Interplay of lipid head group and packing defects in driving amyloid-beta-mediated myelin-like model membrane deformation.

Accumulating evidence suggests that amyloid plaque-associated myelin lipid loss as a result of elevated amyloid burden might also contribute to Alzheimer's disease. The amyloid fibrils are closely associated with lipids under physiological conditions; however, the progression of membrane remodeling events leading to lipid-fibril assembly remains unknown. Here we first reconstitute the interaction of amyloid Beta 40 (Aß-40) with myelin-like model membrane and show that the binding of Aß-40 induces extensive tubulation. To look into the mechanism of membrane tubulation, we chose a set of membrane conditions varying in lipid packing density and net charge that allows us to dissect the contribution of lipid specificity of Aß-40 binding, aggregation kinetics, and subsequent changes in membrane parameters such as fluidity, diffusion, and compressibility modulus. We show that the binding of Aß-40 depends predominantly on the lipid packing defect densities and electrostatic interactions and results in rigidification of the myelin-like model membrane during the early phase of amyloid aggregation. Furthermore, elongation of Aß-40 into higher oligomeric and fibrillar species leads to eventual fluidization of the model membrane followed by extensive lipid membrane tubulation observed in the late phase. Taken together, our results capture mechanistic insights into snapshots of temporal dynamics of Aß-40-myelin-like model membrane interaction and demonstrate how short timescale, local phenomena of binding, and fibril-mediated load generation results in the consequent association of lipids with growing amyloid fibrils.

Amyloids on Membrane Interfaces: Implications for Neurodegeneration.

Membrane interfaces are vital for various cellular processes, and their involvement in neurodegenerative disorders such as Alzheimer's and Parkinson's disease has taken precedence in recent years. The amyloidogenic proteins associated with neurodegenerative diseases interact with the neuronal membrane through various means, which has implications for both the onset and progression of the disease. The parameters that regulate the interaction between the membrane and the amyloids remain poorly understood. The review focuses on the various aspects of membrane interactions of amyloids, particularly amyloid-ß (Aß) peptides and Tau involved in Alzheimer's and α-synuclein involved in Parkinson's disease. The genetic, cell biological, biochemical, and biophysical studies that form the basis for our current understanding of the membrane interactions of Aß peptides, Tau, and α-synuclein are discussed.

Oral health status among transgender young adults: a cross-sectional study.

BACKGROUND: Transgender and gender nonconforming (TGNC) people are a marginalized set of the population that continues to experience health care inequalities. This study aimed to assess oral health parameters including Candida growth and intensity among TGNC adults. METHODS: This cross-sectional study recruited two subgroups: 40 transgender and 40 control adults. Consented participants were interviewed and clinically examined. Data using the WHO oral health assessment forms were obtained. Samples for Candida growth and intensity analysis were collected from the dorsum surface of the tongue. RESULTS: 27.5% of the transgender group was HIV seropositive. Oral nicotine stomatitis and leukoplakia are reported to be the most prevalent intra-oral lesions showing a prevalence of 27.5% and 20%, respectively. The dental and periodontal health parameters of the transgender group were worse than those of the control group. The intensity of Candida colonies was significantly higher in the test group (p = 0.014). CONCLUSION: Poor oral health and significant oral mucosal disorders were reported in transgender adults that have shown a higher rate of behavioral risk factors such as tobacco and alcohol consumption. Further longitudinal studies in different world regions are warranted to understand the barriers to good oral health in transgender adults and how to implement effective prevention and management strategies.

Acquired disorders with hypopigmentation: A clinical approach to diagnosis and treatment.

Acquired hypopigmented skin changes are commonly encountered by dermatologists. Although hypopigmentation is often asymptomatic and benign, occasional serious and disabling conditions present with cutaneous hypopigmentation. A thorough history and physical examination, centered on disease distribution and morphologic findings, can aid in delineating the causes of acquired hypopigmented disorders. The second article in this 2-part continuing medical education series focuses on conditions with a hypopigmented phenotype. Early diagnosis and appropriate management of these disorders can improve a patient's quality of life, halt disease progression, and prevent irreversible disability.

Acquired disorders with depigmentation: A systematic approach to vitiliginoid conditions.

Acquired disorders with depigmentation are commonly encountered by dermatologists and present with a wide differential diagnosis. Vitiligo, the most common disorder of acquired depigmentation, is characterized by well-defined depigmented macules and patches. Other conditions, such as chemical leukoderma, can present with similar findings, and are often easily mistaken for vitiligo. Key clinical features can help differentiate between acquired disorders of depigmentation. The first article in this continuing medical education series focuses on conditions with a vitiligo-like phenotype. Early recognition and adequate treatment of these conditions is critical in providing appropriate prognostication and treatment.

Attenuation of neuroblastoma cell growth by nisin is mediated by modulation of phase behavior and enhanced cell membrane fluidity.

Antimicrobial peptides have been attracting significant attention as potential anti-cancer therapeutic agents in recent times. Yet most antimicrobial peptides seem to possess cytotoxic effects on non-cancerous cells. Nisin, an antimicrobial peptide and FDA approved food preservative, has recently been found to induce selective apoptotic cell death and reduced cell proliferation in different cancer cell lines. However, the mechanism of nisin interaction with cancer cell membranes remains unexplored. Using potentiometric dye-based fluorescence and monolayer surface pressure-area isotherms we find that nisin interaction enhances the fluidity and reduces the dipole potential of a neuroblastoma cell membrane model. The quantified compressibility modulus suggests that the changes in fluidity are predominantly driven by the nisin interaction with the non-raft like regions. However, the measured positive Gibbs free energy of mixing and enthalpy hints that nisin, owing to its unfavorable mixing with cholesterol, might significantly disrupt the raft-like domains.

Biology of human melanocyte development, Piebaldism, and Waardenburg syndrome.

Melanocyte development is orchestrated by a complex interconnecting regulatory network of genes and synergistic interactions. Piebaldism and Waardenburg syndrome are neurocristopathies that arise from mutations in genes involved in this complex network. Our understanding of melanocyte development, Piebaldism, and Waardenburg syndrome has improved dramatically over the past decade. The diagnosis and classification of Waardenburg syndrome, first proposed in 1992 and based on phenotype, have expanded over the past three decades to include genotype. This review focuses on the current understanding of human melanocyte development and the evaluation and management of Piebaldism and Waardenburg syndrome. Management is often challenging and requires a multidisciplinary approach.

Relative versus absolute risk of comorbidities in patients with psoriasis.

BACKGROUND: Psoriasis is associated with numerous comorbidities, often reported in terms of relative risk. Both doctors and the general population tend to overestimate the effects of exposures when presented in relative terms, leading to anxiety and potentially poor treatment decisions. Absolute risks might provide a better basis for risk assessment. OBJECTIVE: To characterize and compare relative and absolute risks of comorbidities in patients with psoriasis. METHODS: A systematic review using Medline identified comorbidities associated with psoriasis, their relative risks, and information for calculating absolute risks. RESULTS: The comorbidities associated with psoriasis with the highest relative risk were nonmelanoma skin cancer, melanoma, and lymphoma, with relative risks of 7.5, 6.12, and 3.61, respectively; the attributable risk for these 3 conditions were 0.64, 0.05, and 0.17 per 1000 person-years, respectively. To attribute 1 event of these conditions to psoriasis would require seeing 1551; 20,135; and 5823 patients, respectively. LIMITATIONS: Database studies might not fully account for confounders, resulting in overestimates of the risk impact of comorbidities. CONCLUSIONS: Presenting attributable risk in the form of the number needed to harm provides a clearer picture of the magnitude of risk and a basis for wiser medical decision making and patient education.

Topical Desoximetasone 0.25% Spray and Its Vehicle Have Little Potential for Irritation or Sensitization.

BACKGROUND: Topical corticosteroids are the most common dermatologic medications and are available in numerous different vehicles. Adherence is limited by traditional vehicles because they are messy and time consuming to apply. The preferred spray formulations have the advantage of being applied with ease, resulting in improved adherence and subsequently improved psoriasis. One limitation of topical treatments, especially spray vehicles, is the potential for irritation and sensitization.

OBJECTIVE: To evaluate the irritation and sensitization potential of topical desoximetasone spray formulation.

METHODS: A multicenter, double-blinded, randomized, controlled study assessed the irritancy and sensitization of 0.25% and 0.05% topical desoximetasone spray. Controls included vehicle, a positive control (0.1% sodium lauryl sulfate), negative control (0.9% saline), and an active comparator control (clobetasol spray). The primary outcome of the study was to evaluate the difference in mean cumulative irritation and potential sensitization response of desoximetasone 0.25% and 0.05% topical sprays.

RESULTS: Of the 297 enrolled, 269 completed the study per protocol for the irritation phase and 250 completed the protocol for the sensitization phase. At 22 days, desoximetasone 0.25 and 0.5% spray were less irritating than clobetasol 0.05% spray; mean irritation score difference of -0.46 and -0.57, respectively. Median total irritation score over the 22 days was 0 for all products. No subjects demonstrated any sensitization reaction to any of the six products. No serious adverse reactions were reported.

LIMITATIONS: Selection bias, use of a healthy population, limits the external validity. In addition, the duration of the study was short lived, unlike numerous inflammatory skin diseases. CONCLUSIONS: Desoximetasone spray has little potential for irritation or sensitization. The availability of another spray option for patients desiring less messy treatment may facilitate better adherence and treatment outcomes.

J Drugs Dermatol. 2017;16(8):755-758.

A Randomized, Double-Blind, Placebo-Controlled Study of the Vasoconstrictor Potency of Topical 0.25% Desoximetasone Spray: A High to Super High Range of Potency (Class I to Class II) Corticosteroid Formulation.

BACKGROUND: Topical corticosteroids offer great efficacy in controlling a wide variety of dermatoses. Traditional ointment vehicles are messy and difficult to apply, which might limit adherence. Alternative vehicle formulations such as topical sprays might improve adherence due to their ease of application. The potency of desoximetasone spray is not fully characterized. OBJECTIVE: To evaluate the relative vasoconstrictive potency of desoximetasone 0.25% topical spray formulation. METHODS: This is a randomized, blinded, single-center study comparing the vasoconstrictive properties of desoximetasone 0.25% topical spray to placebo and seven other known potency topical corticosteroid formulations. The primary endpoint was the degree of vasoconstriction measured using a colorimeter device. RESULTS: Thirty-two healthy subjects met eligibility criteria. Desoximetasone 0.25% topical spray (REGWQ Grouping = A) showed a trend toward greater vasoconstrictive potency compared to clobetasol propionate 0.05% spray (REGWQ Grouping = A). No adverse or serious events were reported. LIMITATIONS: The trial enrolled 90% females, which may affect the external validity of the study. Different populations may respond differently to desoximetasone spray. CONCLUSIONS: Desoximetasone 0.25% topical spray is a high to super high range of potency (Class I to Class II) steroid formulation. Given the cosmetic acceptability of spray products, we anticipate that this type of product would be highly effective for the treatment of inflammatory diseases in clinical practice.

J Drugs Dermatol. 2017;16(10):972-975.

Frequency of Hepatitis C in hospitalized patients with chronic kidney disease.

BACKGROUND AND OBJECTIVES: Hepatitis C and chronic kidney disease (CKD) are major global health problems and are highly prevalent in Pakistan. There is limited information on prevalence of hepatitis C in patients with CKD not yet on dialysis. The objective of this study was to determine the frequency of hepatitis C in hospitalized chronic kidney disease patients at a tertiary care center in Pakistan. METHODS: The study design was cross-sectional in nature. Patients between ages of 20-80 years with CKD not previously on renal replacement therapy and who were admitted to nephrology ward at a tertiary care facility were included. Hepatitis C was tested using 3rd generation enzyme linked immunosorbent assay (ELISA). Hepatitis C RNA was tested by polymerase chain reaction (PCR) in patients with positive ELISA. RESULTS: A total of 180 patients were included in the study. Mean age of patients was 48.7±14.9 years. Of all patients, 105 (58.3%) were males and 75 (41.7%) were females, 152 (84.4%) had hypertension, 113 (62.8%) had diabetes mellitus and 26 (14.9%) had known cardiovascular disease. Mean eGFR of patients was 11.4±9.4 ml/min/1.73 m2. Of all patients with CKD, 49 (27.2%) had hepatitis C test positive by ELISA. Hepatitis C PCR testing was done in 39 patients with hepatitis C ELISA positive status and 29 (74.4%) tested positive. Risk factors and clinical characteristics of patients with and without positive hepatitis C antibody by ELISA were similar. CONCLUSION: A significant proportion of hospitalized CKD patients have hepatitis C. Strict universal infection control measures should be implemented in nephrology wards to prevent transmission of hepatitis C infection.

Lipid Specificity of the Fusion of Bacterial Extracellular Vesicles with the Host Membrane.

Bacterial membrane vesicles (MVs) facilitate the long-distance delivery of virulence factors crucial for pathogenicity. The entry and trafficking mechanisms of virulence factors inside host cells are recently emerging; however, whether bacterial MVs can fuse and modulate the physicochemical properties of the host lipid membrane and membrane lipid parameter for fusion remains unknown. In this study, we reconstituted the interaction of bacterial MVs with host cell lipid membranes and quantitatively showed that bacterial MV interaction increases the fluidity, dipole potential, and compressibility of a biologically relevant multicomponent host membrane upon fusion. The presence of cylindrical lipids, such as phosphatidylcholine, and a moderate acyl chain length of C16 help the MV interaction. While significant binding of bacterial MVs to the raft-like lipid membranes with phase-separated regions of the membrane was observed, however, MVs prefer binding to the liquid-disordered regions of the membrane. Furthermore, the elevated levels of cholesterol tend to hinder the interaction of bacterial MVs, as evident from the favorable excess Gibbs free energy of mixing bacterial MVs with host lipid membranes. The findings provide new insights that might have implications for the regulation of host machinery by bacterial pathogens through manipulation of the host membrane properties.

Leishmania donovani modulates host miRNAs regulating cholesterol biosynthesis for its survival.

Cholesterol reduction by intracellular protozoan parasite Leishmania donovani (L. donovani), causative agent of leishmaniasis, impairs antigen presentation, pro-inflammatory cytokine secretion and host-protective membrane-receptor signaling in macrophages. Here, we studied the miRNA mediated regulation of cholesterol biosynthetic genes to understand the possible mechanism of L. donovani-induced cholesterol reduction and therapeutic importance of miRNAs in leishmaniasis. System-scale genome-wide microtranscriptome screening was performed to identify the miRNAs involved in the regulation of expression of key cholesterol biosynthesis regulatory genes through miRanda3.0. 11 miRNAs out of 2823, showing complementarity with cholesterol biosynthetic genes were finally selected for expression analysis. These selected miRNAs were differentially regulated in THP-1 derived macrophages and in primary human macrophages by L. donovani. Correlation of expression and target validation through luciferase assay suggested two key miRNAs, hsa-miR-1303 and hsa-miR-874-3p regulating the key genes hmgcr and hmgcs1 respectively. Inhibition of hsa-mir-1303 and hsa-miR-874-3p augmented the expression of targets and reduced the parasitemia in macrophages. This study will also provide the platform for the development of miRNA-based therapy against leishmaniasis.

Pharmacological induction of chromatin remodeling drives chemosensitization in triple-negative breast cancer.

Targeted therapies have improved outcomes for certain cancer subtypes, but cytotoxic chemotherapy remains a mainstay for triple-negative breast cancer (TNBC). The epithelial-to-mesenchymal transition (EMT) is a developmental program co-opted by cancer cells that promotes metastasis and chemoresistance. There are no therapeutic strategies specifically targeting mesenchymal-like cancer cells. We report that the US Food and Drug Administration (FDA)-approved chemotherapeutic eribulin induces ZEB1-SWI/SNF-directed chromatin remodeling to reverse EMT that curtails the metastatic propensity of TNBC preclinical models. Eribulin induces mesenchymal-to-epithelial transition (MET) in primary TNBC in patients, but conventional chemotherapy does not. In the treatment-naive setting, but not after acquired resistance to other agents, eribulin sensitizes TNBC cells to subsequent treatment with other chemotherapeutics. These findings provide an epigenetic mechanism of action of eribulin, supporting its use early in the disease process for MET induction to prevent metastatic progression and chemoresistance. These findings warrant prospective clinical evaluation of the chemosensitizing effects of eribulin in the treatment-naive setting.

A comparative study between different pain rating scales in patients of osteoarthritis.

Study was conducted to assess the sensitivity and simplicity of various pain rating scales in patients of osteoarthritis with chronic pain so that most appropriate scale can be identified. Scales included were Wong-Baker Faces Pain Rating Scale (WBS), Numerical Rating Scale (NRS), Faces Pain Scale- Revised (FPS-R), Visual Analogue Scale (VAS) and Verbal Rating Scale (VRS). Patients were asked to indicate their pain on these scales and comment about the simplicity of scales. Median mark for WBS, NRS, FPS-R, VAS and VRS was 10, 10, 10, 9.1 and 10 respectively. P value between WBS, NRS, FPS-R, VAS and VRS was insignificant. Most simple, easy to answer scale (83%) was WBS followed by FPS-R (17%). We conclude that all the scales are sensitive for assessment of the chronic osteoarthritis pain and are not different from each others. The most simple and preferred pain rating scale is WBS for the regional population.

War and oncology: cancer care in five Iraqi provinces impacted by the ISIL conflict.

War and cancer have been intertwined in Iraq for over three decades, a country where the legacies and ongoing impacts of conflict have been commonly associated with both increased cancer rates as well as the deterioration of cancer care. Most recently, the Islamic State of Iraq and the Levant (ISIL) violently occupied large portions of the country's central and northern provinces between 2014 and 2017, causing devastating impacts on public cancer centers across central and northern Iraq. Focusing on the five Iraqi provinces previously under full or partial ISIL occupation, this article examines the immediate and long-term impacts of war on cancer care across three periods (before, during, and after the ISIL conflict). As there is little published data on oncology in these local contexts, the paper relies primarily upon the qualitative interviews and lived experience of oncologists serving in the five provinces studied. A political economy lens is applied to interpret the results, particularly the data related to progress in oncology reconstruction. It is argued that conflict generates immediate and long-term shifts in political and economic conditions that, in turn, shape the rebuilding of oncology infrastructure. The documentation of the destruction and reconstruction of local oncology systems is intended to benefit the next generation of cancer care practitioners in the Middle East and other conflict-affected regions areas in their efforts to adapt to conflict and rebuild from the legacies of war.

Pharmacological Induction of mesenchymal-epithelial transition chemosensitizes breast cancer cells and prevents metastatic progression.

The epithelial-mesenchymal transition (EMT) is a developmental program co-opted by tumor cells that aids the initiation of the metastatic cascade. Tumor cells that undergo EMT are relatively chemoresistant, and there are currently no therapeutic avenues specifically targeting cells that have acquired mesenchymal traits. We show that treatment of mesenchymal-like triple-negative breast cancer (TNBC) cells with the microtubule-destabilizing chemotherapeutic eribulin, which is FDA-approved for the treatment of advanced breast cancer, leads to a mesenchymal-epithelial transition (MET). This MET is accompanied by loss of metastatic propensity and sensitization to subsequent treatment with other FDA-approved chemotherapeutics. We uncover a novel epigenetic mechanism of action that supports eribulin pretreatment as a path to MET induction that curtails metastatic progression and the evolution of therapy resistance.

Technique, Feasibility, Utility, Limitations, and Future Perspectives of a New Technique of Applying Direct In-Scope Suction to Improve Outcomes of Retrograde Intrarenal Surgery for Stones.

Retrograde intrarenal surgery (RIRS) is accepted as a primary modality for the management of renal stones up to 2 cm. The limitations of RIRS in larger volume stones include limited visualization due to the snow-globe effect and persistence of fragments that cannot be removed. We describe a new, simple, cost-effective modification that can be attached to any flexible ureteroscope which allows simultaneous/alternating suction and aspiration during/after laser lithotripsy using the scope as a conduit to remove the fragments or dust from the pelvicalyceal system called direct in-scope suction (DISS) technique. Between September 2020 and September 2021, 30 patients with kidney stones underwent RIRS with the DISS technique. They were compared with 28 patients who underwent RIRS with a 11Fr/13Fr suction ureteral access sheaths (SUASs) in the same period. RIRS and laser lithotripsy were carried out traditionally with a Holmium laser for the SUAS group or a thulium fiber laser for the DISS group. There was no difference in age, gender, and history of renal lithiasis between the two groups. Ten (40%) patients had multiple stones in the DISS groups, whilst there were no patients with multiple stones in the SUAS group. Median stone size was significantly higher in the DISS group [22.0 (18.0−28.8) vs. 13.0 (11.8−15.0) millimeters, p < 0.001]. Median surgical time was significantly longer in the DISS group [80.0 (60.0−100) minutes] as compared to the SUAS group [47.5 (41.5−60.3) minutes, p < 0.001]. Hospital stay was significantly shorter in the DISS group [1.00 (0.667−1.00) vs. 1.00 (1.00−2.00) days, p = 0.02]. Postoperative complications were minor, and there was no significant difference between the two groups. The incidence of residual fragments did not significantly differ between the two groups [10 (33.3%) in the DISS group vs. 10 (35.7%) in the SUAS group, p = 0.99] but 10 (33.3%) patients required a further RIRS for residual fragments in the DISS group, whilst only one (3.6%) patient in the SUAS group required a subsequent shock wave lithotripsy treatment. Our audit study highlighted that RIRS with DISS technique was feasible with an acceptable rate of retreatment as compared to RIRS with SUAS.

Surface view of the lateral organization of lipids and proteins in lung surfactant model systems-a ToF-SIMS approach.

The lateral organization of domain structures is an extremely significant aspect of biomembrane research. Chemical imaging by mass spectrometry with its recent advancement in sensitivity and lateral resolution has become a highly promising tool in biological research. In this review, we focus briefly on the instrumentation, working principle and important concepts related to time-of-flight secondary ion mass spectrometry followed by an overview of lipid/protein fragmentation patterns and chemical mapping. The key issues addressed are the applications of time-of-flight secondary ion mass spectrometry in biological membrane research. Additionally, we briefly review our recent investigations based on time-of-flight secondary ion mass spectrometry to unravel the lateral distribution of lipids and surfactant proteins in lung surfactant model systems as an example that highlights the importance of fluidity and ionic conditions on lipid phase behavior and lipid-protein interactions.