Fetal liver CD34+ contain human immune and endothelial progenitors and mediate solid tumor rejection in NOG mice.

BACKGROUND: Transplantation of CD34+ hematopoietic stem and progenitor cells (HSPC) into immunodeficient mice is an established method to generate humanized mice harbouring a human immune system. Different sources and methods for CD34+ isolation have been employed by various research groups, resulting in customized models that are difficult to compare. A more detailed characterization of CD34+ isolates is needed for a better understanding of engraftable hematopoietic and potentially non-hematopoietic cells. Here we have performed a direct comparison of CD34+ isolated from cord blood (CB-CD34+) or fetal liver (FL-CD34+ and FL-CD34+CD14-) and their engraftment into immunocompromised NOD/Shi-scid Il2rgnull (NOG) mice. METHODS: NOG mice were transplanted with either CB-CD34+, FL-CD34+ or FL-CD34+CD14- to generate CB-NOG, FL-NOG and FL-CD14--NOG, respectively. After 15-20 weeks, the mice were sacrificed and human immune cell reconstitution was assessed in blood and several organs. Liver sections were pathologically assessed upon Haematoxylin and Eosin staining. To assess the capability of allogenic tumor rejection in CB- vs. FL-reconstituted mice, animals were subcutaneously engrafted with an HLA-mismatched melanoma cell line. Tumor growth was assessed by calliper measurements and a Luminex-based assay was used to compare the cytokine/chemokine profiles. RESULTS: We show that CB-CD34+ are a uniform population of HSPC that reconstitute NOG mice more rapidly than FL-CD34+ due to faster B cell development. However, upon long-term engraftment, FL-NOG display increased numbers of neutrophils, dendritic cells and macrophages in multiple tissues. In addition to HSPC, FL-CD34+ isolates contain non-hematopoietic CD14+ endothelial cells that enhance the engraftment of the human immune system in FL-NOG mice. We demonstrate that these CD14+CD34+ cells are capable of reconstituting Factor VIII-producing liver sinusoidal endothelial cells (LSEC) in FL-NOG. However, CD14+CD34+ also contribute to hepatic sinusoidal dilatation and immune cell infiltration, which may culminate in a graft-versus-host disease (GVHD) pathology upon long-term engraftment. Finally, using an HLA-A mismatched CDX melanoma model, we show that FL-NOG, but not CB-NOG, can mount a graft-versus-tumor (GVT) response resulting in tumor rejection. CONCLUSION: Our results highlight important phenotypical and functional differences between CB- and FL-NOG and reveal FL-NOG as a potential model to study hepatic sinusoidal dilatation and mechanisms of GVT.

Explaining disparities in cognitive functioning: a test of competing hypotheses.

This study seeks to examine how the trajectories of total cognition scores exhibited by two birth cohorts vary by race/ethnicity, gender and the level of education. The empirical work of this study is be based on the 1998-2014 Health and Retirement Study (HRS) and the HRS Cross-Wave Tracker file. The analysis is limited to individuals with available information on cognitive functioning, sex, race/ethnicity, wave, highest level of education, and the physical comorbidities associated with cognitive functioning (20,985 from the Traditionalist cohort and 11,077 from the Baby Boomer cohort). Growth curve modelling is used to assess the aims of this study. Findings reveal that the cumulative advantage (disadvantage), persistent inequality and age-as-leveller hypotheses explain heterogeneity in total cognition scores for different race/ethnicity-sex groups, race/ethnicity-education and education-sex groups. These findings suggest that the development of an integrated treatment and screening mechanisms for physical comorbidities and cognitive functioning, and for the design of preventive strategies with the purpose of slowing or avoiding cognitive decline and maintaining healthy cognitive function should have a particular focus on females, racial ethnic minorities and those with low education.

Efficient differentiation of human neutrophils with recapitulation of emergency granulopoiesis in human G-CSF knockin humanized mice.

Neutrophils are critical mediators during the early stages of innate inflammation in response to bacterial or fungal infections. A human hematopoietic system reconstituted in humanized mice aids in the study of human hematology and immunology. However, the poor development of human neutrophils is a well-known limitation of humanized mice. Here, we generate a human granulocyte colony-stimulating factor (hG-CSF) knockin (KI) NOD/Shi-scid-IL2rgnull (NOG) mouse in which hG-CSF is systemically expressed while the mouse G-CSF receptor is disrupted. These mice generate high numbers of mature human neutrophils, which can be readily mobilized into the periphery, compared with conventional NOG mice. Moreover, these neutrophils exhibit infection-mediated emergency granulopoiesis and are capable of efficient phagocytosis and reactive oxygen species production. Thus, hG-CSF KI mice provide a useful model for studying the development of human neutrophils, emergency granulopoiesis, and a potential therapeutic model for sepsis.

Novel Gemcitabine-Re(I) Bisquinolinyl Complex Combinations and Formulations With Liquid Crystalline Nanoparticles for Pancreatic Cancer Photodynamic Therapy.

With less than 10% of 5-year survival rate, pancreatic ductal adenocarcinoma (PDAC) is known to be one of the most lethal types of cancer. Current literature supports that gemcitabine is the first-line treatment of PDAC. However, poor cellular penetration of gemcitabine along with the acquired and intrinsic chemoresistance of tumor against it often reduced its efficacy and hence necessitates the administration of high gemcitabine dose during chemotherapy. Photodynamic therapy (PDT), a more selective and minimally invasive treatment, may be used synergistically with gemcitabine to reduce the doses utilized and dose-related side effects. This study reports the synergistic use of Re(I) bisquinolinyl complex, a transition metal complex photosensitizer with gemcitabine against PDAC. Re(I) bisquinolinyl complex was found to act synergistically with gemcitabine against PDAC in vitro at various ratios. With the aim to enhance cellular uptake and therapeutic efficiency, the Re(I) bisquinolinyl complex and gemcitabine were encapsulated into liquid crystalline nanoparticles (LCNPs) system. The formulations were found to produce homogeneous drug-loaded LCNPs (average size: 159-173 nm, zeta potential +1.06 to -10 mV). Around 70% of gemcitabine and 90% of the Re(I) bisquinolinyl complex were found to be entrapped efficiently in the formulated LCNPs. The release rate of gemcitabine or/and the Re(I) bisquinolinyl complex loaded into LCNPs was evaluated in vitro, and the hydrophilic gemcitabine was released at a faster rate than the lipophilic Re(I) complex. LCNPs loaded with gemcitabine and Re(I) bisquinolinyl complex in a 1:1 ratio illustrated the best anti-cancer activity among the LCNP formulations (IC50 of BxPC3: 0.15 µM; IC50 of SW 1990: 0.76 µM) through apoptosis. The current findings suggest the potential use of transition metal-based photosensitizer as an adjunctive agent for gemcitabine-based chemotherapy against PDAC and the importance of nano-formulation in such application.

Natural HSP90 inhibitors as a potential therapeutic intervention in treating cancers: A comprehensive review.

Heat shock protein 90 (Hsp90) has evolved as a cancerous cell growth regulator by stabilising various oncogenic kinases. Upon the Hsp90 inhibition, the expression of its client proteins is downregulated and thus leads to denaturation of cellular proteins and cancer cell death. Hsp90 inhibitors, particularly those naturally derived from plants, fungi and bacteria, have gained substantial interest as a feasible therapeutic approach for cancer treatment due to their diverse pharmacological properties. In order to gain insights into the potential development of more efficacious Hsp90 inhibitors for cancer treatment, this review is conducted to analyse both in vitro and in vivo data on the chemical and biological activities of natural Hsp90 inhibitors. The systematic search was conducted in databases (PubMed, Scopus and Web of Science) with terms "Hsp90 inhibitor" and "cancer", prompting a total of 61 articles after screening with inclusion criteria. This comprehensive review systematically summarised the efficacy of 14 different classes of naturally derived Hsp90 inhibitors in cancerous cell and animal tumour models by consolidating the primary outcomes in terms of IC50, reduction of tumour size and physicochemical properties. The detailed pharmacodynamic (the structure-activity relationship, mechanism of action) and pharmacokinetics (toxicity, oral bioavailability) of these Hsp90 inhibitors together with the study limitations were discussed. Collectively, these findings emphasise the necessity of comprehending the molecular mechanisms as well as the correlation of Hsp90 and its relative client proteins to drive the generation of viable Hsp90 inhibitors with improved pharmacodynamic and pharmacokinetic profiles.

Multidisciplinary management of chronic atopic dermatitis in children and adolescents: a prospective pilot study.

BACKGROUND: Atopic dermatitis (AD) is a chronic, pruritic disorder affecting 10-20% of children and is associated with psychological issues and impaired quality of life (QoL). The role of psychosocial support in the treatment of AD is increasingly important. We studied the impact of a multidisciplinary clinic (MDC) in the management of AD in a tertiary children's hospital in Singapore. METHODS: We performed a prospective pilot interventional study on 34 pediatric patients with AD and concomitant psychosocial impairment. Patients were recruited into an MDC, comprising a dermatologist, clinical psychologist and medical social worker. AD severity was scored using Scoring Atopic Dermatitis (SCORAD), while QoL was assessed using the Children's Dermatology Life Quality Index Questionnaire (CDLQI) and Family Dermatology Life Quality Index Questionnaire (FDLQI). Biopsychosocial assessments and interventions were also performed. Eighty-three percent of patients received cognitive behavioral therapy, while 40% received social work intervention. RESULTS: There was an overall improvement in mean SCORAD, CDLQI, and FDLQI scores across MDC visits. A correlation between AD severity and QoL was established. A patient satisfaction survey showed improvement in severity, understanding, and control of the disease. CONCLUSION: Our study suggests the effectiveness of a multidisciplinary approach in managing pediatric AD patients with psychosocial co-morbidities.

Antimicrobial and antibiofilm activities of Cu(II) Schiff base complexes against methicillin-susceptible and resistant Staphylococcus aureus.

BACKGROUND: Methicillin-resistance S. aureus (MRSA) possesses the ability to resist multiple antibiotics and form biofilm. Currently, vancomycin remains the last drug of choice for treatment of MRSA infection. The emergence of vancomycin-resistant S. aureus (VRSA) has necessitated the development of new therapeutic agents against MRSA. In this study, the antimicrobial and antibiofilm activities of two copper-complexes derived from Schiff base (SBDs) were tested individually, and in combination with oxacillin (OXA) and vancomycin (VAN) against reference strains methicillin-susceptible and methicillin-resistant Staphylococcus aureus. The toxicity of the SBDs was also evaluated on a non-cancerous mammalian cell line. METHODS: The antimicrobial activity was tested against the planktonic S. aureus cells using the microdilution broth assay, while the antibiofilm activity were evaluated using the crystal violet and resazurin assays. The cytotoxicity of the SBDs was assessed on MRC5 (normal lung tissue), using the MTT assay. RESULTS: The individual SBDs showed significant reduction of biomass and metabolic activity in both S. aureus strains. Combinations of the SBDs with OXA and VAN were mainly additive against the planktonic cells and cells in the biofilm. Both the compounds showed moderate toxicity against the MRC5 cell line. The selectivity index suggested that the compounds were more cytotoxic to S. aureus than the normal cells. CONCLUSION: Both the SBD compounds demonstrated promising antimicrobial and antibiofilm activities and have the potential to be further developed as an antimicrobial agent against infections caused by MRSA.

Markers of the Endothelial Glycocalyx Are Improved following Kidney Transplantation.

INTRODUCTION: The endothelial glycocalyx on the vascular luminal surface contributes to endothelial health and function. Damage to this layer is indicative of vascular injury, reflected by increased levels of its shed constituents in serum and an increase in the perfused boundary region (PBR) when measured in sublingual capillaries using the GlycoCheck™ device. We aimed to examine the longitudinal effects of kidney transplantation on the glycocalyx by measuring biochemical markers of the glycocalyx and endothelial dysfunction and the PBR. METHODS: We recruited healthy controls and stage 5 CKD patients scheduled to undergo a kidney transplant. Investigations were performed before transplant and then 1 and 3 months after transplantation. At each point, blood was collected for hyaluronan, syndecan-1, vascular cell adhesion molecule (VCAM-1), and von Willebrand factor (vWF), and a PBR measurement was performed. RESULTS: Thirty healthy controls and 17 patients undergoing a kidney transplant were recruited (9 cadaveric and 8 live donation; 12 on dialysis and 5 pre-emptive). Before transplant, transplant recipients had greater evidence of glycocalyx damage than controls. After transplant, PBR improved from median 2.22 (range 1.29-2.73) to 1.98 (1.65-2.25) µm, p = 0.024, and syndecan-1 levels decreased from 98 (40-529) to 36 (20-328) ng/mL, p < 0.001. Similarly, VCAM-1 fell from 1,479 (751-2,428) at baseline to 823 (516-1,674) ng/mL, p < 0.001, and vWF reduced from 3,114 (1,549-5,197) to 2,007 (1,503-3,542) mIU/mL, p = 0.002. Serum levels of hyaluronan remained unchanged. CONCLUSION: The combination of reduced PBR and syndecan-1 following transplant suggests that transplantation may improve glycocalyx stability at 3 months after transplant.

Moral Distress and Moral Injury in Nephrology During the COVID-19 Pandemic.

Across the world, challenges for clinicians providing health care during the coronavirus disease 2019 (COVID-19) pandemic are highly prevalent and have been widely reported. Perspectives of provider groups have conveyed wide-ranging experiences of adversity, distress, and resilience. In understanding and responding to the emotional and psychological implications of the pandemic for renal clinicians, it is vital to recognize that many experiences also have been ethically challenging. The COVID-19 pandemic has prompted rapid and extensive transformation of health care systems and widely impacted care provision, heightening the risk of barriers to fulfillment of ethical duties. Given this, it is likely that some clinicians also have experienced moral distress, which can occur if an individual is unable to act in accordance with their moral judgment owing to external barriers. This review presents a global perspective of potential experiences of moral distress in kidney care during the COVID-19 pandemic. Using nephrology cases, we discuss why moral distress may be experienced by health professionals when withholding or withdrawing potentially beneficial treatments owing to resource constraints, when providing care that is inconsistent with local prepandemic best practice standards, and when managing dual professional and personal roles with conflicting responsibilities. We argue that in addition to responsive and appropriate health system supports, resources, and education, it is imperative for health care providers to recognize and prevent moral distress to foster the psychological well-being and moral resilience of clinicians during extended periods of crisis within health systems.

Endothelial glycocalyx damage in kidney disease correlates with uraemic toxins and endothelial dysfunction.

BACKGROUND: Damage to the endothelial glycocalyx is an early indicator of vascular damage and a potential marker of endothelial dysfunction. This study aimed to assess the relationship between markers of glycocalyx damage, endothelial dysfunction, and uraemic toxins in patients with chronic kidney disease. METHODS: Healthy controls, CKD patients, dialysis patients, and kidney transplant recipients had biochemical markers of glycocalyx damage (syndecan-1 and hyaluronan), endothelial dysfunction (von Willebrand factor; vWF and vascular cell adhesion molecule; VCAM-1), and uraemic toxins (indoxyl sulphate and p-cresyl sulphate) measured. In addition, Sidestream Darkfield imaging was performed using the novel GlycoCheck™ device to measure glycocalyx width by the perfused boundary region (PBR) in the sublingual microcirculation. RESULTS: Serum markers of glycocalyx damage were highest in the dialysis group (n = 33), followed by CKD patients (n = 32) and kidney transplant recipients (n = 30) compared to controls (n = 30): hyaluronan: 137 (16-1414), 79 (11-257), 57 (14-218) and 23 (8-116) ng/mL, respectively, p < 0.0001; syndecan-1: 81 (40-529), 46 (21-134), 39 (23-72), and 30 (12-138) ng/mL, respectively, p < 0.0001. Markers of endothelial dysfunction followed a similar pattern. No difference in the width of the PBR was detected between these groups (2.01 ± 0.35, 2.07 ± 0.27, 2.06 ± 0.28, and 2.05 ± 0.3 µm, respectively, p = 0.89). Glycocalyx damage correlated with markers of endothelial dysfunction (log-hyaluronan and log-VCAM-1: r = 0.64, p < 0.001) and levels of uraemic toxins (log-hyaluronan and log-indoxyl sulphate: r = 0.48, p < 0.001). CONCLUSIONS: Levels of biochemical markers of glycocalyx and endothelial cell damage are highest in patients receiving dialysis. Glycocalyx and endothelial damage markers correlated with each other, and with uraemic toxins. Although we could not demonstrate a change in PBR, the biochemical markers suggest that glycocalyx damage is most marked in patients with higher levels of uraemic toxins.

Recent Emergence of Rhenium(I) Tricarbonyl Complexes as Photosensitisers for Cancer Therapy.

Photodynamic therapy (PDT) is emerging as a significant complementary or alternative approach for cancer treatment. PDT drugs act as photosensitisers, which upon using appropriate wavelength light and in the presence of molecular oxygen, can lead to cell death. Herein, we reviewed the general characteristics of the different generation of photosensitisers. We also outlined the emergence of rhenium (Re) and more specifically, Re(I) tricarbonyl complexes as a new generation of metal-based photosensitisers for photodynamic therapy that are of great interest in multidisciplinary research. The photophysical properties and structures of Re(I) complexes discussed in this review are summarised to determine basic features and similarities among the structures that are important for their phototoxic activity and future investigations. We further examined the in vitro and in vivo efficacies of the Re(I) complexes that have been synthesised for anticancer purposes. We also discussed Re(I) complexes in conjunction with the advancement of two-photon PDT, drug combination study, nanomedicine, and photothermal therapy to overcome the limitation of such complexes, which generally absorb short wavelengths.

Comparing the Potential for Irritation of a Ceramide-Based Moisturizer with a Urea-Based Moisturizer for Pediatric Atopic Dermatitis.

INTRODUCTION: Moisturizers are one of the mainstays of the topical treatment of atopic dermatitis (AD). One of the adverse effects of moisturizers is skin irritation, especially on excoriated AD skin. We compared the potential for irritation of two commercially available moisturizer products for the treatment of AD: a ceramide-based moisturizer (Ceradan® Cream; Hyphens Pharma Pte Ltd, Singapore) and a urea 5% moisturizer (Aqurea Lite Cream; ICA Pharma Pte Ltd, Singapore). METHODS: We performed a prospective single-blind randomized controlled study recruiting AD patients aged between 8 and 16 years with symmetrical or near symmetrical scratch marks (excoriations) of at least grade 2 to 3 severity score, according to the Eczema Area and Severity Index (EASI), over bilateral antecubital fossae. Subjects were randomized to receive the ceramide-based moisturizer to either the left or right antecubital fossa or urea 5% cream to the other antecubital fossa. Subjects were asked to grade the immediate skin irritation of both creams on a standard visual analogue scale (VAS) and which cream they would prefer to use as a daily moisturizer. Primary outcome was the mean irritant score of each cream, and secondary outcome was the subjects' preference of either cream as their daily moisturizer. RESULTS: A total of 42 participants were enrolled with a mean age of 11 years 5 months. The ceramide-based cream had a significantly lower mean VAS score (mean 0.69, SD = 1.63) for irritation compared with urea 5% cream (1.43, SD = 1.64) (p = 0.035). More participants also preferred the ceramide-based cream over urea 5% cream (62% versus 38%) as their daily moisturizer, but this did not reach statistical significance (p = 0.164). CONCLUSIONS: A ceramide-based moisturizer may be considered as a suitable choice for children to minimize irritation from moisturizer treatment for AD.

Type-3c Diabetes Mellitus, Diabetes of Exocrine Pancreas - An Update.

BACKGROUND: The incidence of diabetes is increasing steeply; the number of diabetics has doubled over the past three decades. Surprisingly, the knowledge of type 3c diabetes mellitus (T3cDM) is still unclear to the researchers, scientist and medical practitioners, leading towards erroneous diagnosis, which is sometimes misdiagnosed as type 1 diabetes mellitus (T1DM), or more frequently type 2 diabetes mellitus (T2DM). This review is aimed to outline recent information on the etiology, pathophysiology, diagnostic procedures, and therapeutic management of T3cDM patients. METHODS: The literature related to T3cDM was thoroughly searched from the public domains and reviewed extensively to construct this article. Further, existing literature related to the other forms of diabetes is reviewed for projecting the differences among the different forms of diabetes. Detailed and updated information related to epidemiological evidence, risk factors, symptoms, diagnosis, pathogenesis and management is structured in this review. RESULTS: T3cDM is often misdiagnosed as T2DM due to the insufficient knowledge differentiating between T2DM and T3cDM. The pathogenesis of T3cDM is explained which is often linked to the history of chronic pancreatitis, pancreatic cancer. Inflammation, and fibrosis in pancreatic tissue lead to damage both endocrine and exocrine functions, thus leading to insulin/glucagon insufficiency and pancreatic enzyme deficiency. CONCLUSION: Future advancements should be accompanied by the establishment of a quick diagnostic tool through the understanding of potential biomarkers of the disease and newer treatments for better control of the diseased condition.

Dietary habits and physical activity: Results from cluster analysis and market basket analysis.

BACKGROUND: The prevalence of obesity remains a major public health concern and there has been a significant increase in childhood obesity in the USA. AIM: This study seeks to uncover the major patterns of dietary habits in relation to physical activity, together with students' opinions about the quality of food in the school's cafeteria and vending machines. METHODS: The empirical work of this study is based on the 2011 Healthy School Program (HSP) Evaluation. HSP assesses the demographic characteristics as well as the dietary habits and exercise patterns of a representative sample of elementary, middle, and high school students in the USA. RESULTS: Findings suggest that students assigned to different clusters have different eating habits, exercise patterns, weight status, weight management, and opinions about the quality of food in the school's cafeteria and vending machines. There is great variation in dietary profiles and lifestyle behaviors among students who identified themselves as either overweight or unsure about their weight status. CONCLUSIONS: Findings from this study may inform future interventions regarding how to promote student's healthy food choices when they are still in school. Health promotion initiatives should specifically target students with persistently unhealthier dietary profiles.

Healthcare Satisfaction among Older Adults.

OBJECTIVE: This study seeks to examine how older adults rate and identify the importance of attributes associated with healthcare seeking and utilization (eg, affordability, type of facility, and accessibility) in the United States. METHODS: The empirical work of this cross-sectional study is based on the 2014 Health and Retirement Study. Conjoint analysis and cluster analysis are used to assess the objective. RESULTS: There is a pressing need for sound policies that seek to reduce the cost of treatment and consultation and to improve the accessibility of care facility for older adults even though satisfaction pertaining to these attributes (ie, affordability, type of facility, and accessibility) differs across clusters. CONCLUSION: The use of conjoint analysis in conjunction with cluster analysis can serve as a needs assessment tool to help policymakers and practitio- ners gauge older adults' expectations and priorities with respect to healthcare seeking and utilization. By taking the priorities of older adults into account, policymakers and practitioners can allocate healthcare resources more efficiently within budgetary constraints as they redesign and customize their program delivery approaches to meet the specific and relative healthcare needs of older adults in different clusters.

Endothelial glycocalyx in health and kidney disease: Rising star or false Dawn?

The endothelial glycocalyx is a layer comprised of proteins and carbohydrates on the luminal surface of vascular endothelial cells, thought to have an important role in the health and function of the endothelium. Disrupted by various pathophysiological conditions and linked with clinical outcomes, it is increasingly recognized as an early indicator of endothelial injury and a potential marker of vascular injury. In this review, we discuss current methods of assessment (including novel optical approaches), evidence for its use as a marker of vascular disease and its potential role in relation to microalbuminuria and glomerular endothelial dysfunction. Therapeutic strategies for restoration of the glycocalyx following injury are also explored.