PEGylation of Chrysin Improves Its Water Solubility while Preserving the In Vitro Biological Activity.

Chrysin is a natural flavonoid that despite having numerous biological properties, its therapeutic value is limited due to its very low solubility in aqueous media. In this work, chrysin was conjugated with methoxypolyethylene glycols (mPEGs) of different molecular weights (350, 500, 750, and 2000 g/mol), affording PEGylated chrysins with high yields and excellent purities. In all cases, an increase in the water solubility of the conjugates was observed, which was highest when 500 g/mol of mPEG was used in the PEGylation reaction. Furthermore, in aqueous solution, PEGylated chrysins formed aggregates of ellipsoid shape. Electrochemical studies showed that the redox properties were conserved after PEGylation. While in vitro antibacterial and antifungal studies probed that the intrinsic activity was conserved, in vitro antitumor activities against HepG2 (liver carcinoma cells) and PC3 (prostate cancer cell) showed that PEGylated chrysins retained the cytotoxic activity and the ability of induction of apoptosis for the evaluated human cancer cells.

Serum-free light chain test utilisation at a South African academic laboratory and comparison with serum protein electrophoresis results.

Background: Serum protein electrophoresis (SPE), urine protein electrophoresis and immunofixation electrophoresis were traditionally utilised for the diagnosis of monoclonal gammopathies. The quantitative serum-free light chain (SFLC) assay is reportedly more sensitive and has been introduced to recent clinical guidelines. Objective: This study aimed to investigate SFLC test utilisation and describe SPE findings in patients with abnormal SFLC ratios. Methods: A retrospective audit of SFLC analyses was conducted in Cape Town, South Africa, from May 2018 to April 2020. Agreement between abnormal SFLC ratios and SPE results was determined in a sub-group of patients screened for monoclonal gammopathies. Serum-free light chains were analysed using Freelite® Kappa and Lambda assays. Results: Of the 1425 patients included in the audit, 741 (52%) had abnormal SFLC ratios; 636 (45%) had increased and 105 (7%) had decreased SFLC ratios. In a sub-group analysis of 117 new patients with an abnormal SFLC ratio, 57 had a monoclonal protein (M-protein) on SPE (49%), and 60 (51%) did not. Four out of 60 patients without M-protein had a plasma cell dyscrasia, while renal impairment or inflammatory response accounted for the rest. Of the 57 patients with a M-protein and abnormal SFLC ratio, 41 (72%) had a plasma cell dyscrasia, seven (12%) had lymphomas and nine patients (16%) were unclassifiable. Conclusion: Serum-free light chains should be requested when there is a high index of clinical suspicion. Neither SFLC nor SPE should be performed in isolation when screening patients for monoclonal gammopathy, to ensure that no patient is missed. What this study adds: The study adds to the evidence on SFLC test utilisation. Serum protein electrophoresis alone may miss cases of light chain myeloma, while SFLC performed in isolation may produce false positive results in the setting of inflammatory disorders or renal impairment, leading to unnecessary further investigation.

Cytotoxic, antioxidant, and cytoprotective properties of polyphenol-enriched extracts from pecan nutshells in MDA-MB-231 breast cancer cells.

Phenolic compounds present in plants have demonstrated several biological properties such as antioxidant, antitumor, cardioprotective, and antiproliferative. On the other hand, doxorubicin, a chemotherapeutic widely used to treat breast cancer, usually exhibits chronic cardiotoxicity associated with oxidative stress. Therefore, we aimed to study the effects of phenolic compound-enriched extract (PCEE) with doxorubicin in breast cancer. To achieve this, after an SPE-C18 -column purification process of crude extracts obtained from pecan nutshells (Carya illinoinensis), the resulting PCEE was used to evaluate the cytotoxicity and antioxidant properties against the human breast cancer cell line MDA-MB-231 and the normal-hamster ovary cell line CHO-K1. PCEE was selectively cytotoxic against both cell lines, with an IC50 value (≈26.34 mg/L) for MDA-MB-231 lower than that obtained for CHO-K1 (≈55.63 mg/L). As a cytotoxic mechanism, PCEE inhibited cell growth by G2/M cell cycle arrest in MDA-MB-231 cells. Simultaneously, the study of the antioxidant activity showed that PCEE had a cytoprotective effect, evidenced by reduced ROS production in cells with oxidative stress caused by doxorubicin. The results highlight PCEE as a potential antitumor agent, thus revaluing it as an agro-industrial residue.

Bioactivity and molecular docking of lactones isolated from Centaurea pseudosinaica Czerep.

Two cytotoxic sesquiterpene lactones, 17-epichlorohyssopifolin A (1) and chlorjanerin (2), and a monoterpene lactone, loliolide (3) were isolated from Centaurea pseudosinaica. The cytotoxicity of the total extract and terpenoids 1-3 were evaluated against three human cancer cells (HepG2, PC-3, and HT-29), along with the human normal primary epidermal keratinocytes (HEKa) cells. With IC50 values ranging between 0.6 ± 0.04 and 5.0 ± 0.61 µg/mL against HepG2; 0.2 ± 0.01 and 11.9 ± 1.31 µg/mL against PC-3, and 0.04 ± 0.013 and 8.9 ± 0.97 µg/mL against HT-29, the total extract, and lactones 1-3 demonstrated cytotoxic effects. Compound 1 displayed the strongest impact on all cancer cells and a slightly safe effect on the normal cells HEKa. Compound 1 caused accumulation of HepG2 and HT-29 cells in G1 phase as displayed cell cycle analysis. On the other hand, the cell distributions were increased in the S phase in PC-3 cells. Furthermore, 1 caused apoptosis in PC-3 and HePG2 cells with 91.50%, and 79.72 %, respectively. A higher fraction of necrotic cells was observed in HT-29 cells amounting to 23.60%. These results suggested that the promising cytotoxicity exhibited by 1 is brought by the apoptosis induction in the cancer cells, which were evaluated. As the compounds showed antiproliferative effect against the HT-29 cells, the docking simulation was performed aiming at determining how they would interact with the EGFR enzyme, whose PDB: 4I23 is considered one of the two distinct wild types of EGFR enzymes. The antibacterial activity results revealed that 3 showed the most remarkable antibacterial effects, especially against the examined Gram-positive bacteria. The total extract exhibited potent activity against all examined bacteria. The total extract showed a potent antifungal effect against two Candida and two Aspergillus pathogens. The antioxidant activity revealed the potency of the total extract and 3 as antioxidant candidates. The obtained results refer to the importance of Centaurea pseudosinaica as a source of potent antiproliferative agents and the whole plant as an antipathogenic and antioxidant agent.

Microbiota manipulation to increase macrophage IL-10 improves colitis and limits colitis-associated colorectal cancer.

Inflammatory bowel disease (IBD) is a chronic life-long inflammatory disease affecting almost 2 million Americans. Although new biologic therapies have been developed, the standard medical treatment fails to selectively control the dysregulated immune pathways involved in chronic colonic inflammation. Further, IBD patients with uncontrolled colonic inflammation are at a higher risk for developing colorectal cancer (CRC). Intestinal microbes can impact many immune functions, and here we asked if they could be used to improve intestinal inflammation. By utilizing an intestinal adherent E. coli that we find increases IL-10 producing macrophages, we were able to limit intestinal inflammation and restrict tumor formation. Macrophage IL-10 along with IL-10 signaling to the intestinal epithelium were required for protection in both inflammation and tumor development. Our work highlights that administration of immune modulating microbes can improve intestinal outcomes by altering tissue inflammation.

Neurologic manifestations of COVID-19 in critically ill patients: results of the prospective multicenter registry PANDEMIC.

BACKGROUND: Neurologic manifestations are increasingly reported in patients with coronavirus disease 2019 (COVID-19). Yet, data on prevalence, predictors and relevance for outcome of neurological manifestations in patients requiring intensive care are scarce. We aimed to characterize prevalence, risk factors and impact on outcome of neurologic manifestations in critically ill COVID-19 patients. METHODS: In the prospective, multicenter, observational registry study PANDEMIC (Pooled Analysis of Neurologic DisordErs Manifesting in Intensive care of COVID-19), we enrolled COVID-19 patients with neurologic manifestations admitted to 19 German intensive care units (ICU) between April 2020 and September 2021. We performed descriptive and explorative statistical analyses. Multivariable models were used to investigate factors associated with disorder categories and their underlying diagnoses as well as to identify predictors of outcome. RESULTS: Of the 392 patients included in the analysis, 70.7% (277/392) were male and the mean age was 65.3 (SD ± 3.1) years. During the study period, a total of 2681 patients with COVID-19 were treated at the ICUs of 15 participating centers. New neurologic disorders were identified in 350 patients, reported by these centers, suggesting a prevalence of COVID-19-associated neurologic disorders of 12.7% among COVID-19 ICU patients. Encephalopathy (46.2%; 181/392), cerebrovascular (41.0%; 161/392) and neuromuscular disorders (20.4%; 80/392) were the most frequent categories identified. Out of 35 cerebrospinal fluid analyses with reverse transcriptase PCR for SARS-COV-2, only 3 were positive. In-hospital mortality was 36.0% (140/389), and functional outcome (mRS 3 to 5) of surviving patients was poor at hospital discharge in 70.9% (161/227). Intracerebral hemorrhage (OR 6.2, 95% CI 2.5-14.9, p < 0.001) and acute ischemic stroke (OR 3.9, 95% CI 1.9-8.2, p < 0.001) were the strongest predictors of poor outcome among the included patients. CONCLUSIONS: Based on this well-characterized COVID-19 ICU cohort, that comprised 12.7% of all severe ill COVID-19 patients, neurologic manifestations increase mortality and morbidity. Since no reliable evidence of direct viral affection of the nervous system by COVID-19 could be found, these neurologic manifestations may for a great part be indirect para- or postinfectious sequelae of the infection or severe critical illness. Neurologic ICU complications should be actively searched for and treated.

Parental migration status moderates the link between parent-child relationship and children's well-being through psychological distress.

The effects of parental migration on the well-being of left-behind children (LBC) are varied. Several studies demonstrated that parental migration reduces children's psychological health but other research showed contradictory results. This study sought to clarify this issue by examining the mediating role of psychological distress and the moderating role of parental migration status in the association between the parent-child relationship and children's psychological distress. A total of 743 LBC and 688 non-LBC self-reported their parent-child relationship, psychological distress, and well-being. Findings showed that psychological distress mediated the association between parent-child relationship and children's well-being. This denotes that greater parent-child relationship results into lowered levels of psychological distress, and in turn, increases children's emotional, psychological, and social well-being. Moreover, the link between parent-child relationship and psychological distress was found to be contingent to parental migration status. Specifically, the negative association between parent-child relationship and psychological distress was especially strong among LBC in contrast to non- LBC. This implies that children with higher quality relationships with their parents tend to exhibit decreased severity of psychological distress symptoms, especially in children whose parents are working overseas. These results underscore the dynamic role of parent-child relationship in the well-being of LBC, and suggest ways to develop intervention programs that include cultivating skills in managing psychological distress and improving the emotional, psychological, and social well-being of LBC.

Interleukin-1ß secretion induced by mucosa-associated gut commensal bacteria promotes intestinal barrier repair.

The gut microbiota is essential for maintenance and repair of the intestinal epithelial barrier. As shifts in both intestinal epithelial barrier function and microbiota composition are found in inflammatory bowel disease patients, it is critical to understand the role of distinct bacteria in regulating barrier repair. We identified a mouse commensal E. coli isolate, GDAR2-2, that protects mice from Citrobacter rodentium infection and dextran sulfate sodium-induced colitis. Colonization with GDAR2-2 in mice resulted in expansion of CX3CR1+ mononuclear phagocytes, including CX3CR1+ macrophages/dendritic cells and monocytes, along with IL-22-secreting type 3 innate lymphoid cells and improved epithelial barrier function. In vitro co-culture of macrophages with GDAR2-2 resulted in IL-1ß production. In vivo, protection after GDAR2-2 colonization was lost after depletion of CX3CR1+ MNPs, or blockade of IL-1ß or IL-22. We further identified human commensal E. coli isolates that similarly protect mice from C. rodentium infection through CX3CR1+ MNP and IL-1ß production. Together, these findings demonstrate an unexpected role for commensal bacteria in promoting IL-1ß secretion to support intestinal barrier repair.

How Are Attention-deficit Hyperactivity and Internet Gaming Disorders Related in Children and Youth?

OBJECTIVES: This review addresses important practical questions facing clinicians regarding internet gaming disorder (IGD) and attention-deficit/hyperactivity disorder (ADHD) in children and youth (C-Y). The authors investigated data concerning the risk that C-Y who have ADHD will develop IGD, whether effective treatment of ADHD positively influences the course of IGD in C-Y who have both, and other findings that might be of benefit to clinicians who treat C-Y with these conditions. METHODS: We conducted a literature review using 4 databases: PubMed, Scopus, PsychInfo, and Embase. RESULTS: C-Y with ADHD are at greater risk for developing IGD than those without ADHD. A close association exists between the severity of ADHD symptoms and the severity of IGD. It is unknown what proportion of C-Y with ADHD will develop IGD during their developmental trajectory; however, C-Y with IGD are at risk for developing ADHD, and ADHD can also increase the vulnerability of C-Y to IGD. Adolescents with ADHD and IGD have greater deficits in social skills than those with ADHD but no IGD. Lower parental occupational and socioeconomic status and poor family relationships are associated with more severe IGD symptoms. Atomoxetine and methylphenidate are equally effective in alleviating IGD symptoms comorbid with ADHD. CONCLUSIONS: C-Y with ADHD are at increased risk for developing IGD compared with C-Y without ADHD, but it has not been determined at what developmental stage IGD is likely to emerge. Since IGD and ADHD are strongly associated, it is imperative to consider ADHD as a significant risk factor for IGD and vice versa, which can help psychiatrists be alert for early signs of IGD and manage them accordingly.

Magnetic Resonance Imaging Correlates of Multiple Sclerosis Immunopathological Patterns.

OBJECTIVE: Histology reveals that early active multiple sclerosis lesions can be classified into 3 main interindividually heterogeneous but intraindividually stable immunopathological patterns of active demyelination (patterns I-III). In patterns I and II, a T-cell- and macrophage-associated demyelination is suggested, with pattern II only showing signs of a humoral immune response. Pattern III is characterized by inflammatory lesions with an oligodendrocyte degeneration. Patterns suggest pathogenic heterogeneity, and we postulated that they have distinct magnetic resonance imaging (MRI) correlates that may serve as biomarkers. METHODS: We evaluated in an international collaborative retrospective cohort study the MRI lesion characteristics of 789 conventional prebiopsy and follow-up MRIs in relation to their histopathologically classified immunopathological patterns (n = 161 subjects) and lesion edge features (n = 112). RESULTS: A strong association of a ringlike enhancement and a hypointense T2-weighted (T2w) rim with patterns I and II, but not pattern III, was observed. Only a fraction of pattern III patients showed a ringlike enhancement, and this was always atypical. Ringlike enhancement and T2w rims colocalized, and ringlike enhancement showed a strong association with macrophage rims as shown by histology. A strong concordance of MRI lesion characteristics, meaning that different lesions showed the same features, was found when comparing biopsied and nonbiopsied lesions at a given time point, indicating lesion homogeneity within individual patients. INTERPRETATION: We provide robust evidence that MRI characteristics reflect specific morphological features of multiple sclerosis immunopatterns and that ringlike enhancement and T2w hypointense rims might serve as a valuable noninvasive biomarker to differentiate pathological patterns of demyelination. ANN NEUROL 2021;90:440-454.

Prevention and Control of Acute Respiratory Viral Infections in Adult Population: A Systematic Review and Meta-Analysis on Ginseng-Based Clinical Trials.

IntroductionAcute respiratory infections are continuously emerging. Discovered in Wuhan city, China in 2019, COV-SARS-2 and most viral respiratory diseases presently do not have a definitive cure. This paper aims to evaluate the therapeutic effectiveness of ginseng for prevention and control of acute respiratory illness including SARS-COV-2 in adult population. MethodWe performed a systematic literature review using databases PubMed, Medline, Scopus, Google Scholar, Web of Science, and Cochrane library from 1st through the 27th of April 2020. All related articles that reported the use of Ginseng in COVID-19 patients were included in this analysis. Screening was done by 2-independent researchers. The meta-analysis was performed using comprehensive meta-analysis package. Result596 articles were retrieved for the time frame. After screening, 5 articles with RCTs outcomes relevant to the review were selected. Ginseng was found to be effective in the reduction of risk by 38 % and 3-days shorter duration of acute respiratory illness (ARI) in all trials than placebo. ConclusionAs the world continues to race to find a cure, it is important to consider the use of ginseng which has been proven over the years to be effective in the treatment of acute respiratory illnesses. Further studies should however be conducted to determine the right dosage to improve efficacy and prevent adverse events. FundingThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Highlight COVID-19 is very infectious ravaging the globe Millions have been infected and hundreds of thousands lost their lives to COVID-19 Due to absence of vaccines, urgent search for vaccines and drugs is still underway Ginseng has been useful in similar respiratory viral infections in the past Current paper throws more light on the need to consider ginseng for COVID-19 control

Vitrification improves in-vitro embryonic survival in Bos taurus embryos without increasing pregnancy rate post embryo transfer when compared to slow-freezing: A systematic meta-analysis.

Objectives were to use meta-analytic approaches to compare slow-freezing (SF) and vitrification (VF) methods of cryopreservation on in-vitro (n = 12,211) and in-vivo (n = 3473) survival of Bos taurus embryos. The literature was systematically reviewed and data from 40 manuscripts including 78 experiments, and comprising 183 treatment means, were used for the analyses. The in-vitro parameters included rates of re-expansion, hatching, and survival of blastocysts either at 24 h or 72 h post-thawing/warming and total number (TN) of embryonic cells, whereas in-vivo parameters evaluated pregnancy rate between 35 and 60 d post embryo transfer (ET). Mixed models were fitted using MIXED and GLIMMIX procedures of SAS. Additionally, classical meta-analytical statistics were also fitted using METAN and METAREG procedures of STATA. The final models included the fixed effects of methods of cryopreservation and random effects of the experiment. Rates (LSM ± SEM) of re-expansion (0.36 ± 0.07 vs. 0.48 ± 0.08), hatching (0.25 ± 0.05 vs. 0.42 ± 0.07), and survival (0.57 ± 0.09 vs. 0.76 ± 0.07) at 72 h post-thawing/warming were lower (P < 0.05) in SF than VF, respectively. The TN of embryonic cells (96.89 ± 7.15 vs. 117.83 ± 7.15) remained lower (P < 0.05) in SF than VF, however, the relative risk (RR) of pregnancy rate post ET remained similar (RR = 1.0, CI = 0.8-1.2; P > 0.05) between both methods. Collectively, VF technique has a short-term protective effect against cryodamage of preimplantation embryos, however, it might be dysregulating genes involved in pregnancy success post ET in cows.

Emphysematous pyelonephritis in an infant from Sokoto, north-western Nigeria.

INTRODUCTION: Emphysematous pyelonephritis is a life-threatening necrotising bacterial infection of the kidneys. It is rare among children and can be fatal if not promptly identified and treated. CASE PRESENTATION: A 7-month-old male infant presented to the Emergency Paediatric Unit of Usmanu Danfodiyo University Teaching Hospital, Sokoto, Nigeria, on 12 November 2019 with a 5-day history of fever and vomiting, and a 3-day history of a progressively enlarging, left-side abdominal mass. There was associated excessive crying on micturition, refusal to feed and weight loss. He looked ill and was in respiratory distress, irritable, febrile (38.8 °C), moderately dehydrated and pale. His weight and length were 5.5 kg and 64 cm. He had a tender, firm and ballotable abdominal mass on the left flank measuring 8 cm × 10 cm. His pulse rate was 140 beats/min, blood pressure 60/40 millimetres of mercury and respiratory rate was 65 cycles/min. He had widespread coarse crepitations and normal heart sounds on chest auscultation. MANAGEMENT AND OUTCOME: An initial diagnosis of sepsis was made. Other considerations were nephroblastoma and neuroblastoma. Ceftriaxone and blood transfusion were commenced with subsequent administration of intravenous fluids. Further radiologic investigations revealed emphysematous pyelonephritis. The patient had percutaneous drainage and extended spectrum ß-lactamase-producing Escherichia coli (sensitive to meropenem) which was isolated from the aspirate culture after 48 h of incubation. Meropenem could not be commenced because of non-availability and high cost. The patient subsequently deteriorated and died from septic shock. CONCLUSION: Emphysematous pyelonephritis has a fulminant course when not diagnosed promptly and treated adequately.

Thymic development of gut-microbiota-specific T cells.

Humans and their microbiota have coevolved a mutually beneficial relationship in which the human host provides a hospitable environment for the microorganisms and the microbiota provides many advantages for the host, including nutritional benefits and protection from pathogen infection1. Maintaining this relationship requires a careful immune balance to contain commensal microorganisms within the lumen while limiting inflammatory anti-commensal responses1,2. Antigen-specific recognition of intestinal microorganisms by T cells has previously been described3,4. Although the local environment shapes the differentiation of effector cells3-5 it is unclear how microbiota-specific T cells are educated in the thymus. Here we show that intestinal colonization in early life leads to the trafficking of microbial antigens from the intestine to the thymus by intestinal dendritic cells, which then induce the expansion of microbiota-specific T cells. Once in the periphery, microbiota-specific T cells have pathogenic potential or can protect against related pathogens. In this way, the developing microbiota shapes and expands the thymic and peripheral T cell repertoire, allowing for enhanced recognition of intestinal microorganisms and pathogens.

Healthy Intestinal Function Relies on Coordinated Enteric Nervous System, Immune System, and Epithelium Responses.

During both health and disease, a coordinated response between the epithelium, immune system, and enteric nervous system is required for proper intestinal function. While each system responds to a number of common stimuli, their coordinated responses support digestion as well as responses and recovery following injury or pathogenic infections. In this review, we discuss how individual responses to common signals work together to support these critical functions.

Attitudes of pharmacy students towards patient safety: a cross-sectional study from six developing countries.

OBJECTIVE: To evaluate the attitudes of undergraduate pharmacy students towards patient safety in six developing countries. DESIGN: A cross-sectional study. SETTING: Participants were enrolled from the participating universities in six countries. PARTICIPANTS: Undergraduate pharmacy students from the participating universities in six developing countries (Jordan, Saudi Arabia, Kuwait, Qatar, India and Indonesia) were invited to participate in the study between October 2018 and September 2019. PRIMARY OUTCOME: Attitudes towards patient safety was measured using 14-item questionnaire that contained five subscales: being quality-improvement focused, internalising errors regardless of harm, value of contextual learning, acceptability of questioning more senior healthcare professionals' behaviour and attitude towards open disclosure. Multiple-linear regression analysis was used to identify predictors of positive attitudes towards patient safety. RESULTS: A total of 2595 students participated in this study (1044 from Jordan, 514 from Saudi Arabia, 134 from Kuwait, 61 from Qatar, 416 from India and 429 from Indonesia). Overall, the pharmacy students reported a positive attitude towards patient safety with a mean score of 37.4 (SD=7.0) out of 56 (66.8%). The 'being quality-improvement focused' subscale had the highest score, 75.6%. The subscale with the lowest score was 'internalising errors regardless of harm', 49.2%. Female students had significantly better attitudes towards patient safety scores compared with male students (p=0.001). Being at a higher level of study and involvement in or witnessing harm to patients while practising were important predictors of negative attitudes towards patient safety (p<0.001). CONCLUSION: Patient safety content should be covered comprehensively in pharmacy curricula and reinforced in each year of study. This should be more focused on students in their final year of study and who have started their training. This will ensure that the next generation of pharmacists are equipped with the requisite knowledge, core competencies and attitudes to ensure optimal patient safety when they practice.