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OBJECTIVES: Nasal anaesthetic-decongestant sprays are commonly used prior to nasal instrumentation, such as flexible and rigid nasal endoscopy. Co-phenylcaine (lignocaine 5%, phenylephrine 0.5%, ENT Technologies Pty Ltd., Melbourne, VIC, Australia) is a combination spray commonly used for this purpose. However, lignocaine is less potent than other local anaesthetics, and both active constituents of Co-phenylcaine have a bitter taste. It was hypothesised that a combination spray containing tetracaine and oxymetazoline would both offer more potent topical anaesthesia and have a better taste. METHODS: Four anaesthetic-decongestant nasal sprays were tested in 10 healthy participants (Co-phenylcaine, and tetracaine 0.5%, 1% and 2% with oxymetazoline 0.05%). Sensory thresholds were sequentially measured at the head of the inferior turbinate using Semmes-Weinstein monofilaments over the following hour. Participants also rated taste on a Likert-style scale, and reported whether they experienced subjective numbness of the maxillary teeth. RESULTS: A median peak sensory threshold of 60 g (the maximum tested) was observed with Co-phenylcaine, but this threshold was exceeded by all the tetracaine-based sprays. Tetracaine 2% with oxymetazoline 0.05% had a significantly more rapid onset than Co-phenylcaine (4 min vs. 6 min, p < 0.05) and a longer duration of action. Eight participants reported dental numbness after administration of tetracaine 2% with oxymetazoline 0.05%, but only one participant after Co-phenylcaine. Tetracaine-based sprays were generally perceived to taste less unpleasant than Co-phenylcaine. CONCLUSION: Tetracaine 2% with oxymetazoline 0.05% is a more potent and rapidly acting anaesthetic-decongestant spray than Co-phenylcaine, with a longer duration of action.
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KEY POINTS: Novel topical therapeutics require extensive pre-clinical testing to assess efficacy and safety. Antibiofilm or immunosuppressant agents can utilize ex vivo models to measure ciliotoxicity. Agents that are found to be effective and non-toxic ex vivo warrant further investigation in vivo.
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Autoimmune inflammatory diseases, such as rheumatoid arthritis (RA) and ulcerative colitis, are associated with an uncontrolled production of cytokines leading to the pronounced inflammatory response of these disorders. Their therapy is currently focused on the inhibition of cytokine receptors, such as the Janus kinase (JAK) protein family. Tofacitinib and peficitinib are JAK inhibitors that have been recently approved to treat rheumatoid arthritis. In this study, an in-depth analysis was carried out through quantum biochemistry to understand the interactions involved in the complexes formed by JAK1 and tofacitinib or peficitinib. Computational analyses provided new insights into the binding mechanisms between tofacitinib or peficitinib and JAK1. The essential amino acid residues that support the complex are also identified and reported. Additionally, we report new interactions, such as van der Waals; hydrogen bonds; and alkyl, pi-alkyl, and pi-sulfur forces, that stabilize the complexes. The computational results revealed that peficitinib presents a similar affinity to JAK1 compared to tofacitinib based on their interaction energies.
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Adamantano/análogos & derivados , Janus Quinasa 1 , Niacinamida , Niacinamida/análogos & derivados , Piperidinas , Pirimidinas , Pirimidinas/química , Pirimidinas/farmacología , Piperidinas/química , Piperidinas/farmacología , Piperidinas/uso terapéutico , Niacinamida/química , Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 1/metabolismo , Janus Quinasa 1/química , Humanos , Teoría Cuántica , Enfermedades Autoinmunes/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Enlace de Hidrógeno , Inhibidores de las Cinasas Janus/química , Inhibidores de las Cinasas Janus/uso terapéutico , Inhibidores de las Cinasas Janus/farmacología , Adamantano/química , Pirroles/química , Pirroles/farmacología , Simulación del Acoplamiento MolecularRESUMEN
Polymyxin B and ethylenediaminetetraacetic acid are antimicrobials possessing antibiofilm activity. They act by displacement and chelation, respectively, of divalent cations in bacterial membranes and may therefore act synergistically when applied in combination. If so, this combination of agents may be useful for the treatment of diseases like cystic fibrosis (CF), in which biofilms are present on the respiratory epithelium. We used checkerboard assays to investigate the synergy between these agents using reference strains Pseudomonas aeruginosa ATCC 27853 and Staphylococcus aureus ATCC 6538 in planktonic form. We then determined the efficacy of each agent against biofilms of both species grown on 96-pin lids and proceeded to combination testing against the P. aeruginosa reference strain and 10 clinical isolates from patients with CF. Synergism was observed for planktonic forms of both species and for biofilms of P. aeruginosa. The susceptibility of biofilms of P. aeruginosa clinical isolates to these agents was variable compared to the laboratory reference strain. This combination of agents may be useful in the management of biofilm-associated conditions, particularly those amenable to topical therapies. These results provide a basis upon which the antimicrobial and antibiofilm efficacy of preparations containing these agents may be enhanced.IMPORTANCEBacteria living in biofilms produce a protective matrix which makes them difficult to kill. Patients with severe respiratory disease often have biofilms. Polymyxin B is an antibiotic commonly used in topical medications, such as eye drops and nasal sprays. Ethylenediaminetetraacetic acid (EDTA) is used widely as a preservative in medication but also has antimicrobial properties. It has been hypothesized that Polymyxin B and EDTA could have a synergistic relationship: when used in combination their antimicrobial effect is enhanced. Here, we evaluated the levels at which Polymyxin B and EDTA work together to kill common pathogens Pseudomonas aeruginosa and Staphylococcus aureus. We found that Polymyxin B and EDTA were synergistic. This synergy may be useful in the management of planktonic infection with P. aeruginosa and S. aureus, or biofilm infection with P. aeruginosa. This synergy may be beneficial in the treatment of respiratory biofilms, in which P. aeruginosa biofilms are common.
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Antiinfecciosos , Fibrosis Quística , Infecciones por Pseudomonas , Infecciones Estafilocócicas , Humanos , Polimixina B/uso terapéutico , Ácido Edético , Pseudomonas aeruginosa , Staphylococcus aureus , Antibacterianos/uso terapéutico , Antiinfecciosos/uso terapéutico , Biopelículas , Fibrosis Quística/microbiología , Pruebas de Sensibilidad MicrobianaRESUMEN
COVID-19 has highlighted the urgent need for new therapeutic agents to combat the spread of the virus. The main protease of SARS-CoV-2 (Mpro) has emerged as a promising target. In this study, we conducted an in silico investigation to explore the potential of Komaroviquinone, an icetexane diterpene, as a therapeutic agent against COVID-19. We employed molecular docking, molecular dynamics, and QM/MM methodologies to compare the binding affinity, molecular interactions, and stability of Komaroviquinone and the FDA-approved antiviral drug Nirmatrelvir with the SARS-CoV-2 Mpro protein. The study demonstrated that Komaroviquinone exhibits strong interaction with Mpro, with a binding energy comparable to Nirmatrelvir. The ADMET analysis revealed that Barbatusol, Brussonol, and Komaroviquinone possess superior solubility, permeability, and intestinal absorption compared to Nirmatrelvir, as well as more favorable distribution properties and lower toxicity profiles. Notably, Nirmatrelvir displayed toxicity and hepatotoxicity, which were not present in the natural compounds. Thus, it is suggested that Komaroviquinone may be a promising candidate for the development of effective and safer therapeutic agents against COVID-19. Experimental validation is necessary to confirm its potential as a treatment for the disease.
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COVID-19 , Diterpenos , Humanos , Simulación del Acoplamiento Molecular , SARS-CoV-2 , Antivirales/farmacología , Lactamas , Leucina , Nitrilos , Inhibidores de Proteasas/farmacología , Simulación de Dinámica MolecularRESUMEN
Glitches, spin-up events in neutron stars, are of prime interest, as they reveal properties of nuclear matter at subnuclear densities. We numerically investigate the glitch mechanism due to vortex unpinning using analogies between neutron stars and dipolar supersolids. We explore the vortex and crystal dynamics during a glitch and its dependence on the supersolid quality, providing a tool to study glitches from different radial depths of a neutron star. Benchmarking our theory against neutron-star observations, our work will open a new avenue for the quantum simulation of stellar objects from Earth.
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OBJECTIVES: Bacterial biofilms on the sinonasal mucosa, especially biofilms of Staphylococcus aureus, are associated with greater severity and recalcitrance of chronic rhinosinusitis (CRS). There are few, if any, antibiofilm agents suitable for sinonasal application available for the management of this problem. Nasodine® Nasal Spray (Nasodine) is a 0.5% povidone-iodine-based formulation that has been developed for sinonasal application. We investigated the antibiofilm efficacy of Nasodine to determine whether it may be a candidate for the treatment of biofilm-associated CRS. METHODS: Biofilms of S. aureus ATCC 6538 were grown in vitro using the Centers for Disease Control biofilm reactor. Intact biofilms were treated by immersion in 0.9% saline (control), half concentration Nasodine, or full concentration Nasodine for between 5 min and 6 h. Further biofilm cells were dispersed into suspension then treated for between 30 s and 5 min. Surviving bacteria were then enumerated by culture and counting colonies, and the log10 reduction in viable bacteria was compared with control. RESULTS: Nasodine demonstrated time and concentration-dependent bacterial killing against intact biofilm. Statistically significant reductions in viable bacteria from intact biofilms were seen with exposures as brief as 5 min. Nasodine consistently eradicated dispersed biofilm within 1 min. CONCLUSION: Nasodine is highly active against biofilms of S. aureus ATCC 6538 in vitro. Biofilm killing is impeded by the presence of the intact biofilm structure. LAY SUMMARY: In chronic rhinosinusitis (CRS), bacterial communities called biofilms are associated with more severe inflammation. An iodine-based nasal spray called Nasodine almost completely eradicates bacterial biofilms after 6 h of exposure. Nasodine may be useful for treating CRS. Laryngoscope, 133:2490-2495, 2023.
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Rinitis , Sinusitis , Humanos , Staphylococcus aureus , Rociadores Nasales , Sinusitis/complicaciones , Biopelículas , Povidona Yodada/farmacología , Enfermedad Crónica , Rinitis/complicacionesRESUMEN
The role of bacterial biofilms in chronic and recalcitrant diseases is widely appreciated, and the treatment of biofilm infection is an increasingly important area of research. Chronic rhinosinusitis (CRS) is a complex disease associated with sinonasal dysbiosis and the presence of bacterial biofilms. While most biofilm-related diseases are associated with highly persistent but relatively less severe inflammation, the presence of biofilms in CRS is associated with greater severity of inflammation and recalcitrance despite appropriate treatment. Oral antibiotics are commonly used to treat CRS but they are often ineffective, due to poor penetration of the sinonasal mucosa and the inherently antibiotic resistant nature of bacteria in biofilms. Topical non-antibiotic antibiofilm agents may prove more effective, but few such agents are available for sinonasal application. We review compounds with antibiofilm activity that may be useful for treating biofilm-associated CRS, including halogen-based compounds, quaternary ammonium compounds and derivatives, biguanides, antimicrobial peptides, chelating agents and natural products. These include preparations that are currently available and those still in development. For each compound, antibiofilm efficacy, mechanism of action, and toxicity as it relates to sinonasal application are summarised. We highlight the antibiofilm agents that we believe hold the greatest promise for the treatment of biofilm-associated CRS in order to inform future research on the management of this difficult condition.
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Cancer is a group of diseases involving disordered growth of abnormal cells with the potential to invade and spread to other parts of the body. Today, immunotherapy is the most efficient treatment, with fewer side effects. Notably, the employment of monoclonal antibodies to inhibit checkpoint proteins, such as CTLA-4, has caused much excitement among cancer immunotherapy researchers. Thus, in-depth analysis through quantum biochemistry and molecular dynamics simulations was performed to understand the complex formed by ipilimumab and its target CTLA-4. Our computational results provide a better understanding of the binding mechanisms and new insights about the CTLA-4: ipilimumab interaction, identifying essential amino acid residues to support the complex. Additionally, we report new interactions such as aromatic-aromatic, aromatic-sulfur, and cation-pi interactions to stabilize the CTLA-4:ipilimumab complex. Finally, quantum biochemistry analyses reveal the most important amino acid residues involved in the CTLA-4:ipilimumab interface, which were used to design synthetic peptides to inhibit CTLA-4. The computational results presented here provide a better understanding of the CTLA-4:ipilimumab binding mechanisms, and can support the development of alternative antibody-based drugs with high relevance in cancer immunotherapy.
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Antineoplásicos/uso terapéutico , Antígeno CTLA-4/inmunología , Diseño de Fármacos , Inmunoterapia , Ipilimumab/uso terapéutico , Neoplasias/inmunología , Neoplasias/terapia , Péptidos/uso terapéutico , Antígeno CTLA-4/química , Electricidad , Humanos , Ipilimumab/química , Simulación de Dinámica Molecular , Péptidos/química , Unión Proteica , Proteolisis , TermodinámicaRESUMEN
CONTEXT.: In the early 1900s, it was common practice to retain, prepare, and display instructive pathologic specimens to teach pathology to medical trainees and practitioners; these collections were called medical museums. Maude Abbott, MD, established her reputation by developing expertise in all aspects of medical museum work. She was a founder of the International Association of Medical Museums (later renamed the International Academy of Pathology) and became an internationally renowned expert on congenital heart disease. Her involvement in the Canadian Medical War Museum (CMWM) is less well known. OBJECTIVE.: To explore Abbott's role in the development of the CMWM during and after World War I and to trace its history. DESIGN.: Available primary and secondary historical sources were reviewed. RESULTS.: Instructive pathologic specimens derived from Canadian soldiers dying during World War I were shipped to the Royal College of Surgeons in London, which served as a clearinghouse for museum specimens from Dominion forces. The Canadian specimens were repatriated to Canada, prepared by Abbott, and displayed at several medical meetings. Abbott, because she was a woman, could not enlist and so she reported to a series of enlisted physicians with no expertise in museology. Plans for a permanent CMWM building in Ottawa eventually failed and Abbott maintained the collection at McGill (Montreal, Quebec, Canada) until her death in 1940. We trace the CMWM after her death. CONCLUSIONS.: Sadly, after Abbott had meticulously prepared these precious teaching specimens so that their previous owners' ultimate sacrifice would continue to help their military brethren, the relics were bureaucratically lost.
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Museos/historia , Patología/historia , Médicos Mujeres/historia , Canadá , Historia del Siglo XIX , Historia del Siglo XX , Humanos , Primera Guerra MundialRESUMEN
OBJECTIVE One of the greatest challenges of pediatric neurosurgery training is balancing the training needs of the trainee against patient safety and parental expectation. The traditional "see one, do one, teach one" approach to training is no longer acceptable in pediatric neurosurgery. The authors have developed the baby Modeled Anatomical Replica for Training Young Neurosurgeons (babyMARTYN). The development of this new training model is described, its feasibility as a training tool is tested, and a new approach of integrating simulation into day-to-day training is suggested. METHODS In part 1 (development), a prototype skull was developed using novel model-making methods. In part 2 (validation), 18 trainee neurosurgeons (at various stages in training) performed the following 4 different procedures: 1) evacuation of a posterior fossa hematoma; 2) pterional craniotomy; 3) tapping of the fontanelle to obtain a CSF specimen; and 4) external ventricular drain insertion. Completion of the procedural stages (scored using a curriculum-based checklist) was used to test the feasibility of babyMARTYN as a training tool. Likert scale-based questionnaires were used to assess the model for face and content validity. Training benefit was assessed using pre- and posttraining ratings on the Physician Performance Diagnostic Inventory Scale (PPDIS). To determine the significance of improvement in median PPDIS score, the Wilcoxon matched-pairs signed-rank test was performed. RESULTS In part 1 (development), the model was successfully developed with good fidelity. In part 2 (validation), the validation data demonstrated feasibility, face, and content validity. The PPDIS score significantly increased for all groups after babyMARTYN training, thereby indicating a potential future role for babyMARTYN in the training of pediatric neurosurgeons. CONCLUSIONS This recent collaborative neurosurgical development by the Royal College of Surgeons of England is designed to supplement current neurosurgical training. High-fidelity, portable, operation-specific models enable preoperative planning and have the potential to be used in an operating room environment prior to novel operations. A "see one, simulate one, do one" approach for pediatric neurosurgical training using babyMARTYN is suggested.
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Educación de Postgrado en Medicina/métodos , Modelos Anatómicos , Procedimientos Neuroquirúrgicos/educación , Pediatras/educación , Médicos , Humanos , Lactante , Masculino , Procedimientos Neuroquirúrgicos/métodos , Análisis de RegresiónRESUMEN
INTRODUCTION: The Modelled Anatomical Replica for Training Young Neurosurgeons (MARTYN) is a novel simulation model developed by the Royal College of Surgeons England (RCSEng). This study describes the development of the model and aims to determine its feasibility as a potential future training tool. METHODS AND MATERIALS: Traditional model-making methods were used to develop a prototype. Initial procedural trials tested the feasibility of the model. Eighteen participants, grouped by experience (nine novices, four intermediates and five experienced), completed two tasks: a craniotomy and a burr hole followed by insertion of an external ventricular drain (EVD). Subjective data on confidence, usefulness, realism and preference to other training modalities were collected via a standardised questionnaire and a 5-point Likert scale. RESULTS: Preliminary trials of the model prototype demonstrated feasibility. The novice group had the greatest self-reported benefit from MARTYN training, with significant increases in self-rated confidence in both the craniotomy (p < 0.01) and EVD insertion (p < 0.05) procedures. MARTYN was reported to having good visual and tactile realism overall with the bone component being considered highly realistic. The model was reported to be a useful training tool. When asked to rank preferred training modalities, operative experience was chosen first with cadaveric training and MARTYN consistently scoring a second choice. CONCLUSIONS: MARTYN was developed with the intention to fill the current niche for an inexpensive synthetic model head. This study shows that the use of MARTYN for training is both feasible and realistic. We demonstrate a preliminary face and construct validity of the model in this pilot study. With the reduction in working hours, we believe this model will be a suitable supplement to the current ST 1-3 level cadaveric training and will have a positive impact on patient safety.
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Modelos Anatómicos , Neurocirugia/educación , Humanos , Estudios de Validación como AsuntoRESUMEN
Microalgae have the ability to grow rapidly, synthesize and accumulate large amounts (approximately 20-50% of dry weight) of lipids. A successful and economically viable algae based oil industry will depend on the selection of appropriate microalgal strains and the selection of the most suitable lipid extraction method. In this paper, five extraction methods were evaluated regarding the extraction of lipids from Chlorella vulgaris: Bligh and Dyer, Chen, Folch, Hara and Radin, and Soxhlet. Furthermore, the addition of silica powder was studied to evaluate the introduction of more shear stress to the system as to increase the disruption of cell walls. Among the studied methods, the Bligh and Dyer method assisted by ultrasound resulted in the highest extraction of oil from C. vulgaris (52.5% w/w). Addition of powder silica did not improve the extraction of oil.
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Fraccionamiento Químico/métodos , Chlorella vulgaris/química , Lípidos/aislamiento & purificación , Microalgas/química , Ultrasonido/métodos , Dióxido de Silicio/químicaRESUMEN
Accurate surface anatomy is essential for safe clinical practice. Numerous inconsistencies in clinically important surface markings exist between and within anatomical reference texts. The aim of this study was to investigate key thoracic surface anatomical landmarks in vivo using computed tomographic (CT) imaging. High-resolution thoracic CT scans from 153 supine adults (mean age 63, range 19-89 years; 53% female) taken at end tidal inspiration were analyzed by dual consensus reporting to determine the surface anatomy of the sternal angle, central veins, heart, lungs, and diaphragm. Patients with kyphosis/scoliosis, distorting space-occupying lesions, or visceromegaly were excluded. The position of the cardiac apex, formation of the brachiocephalic veins, and vertebral levels of the sternal angle, xiphisternal joint, and aortic hiatus were consistent with commonly accepted surface markings although there was a wide range of normal variation. In contrast, common surface markings were markedly inaccurate for the following: the position of the tracheal bifurcation, aortic arch, and azygos vein termination (below the plane of the sternal angle at T5-T6 vertebral level in most individuals); the superior vena cava/right atrial junction (most often behind the fourth costal cartilage); the lower border of the lung (adjacent to T12 vertebra posteriorly); and the level at which the inferior vena cava and esophagus traverse the diaphragm (T11 in most). Surface anatomy must be reappraised using modern imaging in vivo if it is to be evidence based and fit for purpose. The effects of gender, age, posture, respiration, build, and ethnicity also deserve greater emphasis.
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Anatomía/educación , Educación Médica , Tórax/anatomía & histología , Adulto , Anciano , Anciano de 80 o más Años , Anatomía/normas , Medicina Basada en la Evidencia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Radiografía Torácica/métodos , Radiografía Torácica/normas , Reproducibilidad de los Resultados , Libros de Texto como Asunto , Tomografía Computarizada por Rayos X/métodos , Adulto JovenRESUMEN
Accurate surface anatomy is a key component of safe clinical practice. But how consistent are modern clinical and surface anatomy texts in their reporting of common surface anatomy landmarks? Thirteen popular texts in common use were analyzed in detail: one clinical and anatomical reference text; seven clinical anatomy texts; two surface anatomy texts; and three clinical examination texts. Content relating to surface anatomy was reviewed, summarized, and assessed for consistency. Four main findings emerged: (i) there are numerous inconsistencies in clinically important surface markings (e.g., the femoral artery in the groin, superficial and deep inguinal rings, and accessory nerve in the posterior triangle), including inconsistencies within some texts; (ii) there is a consensus on many surface markings, e.g., the spleen and termination of the spinal cord; (iii) few texts address variation in surface anatomy related to age, sex, body mass, posture, respiration, and ethnicity; and (iv) the three standard clinical examination texts included in this review contain comparatively little surface anatomy. Seven surface anatomy landmarks were redefined within an evidence-based framework: termination of the spinal cord, supracristal plane, base of the appendix, renal length, the deep inguinal ring, the femoral artery in the groin, and the accessory nerve in the posterior triangle of the neck. An evidence-based framework is essential if surface anatomy is to be accurate and clinically relevant.
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Anatomía/educación , Libros de Texto como Asunto/normas , Educación Médica/normas , Medicina Basada en la Evidencia , Humanos , Ilustración MédicaRESUMEN
Interleukin-6 (IL6) is an important pleiotropic cytokine that is regulated at the transcriptional level. To date, most work on its regulation has focused on a 1.2kb region 5' from the start of transcription, similar to published reports on other cytokine genes. This report demonstrates for the first time that a cytokine gene can be regulated by cis-acting regions much further upstream than previously examined. Comparative genomic analysis showed that a 120 kb region contains blocks of sequence conservation between human and rodent genomes, and that a 15 kb region proximal to the start of transcription contains 10 highly homologous sequence blocks of between 100 and 250 bp. By means of a reporter gene assay, a novel transcriptionally active region located between -5307 and -5202 bp upstream from the start of transcription was identified. Electrophoretic mobility shift assays showed nuclear protein(s) binding to this region, thus raising the possibility that the regulatory activity shown by the reporter gene constructs may be mediated by these proteins. These results suggest that the regulation of IL6 expression involves a much larger upstream region than previously examined and the control of IL6 transcription is likely to be regulated by a complex mechanism of modular cis-regulatory elements.
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Regulación de la Expresión Génica/fisiología , Interleucina-6/genética , Regiones Promotoras Genéticas/genética , Animales , Humanos , Interleucina-6/biosíntesis , Ratones , Polimorfismo Genético , Ratas , Transcripción Genética/fisiologíaRESUMEN
Patients with systemic juvenile idiopathic arthritis (sJIA) have a characteristic daily spiking fever and elevated levels of inflammatory cytokines. Members of the interleukin-1 (IL-1) gene family have been implicated in various inflammatory and autoimmune diseases, and treatment with the IL-1 receptor antagonist, Anakinra, shows remarkable improvement in some patients. This work describes the most comprehensive investigation to date of the involvement of the IL-1 gene family in sJIA. A two-stage case-control association study was performed to investigate the two clusters of IL-1 family genes using a tagging single nucleotide polymorphism (SNP) approach. Genotyping data of 130 sJIA patients and 151 controls from stage 1 highlighted eight SNPs in the IL1 ligand cluster region and two SNPs in the IL1 receptor cluster region as showing a significant frequency difference between the populations. These 10 SNPs were typed in an additional 105 sJIA patients and 184 controls in stage 2. Meta-analysis of the genotypes from both stages showed that three IL1 ligand cluster SNPs (rs6712572, rs2071374 and rs1688075) and one IL1 receptor cluster SNP (rs12712122) show evidence of significant association with sJIA. These results indicate that there may be aberrant control of the activity of the IL-1 family in sJIA patients causing the increased susceptibility to the disease.
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Artritis Juvenil/genética , Genes , Predisposición Genética a la Enfermedad , Variación Genética , Interleucina-1/genética , Receptores de Interleucina-1/genética , Adolescente , Adulto , Alelos , Estudios de Casos y Controles , Cromosomas Humanos Par 2 , Estudios de Cohortes , Frecuencia de los Genes , Genotipo , Haplotipos , Humanos , Desequilibrio de Ligamiento , Familia de Multigenes , Polimorfismo de Nucleótido SimpleRESUMEN
Hyperactivation of Cdc2 in fission yeast causes cells to undergo a lethal premature mitosis, a phenomenon called mitotic catastrophe. This phenotype is observed in cdc2-3w wee1-50 cells at high temperature and is suppressed by a single recessive mutant, mcs3-12. Mcs3 acts independently of the Wee1 kinase and Cdc25 phosphatase, two major regulators of Cdc2. We have isolated multicopy suppressors of the cell cycle arrest phenotype of mcs3-12 wee1-50 cdc25-22 cells, but did not identify the mcs3 gene itself. Instead several known mitotic regulators were isolated, including the Cdc25 phosphatase, Wis2 cyclophilin, Cek1 kinase, and an Hsp90 homologue, Swo1. We also isolated clones encoding non-functional, truncated forms of the Wee1 kinase and Dis2 type 1 phosphatase. In addition we identified a multicopy suppressor that encodes a structural homologue of the budding yeast SPO12 gene. We find that overexpression of fission yeast spo12 not only suppresses the phenotype of the mcs3-12 wee1-50 cdc25-22 strain, but also that of a win1-1 wee1-50 cdc25-22 strain at high temperature, indicating that the function of spo12 is not directly related to mcs3. We show that spo12 mRNA is periodically expressed during the fission yeast cell cycle, peaking at the G2/M transition coincidently with cdc15. Deletion of spo12, however, has no overt effect on either the mitotic or meiotic cell cycles, except when the function of the major B type cyclin, Cdc13, is compromised.
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Proteínas de Ciclo Celular/genética , Proteínas Fúngicas/genética , Genes Supresores , Proteína Quinasa 3 Activada por Mitógenos , Mitosis/genética , Proteínas Nucleares , Proteínas de Saccharomyces cerevisiae , Proteínas de Schizosaccharomyces pombe , Schizosaccharomyces/genética , Alelos , Secuencia de Aminoácidos , Proteína Quinasa CDC2/metabolismo , Ciclina B/genética , Elementos Transponibles de ADN , Eliminación de Gen , Proteínas HSP90 de Choque Térmico/genética , Proteínas Quinasas Activadas por Mitógenos/genética , Modelos Genéticos , Datos de Secuencia Molecular , Mutación , Fenotipo , Fosfoproteínas Fosfatasas/genética , Plásmidos/metabolismo , Proteína Fosfatasa 1 , Proteínas Tirosina Quinasas/genética , ARN Mensajero/metabolismo , Homología de Secuencia de Aminoácido , Supresión Genética , Temperatura , Factores de TiempoRESUMEN
The combination of ampicillin with á-lactamase inhibitor, sulbactam, was evaluated in patients requiring empirical therapy for mixed aerobic/anaerobic infections. One patient exhibited an adverse drug reaction in response to a test dose and was not included in the study. Sixteen patients received ampicillin/sulbactam as the sole antimicrobial therapy. Three patients with abdominal symptoms received ampicillin/sulbactam at a dose of 1.5 gq6h, for five days. The remaining 13 patients presented with foot infections and received ampicillin/sulbactam at the same dose, for a mean of 7.8 days (range 3-14 days). The mean age of patients with foot infections was 73 years (range 57-94) and diabetes mellitus was an underlying condition in six (46 percent). Treatment was successful in 14 patients (88 percent). Ampicillin/sulbactam was well tolerated and no major adverse drug reactions were tolerated. Sensitivity tests were performed on isolated of Staphylococcus aureus and Gram-negative enteric bacilli (coliforms). All 24 isolates of S.aureus were penicillinase producers, but were sensitive to cloxacillin, erythromycin, cefadroxil and ampicillin/sulbactam. Of the coliform isolates, 126/321 (39.25 percent) were sensitive to ampicillin, while 290 (90.3 percent) were sensitive to ampicillin/sulbactam. We conclude that ampicillin/sulbactam may be a suitable agent for empirical therapy of infection in surgical patients, particularly those likely to have polymicrobial infections (AU)