose-response studies, maximal responses and EC50 values to any of the aforementioned agonists were not affected by hyperoxia either. We conclude that arteries and arterioles from healthy mice are not intrinsically sensitive to hyperoxic conditions. The present ex-vivo model is therefore not suitable for further research into mechanisms of hyperoxic vasoconstriction.

[Carbapenem-resistant bacteria transferred to the Netherlands: patients colonised during hospitalisation in Romania]. / Carbapenemresistente bacteriën overgebracht naar Nederland.

Three patients were recently transferred to two Intensive Care Units (ICUs) in the Netherlands from two different ICUs in Bucharest, Romania. The patients appeared to be colonised with several, partly identical, carbapenemase-producing bacteria (CPB) after a short hospitalisation in Romania. In this article, we show that it is important to be aware of the possibility that patients are colonised with CPB after a short hospitalisation abroad. This has consequences for infection prevention measurements, but probably also for the discontinuation of selective bowel decontamination in the ICU.

Hyperoxia: At what level of SpO2 is a patient safe? A study in mechanically ventilated ICU patients.

BACKGROUND: Concerns have been expressed regarding a possible association between arterial hyperoxia and adverse outcomes in critically ill patients. Oxygen status is commonly monitored noninvasively by peripheral saturation monitoring (SpO2). However, the risk of hyperoxia above specific SpO2 levels in critically ill patients is unknown. The purpose of this study was to determine a threshold value of SpO2 above which the prevalence of arterial hyperoxia distinctly increases. METHODS: This is a cross-sectional study in adult mechanically ventilated intensive care patients in a tertiary referral center. In 100 patients, we collected 200 arterial blood gases (ABG) and simultaneously registered SpO2 levels, as well as hemodynamic and ventilation parameters and vasoactive medication. Patients under therapeutic hypothermia were excluded. RESULTS: The risk of arterial hyperoxia, defined as PaO2>100mmHg or >125mmHg, was negligible when SpO2 was ≤95% or ≤96%, respectively. The majority (89% and 54%, respectively for PaO2>100mmHg and 125mmHg) of ICU patients with SpO2 of 100% had arterial hyperoxia. The relation between SpO2 and PaO2 was not clearly affected by hemodynamic or other clinical variables (pH, pCO2, body temperature, recent blood transfusion). CONCLUSION: In critically ill patients, the prevalence of arterial hyperoxia increases when SpO2 is >95%. Above this saturation level, supplemental oxygen should be administered with caution in patients potentially susceptible to adverse effects of hyperoxia.

[Efficient treatment of chronic respiratory failure associated with morbid obesity].

Severe obesity sometimes leads to chronic respiratory failure. This condition is termed obesity-hypoventilation or Pickwickian syndrome. This article reports clinical observation illustrating effectiveness of noninvasive pressure support ventilation for the treatment of hypercapnic respiratory failure in a patient with morbid obesity. The treatment strategies for such patients are discussed.

Cardiovascular effects of hyperoxia during and after cardiac surgery.

During and after cardiac surgery with cardiopulmonary bypass, high concentrations of oxygen are routinely administered, with the intention of preventing cellular hypoxia. We systematically reviewed the literature addressing the effects of arterial hyperoxia. Extensive evidence from pre-clinical experiments and clinical studies in other patient groups suggests predominant harm, caused by oxidative stress, vasoconstriction, perfusion heterogeneity and myocardial injury. Whether these alterations are temporary and benign, or actually affect clinical outcome, remains to be demonstrated. In nine clinical cardiac surgical studies in low-risk patients, higher oxygen targets tended to compromise cardiovascular function, but did not affect clinical outcome. No data about potential beneficial effects of hyperoxia, such as reduction of gas micro-emboli or post-cardiac surgery infections, were reported. Current evidence is insufficient to specify optimal oxygen targets. Nevertheless, the safety of supraphysiological oxygen suppletion is unproven. Randomised studies with a variety of oxygen targets and inclusion of high-risk patients are needed to identify optimal oxygen targets during and after cardiac surgery.

Species distribution and susceptibility profile to fluconazole, voriconazole and MXP-4509 of 551 clinical yeast isolates from a Romanian multi-centre study.

This is the first multi-centre study regarding yeast infections in Romania. The aim was to determine the aetiological spectrum and susceptibility pattern to fluconazole, voriconazole and the novel compound MXP-4509. The 551 isolates were identified using routine laboratory methods, matrix-assisted laser desorption ionisation time-of-flight mass spectrometry (MALDI-TOF MS) and DNA sequence analysis. Susceptibility testing was performed using the European Committee for Antimicrobial Susceptibility Testing (EUCAST) method and breakpoints. The yeasts originated from superficial infections (SUP, 51.5 %), bloodstream infections (BSI, 31.6 %) and deep-seated infections (DEEP, 16.9 %), from patients of all ages. Nine genera and 30 species were identified. The 20 Candida species accounted for 94.6 % of all isolates. C. albicans was the overall leading pathogen (50.5 %). Lodderomyces elongisporus is reported for the first time as a fungaemia cause in Europe. C. glabrata and Saccharomyces cerevisiae, as well as the non-Candida spp. and non-albicans Candida spp. groups, showed decreased fluconazole susceptibility (<75 %). The overall fluconazole resistance was 10.2 %. C. krusei accounted for 27 of the 56 fluconazole-resistant isolates. The overall voriconazole resistance was 2.5 % and was due mainly to C. glabrata and C. tropicalis isolates. Fluconazole resistance rates for the three categories of infection were similar to the overall value; voriconazole resistance rates differed: 4 % for BSI, 3.2 % for DEEP and 1.4 % for SUP. The antifungal activity of MXP-4509 was superior to voriconazole against C. glabrata and many fluconazole-resistant isolates. There was a large percentage of non-albicans Candida isolates. A large part of the high fluconazole resistance was not acquired but intrinsic, resulting from the high percentage of C. krusei.

[EFFICIENT TREATMENT OF CHRONIC RESPIRATORY INSUFFICIENCY IN PATIENTS WITH KYPHOSCOLIOSIS].

We report efficient treatment of chronic respiratory insufficiency in patients with congenital kyphoscoliosis by non-invasive auxiliary ventilation and low-flow oxygen therapy. It proved possible to effectively control severe chronic respiratory insufficiency under conditions of a pulmonological ward without application of means and measures of intensive therapy.

[Antiviral activity and possible mechanisms of action of moraprenil phosphates during experimental infection caused by herpes simplex type 1 virus].

AIM: Study of antiviral activity of moraprenil phosphates (MPP) against herpes simplex type 1 virus (HSV1) in vitro and during experimental infection caused by HSV1 in mice. MATERIALS AND METHODS: Activity of MPP in vitro was tested by the ability to suppress formation of symplasts in VERO cells infected with HSV1, strain VR-3. A series of MPP that suppress virus-induced symplast-formation by 30 times was selected for in vivo experiments. Anti-viral activity of MPP in vivo was studied in HSV-1 infected mice after administration of either prophylaxis or therapy regimens. RESULTS: MPP at the dose of 20 microg/mice during s/c administration exhibited a pronounced prophylactic-therapeutic effect. Effectiveness of MPP during clinically evident herpes against the background of developing neurologic symptoms was demonstrated for the first time. Visual observation of the mice, that had received MPP as the first clinical symptoms of the disease appeared, has shown that against the background of preparation injection the clinical signs have ceased after 2 - 3 days and did not registered at least for the whole duration of the observation period (14 days). CONCLUSION: Active herpes infection is accompanied by the increase of FoxP3 expression in-thymus was shown. Possible mechanisms of anti-viral effect of MPP are discussed.

[Taxonomic status of the Chim virus (CHIMV) (Bunyaviridae, Nairovirus, Qalyub group) isolated from the Ixodidae and Argasidae ticks collected in the great gerbil (Rhombomys opimus Lichtenstein, 1823) (Muridae, Gerbillinae) burrows in Uzbekistan and Kazakhstan].

Full-length genome of the Chim virus (CHIMV) (strain LEIV-858Uz) was sequenced using the next-generation sequencing approach (ID GenBank: KF801656). The CHIMV/LEIV-858Uz was isolated from the Ornithodoros tartakovskyi Olenev, 1931 ticks collected in the great gerbil (Rhombomys opimus Lichtenstein, 1823) burrow in Uzbekistan near Chim town (Kashkadarinsky region) in July of 1971. Later, four more CHIMV strains were isolated from the O. tartakovskyi, O. papillipes Birula, 1895, Rhipicephalus turanicus Pomerantsev, 1936 collected in the great gerbil burrows in Kashkadarinsky, Bukhara, and Syrdarya regions of Uzbekistan, and three strains--from the Hyalomma asiaticum Schulze et Schlottke, 1930 from the great gerbil burrows in Dzheskazgan region of Kazakhstan. The virus is a potential pathogen of humans and camels. The phylogenetic analysis revealed that the CHIMV is a novel member of the Nairovirus genus (Bunyaviridae) and closely related to the Qalyub virus (QYBV), which is prototype for the group of the same name. The amino acid homology between the CHIMV and QYBV is 87% for the RdRp catalytic center (L-segment) that is coincident with both QYBV and CHIMV associated with the Ornithodoros ticks and burrow of rodents as well. The CHIMV homologies with other nairoviruses are 30-40% for the amino acid sequences of precursor polyprotein GnGc (M-segment), whereas 50%--for the nucleocapsid N (S-segment). The data obtained permit to classify the CHIMV as a member of the QYBV group in the genus of Nairovirus (Bunyaviridae).