Toward the Control of the Creation of Mixed Monolayers on Glassy Carbon Surfaces by Amine Oxidation.

A versatile and simple methodology for the creation of mixed monolayers on glassy carbon (GC) surfaces was developed, using an osmium-bipyridyl complex and anthraquinone as model redox probes. The work consisted in the electrochemical grafting on GC of a mixture of mono-protected diamine linkers in varying ratios which, after attachment to the surface, allowed orthogonal deprotection. After optimisation of the deprotection conditions, it was possible to remove one of the protecting groups selectively, couple a suitable osmium complex and cap the residual free amines. The removal of the second protecting group allowed the coupling of anthraquinone. The characterisation of the resulting surfaces by cyclic voltammetry showed the variation of the surface coverage of the two redox centres in relation to the initial ratio of the linking amine in solution.

Synthesis and evaluation of a (3R,6S,9S)-2-oxo-1-azabicyclo[4.3.0]nonane scaffold as a mimic of Xaa-trans-Pro in poly-L-proline type II helix conformation.

We describe the development of a small-molecule mimic of Xaa-trans-Pro dipeptide in poly-l-proline type II helix conformation, based upon a (3R,6S,9S)-2-oxo-1-azabicyclo[4.3.0]nonane core structure. Stereoselective synthesis of the mimic from l-pyroglutamic acid is achieved in twelve linear steps and 9.9% yield. Configurational and conformational analyses are conducted using a combination of (1)H NMR spectroscopy, X-ray crystallography and circular dichroism spectroscopy; and evaluation of the mimic as a promising surrogate dipeptide, in a protein-protein interaction between the SH3 domain of human Fyn kinase (Fyn SH3) and peptidomimetics of its biological ligand, are conducted by (1)H-(15)N HSQC NMR titration experiments.

Design of maleimide-functionalised electrodes for covalent attachment of proteins through free surface cysteine groups.

Mixed two-component monolayers on glassy carbon are prepared by electrochemical oxidation of N-(2-aminoethyl)acetamide and mono-N-Boc-hexamethylenediamine in mixed solution. Subsequent N-deprotection, amide coupling and solid-phase synthetic steps lead to electrode-surface functionalisation with maleimide, with controlled partial coverage of this cysteine-binding group at appropriate dilution for covalent immobilisation of a model redox-active protein, cytochrome c, with high coverage (≈7.5 pmol cm(-2) ).

Local control and toxicity outcomes in brainstem metastases treated with single fraction radiosurgery: is there a volume threshold for toxicity?

Gamma Knife Radiosurgery (GKRS) has been reported in the treatment of brainstem metastases while dose volume toxicity thresholds remain mostly undefined. A retrospective review of 52 brainstem metastases in 44 patients treated with GKRS was completed. A median dose of 18 Gy (range 10-22 Gy) was prescribed to the tumor margin (median 50 % isodose). 25 patients had undergone previous whole brain radiation therapy. Toxicity was graded by the LENT-SOMA scale. Mean and median follow-up was 10 and 6 months. Only 3 of the 44 patients are living. Multiple brain metastases were treated in 75 % of patients. Median size of lesions was 0.134 cc, (range 0.013-6.600 cc). Overall survival rate at 1 year was 32 % (95 % CI 51.0-20.1 %) with a median survival time of 6 months (95 % CI 5.0-16.5). Local control rate at 6 months and 1 year was 88 % (95 % CI 70-95 %) and 74 % (95 % CI 52-87 %). Cause of death was neurologic in 17 patients, non-neurologic in 20 patients, and unknown in four. Four patients experienced treatment related toxicities. Univariate analysis of tumor volume revealed that volume greater than 1.0 cc predicted for toxicity. A strategy of using lower marginal doses with GKRS to brain stem metastases appears to lead to a lower local control rate than seen with lesions treated within the standard dose range in other locations. Tumor size greater than 1.0 cc predicted for treatment-related toxicity.

Inhalation Pneumonitis Caused by Nebulized Hydrogen Peroxide.

Hydrogen peroxide is a chemical commonly used as a household antiseptic for cleaning and disinfecting. No cases of acute hydrogen peroxide inhalation-induced lung injury are previously described. We present a case of acute chemical pneumonitis caused by mixing hydrogen peroxide in a nighttime continuous positive airway pressure device's humidifier used for obstructive sleep apnea to prevent COVID-19 infection. The patient endorsed mixing hydrogen peroxide with distilled water in his nighttime continuous positive airway pressure device's humidifier at a ratio of 1:3-1:2 for the previous week before admission based on a friend's advice in preventing COVID-19. The presenting chest X-ray showed new multifocal consolidations with interstitial markings and alveolar edema throughout both lungs. Chest computed tomography (CT) imaging demonstrated multifocal, bilateral, hazy consolidations with increased interstitial markings and bilateral pleural effusions. The patient was subsequently initiated on systemic glucocorticoid therapy, significantly improving hypoxemia and dyspnea. Inhalation of hydrogen peroxide may produce acute pneumonitis distinct from what has been described previously with chronic inhalation. Given this case, systemic glucocorticoid therapy may be considered a viable treatment option for acute hydrogen peroxide-associated inhalation lung injury causing pneumonitis.

Intensive care unit presentation of central corneal descemetocele secondary to Methicillin-Resistant staphylococcal infection superimposed by a hypopyon: a case report.

A descemetocele is a rare type of keratopathy that occurs when an intact descemet's membrane of the eye undergoes a herniation through an overlying stroma. Previous literature has documented corneal damage via bacterial enzymes, especially, Pseudomonas and Neisseria species. Most recent prospective interventional studies showed treatment of these infections. Case presentation: This report presents the first instance of a methicillin-resistant Staphylococcus aureus descemetocele presentation in a 51-year-old African American male, with co-presenting hypopyon sequelae successfully managed conservatively in an intensive care unit setting. Clinical discussion: An instance of a methicillin-resistant Staphylococcus aureus has not yet been documented in the literature. Likewise, a co-presentation with a hypopyon, which is known as a formation of inflammatory debris rich in white blood cells has not been studied. Conclusion: The presence of a hypopyon in the instances of bacterial descemetocele herniation should be further evaluated to see if there are associations with conservative, nonsurgical intervention outcomes.

Beyond Trauma: High-Volume Critical Care Medicine in a Military Medical Center-Based Military-Civilian Partnership.

INTRODUCTION: Critical Care Internal Medicine (CCIM) is vital to the U.S. Military as evidenced by the role CCIM played in the COVID-19 pandemic response and wartime operations. Although the proficiency needs of military surgeons have been well studied, this has not been the case for CCIM. The objective of this study was to compare the patient volume and acuity of military CCIM physicians working solely at Military Treatment Facilities (MTFs) with those at MTFs also working part-time in a military-civilian partnership (MCP) at the University Medical Center of Southern Nevada (UMC). MATERIALS AND METHODS: We analyzed FY2019 critical care coding data from the Military Health System and UMC comparing the number of critical care encounters, the number of high-acuity critical care encounters, and the Abilities/Activity component of the Knowledge, Skills, and Abilities/Clinical Activity (KSA) score. This analysis was restricted to critical care encounters defined by Current Procedural Terminology codes for critical care (99291 and 99292). A critical care encounter was considered high acuity if the patient had ICD-10 codes for shock, respiratory failure, or cardiac arrest or had at least three codes for critical care in the same episode. RESULTS: The five AF CCIM physicians in the MCP group performed 2,019 critical care encounters in 206 days, with 63.1% (1,273) being defined as high acuity. The total number of MTF critical care encounters was 16,855 across all providers and services, with 28.9% (4,864) of encounters defined as high acuity. When limited to CCIM encounters, MTFs had 6,785 critical care encounters, with 32.0% being high acuity (2,171). Thus, the five AF CCIM physicians, while working 206 days at the UMC, equated to 12.0% (2,019/16,855) of the total critical care MTF encounters, 27.2% (1,273/4,684) of the total high-acuity MTF critical care encounters, and 29.8% (2,019/6,785) of the MTF CCIM encounters, with 58.6% (1,273/2,171) of the MTF CCIM high-acuity encounters.The USAF CCIM physicians in the MCP group performed 454,395 KSAs in 206 days, with a KSA density per day of 2,206. In the MTF group, CCIM providers generated 2,344,791 total KSAs over 10,287 days, with a KSA density per day of 227.9. Thus, the five CCIM physicians at the UMC accounted for 19.38% of the MTF CCIM KSAs, with a KSA density over 10 times higher (2,206 vs. 227.9). CONCLUSIONS: The volume and acuity of critical care at MTFs may be insufficient to maintain CCIM proficiency under the current system. Military-civilian partnerships are invaluable in maintaining clinical proficiency for military CCIM physicians and can be done on a part-time basis while maintaining beneficiary care at an MTF. Future CCIM expeditionary success is contingent on CCIM physicians and team members having the required CCIM exposure to grow and maintain clinical proficiency.Limitations of this study include the absence of off-duty employment (moonlighting) data and difficulty filtering military data down to just CCIM physicians, which likely caused the MTF CCIM data to be overestimated.

High-throughput synthesis and electrochemical screening of a library of modified electrodes for NADH oxidation.

We report the combinatorial preparation and high-throughput screening of a library of modified electrodes designed to catalyze the oxidation of NADH. Sixty glassy carbon electrodes were covalently modified with ruthenium(II) or zinc(II) complexes bearing the redox active 1,10-phenanthroline-5,6-dione (phendione) ligand by electrochemical functionalization using one of four different linkers, followed by attachment of one of five different phendione metal complexes using combinatorial solid-phase synthesis methodology. This gave a library with three replicates of each of 20 different electrode modifications. This library was electrochemically screened in high-throughput (HTP) mode using cyclic voltammetry. The members of the library were evaluated with regard to the surface coverage, midpeak potential, and voltammetric peak separation for the phendione ligand, and their catalytic activity toward NADH oxidation. The surface coverage was found to depend on the length and flexibility of the linker and the geometry of the metal complex. The choices of linker and metal complex were also found to have significant impact on the kinetics of the reaction between the 1,10-phenanthroline-5,6-dione ligand and NADH. The rate constants for the reaction were obtained by analyzing the catalytic currents as a function of NADH concentration and scan rate, and the influence of the surface molecular architecture on the kinetics was evaluated.

Mass transport controlled oxygen reduction at anthraquinone modified 3D-CNT electrodes with immobilized Trametes hirsuta laccase.

Carbon nanotubes covalently modified with anthraquinone were used as an electrode for the immobilization of Trametes hirsuta laccase. The adsorbed laccase is capable of oxygen reduction at a mass transport controlled rate (up to 3.5 mA cm(-2)) in the absence of a soluble mediator. The storage and operational stability of the electrode are excellent.

Critical asthma syndrome in trauma patients - A case report and literature review.

Critical asthma syndrome (CAS) is an umbrella term for many acute, life-threatening, and treatment resistant variants of asthma exacerbation, including refractory asthma, near fatal asthma, and status asthmaticus. The asthma mortality rate has steadily increased through the last decade and disproportionately affects women, African-Americans, patients of low socioeconomic status, and adults over the age of 55. Increased awareness of the diagnosis and therapies for CAS can help establish a therapeutic strategy for asthma beyond corticosteroids, bronchodilators, and other conventional treatments. A 37 year-old African American woman presented to our Level 1 Trauma Center after a high-speed motor vehicle crash and was intubated on arrival for airway protection. The patient developed diffuse wheezing and persistent tachycardia, with elevated peak airway pressures and air trapping on mechanical ventilation. Her symptoms were refractory to inhaled steroids, systemic steroids, intravenous magnesium, continuous albuterol administration and ventilator optimization. Heliox, an admixture of 80:20 percent helium to oxygen, was initiated to assist with laminar flow. Throughout the next 24 h, the patient's air trapping improved, subsequently decreasing intrathoracic pressure, improving venous return and resolving her tachycardia. The patient's multiple orthopedic injuries were treated and she was eventually weaned off of Heliox, steroids, and continuous albuterol. She was extubated and endorsed a history of poorly controlled asthma requiring hospitalizations and multiple intubations. Recognition of CAS can be challenging in the trauma patient with distracting injuries. This case illustrates the utility of a stepwise approach to a trauma patient suffering from CAS, and should encourage further research into novel therapies when conventional treatment fails. Given that the populations most affected by CAS are often also subject to a disproportionate burden of trauma, trauma surgeons should maintain both a vigilance for the syndrome as well as a working knowledge of the treatment modalities available.

The Las Vegas military-civilian partnership: An origin story and call to action.

ABSTRACT: Military-civilian partnerships (MCPs) in urban American trauma centers have existed for more than 60 years to assist in the development and maintenance of wartime skills of military medical professionals. In the last 5 years, MCPs have gained congressional support, and their number and variety have grown substantially. The historical impact of these flagship trauma MCPs is well documented, with bidirectional benefit in the advancement of trauma care during the wars in Iraq and Afghanistan both deployed and stateside, and the future aim of MCPs lies primarily in mitigating the "peacetime effect." The majority of data regarding MCPs; however, focus on trauma care and are biased toward surgeons specifically. The Las Vegas (LV) MCP began in 2002 with the similar goal of sustaining Air Force (AF) expeditionary medical skills by embedding AF medics from nearby Nellis Air Force Base (AFB) into University Medical Center of Southern Nevada (UMC), the only Level 1 Trauma Center in Nevada. Over nearly 20 years, the LV-MCP has evolved into an innovative market-based collaboration composed of numerous relationships and programs that are designed to develop and sustain critical skills for military medical personnel in all aspects of expeditionary medicine. This includes AF medical personnel providing care to federal beneficiaries as well as civilian patients in a variety of medical settings. The partnership's central coordinating authority, the Office of Military Medicine-Las Vegas (OMM-LV), brings together military and civilian organizations with distinct and intersecting missions to support the greater LV population and the DoD mission of readiness. The LV-MCP is presented here as a model for the future of MCPs within the integrated local and national trauma and medical systems.

Selective anticancer activity of a hexapeptide with sequence homology to a non-kinase domain of Cyclin Dependent Kinase 4.

BACKGROUND: Cyclin-dependent kinases 2, 4 and 6 (Cdk2, Cdk4, Cdk6) are closely structurally homologous proteins which are classically understood to control the transition from the G1 to the S-phases of the cell cycle by combining with their appropriate cyclin D or cyclin E partners to form kinase-active holoenzymes. Deregulation of Cdk4 is widespread in human cancer, CDK4 gene knockout is highly protective against chemical and oncogene-mediated epithelial carcinogenesis, despite the continued presence of CDK2 and CDK6; and overexpresssion of Cdk4 promotes skin carcinogenesis. Surprisingly, however, Cdk4 kinase inhibitors have not yet fulfilled their expectation as 'blockbuster' anticancer agents. Resistance to inhibition of Cdk4 kinase in some cases could potentially be due to a non-kinase activity, as recently reported with epidermal growth factor receptor. RESULTS: A search for a potential functional site of non-kinase activity present in Cdk4 but not Cdk2 or Cdk6 revealed a previously-unidentified loop on the outside of the C'-terminal non-kinase domain of Cdk4, containing a central amino-acid sequence, Pro-Arg-Gly-Pro-Arg-Pro (PRGPRP). An isolated hexapeptide with this sequence and its cyclic amphiphilic congeners are selectively lethal at high doses to a wide range of human cancer cell lines whilst sparing normal diploid keratinocytes and fibroblasts. Treated cancer cells do not exhibit the wide variability of dose response typically seen with other anticancer agents. Cancer cell killing by PRGPRP, in a cyclic amphiphilic cassette, requires cells to be in cycle but does not perturb cell cycle distribution and is accompanied by altered relative Cdk4/Cdk1 expression and selective decrease in ATP levels. Morphological features of apoptosis are absent and cancer cell death does not appear to involve autophagy. CONCLUSION: These findings suggest a potential new paradigm for the development of broad-spectrum cancer specific therapeutics with a companion diagnostic biomarker and a putative functional site for kinase-unrelated activities of Cdk4.

Dimeric self-assembly of pyridyl guanidinium carboxylates in polar solvents.

A series of pyridyl guanidinium-carboxylates has been prepared and the dimeric self-assembly of these studied in H(2)O/DMSO mixtures, principally using dilution isothermal calorimetry. Compounds 5 and 6, incorporating an aromatic ring in the "tethering" region between the guanidinium and carboxylate groups, demonstrate the strongest dimerisation in neat DMSO. X-ray crystal structures of 5 and 6 reveal two different dimerisation architectures in the solid-state, but both involve carboxylate-guanidinium salt bridges as anticipated, and π-π interactions. Compounds 10-16 incorporating peptidic fragments between the guanidinium and carboxylate groups, showed reduced dimerisation strength with increased amino acid content, but also sustained dimerisation under increasingly aqueous conditions, up to 50% H(2)O/DMSO in the case of 14 and 15. The extent of our study in H(2)O/DMSO mixtures was determined by substrate solubility of 10-16, and not the limit of self-assembly.

Synthesis of dihydrodehydrodiconiferyl alcohol: the revised structure of lawsonicin.

Structural revision of lawsonicin, a natural product of Lawsonia alba, is reported based upon comparison of its spectral data with that of the naturally occurring dihydrobenzo[b]furan neolignan (rac)-trans-dihydrodehydrodiconiferyl alcohol, which is found to be identical. A concise synthesis of dihydrodehydrodiconiferyl alcohol, via Rh(2)[S-DOSP](4)-catalysed intramolecular C-H insertion, is described.

Monolayer anthracene and anthraquinone modified electrodes as platforms for Trametes hirsuta laccase immobilisation.

Surface modification techniques are essential to the construction of enzyme based elements of biofuel cells and biosensors. In this article we report on the preparation and characterisation of modified carbon electrodes which were used as supports for the immobilisation of laccase from Trametes hirsuta. The electrodes were electrochemically modified with diamine or diazonium linkers followed by attachment of either anthracene or anthraquinone head groups using solid phase chemical methodology. These well defined surfaces were found to effectively bind laccase and to provide direct electrical contact to the enzyme active site, as evidenced by XPS, EIS and voltammetry, respectively. The influence of the type of linker and head group on enzyme binding and bioelectrocatalytic activity are evaluated.

Identification of major phenolic compounds from Nephelium lappaceum L. and their antioxidant activities.

Nephelium lappaceum is a tropical fruit whose peel possesses antioxidant properties. Experiments on the isolation and identification of the active constituents were conducted, and on their antioxidant activity using a lipid peroxidation inhibition assay. The methanolic extract of N. lappaceum peels exhibited strong antioxidant properties. Sephadex LH-20 chromatography was utilized in the isolation of each constituent and the antioxidant properties of each was studied. The isolated compounds were identified as ellagic acid (EA) (1), corilagin (2) and geraniin (3). These compounds accounted for 69.3% of methanolic extract, with geraniin (56.8%) as the major component, and exhibited much greater antioxidant activities than BHT in both lipid peroxidation (77-186 fold) and DPPH* (42-87 fold) assays. The results suggest that the isolated ellagitannins, as the principal components of rambutan peels, could be further utilized as both a medicine and in the food industry.

Dimeric supramolecular motifs of two carboxylate-guanidinium compounds.

The structures of N-benzyl-N'-{6-[(4-carboxylatobenzyl)aminocarbonyl]-2-pyridylmethyl}guanidinium, C(23)H(23)N(5)O(3), (I), and N-[2-(benzylaminocarbonyl)ethyl]-N'-{6-[(4-carboxylatobenzyl)aminocarbonyl]-2-pyridylmethyl}guanidinium monohydrate, C(26)H(28)N(6)O(4).H(2)O, (II), both form three-dimensional supramolecular hydrogen-bonded networks based on a dimeric primary synthon involving carboxylate-guanidinium linkages. The differences in the geometries and hydrogen-bonding connectivities are driven by the additional methylpropionamide group and water of crystallization of (II).

Covalent modification of glassy carbon surfaces by using electrochemical and solid-phase synthetic methodologies: application to bi- and trifunctionalisation with different redox centres.

Glassy carbon electrodes functionalised with two redox centres have been prepared by using electrochemical and solid-phase synthetic methodologies. Initially the individual coupling of anthraquinone, nitrobenzene and dihydroxybenzene to a glassy carbon electrode bearing an ethylenediamine linker was optimised by using different coupling agents and conditions. Bifunctionalisation was then carried out, either simultaneously, with a mixture of nitrobenzene and dihydroxybenzene, or sequentially, with anthraquinone then nitrobenzene and with anthraquinone then dihydroxybenzene. Characterisation of these electrodes by cyclic voltammetry and differential pulse voltammetry clearly proved the attachment of the pairs of redox centres to the glassy carbon electrode. Their partial surface coverages can be controlled by varying the coupling agent or by controlling the substrate concentration during the solid-phase coupling process. Trifunctionalisation was also realised according to this methodology.

Circulating cytokine levels in prostate cancer patients undergoing radiation therapy: influence of neoadjuvant total androgen suppression.

BACKGROUND: The purpose of this study was to investigate the immunological impact of combining neoadjuvant total androgen suppression (TAS) with radiotherapy (xRT) in the treatment of prostate cancer by monitoring blood cytokine levels. PATIENTS AND METHODS: Participants were stage I-II prostate cancer patients receiving xRT alone (n=18) or TAS+xRT (n=19) under the procedures outlined in RTOG protocols #94-08 and #94-13. Peripheral blood samples were collected immediately prior to TAS (xRT+TAS group), immediately prior to xRT, 24 hours after initiation of xRT, and weekly during xRT. Samples were monitored for the immunoregulatory cytokines interleukin (IL)-1beta, IL-6 and transforming growth factor (TGF)beta using ELISA procedures. RESULTS: Following initiation of xRT, both patient groups demonstrated an immediate elevation of the proinflammatory cytokines IL-1beta and IL-6 in their plasma. These cytokine levels appeared to peak after 1-2 weeks of xRT before returning toward pre xRT levels. In contrast, the profibrotic cytokine TGFbeta appeared to decrease immediately following initiation of xRT, but, subsequently, underwent two distinct waves of elevation, occurring at 1-2 weeks and 5-6 weeks into the xRT. Surprisingly, while the temporal pattern of plasma cytokine response was similar in both treatment groups, the magnitude of cytokine expression was noticeably different, appearing to be significantly affected by the addition of TAS. Indeed, administration of neoadjuvant TAS appeared to bring about a marked elevation of IL-1beta and IL-6 and a significant reduction in TGFbeta when compared to patients receiving xRT alone. CONCLUSION: The precise mechanisms underlying this TAS-related increase of the proinflammatory cytokines IL-1beta and IL-6 and decrease of the profibrotic cytokine TGFbeta remain unclear. However, previous reports have documented that androgens tend to be immunosuppressive in nature. It is conceivable, therefore, that administration of TAS shifts the ratio of proinflammatory and profibrotic cytokines toward a more immunostimulatory state.

Radioprotection of murine gastrointestinal epithelium by interleukin-1alpha involves down-regulation of the apoptotic response.

BACKGROUND: Interleukin-1alpha (IL-1) is known to radioprotect the gastrointestinal tract, but the mechanism by which this protection occurs remains unclear. These studies were undertaken to investigate whether the radioprotective potential of IL-1 may be linked to an ability to reduce apoptosis within the gastrointestinal crypts. MATERIALS AND METHODS: IL-1 was administered to C57Bl/6 mice 24 hours prior to receiving 8 Gy abdominal X-irradiation (xRT). At designated times, experimental mice were sacrificed, jejunal tissue removed, and paraffin-embedded sections analyzed for apoptosis indices (AI) and immunohistochemical determination of active caspase-3, -8 and -9. RESULTS: AI data demonstrated that 8 Gy irradiation resulted in a marked jejunal apoptotic response, but IL-1 pretreatment significantly attenuated this response. Concomitant with this attenuation, reduced levels of caspase-3 and 9, but not caspase-8, activation were observed, particularly within goblet cells. CONCLUSION: The results outlined herein suggest that radioprotection by IL-1 is mediated, at least in part, through a reduction in the apoptotic response which appears to involve down-regulation of the intrinsic apoptotic pathway.