Gingival Necrosis Related to Sepsis-Induced Agranulocytosis Due to Pseudomonas aeruginosa Bacteraemia: A Case Report.

Background: There have been no reports of sepsis-induced agranulocytosis causing gingival necrosis in otherwise medically healthy patients to the authors' best knowledge. Even though there are several case reports of gingival necrosis secondary to medication-induced agranulocytosis, they have not systematically described the natural progression of agranulocytosis-related gingival necrosis. Methods: This paper presents a case report of a 29-year-old female Indian patient with generalised gingival necrosis and constitutive signs of intermittent fever, nausea, and vomiting. She also complained of abdominal pains. Blood counts showed agranulocytosis, and the patient was admitted for a workup of the underlying cause. Parenteral broad-spectrum antibiotics were administered, which brought about clinical resolution. Results: Her gingival necrosis was attributed to sepsis-induced agranulocytosis triggered by Pseudomonas aeruginosa bacteraemia, and upon clinical recovery, spontaneous exfoliation left behind exposed bone. Secondary healing over the exposed alveolar bone was noted after a year-long follow-up, albeit with some residual gingival recession. Conclusions: Oral manifestations of gingival necrosis, when present with concomitant constitutive symptoms, could indicate a serious underlying systemic condition that could be potentially life-threatening if left untreated. Dentists should be cognizant of this possibility so that timely intervention is not delayed.

Nanoarchitectonics-based model membrane platforms for probing membrane-disruptive interactions of odd-chain antimicrobial lipids.

The use of nanoscience tools to investigate how antimicrobial lipids disrupt phospholipid membranes has greatly advanced molecular-level biophysical understanding and opened the door to new application possibilities. Until now, relevant studies have focused on even-chain antimicrobial lipids while there remains an outstanding need to investigate the membrane-disruptive properties of odd-chain antimicrobial lipids that are known to be highly biologically active. Herein, using the quartz crystal microbalance-dissipation (QCM-D) and electrochemical impedance spectroscopy (EIS) techniques, we investigated how an 11-carbon, saturated fatty acid and its corresponding monoglyceride-termed undecanoic acid and monoundecanoin, respectively-disrupt membrane-mimicking phospholipid bilayers with different nanoarchitectures. QCM-D tracking revealed that undecanoic acid and monoundecanoin caused membrane tubulation and budding from supported lipid bilayers, respectively, and were only active above their experimentally determined critical micelle concentration (CMC) values. Monoundecanoin was more potent due to a lower CMC and electrochemical impedance spectroscopy (EIS) characterization demonstrated that monoundecanoin caused irreversible membrane disruption of a tethered lipid bilayer platform at sufficiently high compound concentrations, whereas undecanoic acid only induced transient membrane disruption. This integrated biophysical approach also led us to identify that the tested 11-carbon antimicrobial lipids cause more extensive membrane disruption than their respective 12-carbon analogues at 2 × CMC, which suggests that they could be promising molecular components within next-generation antimicrobial nanomedicine strategies.

Mutations of 1p genes do not consistently abrogate tumor suppressor functions in 1p-intact neuroblastoma.

BACKGROUND: Deletion of 1p is associated with poor prognosis in neuroblastoma, however selected 1p-intact patients still experience poor outcomes. Since mutations of 1p genes may mimic the deleterious effects of chromosomal loss, we studied the incidence, spectrum and effects of mutational variants in 1p-intact neuroblastoma. METHODS: We characterized the 1p status of 325 neuroblastoma patients, and correlated the mutational status of 1p tumor suppressors and neuroblastoma candidate genes with survival outcomes among 100 1p-intact cases, then performed functional validation of selected novel variants of 1p36 genes identified from our patient cohort. RESULTS: Among patients with adverse disease characteristics, those who additionally had 1p deletion had significantly worse overall survival. Among 100 tumor-normal pairs sequenced, somatic mutations of 1p tumor suppressors KIF1Bß and CHD5 were most frequent (2%) after ALK and ATRX (8%), and BARD1 (3%). Mutations of neuroblastoma candidate genes were associated with other synchronous mutations and concurrent 11q deletion (P = 0.045). In total, 24 of 38 variants identified were novel and predicted to be deleterious or pathogenic. Functional validation identified novel KIF1Bß I1355M variant as a gain-of-function mutation with increased expression and tumor suppressive activity, correlating with indolent clinical behavior; another novel variant CHD5 E43Q was a loss-of-function mutation with decreased expression and increased long-term cell viability, corresponding with aggressive disease characteristics. CONCLUSIONS: Our study showed that chromosome 1 gene mutations occurred frequently in 1p-intact neuroblastoma, but may not consistently abrogate the function of bonafide 1p tumor suppressors. These findings may augment the evolving model of compounding contributions of 1p gene aberrations toward tumor suppressor inactivation in neuroblastoma.

Lipid Nanoparticle Technology for Delivering Biologically Active Fatty Acids and Monoglycerides.

There is enormous interest in utilizing biologically active fatty acids and monoglycerides to treat phospholipid membrane-related medical diseases, especially with the global health importance of membrane-enveloped viruses and bacteria. However, it is difficult to practically deliver lipophilic fatty acids and monoglycerides for therapeutic applications, which has led to the emergence of lipid nanoparticle platforms that support molecular encapsulation and functional presentation. Herein, we introduce various classes of lipid nanoparticle technology and critically examine the latest progress in utilizing lipid nanoparticles to deliver fatty acids and monoglycerides in order to treat medical diseases related to infectious pathogens, cancer, and inflammation. Particular emphasis is placed on understanding how nanoparticle structure is related to biological function in terms of mechanism, potency, selectivity, and targeting. We also discuss translational opportunities and regulatory needs for utilizing lipid nanoparticles to deliver fatty acids and monoglycerides, including unmet clinical opportunities.

Unraveling How Ethanol-Induced Conformational Changes Affect BSA Protein Adsorption onto Silica Surfaces.

Protein adsorption at solid-liquid interfaces is highly relevant to a wide range of applications such as biosensors, drug delivery, and pharmaceuticals. Understanding how protein conformation in bulk solution impacts adsorption behavior is fundamentally important and could also lead to the development of improved protein-based coatings. To date, relevant studies have been conducted in aqueous solutions, while it remains largely unknown how organic solvents and more specifically solvent-induced conformational changes might influence protein adsorption. Herein, using the quartz crystal microbalance-dissipation (QCM-D) and localized surface plasmon resonance (LSPR) techniques, we systematically investigated the real-time adsorption behavior of bovine serum albumin (BSA) protein onto silica surfaces in different water-ethanol mixtures ranging from 0 to 60% (v/v) ethanol. The results showed that there was greater protein adsorption at higher ethanol fractions in the 10-30% range, while more complex adsorption profiles were observed in the 40-60% range. The combination of QCM-D and LSPR measurements led us to further identify specific cases in water-ethanol mixtures where washing steps caused densification of the adsorbed protein layer as opposed to typical desorption of weakly adsorbed molecules in aqueous conditions. We discuss mechanistic factors that drive these overall adsorption trends by taking into account how ethanol fraction affects BSA conformation in bulk solution. Together, our findings demonstrate that BSA proteins can adsorb onto silica surfaces across a wide range of water-ethanol mixture conditions, while specific adsorption profiles depended on the ethanol fraction in a manner closely linked to solution-phase conformational properties.

Factors affecting medication adherence among pre-dialysis chronic kidney disease patients: a systematic review and meta-analysis of literature.

BACKGROUND: Medication adherence plays an essential role in slowing the progression of chronic kidney disease (CKD). This review aims to summarise factors affecting medication adherence among these pre-dialysis CKD patients. METHODS: A systematic review of the literature was performed in Medline®, Embase®, SCOPUS® and CINAHL®. Peer-reviewed, English language articles which evaluated factors associated with medication adherence among pre-dialysis CKD patients were included. Meta-analysis was performed to assess the pooled medication adherence rates across studies. Factors identified were categorised using the World Health Organization's five dimensions of medication adherence (condition, patient, therapy, health-system, and socio-economic domains). RESULTS: Of the 3727 articles reviewed, 18 articles were included. The pooled adherence rate across studies was 67.4% (95% CI 61.4-73.3%). The most studied medication class was anti-hypertensives (55.6%). A total of 19 factors and 95 sub-factors related to medication adherence were identified. Among condition-related factors, advanced CKD was associated with poorer medication adherence. Patient-related factors that were associated with lower medication adherence included misconceptions about medication and lack of perceived self-efficacy in medication use. Therapy-related factors which were associated with poorer medication adherence included polypharmacy while health system-based factors included loss of confidence in the physician. Socioeconomic factors such as poor social support and lower education levels were associated with poorer medication adherence. CONCLUSION: Factors associated with poor medication adherence among pre-dialysis CKD patients were highlighted in this review. This will aid clinicians in designing interventions to optimise medication adherence among pre-dialysis CKD patients.

Glycyrrhizin affects monocyte migration and apoptosis by blocking HMGB1 signaling.

Monocytes serve an important role in systemic inflammation. High mobility group box­1 protein (HMGB1) promotes recruitment and suppresses apoptosis in monocytes through the receptor for advanced glycation end products/ nuclear factor (NF)­κB and toll­like receptor 4/mitogen­activated protein kinase (MAPK)/extracellular signal­regulated kinase (ERK) signaling pathways. Glycyrrhizin (GL), an effective component of licorice, weakens the proinflammatory effect of HMGB1. The present study investigated the effect of GL on the migration and apoptosis of monocytes associated with HMGB1 signaling. THP­1 cells were used to evaluate the behavior of monocytes in response to GL treatment, and the downstream pathways were investigated. GL suppressed HMGB1­induced monocyte migration and increased HMGB1­inhibited monocyte apoptosis. GL inhibited the activation of the NF­κB and MAPK/ERK signaling pathways induced by HMGB1 and decreased the expression of monocyte chemoattractant protein­1 (MCP­1) and myeloid cell leukemia 1 (Mcl­1). Taken together, the results indicated that GL may suppress the migration of monocytes and induce apoptosis to reduce systemic inflammation by blocking downstream NF­κB/MCP­1 and MAPK/ERK/Mcl­1 signaling pathways.