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BACKGROUND: The purpose of this study is to analyze the long-term evolution of patients with small choroidal melanocytic tumors (SCMTs) undergoing observation, and to assess their rate of transformation into melanomas and survival. METHODS: A retrospective single-cohort study of patients with SCMTs (1-3 mm in height and 5-10 mm in base) diagnosed from January 1992 to February 2023 was carried out, with observation as the initial treatment. The main criterion for a transformation into melanoma is considered to be an increase in size of more than 1 mm in height and/or more than 1 mm in base measured on an ultrasound/retinography, recorded in two consecutive visits separated by one to three months. RESULTS: 243 patients were included with a mean age of 65.3 years and a mean follow-up of 7.9 years (6 months-27.9 years); 27 patients showed tumor growth. The probabilities of growth at 5, 10, and 15 years are 10%, 14%, and 17%, respectively. Regarding survival, 22 patients died and only 3 deaths were due to melanoma metastasis. Survival rates at 5 and 10 years are 99% and 97%. CONCLUSIONS: Observation is a viable therapeutic option for SCMTs, avoiding the side effects of treatment, considering the majority of these tumors do not progress to melanoma. With close monitoring, patients can be treated promptly upon detecting a transformation. Additionally, the findings confirm that small melanocytic tumors can lead to metastatic disease, albeit at a low rate.
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Meckel's cave tumour, a rare benign tumour originating from the Schwann cells surrounding the trigeminal nerve within the Meckel's cave region, can present with a variety of clinical manifestations. We report a case of a 44-year-old male patient who presented with symptoms of tear deficiency, including dryness, ocular discomfort, and blurred vision. Diagnostic evaluation revealed the presence of a Meckel's cave tumour harming the trigeminal nerve, leading to alacrimia. This case highlights the association between Meckel's cave tumour and tear deficiency disorders.
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This work focuses on the δ receptor (DOR), a G protein-coupled receptor (GPCR) belonging to the opioid receptor group. DOR is expressed in numerous tissues, particularly within the nervous system. Our study explores computationally the receptor's interactions with various ligands, including opiates and opioid peptides. It elucidates how these interactions influence the δ receptor response, relevant in a wide range of health and pathological processes. Thus, our investigation aims to explore the significance of DOR as an incoming drug target for pain relief and neurodegenerative diseases and as a source for novel opioid non-narcotic analgesic alternatives. We analyze the receptor's structural properties and interactions using Molecular Dynamics (MD) simulations and Gaussian-accelerated MD across different functional states. To thoroughly assess the primary differences in the structural and conformational ensembles across our different simulated systems, we initiated our study with 1 µs of conventional Molecular Dynamics. The strategy was chosen to encompass the full activation cycle of GPCRs, as activation processes typically occur within this microsecond range. Following the cMD, we extended our study with an additional 100 ns of Gaussian accelerated Molecular Dynamics (GaMD) to enhance the sampling of conformational states. This simulation approach allowed us to capture a comprehensive range of dynamic interactions and conformational changes that are crucial for GPCR activation as influenced by different ligands. Our study includes comparing agonist and antagonist complexes to uncover the collective patterns of their functional states, regarding activation, blocking, and inactivation of DOR, starting from experimental data. In addition, we also explored interactions between agonist and antagonist molecules from opiate and opioid classifications to establish robust structure-activity relationships. These interactions have been systematically quantified using a Quantitative Structure-Activity Relationships (QSAR) model. This research significantly contributes to our understanding of this significant pharmacological target, which is emerging as an attractive subject for drug development.
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Simulación de Dinámica Molecular , Receptores Opioides delta , Receptores Opioides delta/metabolismo , Receptores Opioides delta/química , Humanos , Ligandos , Analgésicos Opioides/farmacología , Analgésicos Opioides/química , Unión Proteica , Conformación ProteicaRESUMEN
OBJECTIVES: This study aimed to evaluate the effectiveness of dalbavancin as sequential therapy in patients with infective endocarditis (IE) due to gram positive bacteria (GPB) in a real-life heterogenous cohort with comorbid patients. METHODS: A single center retrospective cohort study including all patients with definite IE treated with dalbavancin between January 2017 and February 2022 was developed. A 6-month follow-up was performed. The main outcomes were clinical cure rate, clinical and microbiological relapse, 6-month mortality, and adverse effects (AEs) rate. RESULTS: The study included 61 IE episodes. The median age was 78.5 years (interquartile range [IQR] 63.2-85.2), 78.7% were male, with a median Charlson comorbidity index of 7 (IQR 4-9) points. Overall, 49.2% suffered native valve IE. The most common microorganism was Staphylococcus aureus (26.3%) followed by Enterococcus faecalis (21.3%). The median duration of initial antimicrobial therapy and dalbavancin therapy were 27 (IQR 20-34) and 14 days (IQR 14-28) respectively. The total reduction of hospitalization was 1090 days. The most frequent dosage was 1500mg of dalbavancin every 14 days (96.7%). An AE was detected in 8.2% of patients, only one (1.6%) was attributed to dalbavancin (infusion reaction). Clinical cure was achieved in 86.9% of patients. One patient (1.6%) with Enterococcus faecalis IE suffered relapse. The 6-month mortality was 11.5%, with only one IE-related death (1.6%). CONCLUSION: This study shows a high efficacy of dalbavancin in a heterogeneous real-world cohort of IE patients, with an excellent safety profile. Dalbavancin allowed a substantial reduction of in-hospital length of stay.
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Infectious diseases account for about 3 million deaths per year. The advent of molecular techniques has led to an enormous improvement in their diagnosis, both in terms of sensitivity and specificity and in terms of the speed with which a clinically useful result can be obtained. Digital PCR, or 3rd generation PCR, is based on a series of technical modifications that result in more sensitive techniques, more resistant to the action of inhibitors and capable of direct quantification without the need for standard curves. This review presents the main applications that have been developed for the diagnosis of viral, bacterial, and parasitic infections and the potential prospects for the clinical use of this technology.
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Allosteric modulation plays a critical role in enzyme functionality and requires a deep understanding of the interactions between the active and allosteric sites. γ-Secretase (GS) is a key therapeutic target in the treatment of Alzheimer's disease (AD), through its role in the synthesis of amyloid ß peptides that accumulate in AD patients. This study explores the structure and dynamic effects of GS modulation by E2012 binding, employing well-tempered metadynamics and conventional molecular dynamics simulations across three binding scenarios: (1) GS enzyme with and without L458 inhibitor, (2) the GS-substrate complex together with the modulator E2012 in two different binding modes, and (3) E2012 interacting with a C99 substrate fragment. Our findings reveal that the presence of L458 induces conformational changes that contribute to stabilization of the GS enzyme dynamics, previously reported as a key factor that allowed the resolution of the cryo-EM structure and the enhanced binding of E2012. Furthermore, we identified the most favorable binding site for E2012 within the GS-substrate complex, uncovering significant modulatory effects and a complex network of interactions that influence the position of the substrate for catalysis. In addition, we explore a potential substrate-modulator binding before the formation of the enzyme-substrate complex. The insights gained from our study emphasize the importance of these interactions in the development of potential therapeutic interventions that target the functionality of the GS enzyme in AD.
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Alanina/análogos & derivados , Secretasas de la Proteína Precursora del Amiloide , Simulación de Dinámica Molecular , Unión Proteica , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Secretasas de la Proteína Precursora del Amiloide/química , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Especificidad por Sustrato , Humanos , Conformación Proteica , Regulación Alostérica/efectos de los fármacos , AzepinasRESUMEN
Background: The aim of this study was to evaluate patients' knowledge and perceptions of the use of systemic antibiotics in the treatment of endodontic infections and to determine the possible contribution of patients to the development of bacterial resistance. Methods: A total of 550 patients were asked to respond to a survey on the perception of systemic antibiotic use in the treatment of endodontic infections and antibiotic resistance during January 2022 and March 2023. A bivariate and multivariate analysis was performed to determine possible correlates in the population regarding antibiotic use in the endodontic world. Results: A total of 514 patients were included in the study, 65.9% of whom were women. While 34.6% of the population studied thought that it was always necessary to take antibiotics prior to endodontics, 49.4% considered that they were necessary after endodontics, regardless of the clinical symptoms. The prevalence of self-medication was 17.3%, and women self-medicate more than men, with significant differences (p < 0.05), although they have a greater knowledge of antibiotic resistance than men (p < 0.05). Forty-four percent of the population expected to take antibiotics when faced with dental pain, mainly women (p < 0.05). Conclusions: The general population is contributing to the serious problem of bacterial resistance. It is necessary to promote educational strategies focused on the correct use of antibiotics in the community. The worst results were found mainly in the population with a low level of education. The level of education was the variable that most influenced the knowledge and attitudes of the population, followed by the sex of the participants.
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Resumen La sífilis es una de las infecciones de transmisión sexual con mayor incidencia en la Argentina. Para su diagnóstico, el Ministerio de Salud de la Nación avala distintos algoritmos, entre ellos, el algoritmo tradicional y el reverso. En el algoritmo tradicional, la VDRL constituye la prueba de screening y los resultados positivos se confirman con la prueba treponémica de aglutinación de partículas (TPPA). El algoritmo reverso con un test rápido, avalado más recientemente, consiste en la realización de un test rápido treponémico como screening y posterior VDRL en las muestras que resulten positivas. Se realizó una comparación entre ambos algoritmos para evaluar si era factible y conveniente la implementación del algoritmo reverso con un test rápido en el laboratorio del H.I.G.A. Dr. Oscar Alende. El objetivo fue determinar la concordancia entre el algoritmo tradicional, utilizado actualmente en la institución (VDRL seguido por TPPA), y el nuevo algoritmo propuesto (test rápido treponémico Alere Determine Syphilis TP seguido por VDRL-USR). Para ello se realizó un estudio prospectivo de desempeño de métodos cualitativos. Se realizó VDRL-USR, TPPA y test rápido Alere Determine Syphilis TP en muestras de 580 pacientes, de los cuales 558 cumplieron con los criterios de inclusión. Se obtuvieron 51 muestras con resultados positivos y 507 con resultados negativos para el diagnóstico de sífilis por ambos algoritmos, con un porcentaje de concordancia global del 100%, lo cual indica que podría reemplazarse el algoritmo tradicional por el reverso en aquellas situaciones que lo requieran en la población estudiada.
Abstract Syphilis is one of the sexually transmitted infections with the highest incidence in Argentina. For its diagnosis, the Ministry of Health of the Nation endorses different algorithms, among them, the traditional algorithm and the reverse. In the traditional algorithm, VDRL constitutes the screening test and positive results are confirmed with particle agglutination assay TPPA. The reverse algorithm with rapid test, endorsed more recently, consists of performing a rapid treponemal test as screening and subsequent VDRL in the samples that are positive. A comparison was made between both algorithms to evaluate if the implementation of the reverse algorithm with rapid test in Dr. Oscar Alende Hospital would be feasible and convenient. The objective of this work was to determine the concordance between the traditional algorithm, currently used in the institution (VDRL followed by TPPA), and the new algorithm proposed (rapid treponemal test Alere Determine Syphilis TP followed by VDRL-USR). For that purpose, a prospective study of the performance of qualitative methods was carried out. VDRL-USR, TPPA and Alere Determine Syphilis TP Rapid Test were performed on samples from 580 patients, of which 558 met the inclusion criteria. A total of 51 samples with positive results and 507 with negative results for the diagnosis of syphilis were obtained by both algorithms, with an overall concordance percentage of 100%, which indicates that the traditional algorithm could be replaced by the reverse in those situations that require it in the studied population.
Resumo A sífilis é uma das infecções sexualmente transmissíveis com maior incidência na Argentina. Para o seu diagnóstico, o Ministério da Saúde da Nação endossa diversos algoritmos, incluindo o algoritmo tradicional e o reverso. No algoritmo tradicional, o VDRL constitui o teste de triagem e os resultados positivos são confirmados com o teste treponêmico de aglutinação de partículas (TPPA). O algoritmo reverso com teste rápido, endossado mais recentemente, consiste na realização de um teste rápido treponêmico como triagem e posterior VDRL nas amostras positivas. Foi feita uma comparação entre os dois algoritmos para avaliar se a implementação do algoritmo reverso com um teste rápido no laboratório H.I.G.A. Dr. Óscar Alende era viável e conveniente. O objetivo foi determinar a concordância entre o algoritmo tradicional, atualmente utilizado na instituição (VDRL seguido de TPPA), e o novo algoritmo proposto (teste rápido treponêmico Alere Determine Syphilis TP seguido de VDRL-USR). Para tanto, foi realizado um estudo prospectivo de desempenho de métodos qualitativos. O VDRL- -USR, o TPPA e o teste rápido Alere Determine Syphilis TP foram realizados em amostras de 580 pacientes, dos quais 558 preencheram os critérios de inclusão. Foram obtidas 51 amostras com resultados positivos e 507 com resultados negativos para o diagnóstico de sífilis por ambos os algoritmos, com um percentual de concordância global de 100%, o que indica que o algoritmo tradicional poderia ser substituído pelo reverso nas situações que o exigissem na população estudada.
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BACKGROUND: Liposuction is considered one of the most common procedures in plastic surgery. However, major postoperative complications such as visceral injury, fluid overload, and necrotizing fasciitis still occur. Likewise, minor complications such as ecchymosis, seromas, infections, and contour irregularities that do not threaten the life of the patient do generate significant dissatisfaction. Current evidence regarding the management of fibrosis after previous liposuction remains limited. OBJECTIVES: The objective of this article is to standardize a management algorithm based on the extensive experience and successful results of the primary author (G.M.). METHODS: Patients who underwent secondary liposculpture between August 2022 and May 2023 were evaluated prospectively. Inclusion criteria comprised females between 18 and 60 years old, nonsmokers, with a BMI < 35â kg/m2 and a history of previous body contouring surgeries. Identification of the patient's skin condition and subcutaneous lesions in the adipose tissue were obtained in detail. Statistical analysis of preoperative and postoperative medical photographs was also performed with the Fiji Biological image analyzer. RESULTS: Photographic analysis of preoperative and postoperative photographs showed a statistically significant difference between the areas affected by fibrosis (P < .001). The most frequent clinical findings were depressions in 99% of the females (74), followed by soft nodules in 95% (70), hard nodules in 81% (61), adhesions in 47% (35), and finally cutaneous bursas in 4%. CONCLUSIONS: Our classification system and management algorithm for fibrosis and contour irregularities is a safe and reliable tool. Results were objectively verified, yielding statistically significant outcomes.
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Algoritmos , Fibrosis , Lipectomía , Complicaciones Posoperatorias , Humanos , Femenino , Adulto , Persona de Mediana Edad , Lipectomía/métodos , Lipectomía/efectos adversos , Adulto Joven , Estudios Prospectivos , Adolescente , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/diagnóstico , Contorneado Corporal/métodos , Contorneado Corporal/efectos adversos , Fotograbar , Resultado del TratamientoRESUMEN
BACKGROUND: A paucity of predictive models assessing risk factors for COVID-19 mortality that extend beyond age and gender in Latino population is evident in the current academic literature. OBJECTIVES: To determine the associated factors with mortality, in addition to age and sex during the first year of the pandemic. DESIGN: A case-control study with retrospective revision of clinical and paraclinical variables by systematic revision of clinical records was conducted. Multiple imputations by chained equation were implemented to account for missing variables. Classification and regression trees (CART) were estimated to evaluate the interaction of associated factors on admission and their role in predicting mortality during hospitalisation. No intervention was performed. SETTING: High-complexity centre above 2640 m above sea level (masl) in Colombia. PARTICIPANTS: A population sample of 564 patients admitted to the hospital with confirmed COVID-19 by PCR. Deceased patients (n=282) and a control group (n=282), matched by age, sex and month of admission, were included. MAIN OUTCOME MEASURE: Mortality during hospitalisation. MAIN RESULTS: After the imputation of datasets, CART analysis estimated 11 clinical profiles based on respiratory distress, haemoglobin, lactate dehydrogenase, partial pressure of oxygen to inspired partial pressure of oxygen ratio, chronic kidney disease, ferritin, creatinine and leucocytes on admission. The accuracy model for prediction was 80.4% (95% CI 71.8% to 87.3%), with an area under the curve of 78.8% (95% CI 69.63% to 87.93%). CONCLUSIONS: This study discloses new interactions between clinical and paraclinical features beyond age and sex influencing mortality in COVID-19 patients. Furthermore, the predictive model could offer new clues for the personalised management of this condition in clinical settings.
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COVID-19 , Humanos , Estudios de Casos y Controles , SARS-CoV-2 , Estudios Retrospectivos , Oxígeno , Mortalidad HospitalariaRESUMEN
OBJECTIVE: Superior laryngeal nerve (SLN) block consists of injection of steroid and anesthetic at the internal branch of the SLN entry site. Prior case series have demonstrated beneficial effects on neurogenic cough. SLN blocks have also recently shown benefit for paralaryngeal pain. We describe short-term outcomes for multiple symptoms of irritable larynx syndrome (ILS) including neurogenic cough, dysphonia related to laryngeal hypersensitivity, inducible laryngeal obstruction (ILO), paralaryngeal pain, and isolated globus. METHODS: Retrospective review from 2 institutions of patients undergoing a single SLN block for the indications listed. Variables include age, sex, indication(s), known vagus neuropathy, and patient-reported outcomes at short-term follow-up. RESULTS: A total of 209 patients were included (59 males, 150 females; age: 58 ± 13 years). Twenty-six patients (12%) had a history of a vagus nerve injury. Indications included neurogenic cough (n = 149), dysphonia related to laryngeal hypersensitivity (n = 66), paralaryngeal pain (n = 50), ILO (n = 23), and isolated globus (n = 3). Some patients had multiple indications. Significant improvements in patient-reported measures occurred after a single SLN block within 2 to 4 weeks for neurogenic cough (cough severity index; 25.2 ± 11.2 to 19.0 ± 12.8; P < .001), dysphonia (voice handicap index-10; 22.1 ± 12.2-18.0 ± 13.3; P = .005), and ILO (dyspnea index; 21.0 ± 14.9-14.7 ± 15.7; P = .017). Subjective pain improved in 23 of 39 patients with paralaryngeal pain. There was no observed improvement for isolated globus. Presence of known vagal neuropathy or therapy around the time of SLN block did not affect outcome. CONCLUSION: SLN block can be an effective component of treatment for a variety of ILS symptoms. Patients may experience some improvement after 1 injection. LAY SUMMARY: Symptoms of irritable larynx syndrome, such as neurogenic cough, paralaryngeal pain, inducible laryngeal obstruction, and dysphonia related to laryngeal hypersensitivity can be challenging to manage. In-office Superior Laryngeal Nerve blocks can serve as a quick, well tolerated, adjunctive treatment with positive short-term outcomes. LEVEL OF EVIDENCE: 4.
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Obstrucción de las Vías Aéreas , Disfonía , Enfermedades de la Laringe , Laringe , Masculino , Femenino , Humanos , Persona de Mediana Edad , Anciano , Disfonía/diagnóstico , Disfonía/etiología , Disfonía/terapia , Nervios Laríngeos , Tos/etiología , Tos/terapia , DolorRESUMEN
ABSTRACT: Neural mobilisations (NM) have been advocated for the treatment of nerve-related cervicobrachial pain; however, it is unclear what types of patients with nerve-related cervicobrachial pain (if any) may benefit. Medline, Web of Science, Scopus, PeDro, Cinahl, and Cochrane databases were searched from inception until December 2022. Randomised controlled trials were included if they assessed the effectiveness of NM in nerve-related cervicobrachial pain, and outcome measures were pain intensity and/or disability. Studies were classified according to their inclusion/exclusion criteria as radiculopathy , Wainner cluster , Hall , and Elvey cluster or other . Meta-analyses with subgroup analyses were performed. Risk of bias was assessed using Cochrane Rob2 tool. Twenty-seven studies were included. For pain and disability reduction, NM was found to be more effective than no treatment (pooled pain mean difference [MD] = -2.81, 95% confidence interval [CI] = -3.81 to -1.81; pooled disability standardized mean difference = -1.55, 95% CI = -2.72 to -0.37), increased the effectiveness of standard physiotherapy as an adjuvant when compared with standard physiotherapy alone (pooled pain MD = -1.44, 95% CI = -1.98 to -0.89; pooled disability MD = -11.07, 95% CI = -16.38 to -5.75) but was no more effective than cervical traction (pooled pain MD = -0.33, 95% CI = -1.35 to 0.68; pooled disability MD = -10.09, 95% CI = -21.89 to 1.81). For disability reduction, NM was found to be more effective than exercise (pooled MD = -18.27, 95% CI = -20.29 to -17.44). In most comparisons, there were significant differences in the effectiveness of NM between the subgroups. Neural mobilisations was consistently more effective than all alternative interventions (no treatment, traction, exercise, and standard physiotherapy alone) in 13 studies classified as Wainner cluster . PROSPERO registration: CRD42022376087.
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Dolor , Modalidades de Fisioterapia , HumanosRESUMEN
Beyond their nutritional benefits, vitamins could decrease the risk of chronic diseases due to their potent antioxidant capacity. The present work is aimed at reviewing the state of the art regarding (1) the vitamins involved in oxidative stress prevention in accordance with the requirements established by the European Food Safety Authority (EFSA) and (2) the foods of plant origin that are sources of those vitamins and have potential benefits against oxidative stress in humans. According to the European regulations based on EFSA scientific evidence, riboflavin, vitamin C, and vitamin E are those vitamins subjected to the approved health claim "contribute to the protection of cells from oxidative stress". Scientific studies conducted in humans with some natural food sources of riboflavin (almonds, wheat germ, mushrooms, oat bran), vitamin C (guava, kale, black currant, Brussels sprouts, broccoli, orange), and vitamin E (hazelnuts, almonds, peanuts, pistachio nuts, extra virgin olive oil, dates, rye) have been performed and published in the literature. However, no food of plant origin has obtained a favorable EFSA opinion to substantiate the approval of health claims related to its potential properties related to oxidative stress prevention. Further studies (concretely, well-controlled human intervention studies) must be carried out in accordance with EFSA requirements to provide the highest level of scientific evidence that could demonstrate the potential relationship between foods of plant origin and antioxidant capacity. This review could be useful for the scientific community to study the application of health claims referring to the antioxidant capacity potentially exerted by foods of plant origin.
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Antioxidantes , Vitaminas , Humanos , Vitaminas/farmacología , Antioxidantes/farmacología , Estrés Oxidativo , Inocuidad de los Alimentos , Vitamina A , Vitamina K , Vitamina E , Ácido Ascórbico , RiboflavinaRESUMEN
Micronutrients play a critical role in pregnant women, a vulnerable group with higher nutritional requirements. The first strategy to achieve adequate micronutrients intake should always be through a healthy and balanced diet. In the case where the diet is not enough to meet these requirements, food supplements should be prescribed under supervision to complement the diet, and these products must bear reliable information about the declared nutritional contents and health benefits. Based on the data provided by the Coordinated System of Fast Interchange of Information (SCIRI) and to know the current national situation, this work addresses the assessment of the content and the adequacy of health claims related to some micronutrients (vitamin C, vitamin B9, iron, copper, manganese, zinc, calcium, magnesium) contained in food supplements for pregnant women commercialized in Spain. Analytical results coincided with the declared values and were covered by the ranges of tolerances, and samples met the requirements to use health claims. Although the samples could even include more claims, manufacturers could have selected those which either best addressed pregnant women's conditions or best aligned with marketing intentions. This study confirms an adequate use of health claims in food supplement samples, which could be interesting for strengthening consumers' confidence in the benefits shown in the labeling and for encouraging the use of health claims as a useful tool for making better-informed purchasing decisions.
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Micronutrientes , Mujeres Embarazadas , Humanos , Femenino , Embarazo , Suplementos Dietéticos , Dieta , Vitaminas , Necesidades NutricionalesRESUMEN
IMPORTANCE: Mitochondria constitute major sources of H2O2 and other reactive oxygen species in eukaryotic cells. The division of these organelles is crucial for multiple processes in cell biology and relies on highly regulated mechano-GTPases that are oligomerization dependent and belong to the dynamin-related protein family, like A. nidulans DnmA. Our previous work demonstrated that H2O2 induces mitochondrial constriction, division, and remodeling of the outer membrane. Here, we show that H2O2 also induces a DnmA aggregation consistent with higher-order oligomerization and its recruitment to mitochondria. The study of this response uncovered that H2O2 induces the depolymerization and reorganization of actin as well as the critical role that cysteines 450 and 776 play in DnmA function. Our results provide new insights into the mechanisms of reactive oxygen species cell signaling and how they can regulate the dynamics of the actin cytoskeleton and the division of mitochondria and peroxisomes.
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CONTEXT: 2,2,2-Trifluoroethanol has been widely used to study the structure and dynamic properties of intrinsically disordered proteins. Experimentally, it is known that TFE-water mixtures stabilize secondary structures of IDPs, and therefore, it allows the studying of conformational ensembles of these proteins. In the last decades, molecular dynamic simulations have helped study the IDPs' conformational ensemble. Unfortunately, conventional MD requires very long simulation times to describe the properties of IDPs. Therefore, a variety of accelerated sampling techniques have been developed and employed. The TFE-water mixture arrangement description through MD has faced substantial difficulties since emulating the TFE nanocrowding at certain TFE:H[Formula: see text]O ratios (around 15-40% of TFE). In this work, we determine the most suitable conditions that reproduce experimentally reported properties of TFE-water mixtures. We compared the employment of conventional MD and GaMD simulations and various water parameters. Our results show that the combination of parameters that better reproduce the experimental information is the combination of the TIP4PD water model and GaMD simulations. Therefore, these conditions help accurately describe the structural ensemble of IDPs in TFE-water mixtures. METHODS: Conventional MD and GaMD simulations were performed under AMBER 18 software. The TFE and water molecules were described using GAFF2 and a variety of water models, such as TIP3P, TIP4P2005, TIP4PD, and TIP5P, respectively. The systems were simulated a 100 ns at 298 K.
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El carcinoma de células escamosas (CCE) de la piel es la segunda forma más frecuente de cáncer de piel, caracterizado por el crecimiento anormal y acelerado de las células escamosas. Detectado a tiempo, la mayoría de los CCE se pueden curar. Puede aparecer como manchas rojas escamosas, llagas abiertas, piel áspera, engrosada o verrugosa, o crecimientos elevados con una depresión en el medio y puede formar costras, picar o sangrar y suele ser más habitual en zonas expuestas al sol. La radiodermitis es un problema habitual en personas que reciben radioterapia como tratamiento para el cáncer, apareciendo en más del 95% de los casos. La intensidad de la reacción depende del tipo de radiación, la dosis total y la dosis de fracción, el área afectada, latécnica de tratamiento, la administración simultánea de quimioterápicos, además de factores del propio individuo (enfermedades crónicas, tabaquismo, estado nutricional, etc.). Con este caso, nos disponemos a demostrar la eficacia de la combinación de colagenasa bacteriana y ácido hialurónico como un óptimo procedimiento para el abordaje de este tipo de lesiones. El uso de este producto en nuestra consulta en pacientes con diferentes etiologías y como procedimiento para el abordaje de preparación del lecho de la herida (PLH), nos animó a comprobar su eficacia en lesiones de estas características. (AU)
Squamous cell carcinoma (SCC) of the skin is the second most common form of skin cancer, characterized by the abnormal and accelerated growth of squamous cells. Detected early, most SCC can be healed. It may appear as red scaly patches, open sores, rough, thickened or warty skin, or raised growths with a depression in the middle and may crust, itch or bleed and is more common in sun-exposed areas. Radiodermitis is a common problem in people receiving radiationtherapy as a cancer treatment, occurring in more than 95% of cases. The intensity of the reaction depends on the type of radiation, the total dose and the fraction dose, the affected area, the treatment technique, the simultaneous administration of chemotherapy, as well as individual factors (chronic diseases, smoking, nutritional status, etc.). With this case, we will demonstrate the efficacy of the combination of bacterial collagenase and hyaluronic acid as an optimal procedure for the treatment of this type of wounds. The use of this product in our practice in patients with different etiologies and as a procedure for the wound bed preparation approach encouraged us to prove its efficacy in wounds of these characteristics. (AU)
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Humanos , Masculino , Anciano , Radiodermatitis/tratamiento farmacológico , Colagenasas/uso terapéutico , Ácido Hialurónico/uso terapéutico , Carcinoma de Células Escamosas/complicaciones , Carcinoma de Células Escamosas/radioterapia , DesbridamientoRESUMEN
Protein-protein association events are involved in many physiological and pathological processes. Cataract disease is a pathology that manifests protein aggregation of crystallins. ß-Crystallins are present in a high proportion in the eye lens. Therefore, the structural study of the dimerization properties of crystallins can shed light on the first stages of protein aggregation. In the present work, we examine the protein-protein association profiles of the human ßB2-crystallin by employing extensive coarse-grained molecular dynamics (CG-MD) and the Markov state analysis. Interestingly, our results clearly show important changes in the protein dimerization kinetics between wt-HßB2C and the deamidated systems. The two systems show dimeric conformations. However, the association and dissociation rates are very different. Our results show that the deamidated system can associate faster and dissociate slower than the wt- HßB2C. The deamidated system is in a slightly opened conformation with the Greek-key motifs well folded, suggesting that a complete unfolding of the protein is not required for aggregation. Our results describe the first stages of crystallin aggregation due to post-translational modifications.
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BACKGROUND: Nausea and vomiting is a very prevalent condition during pregnancy. Combination of doxylamine and pyridoxine is placed as first-line pharmacological option for its treatment in most clinical guidelines. Among different release forms available, Cariban® is a fixed-dose combination of doxylamine/pyridoxine 10/10 mg, formulated as modified-release capsules. OBJECTIVES: In the present study, we aimed to characterize the bioavailability performance of Cariban® in vitro and in vivo. METHODS: An in vitro dissolution test was performed to evaluate the release profile of Cariban®, together with immediate- and delayed-release formulations available on the market. A single-center, single-dose, open-label bioavailability study following Cariban® administration in 12 healthy adult female patients was carried out to explore the drug behavior in vivo (protocol NBR-002-13; EUDRA-CT 2013-005422-35). These data were additionally used to perform a computational pharmacokinetic simulation of the posology approved for this drug. RESULTS: Cariban® capsules demonstrate a prolonged-release performance, with an early, gradual, and progressive release of both actives until reaching a complete dissolution after 4-5 h in solution. The pharmacokinetic features of these capsules show that doxylamine and pyridoxine metabolites are early absorbed, being all detectable in plasma within 1 h following oral administration. Computational pharmacokinetic simulation predicts that different posology provides distinct profiles of metabolites in plasma, with 1-1-2 (morning-midafternoon-night) being the one that concentrates higher plasma levels but lower dose dumping for 24 h. CONCLUSION: Cariban® behaves as a prolonged-release formulation, which correlates with rapid absorption and arising of the actives in the plasma, but also long-lasting and sustained bioavailability, especially when administered following the complete posology. These results would underlie its demonstrated efficacy to relieve nausea and vomiting of pregnancy (NVP) under clinical settings.
Asunto(s)
Antieméticos , Complicaciones del Embarazo , Adulto , Femenino , Humanos , Embarazo , Antieméticos/farmacocinética , Antieméticos/uso terapéutico , Disponibilidad Biológica , Cápsulas , Preparaciones de Acción Retardada , Doxilamina/farmacocinética , Combinación de Medicamentos , Náusea , Complicaciones del Embarazo/tratamiento farmacológico , Piridoxina/farmacocinética , Piridoxina/uso terapéutico , Vómitos/tratamiento farmacológicoRESUMEN
BACKGROUND/PURPOSE: Optical coherence tomography angiography has been used to evaluate the posterior segment in a wide variety of pathologies because it is a noninvasive image technique, but its role in the evaluation of the retina in a case of carotid cavernous sinus fistula has not been described yet. METHODS RESULTS: We present a patient who consulted with spontaneous left superior eyelid hematoma and was diagnosed with left indirect carotid cavernous sinus fistula. In this study, optical coherence tomography angiography was used to evaluate the different macular capillary plexuses in a patient with carotid cavernous sinus fistula and a clinical situation of secondary local venous stasis before and after percutaneous embolization. Augmented vessel density was seen in superficial and deep capillary plexuses and in choriocapillaris before the percutaneous embolization, and a decrease of the parameters was seen after the treatment. CONCLUSION: All macular capillary plexuses presented with augmented vessel density levels that normalized after treatment. These findings were previously undescribed, and they suggest that optical coherence tomography angiography may be useful to initially evaluate patients with carotid cavernous sinus fistula who are planned to undergo embolization and to follow them up until normalization of the vascular structures is reported.