Potential immunomodulatory effects of CAS+IMD monoclonal antibody cocktail in hospitalized patients with COVID-19.

BACKGROUND: Passive administration of SARS-CoV-2 neutralizing monoclonal antibodies (mAbs), such as CAS + IMD (Casirivimab + Imdevimab) antibody cocktail demonstrated beneficial effects on clinical outcomes in hospitalized patients with COVID-19 who were seronegative at baseline and outpatients. However, little is known about their impact on the host immunophenotypes. METHODS: We conducted an immunoprofiling study in 46 patients from a single site of a multi-site trial of CAS + IMD in hospitalized patients. We collected longitudinal samples during October 2020 âˆ¼ April 2021, prior to the emergence of the Delta and Omicron variants and the use of COVID-19 vaccines. All collected samples were analyzed without exclusion and post-hoc statistical analysis was performed. We examined the dynamic interplay of CAS + IMD with host immunity applying dimensional reduction approach on plasma proteomics and high dimensional flow cytometry data. FINDINGS: Using an unbiased clustering method, we identified unique immunophenotypes associated with acute inflammation and disease resolution. Compared to placebo group, administration of CAS + IMD accelerated the transition from an acute inflammatory immunophenotype, to a less inflammatory or "resolving" immunophenotype, as characterized by reduced tissue injury, proinflammatory markers and restored lymphocyte/monocyte imbalance independent of baseline serostatus. Moreover, CAS + IMD did not impair the magnitude or the quality of host T cell immunity against SARS-CoV-2 spike protein. INTERPRETATION: Our results identified immunophenotypic changes indicative of a possible SARS-CoV-2 neutralizing antibodies-induced anti-inflammatory effect, without an evident impairment of cellular antiviral immunity, suggesting that further studies of Mabs effects on SAS-CoV-2 or other viral mediated inflammation are warranted. FUNDING: Regeneron Pharmaceuticals Inc and federal funds from the Department of Health and Human Services; Administration for Strategic Preparedness and Response; Biomedical Advanced Research and Development Authority, under OT number: HHSO100201700020C.

Peripheral Odontogenic Myxoma of Zygoma and Orbital Region - A Unique Case Report with Review of Literature.

Rationale: Peripheral odontogenic myxoma (POM) is a rare mesenchymal tumour and it is the first case report of POM involving orbital and zygoma region. Patient Concerns: A 16-year-old male presented with a painless, slow-growing swelling over his left infratemporal region. Diagnosis: The histopathological examination of the tumour was diagnosed as POM. Treatment: The patient was treated by surgical removal of tumour under general anaesthesia. Outcomes: The patient has been under follow-up for the past 2.5 years and there has been no recurrence. Take-away Lessons: POM is a rare mesenchymal tumour. To our knowledge, this is only the second report of a POM of the infratemporal region and the first report of a myxoma, which extends into the zygomatic region and lateral wall of the orbit.

Molecular Dynamics Simulations Help Determine the Molecular Mechanisms of Lasioglossin-III and Its Variant Peptides' Membrane Interfacial Interactions.

Lasioglossin-III (LL-III) is a potent broad-spectrum antimicrobial peptide used in diverse antimicrobial applications. In this work, coarse-grained and all-atom molecular dynamics simulation strategies were used in tandem to interpret the molecular mechanisms involved in the interfacial dynamics of LL-III and its recombinant variants during interactions with diverse cell membrane systems. Our results indicate that the membrane charges act as the driving force for initiating the membrane-peptide interactions, while the hydrophobic or van der Waals forces help to reinforce the membrane-peptide bindings. The optimized charge-hydrophobicity ratio of the LL-III peptides helps ensure their high specificity toward bacterial membranes compared to mammalian membrane systems, which also helps explain our experimental observations. Overall, we hope that our work gives new insight into the antimicrobial action of LL-III peptides and that the adopted simulation strategy will help other scientists and engineers extract maximal information from complex molecular simulations using minimal computational power.

Two photon imaging probe with highly efficient autofluorescence collection at high scattering and deep imaging conditions.

In this paper, we present a 2-photon imaging probe system featuring a novel fluorescence collection method with improved and reliable efficiency. The system aims to miniaturize the potential of 2-photon imaging in the metabolic and morphological characterization of cervical tissue at sub-micron resolution over large imaging depths into a flexible and clinically viable platform towards the early detection of cancers. Clinical implementation of such a probe system is challenging due to inherently low levels of autofluorescence, particularly when imaging deep in highly scattering tissues. For an efficient collection of fluorescence signals, our probe employs 12 0.5 NA collection fibers arranged around a miniaturized excitation objective. By bending and terminating a multitude of collection fibers at a specific angle, we increase collection area and directivity significantly. Positioning of these fibers allows the collection of fluorescence photons scattered away from their ballistic trajectory multiple times, which offers a system collection efficiency of 4%, which is 55% of what our bench-top microscope with 0.75 NA objective achieves. We demonstrate that the collection efficiency is largely maintained even at high scattering conditions and high imaging depths. Radial symmetry of arrangement maintains uniformity of collection efficiency across the whole FOV. Additionally, our probe can image at different tissue depths via axial actuation by a dc servo motor, allowing depth dependent tissue characterization. We designed our probe to perform imaging at 775 nm, targeting 2-photon autofluorescence from NAD(P)H and FAD molecules, which are often used in metabolic tissue characterization. An air core photonic bandgap fiber delivers laser pulses of 100 fs duration to the sample. A miniaturized objective designed with commercially available lenses of 3 mm diameter focuses the laser beam on tissue, attaining lateral and axial imaging resolutions of 0.66 µm and 4.65 µm, respectively. Characterization results verify that our probe achieves collection efficiency comparable to our optimized bench-top 2-photon imaging microscope, minimally affected by imaging depth and radial positioning. We validate autofluorescence imaging capability with excised porcine vocal fold tissue samples. Images with 120 µm FOV and 0.33 µm pixel sizes collected at 2 fps confirm that the 300 µm imaging depth was achieved.

Aesthetic Reconstruction Based on Facial Subunit Principle for Basal Cell Carcinoma of the Face: A Retrospective Analysis.

Background and objective Basal cell carcinoma (BCC) is the most common malignancy of the skin. Reconstruction of post-excisional defects in BCC should follow the subunit principle for better outcomes. The location of BCC of the face is determined based on facial units; however, very few studies have described the involvement of multiple units and multiple subunits in BCC. In this study, we aimed to provide valuable insights into the management of BCC involving various facial units and subunits, thereby contributing to improved patient care and outcomes. Materials and methods We conducted a retrospective study at the Plastic Surgery Department of the SCB Medical College in Cuttack, Odisha, from January 2020 to January 2022, after obtaining ethical approval from the SCB Medical College IRB (no: 1155). We examined 35 patients with BCC of the face. The inclusion criteria were as follows: patients with early-stage and primary tumors that were mobile, not attached to underlying bone or cartilage, and amenable to surgical resection. Conversely, patients with late-stage, neglected, and recurrent tumors, fixed tumors, or those infiltrating the underlying bone or cartilage were excluded from the study. Data collection involved retrieving pertinent information from medical records, including parameters such as age, sex, tumor site, type of flap utilized, follow-up, and any complications observed. The tumor sites were further divided into six separate groups based on facial aesthetic units: the forehead, the nose, the area around the eyes, the cheek, the mouth, and the area around the ear, each with its own subunits. Results A total of 35 patients were included in this study, comprising 15 males (42.85%) and 20 females (57.15%), with a male-to-female ratio of 1:1.33. The ages of the patients ranged from 42 to 68 years. Among the facial units, the nose was the most commonly involved (in seven cases), while the lip was the least commonly affected (in one case). In 24 cases, a single unit was involved, while 11 cases involved multiple units. Furthermore, single subunits were affected in 18 cases, double subunits in 10 cases, three subunits in five cases, four subunits in one case, and five subunits in another case. Notably, no cases exhibited flap necrosis, wound dehiscence, wound hematoma, or seroma, indicating excellent surgical outcomes. All flaps remained viable, and all patients were followed up for a minimum of one year, with no reported recurrence during the follow-up period ranging from 6 to 18 months, reaffirming the effectiveness of the treatment approach. Conclusions For small, superficial lesions, full-thickness skin grafts (FTSG) are a suitable treatment option. However, when dealing with larger lesions that encompass multiple subunits, the preferred approach involves reconstructing with locoregional flaps. It is essential to plan the procedure carefully, taking into account the goal of positioning the final scar along the junction of facial subunits. This strategic plan aims to achieve superior aesthetic outcomes.

Auranofin coated catheters inhibit bacterial and fungal biofilms in a murine subcutaneous model.

Microbe entry through catheter ports can lead to biofilm accumulation and complications from catheter-related bloodstream infection and ultimately require antimicrobial treatment and catheter replacement. Although strides have been made with microbial prevention by applying standardized antiseptic techniques during catheter implantation, both bacterial and fungal microbes can present health risks to already sick individuals. To reduce microbial adhesion, murine and human catheters were coated with polyurethane and auranofin using a dip coating method and compared to non-coated materials. Upon passage of fluid through the coated material in vitro, flow dynamics were not impacted. The unique antimicrobial properties of the coating material auranofin has shown inhibitory activity against bacteria such as Staphylococcus aureus and fungi such as Candida albicans. Auranofin coating on catheters at 10mg/mL reduced C. albicans accumulation in vitro from 2.0 x 108 to 7.8 x 105 CFU for mouse catheters and from 1.6 x 107 to 2.8 x 106 for human catheters, showing an impact to mature biofilms. Assessment of a dual microbe biofilm on auranofin-coated catheters resulted in a 2-log reduction in S. aureus and a 3-log reduction in C. albicans compared to uncoated catheters. In vivo assessment in a murine subcutaneous model demonstrated that catheters coated with 10 mg/mL auranofin reduced independent S. aureus and C. albicans accumulation by 4-log and 1-log, respectively, compared to non-coated catheters. In conclusion, the auranofin-coated catheters demonstrate proficiency at inhibiting multiple pathogens by decreasing S. aureus and C. albicans biofilm accumulation.

Detection and classification of atrial and ventricular cardiovascular diseases to improve the cardiac health literacy for resource constrained regions.

ECG is a non-invasive way of determining cardiac health by measuring the electrical activity of the heart. A novel detection technique for feature points P, QRS and T is investigated to diagnose various atrial and ventricular cardiovascular anomalies with ECG signals for ambulatory monitoring. Before the system is worthy of field trials, it is validated with several databases and recorded their response. The QRS complex detection is based on the Pan Tompkins algorithm and difference operation method that provides positive predictivity, sensitivity and false detection rate of 99.29%, 99.49% and 1.29%, respectively. Proposed novel T wave detection provides sensitivity of 97.78%. Also, proposed P wave detection provides positive predictivity, sensitivity and false detection rate of 99.43%, 99.4% and 1.15% for the control study (normal subjects) and 82.68%, 94.3% and 25.4% for the case (patients with cardiac anomalies) study, respectively. Disease detection such as arrhythmia is based on standard R-R intervals while myocardial infarction is based on the ST-T deviations where the positive predictivity, sensitivity and accuracy are observed to be 94.6%, 84.2% and 85%, respectively. It should be noted that, since the frontal leads are only used, the anterior myocardial infarction cases are detected with the injury pattern in lead avl and ST depression in reciprocal leads. Detection of atrial fibrillation is done for both short and long duration signals using statistical methods using interquartile range and standard deviations, giving very high accuracy, 100% in most cases. The system hardware for obtaining the 2 lead ECG signal is designed using commercially available off the shelf components. Small field validation of the designed system is performed at a Public Health Centre in Gujarat, India with 42 patients (both cases and controls). 78.5% accuracy was achieved during the field validation. It is thus concluded that the proposed method is ideal for improvisation in cardiac health monitoring outreach in resource constrained regions.

Antimicrobial Peptides and Small Molecules Targeting the Cell Membrane of Staphylococcus aureus.

Clinical management of Staphylococcus aureus infections presents a challenge due to the high incidence, considerable virulence, and emergence of drug resistance mechanisms. The treatment of drug-resistant strains, such as methicillin-resistant S. aureus (MRSA), is further complicated by the development of tolerance and persistence to antimicrobial agents in clinical use. To address these challenges, membrane disruptors, that are not generally considered during drug discovery for agents against S. aureus, should be explored. The cell membrane protects S. aureus from external stresses and antimicrobial agents, but membrane-targeting antimicrobial agents are probably less likely to promote bacterial resistance. Nontypical linear cationic antimicrobial peptides (AMPs), highly modified AMPs such as daptomycin (lipopeptide), bacitracin (cyclic peptide), and gramicidin S (cyclic peptide), are currently in clinical use. Recent studies have demonstrated that AMPs and small molecules can penetrate the cell membrane of S. aureus, inhibit phospholipid biosynthesis, or block the passage of solutes between the periplasm and the exterior of the cell. In addition to their primary mechanism of action (MOA) that targets the bacterial membrane, AMPs and small molecules may also impact bacteria through secondary mechanisms such as targeting the biofilm, and downregulating virulence genes of S. aureus. In this review, we discuss the current state of research into cell membrane-targeting AMPs and small molecules and their potential mechanisms of action against drug-resistant physiological forms of S. aureus, including persister cells and biofilms.

Antibiotic-resistant bacteria in bovine milk in India.

Antibiotic resistance (ABR) is a global issue that draws the attention of all healthcare experts in the veterinary and medical fields. Of various factors, indiscriminate and unregulated antibiotic usage in the animals reared for food production, especially in cows and buffaloes suffering from mastitis, contribute significantly to the rising incidence of resistant bacteria. A literature survey reveals the spread of resistant strains of mastitis-causing bacteria, like Staphylococcus aureus and Escherichia coli, to humans. In addition, antibiotic residues detected in milk samples against all major groups of antibiotics are likely to enter the human body through the food chain and aggravate the condition. The cumulative effects of ABR have emerged as a silent killer. The benefits of systematic surveillance on ABR in India are yet to be available. Here is an attempt to understand the ABR burden in India associated with bovine milk and its mitigation strategies.

Bilateral disc edema: An unusual presentation of renal tuberculosis in a child.

Renal tuberculosis (TB) is a rare clinical disorder in the pediatric population. A 15-year-old female presented with intermittent blurring of vision in both eyes associated with fever, abdominal pain, and weight loss. Fundus examination showed bilateral disc edema. Her blood pressure was 220/110 mmHg. Renal parameters were deranged with bilaterally enlarged kidneys. Renal biopsy was suggestive of epithelioid cell granuloma with Langhans type giant cells. The patient was diagnosed with as a case of refractory hypertension due to tubercular interstitial nephritis with bilateral Grade IV hypertensive retinopathy. She was started on antitubercular therapy and antihypertensives. There was a complete resolution of disc edema 2 months following initiation of therapy. Optic disc edema can be a presenting sign in renal TB. Early diagnosis and prompt referral can be associated with good visual and systemic outcomes.

Bactericidal and biocatalytic temperature responsive microgel based self-cleaning membranes for water purification.

The present study focuses on creating an antimicrobial and biocatalytic smart gating membrane by synthesizing unique core-shell microgels. The core-shell microgels are synthesized by grafting short chains of poly(ethylenimine) (PEI) onto a poly((N-isopropyl acrylamide)-co-glycidyl methacrylate)) (P(NIPAm-co-GMA)) core. Subsequently, the produced microgels are utilized as a substrate for synthesizing and stabilizing silver nanoparticles (Ag NPs) through an in-situ approach. These Ag NPs immobilized microgels are then suction filtered over a polyethylene terephthalate (PET) track-etched support to create cross-linked composite microgel membranes (CMMs). After structural and permeation characterization of the prepared CMMs, the laccase enzyme is then covalently grafted to the surface of the membrane and tested for its effectiveness in degrading Reactive red-120 dye. The laccase immobilized biocatalytic CMMs show effective degradation of the Reactive red-120 by 71%, 48%, and 34% at pH 3, 4, and 5, respectively. Furthermore, the immobilized laccase enzyme showed better activity and stability in terms of thermal, pH, and storage compared to the free laccase, leading to increased reusability. The unique combination of Ag NPs and laccase on a thermoresponsive microgel support resulted in a responsive self-cleaning membrane with excellent antimicrobial and dye degradation capabilities for environmentally friendly separation technology.

Biological Evaluation of the Antibacterial Retinoid CD437 in Cutibacterium acnes Infection.

Acne vulgaris is a complex skin disease involving infection by Cutibacterium acnes, inflammation, and hyperkeratinization. We evaluated the activity of the retinoid 6-[3-(adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) and 16 other retinoid analogs as potential anti-C. acnes compounds and found that CD437 displayed the highest antimicrobial activity with an MIC against C. acnes (ATCC 6919 and HM-513) of 1 µg/mL. CD437 demonstrated an MBC of 2 µg/mL compared to up to 64 µg/mL for the retinoid adapalene and up to 16 µg/mL for tetracycline, which are commonly used clinically to treat acne. Membrane permeability assays demonstrated that exposure of C. acnes ATCC 6919 to CD437 damaged the integrity of C. acnes ATCC 6919 bacterial membranes, and this finding was confirmed with scanning electron microscopy. Additionally, CD437 downregulated the expression of C. acnes ATCC 6919 virulence factors, including the genes encoding Christie-Atkins-Munch-Petersen factor 1 (CAMP1), CAMP2, glycerol-ester hydrolase B (GehB), sialidase B, and neuraminidase. In a mouse skin infection model of C. acnes ATCC 6919, topical treatment with CD437 ameliorated skin lesions and reduced the bacterial burden in situ (P < 0.001). In human NHEK primary cells, CD437 reduced the transcriptional levels of the coding genes for inflammatory cytokines (interleukin-1α, ~10-fold; interleukin-6, ~20-fold; interleukin-8, ~30-fold; and tumor necrosis factor-alpha, ~6-fold) and downregulated the transcriptional levels of KRT10 (~10-fold), FLG (~4-fold), and TGM1 (~2-fold), indicating that CD437 can diminish inflammation and hyperkeratinization. In summary, CD437 deserves further attention for its dual function as a potential acne therapeutic that potentially acts on both the pathogen and the host.

Peptide Stability Is Important but Not a General Requirement for Antimicrobial and Antibiofilm Activity In Vitro and In Vivo.

Peptide stability to proteases has been a major requirement for developing peptide therapeutics. This study investigates the effects of peptide stability on antimicrobial and antibiofilm activity under various conditions. For this purpose, two human cathelicidin-derived peptides differing in stability to proteases were utilized. While GF-17, a peptide derived from the major antimicrobial region of human LL-37, can be rapidly cleaved by proteases, the engineered peptide 17BIPHE2 is resistant to multiple proteases. In the standard antimicrobial susceptibility, killing kinetics, and membrane permeabilization assays conducted in vitro using planktonic bacteria, these two peptides displayed similar potency. The two peptides were also similarly active against methicillin-resistant Staphylococcus aureus (MRSA) USA300 prior to biofilm formation. However, 17BIPHE2 was superior to GF-17 in disrupting preformed biofilms probably due to both enhanced stability and slightly higher DNA binding capacity. In a wax moth model, 17BIPHE2 better protected insects from MRSA infection-caused death than GF-17, consistent with the slower degradation of 17BIPHE2 than GF-17. Here, peptide antimicrobial activity was found to be critical for in vivo efficacy. When incorporated in the nanofiber/microneedle delivery device, GF-17 and 17BIPHE2 displayed a similar effect in eliminating MRSA in murine chronic wounds, underscoring the advantage of nanofibers in protecting the peptide from degradation. Since nanoformulation can ease the requirement of peptide stability, it opens the door to a direct use of natural peptides or their cocktails for antimicrobial treatment, accelerating the search of effective antibiofilm peptides to treat chronic wounds.

Water, Sanitation, and Hygiene Practices and Their Association With Childhood Diarrhoea in Rural Households of Mayurbhanj District, Odisha, India.

INTRODUCTION: Diarrhoeal disease is one of the major causes of childhood morbidity and mortality in India. It affects all ages, yet very few studies have been found regarding the young and older children affected by diarrhoea and its etiology. About 2.2 million deaths are attributed to diarrhoea alone in India every year. However, a large number of diarrhoeal cases may be avoided with proper sanitation and hygiene practices. The primary aim of this study was to assess the current water, sanitation, and hygiene (WASH) practises among mothers and diarrhoea among their children (6 months to 11 years) in rural households of the Mayurbhanj district, Odisha. Further, the association between WASH practises and childhood diarrhoeal disease was assessed. METHODS: A community-based cross-sectional survey was conducted among 430 mothers by using a pre-tested structured questionnaire adapted from previous studies. Data collection was done using the software Epicollect5 by the trained data collector. The data were further transformed to Statistical Package for Social Sciences (SPSS, IBM Corp., Armonk, NY) version 23 for analysis to find out potential risk factors. A multistage sampling technique was used to find subjects. RESULTS: Out of 430 households, 21.6% of respondents reported that their children were suffering from diarrhoea in the last two weeks from the day of the survey. Nearly 63.8% of respondents mentioned that they used to supply water as a principal source for household purposes. This study found that children of households near waste piles are more at risk of having diarrhoea than those households living far from the waste pile [AOR: 4.996; 95% CI: (2.173, 11.487)]. In the management of household wastes, households who are throwing waste here and there are 3.276 times more at risk of having diarrhoea than households who are managing the wastes by themselves by burning them outside the home [AOR: 3.276; 95%CI: (1.463, 7.042)]. In the disposal of child faeces, it was found that the household children's faeces disposed of in the garbage or dumping site are 2.438 times more at risk of having diarrhoea than those who are flushing the faeces in the latrine [AOR: 2.438; 95%CI: (1.284, 4.631)]. Also, using footwear less often was found to be highly associated with an increase in the incidence of diarrhoea (AOR: 1.634; 95% CI (.815, 3.276). CONCLUSION: Findings indicate that creating awareness about the benefits of proper management of household waste and using footwear on a regular basis is the priority to avoid childhood diarrhoea. Further, area-specific planning and programme allocation of resources is necessary to prevent childhood diarrhoea.

Linearized teixobactin is inactive and after sequence enhancement, kills methicillin-resistant Staphylococcus aureus via a different mechanism.

Staphylococcus aureus is a highly adaptable pathogen that can rapidly develop resistance to conventional antibiotics such as penicillin. Recently, teixobactin was discovered from uncultivated soil bacteria by using the i-chip technology. This depsipeptide forms an ester bond between the backbone C-terminal isoleucine carboxylic acid and the hydroxyl group of threonine at position 8. Also, it contains multiple nonstandard amino acids, making it costly to synthesize. This study reports new peptides designed by linearizing teixobactin. After linearization and conversion to normal amino acids, teixobactin lost its antibacterial activity. Using this inactive template, a series of peptides were designed via hydrophobic patching and residue replacements. Three out of the five peptides were active. YZ105, only active against Gram-positive bacteria, however, showed the highest cell selectivity index. Different from teixobactin, which inhibits cell wall synthesis, YZ105 targeted the membranes of methicillin-resistant S. aureus (MRSA) based on kinetic killing, membrane permeation, depolarization, and scanning electron microscopy studies. Moreover, YZ105 could kill nafcillin-resistant MRSA, Staphylococcal clinical strains, and disrupted preformed biofilms. Taken together, YZ105, with a simpler sequence, is a promising lead for developing novel anti-MRSA agents.

In Vitro and In Vivo Bactericidal and Antibiofilm Efficacy of Alpha Mangostin Against Staphylococcus aureus Persister Cells.

The formation of persister cells is associated with recalcitrance and infections. In this study, we examined the antimicrobial property of alpha mangostin, a natural xanthone molecule, against methicillin-resistant Staphylococcus aureus (MRSA) persisters and biofilm. The MIC of alpha mangostin against MRSA persisters was 2 µg/ml, and activity was mediated by causing membrane permeabilization within 30 min of exposure. The membrane activity of alpha mangostin was further studied by fast-killing kinetics of MRSA persiste r cells and found that the compound exhibited 99.99% bactericidal activity within 30 min. Furthermore, alpha mangostin disrupted established MRSA biofilms and inhibited bacterial attachment as biofilm formation. Alpha mangostin down-regulated genes associated with the formation of persister cells and biofilms, such as norA, norB, dnaK, groE, and mepR, ranging from 2 to 4-folds. Alpha mangostin at 16 µg/ml was non-toxic (> 95% cell survival) to liver-derived HepG2 and lung-derived A549 cells, similarly. Still, alpha mangostin exhibited 50% cell lysis of human RBC at 16 µg/ml. Interestingly, alpha mangostin was effective in vivo at increasing the survival up to 75% (p<0.0001) of Galleria mellonella larvae infected with MRSA persister for 120 h. In conclusion, we report that alpha mangostin is active against MRSA persisters and biofilms, and these data further our understanding of the antistaphylococcal activity and toxicity of this natural compound.

Design and Evaluation of Short Bovine Lactoferrin-Derived Antimicrobial Peptides against Multidrug-Resistant Enterococcus faecium.

Enterococcus faecium has become an important drug-resistant nosocomial pathogen because of widespread antibiotic abuse. We developed short and chemically simple antimicrobial peptides (AMPs) with a selective amino acid composition, fixed charge, and hydrophobicity ratio based on the core antimicrobial motif of bovine lactoferrin (LfcinB6). Among these peptides, 5L and 6L (both 12 residues long) demonstrated a narrow spectrum and high antibacterial activity against drug-resistant E. faecium isolates with a minimal inhibitory concentration (MIC) that ranged from 4-16 µg/mL. At 32 µg/mL, peptides 5L and 6L inhibited E. faecium strain C68 biofilm formation by 90% and disrupted established biofilms by 75%. At 40 µg/mL, 5L reduced 1 × 107E. faecium persister cells by 3 logs within 120 min of exposure, whereas 6L eliminated all persister cells within 60 min. At 0.5× MIC, 5L and 6L significantly downregulated the expression of a crucial biofilm gene ace by 8 folds (p = 0.02) and 4 folds (p = 0.01), respectively. At 32 µg/mL, peptides 5L and 6L both depolarized the E. faecium membrane, increased fluidity, and eventually ruptured the membrane. Physiologically, 5L (at 8 µg/mL) altered the tricarboxylic acid cycle, glutathione, and purine metabolism. Interestingly, in an ex vivo model of porcine skin infection, compared to no treatment, 5L (at 10× MIC) effectively eliminated all 1 × 106 exponential (p = 0.0045) and persister E. faecium cells (p = 0.0002). In conclusion, the study outlines a roadmap for developing narrow-spectrum selective AMPs and presents peptide 5L as a potential therapeutic candidate to be explored against E. faecium.

Drug-Induced Oromandibular Dystonia Presenting as Chronic Temporomandibular Joint Dislocation: A Rare Case Report.

Approximately 15%-30% of patients receiving neuroleptic medication for a longer duration develop drug-induced dystonia. There are many variations of oromandibular dystonia (OMD), but the most common one is involuntary jaw-opening dystonia. A rare case of chronic mandibular dislocation under long-term neuroleptic therapy is reported with clinical features, diagnosis, and various treatment modalities. Chronic dislocation leads to changes in associated soft tissue and muscles. Therefore, besides alteration of bony articular surfaces (eminectomy), soft tissue remodeling is required to achieve the perfect balance for temporomandibular joint (TMJ) working and occlusion. Drug-induced orofacial dystonia presenting as chronic TMJ dislocation is rare. Therefore, in long-standing chronic dislocation cases during treatment, biomechanics of TMJ, its complex neurological system, and the physiology of the masticatory system should be considered to customize the treatment plan.