On the feasibility of minimally invasive Le Fort I with patient-specific implants: Proof of concept.

A novel approach to Le Fort I osteotomy is presented, integrating patient-specific implants (PSIs), osteosynthesis and cutting guides within a minimally invasive surgical framework, and the accuracy of the procedure is assessed through 3D voxel-based superimposition. The technique was applied in 5 cases. Differences between the surgical plan and final outcome were evaluated as follows: a 2-mm color scale was established to assess the anterior surfaces of the maxilla, mandible and chin, as well as the condylar surfaces. Measurements were made at 8 specific landmarks, and all of them showed a mean difference of less than 1 mm. In conclusion, the described protocol allows for minimally invasive Le Fort I osteotomy using PSIs. Besides, although the accuracy of the results may be limited by the small sample size, the findings are consistent with those reported in the literature. A prospective comparative study is needed to obtain statistically significant results and draw meaningful conclusions.

Does Aesthetic Osseous Genioplasty Impact Upper Airway Volume?

BACKGROUND: Although maxillomandibular advancement is the treatment of choice for obstructive sleep apnea syndrome (OSAS) in the presence of underlying maxillomandibular complex hypoplasia, there is still a gap in the literature regarding the impact of genioplasty upon upper airway volume (UAV). OBJECTIVES: The aim of this study was to evaluate the impact of isolated osseous genioplasty upon UAV. METHODS: A retrospective analysis of all patients subjected to isolated osseous genioplasty between July 2015 and July 2022 was conducted. Cone-beam computed tomography was performed preoperatively and postoperatively to assess the chin and hyoid 3-dimensional (3D) spatial position and UAV changes after surgery. RESULTS: A total of 44 patients were included in the study. Regarding surgical movements of the chin, almost all patients received a sagittal movement (n = 42; 39 forward and 3 backward), while in 8 patients a vertical movement (5 upward and 3 downward) was applied, and in 6 patients the chin was centered. Statistically significant increases in total UAV (P = .014) and at the level of the oropharynx (P = .004) were observed. Specifically, chin centering, upward and forward movements enlarged the oropharynx volume (P = .006, .043 and .065, respectively). Chin advancement enlarged the hypopharynx volume (P = .032), as did upward movement of the hyoid bone (P < .001). CONCLUSIONS: Results of the study suggest that aesthetic osseous genioplasty impacts the UAV: each 3D spatial chin movement differently impacts the upper airway by enlarging or narrowing it. However, further studies addressing the apnea-hypopnea index are required to assess its effectiveness in treating OSAS.

Esophagogastric Junction Contractile Integral (EGJ-CI) in Various Phenotypes of Gastroesophageal Reflux Disease (GERD)

Introduction: Two parameters of high-resolution esophageal manometry are used to observe the function of the esophagogastric junction (EGJ): the anatomical morphology of the EGJ and contractile vigor, which is evaluated with the esophagogastric junction contractile integral (EGJ-CI). To date, how these parameters behave in different gastroesophageal reflux disease (GERD) phenotypes has not been evaluated. Materials and methods: An analytical observational study evaluated patients with GERD confirmed by pH-impedance testing and endoscopy undergoing high-resolution esophageal manometry. The anatomical morphology of the EGJ and EGJ-CI was assessed and compared between reflux phenotypes: acid, non-acid, erosive, and non-erosive. Results: 72 patients were included (63% women, mean age: 54.9 years), 81.9% with acid reflux and 25% with erosive esophagitis. In the latter, a decrease in EGJ-CI (median: 15.1 vs. 23, p = 0.04) and a more significant proportion of patients with type IIIa and IIIb EGJ (83.3% vs 37.1%, p < 0.01) were found. No significant differences existed in the manometric parameters of patients with and without acid and non-acid reflux. Conclusion: In our population, EGJ-CI significantly decreased in patients with erosive GERD, suggesting that it could be used to predict this condition in patients with GERD. This finding is also related to a higher proportion of type III EGJ and lower pressure at end-inspiration of the lower esophageal sphincter in this reflux type.

Introducción: Para observar la función de la unión esofagogástrica (UEG) se utilizan dos parámetros de la manometría esofágica de alta resolución: la morfología anatómica de la UEG y el vigor contráctil, el cual se evalúa con la integral de contractilidad distal de la unión esofagogástrica (IC-UEG). Hasta el momento, no se ha evaluado cómo se comportan estos parámetros en los diferentes fenotipos de enfermedad por reflujo gastroesofágico (ERGE). Metodología: Estudio observacional analítico en el que se evaluaron pacientes con ERGE confirmado por pH-impedanciometría y endoscopia, llevados a manometría esofágica de alta resolución. Se evaluó la morfología anatómica de la UEG y la IC-UEG, y se comparó entre los diferentes fenotipos de reflujo: ácido, no ácido, erosivo y no erosivo. Resultados: Se incluyó a 72 pacientes (63% mujeres, edad media: 54,9 años), 81,9% con reflujo ácido y 25% con esofagitis erosiva. En este último grupo se encontró una disminución de la IC-UEG (mediana: 15,1 frente a 23, p = 0,04) y una mayor proporción de pacientes con UEG tipo IIIa y IIIb (83,3% frente a 37,1%, p < 0,01). No se encontraron diferencias significativas en los parámetros manométricos de los pacientes con y sin reflujo ácido y no ácido. Conclusión: En nuestra población, la IC-UEG estuvo significativamente disminuida en los pacientes con ERGE erosivo, lo que sugiere que podría ser utilizada como un predictor de esta condición en pacientes con ERGE. Este hallazgo también se relaciona con mayor proporción de UGE tipo III y menor presión al final de la inspiración del esfínter esofágico inferior en este tipo de reflujo.

Ultrasonido endoscópico (USE) y colangio-pancreatografía endoscópica retrógrada (CPRE) sin fluoroscopia en el tratamiento de la coledocolitiasis durante el embarazo: reporte de 2 casos / Endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP) without fluoroscopy for the treatment of choledocholithiasis during pregnancy: Report of 2 cases

Resumen La enfermedad litiásica biliar es una patología frecuente en mujeres embarazadas, y las complicaciones relacionadas con los cálculos biliares durante el embarazo pueden generar desenlaces adversos tanto en la madre como en el feto. La coledocolitiasis en el embarazo requiere de una aproximación diagnóstica adecuada y su manejo busca minimizar los riesgos de las intervenciones médicas. Se describen dos casos de mujeres embarazadas quienes presentan coledocolitiasis documentada por colangiorresonancia. Se realizó el tratamiento con la combinación de ultrasonido endoscópico (USE) y colangiopancreatografía endoscópica retrógrada (CPRE) sin fluoroscopia, con lo cual se logró resolver la coledocolitiasis sin exponer al feto a radiación ionizante, se confirmó la permeabilización del colédoco y se observó una adecuada evolución posoperatoria tanto materna como fetal.

Abstract Biliary lithiasis is a common condition in pregnant women, and complications related to gallstones during pregnancy can lead to adverse outcomes in both the mother and the fetus. Choledocholithiasis during pregnancy requires an adequate diagnostic approach to minimize the risks of medical interventions. The following are two cases of pregnant women with choledocholithiasis diagnosed using magnetic resonance cholangiography. Treatment included a combination of endoscopic ultrasound and retrograde endoscopic cholangiopancreatography (ERCP) without fluoroscopy, achieving the resolution of choledocholithiasis, without exposing the fetus to ionizing radiation, confirming the permeabilization of the common bile duct, and observing an adequate postoperative evolution of both the mother and the fetus.

Actualización en la interpretación de la medición del pH e impedanciometría / Updated interpretation of Impedance-pH monitoring

Resumen La enfermedad por reflujo gastroesofágico (ERGE) se define como el tránsito anormal del contenido gástrico hacia el esófago, que se da por una alteración de la barrera antirreflujo, causando síntomas o complicaciones. Para su correcto diagnóstico y abordaje terapéutico, se requiere de la integración de hallazgos clínicos, endoscópicos y monitorización del pH esofágico en 24 horas con o sin impedanciometría, la cual debe ser realizada con especificaciones técnicas, y su interpretación debe basarse en la mejor evidencia clínica disponible, con el objetivo de tener diagnósticos precisos que permitan tomar las mejores decisiones con los pacientes. Recientemente, en el Consenso de Lyon se han incorporado nuevas directrices para el diagnóstico de ERGE por monitorización de pH esofágico, las cuales se revisan en este artículo.

Abstract Gastroesophageal reflux disease (GERD) is defined as the abnormal transit of gastric contents into the esophagus. It is caused by an alteration of the anti-reflux barrier, causing multiple symptoms or complications. In order to achieve accurate diagnosis and proper therapeutic approach, integration of clinical findings, endoscopic findings and 24-hour esophageal pH monitoring, with or without impedancometry, is required. These tests must be performed following technical specifications and their interpretation must be based on the best clinical evidence available to obtain accurate diagnoses that allow making the best decisions to the benefit of patients. Recently, the Lyon Consensus incorporated new guidelines for the diagnosis of GERD by esophageal pH monitoring, which are reviewed in this paper.

Feedlot growth, carcass characteristics and meat quality of hair breed male lambs exposed to seasonal heat stress (winter vs. summer) in an arid climate.

Twenty Dorper × Katahdin male lambs (body weight = 33.9 ±â€¯0.4 kg and age = 4.5 months) were individually housed for a 30-d feeding period to evaluate the effects of seasonal heat stress (winter [n = 10] vs. summer [n = 10]) on feedlot performance, carcass traits, wholesale cut yields and meat quality. Heat stress environmental conditions prevailed in summer and mostly thermoneutral in winter. Overall growth rate and feed efficiency, as well as empty body weight at slaughter, cold carcass weight, omental fat percentage, and loin yield were lower in summer than in winter. Kidney-pelvic-heart fat deposition and yields of hot carcass, neck and shoulder increased during summer. Postmortem aging of meat during 14 d exhibited higher lightness, redness, yellowness and toughness in summer. In conclusion, summer heat stress decreased growth and feed efficiency without affecting feed intake of hair male lambs. Additionally, heat stress improved carcass yield with no detrimental changes on meat quality.

Design and synthesis of bridged piperidine and piperazine isosteres.

We have developed versatile methods toward the synthesis of a variety of piperidine/piperazine bridged isosteres of pridopidine. The compounds were assessed against the D2 receptor in agonist and antagonist modes and against the D4 receptor in agonist mode. hERG Binding and the ADME profiles were studied.

Structure-Based Design of a Eukaryote-Selective Antiprotozoal Fluorinated Aminoglycoside.

Aminoglycosides (AG) are antibiotics that lower the accuracy of protein synthesis by targeting a highly conserved RNA helix of the ribosomal A-site. The discovery of AGs that selectively target the eukaryotic ribosome, but lack activity in prokaryotes, are promising as antiprotozoals for the treatment of neglected tropical diseases, and as therapies to read-through point-mutation genetic diseases. However, a single nucleobase change A1408G in the eukaryotic A-site leads to negligible affinity for most AGs. Herein we report the synthesis of 6'-fluorosisomicin, the first 6'-fluorinated aminoglycoside, which specifically interacts with the protozoal cytoplasmic rRNA A-site, but not the bacterial A-site, as evidenced by X-ray co-crystal structures. The respective dispositions of 6'-fluorosisomicin within the bacterial and protozoal A-sites reveal that the fluorine atom acts only as a hydrogen-bond acceptor to favorably interact with G1408 of the protozoal A-site. Unlike aminoglycosides containing a 6'-ammonium group, 6'-fluorosisomicin cannot participate in the hydrogen-bonding pattern that characterizes stable pseudo-base-pairs with A1408 of the bacterial A-sites. Based on these structural observations it may be possible to shift the biological activity of aminoglycosides to act preferentially as antiprotozoal agents. These findings expand the repertoire of small molecules targeting the eukaryotic ribosome and demonstrate the usefulness of fluorine as a design element.

Design and synthesis of novel N-sulfonyl-2-indoles that behave as 5-HT6 receptor ligands with significant selectivity for D3 over D2 receptors.

All clinically-used antipsychotics display similar affinity for both D2 (D2R) and D3 (D3R) receptors, and they likewise act as 5-HT2A receptor antagonists. They provide therapeutic benefit for positive symptoms, but no marked or consistent improvement in neurocognitive, social cognitive or negative symptoms. Since blockade of D3 and 5-HT6 (5-HT6R) receptors enhances neurocognition and social cognition, and potentially improves negative symptoms, a promising approach for improved treatment for schizophrenia would be to develop drugs that preferentially act at D3R versus D2R and likewise recognize 5-HT6R. Starting from the high affinity 5-HT6R ligands I and II, we identified compounds 11a and 14b that behave as 5-HT6R ligands with significant selectivity for D3R over D2R.

Anticoagulación oral en el adulto mayor frágil con fibrilación auricular / Oral anti-clotting in the fragile elderly with atrial fibrillation

Introducción: El envejecimiento incrementa el riesgo de trombosis y fenómenos embólicos, trae cambios fisiológicos y comorbilidades como la fibrilación auricular que hacen complejo el inicio y la seguridad de la anticoagulación. A pesar de la mayor disponibilidad de clínicas de anticoagulación y nuevos anticoagulantes orales, es bajo el porcentaje de adultos mayores que están anticoagulados aunque tengan indicación plena y ausencia de contraindicaciones. Objetivo: Revisar las principales estrategias para predecir y disminuir el riesgo de sangrado con el empleo de anticoagulantes orales en pacientes adultos mayores frágiles. Metodología: Se realizó una búsqueda sistemática sobre estudios que evaluaran la seguridad y eficacia de anticoagulantes orales en pacientes con fibrilación auricular en adultos mayores de 65 años, y una búsqueda de estudios sobre el síndrome de fragilidad y su impacto en el adulto mayor anticoagulado. Resultados y Discusión: Se ha denominado fragilidad al porcentaje de adultos mayores que presentan un mayor deterioro de sus sistemas biológico, físico y cognitivo, conduciendo a una mayor probabilidad de desenlaces adversos en salud, discapacidad y muerte. Se han estudiado características clínicas que permiten identificar pacientes como frágiles; el fenotipo de fragilidad de Linda Fried evalúa esas características; además, existen estrategias de monitoreo de los anticoagulantes orales que deben ser conocidos para minimizar el riesgo de eventos adversos. Conclusiones: el anciano frágil presenta factores de riesgo que probablemente afectan la eficacia y seguridad de la terapia con anticoagulantes orales. Las guías clínicas existentes no proveen la suficiente evidencia y no consideran de manera multidimensional al paciente geriátrico...(AU)

Introduction: Aging increases the risk of thrombosis and embolic phenomena. It also brings physiological changes, and comorbidities such as atrial fibrillation that makes complex the onset and safety of anti-clotting. Despite the greater availability of anti-clotting clinics and new oral anticoagulants, the percentage of elderly who are anticoagulated is low, even though they have indications and no contraindications. Objective: To review the main strategies to predict and reduce the risk of bleeding with the use of oral anti-clotting in fragile elderly patients. Methodology: A systematic search was conducted on studies evaluating the safety and efficacy of oral anticoagulants in patients with atrial fibrillation in adults older than 65 years, and a search for studies on the frailty syndrome and its impact on the elderly anticoagulated. Results and Discussion: Fragility has been termed to the percentage of elderly who were diagnosed with a greater deterioration of their biological, physical and cognitive systems, leading to a greater probability of adverse outcomes in health, disability and death. Some clinical features have been studied to identify patients as fragile; Linda Fried's frailty phenotype evaluates these characteristics; furthermore, there are strategies for monitoring oral anticoagulants that should be known to reduce the risk of adverse events. Conclusions: The frail elderly has some risk factors that are likely to affect the efficacy and safety of oral anti-clotting therapy. Existing clinical guidelines do not provide enough evidence and do not consider the elderly patient in a multidimensional manner...(AU)

Introdução: O envelhecimento aumenta o risco de trombose e embolias, traz mudanças fisiológicas e comorbidades como a fibrilhação auricular que fazem complexo o inicio e a segurança da anticoagulação. Apesar do aumento da disponibilidade das clínicas de anticoagulação e novos anticoagulantes orais, é baixa a percentagem de adultos mais velhos que tomam anticoagulantes ou que tenham a indicação completa e ausência de contra-indicações. Objetivo: Revisar as principais estratégias de prever e reduzir o risco de sangramento com o uso de anticoagulantes orais nos pacientes idosos mais frágeis. Metodologia: Se fez uma revisão sistemática de estudos que avaliaram a segurança e eficácia de anticoagulantes orais nos pacientes com fibrilhação auricular em adultos com mais de 65 anos, e uma busca dos estudos sobre o síndrome de fragilidade e o seu impacto nos idosos anticoagulado. Resultados e Discussão: Foi chamada de fragilidade a percentagem de pessoas idosas com maior deterioro de seus sistemas biológicos, físicos e cognitivos, levando-as a uma probabilidade maior de resultados adversos na saúde, invalidez e morte. Foram estudadas as características clínicas que identificam pacientes como pacientes frágil; o fenótipo de fragilidade de Linda Fried avalia estas características; além disto, existem estratégias adicionais de monitoramento de anticoagulantes orais que devem ser conhecidos para minimizar o risco de fatos adversos. Conclusões: Os idosos frágeis presentam fatores de risco que podem afectar a eficácia e segurança da terapia com anticoagulantes orais. As diretrizes clínicas existentes não são claras nem as provas são suficientes. Além disto, não consideram de forma multidimensional aos pacientes geriátricos...(AU)

Toward Overcoming Staphylococcus aureus Aminoglycoside Resistance Mechanisms with a Functionally Designed Neomycin Analogue.

Deoxygenation of the diol groups in rings A and D of neomycin in combination with the introduction of an N1-(l)-HABA group in the 2-deoxystreptamine subunit (ring B) leads to a novel and potent antibiotic (1) with activity against strains of S. aureus carrying known aminoglycoside resistance determinants, as well as against an extended panel of Methicillin-resistant S. aureus isolates (n = 50). Antibiotic 1 displayed >64 fold improvement in MIC50 and MIC90 against this MRSA collection when compared to the clinically relevant aminoglycosides amikacin and gentamicin. The synthesis was achieved in six steps and 15% overall yield.

Identification of a novel series of potent RON receptor tyrosine kinase inhibitors.

A novel series of N-(3-fluoro-4-(2-substituted-thieno[3,2-b]pyridin-7-yloxy)phenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamides targeting RON receptor tyrosine kinase was designed and synthesized. SAR study of the series allowed us to identify compounds possessing either inhibitory activity of RON kinase enzyme in the low nanomolar range with low residual activity against the closely related c-Met or potent dual inhibitory activity against RON and c-Met, with no significant activity against VEGFR2 in both cases.

N3-arylmalonamides: a new series of thieno[3,2-b]pyridine based inhibitors of c-Met and VEGFR2 tyrosine kinases.

A family of thieno[3,2-b]pyridine based small molecule inhibitors of c-Met and VEGFR2 were designed based on lead structure 2. These compounds were shown to have IC(50) values in the low nanomolar range in vitro and were efficacious in human tumor xenograft models in mice in vivo.

N-(4-(6,7-Disubstituted-quinolin-4-yloxy)-3-fluorophenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides: a novel series of dual c-Met/VEGFR2 receptor tyrosine kinase inhibitors.

A series of N-(4-(6,7-disubstituted-quinolin-4-yloxy)-3-fluorophenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides targeting c-Met and VEGFR2 tyrosine kinases was designed and synthesized. The compounds were potent against these two enzymes with IC(50) values in the low nanomolar range in vitro, possessed favorable pharmacokinetic profiles and showed high efficacy in vivo in several human tumor xenograft models in mice.

SAR around (l)-S-adenosyl-l-homocysteine, an inhibitor of human DNA methyltransferase (DNMT) enzymes.

The inhibitory activity of base-modified SAH analogues and the specificity of inhibiting human DNMT1 and DNMT3b2 enzymes was explored. The 6-amino group was essential while the 7-N of the adenine ring of SAH could be replaced by CH- without loss of activity against both enzymes. The introduction of small groups at the 2-position of the adenine moiety favors DNMT1 over DNMT3b2 inhibition whereas alkylation of the N(6)-amino moiety favors the inhibition of DNMT3b2 enzyme.

Constrained (l-)-S-adenosyl-l-homocysteine (SAH) analogues as DNA methyltransferase inhibitors.

Potent SAH analogues with constrained homocysteine units have been designed and synthesized as inhibitors of human DNMT enzymes. The five membered (2S,4S)-4-mercaptopyrrolidine-2-carboxylic acid, in 1a, was a good replacement for homocysteine, while the corresponding six-member counterpart was less active. Further optimization of 1a, changed the selectivity profile of these inhibitors. A Chloro substituent at the 2-position of 1a, compound 1d, retained potency against DNMT1, while N(6) alkylation, compound 7a, conserved DNMT3b2 activity. The concomitant substitutions of 1a at both 2- and N(6) positions reduced activity against both enzymes.

N-(3-fluoro-4-(2-arylthieno[3,2-b]pyridin-7-yloxy)phenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides: a novel series of dual c-Met/VEGFR2 receptor tyrosine kinase inhibitors.

A series of N-(3-fluoro-4-(2-arylthieno[3,2-b]pyridin-7-yloxy)phenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides targeting c-Met and VEGFR2 tyrosine kinases was designed and synthesized. The compounds were potent against these two enzymes with IC(50) values in the low nanomolar range in vitro, possessed favorable pharmacokinetic profiles and showed high efficacy in vivo in several human tumor xenograft models in mice.

Discovery of a novel and potent series of thieno[3,2-b]pyridine-based inhibitors of c-Met and VEGFR2 tyrosine kinases.

A series of thieno[3,2-b]pyridine-based inhibitors of c-Met and VEGFR2 tyrosine kinases is described. The compounds demonstrated potency with IC(50) values in the low nanomolar range in vitro while the lead compound also showed in vivo activity against various human tumor xenograft models in mice. Further exploration of this class of compounds is underway.

Design and synthesis of 4-[(s-triazin-2-ylamino)methyl]-N-(2-aminophenyl)-benzamides and their analogues as a novel class of histone deacetylase inhibitors.

Inhibition of histone deacetylases (HDAC) is emerging as a new strategy in human cancer therapy. The synthesis and biological evaluation of a variety of 4-(heteroarylaminomethyl)-N-(2-aminophenyl)-benzamides is presented herein. From the different series bearing a six-membered heteroaromatic ring studied, the s-triazine series showed the best HDAC1 enzyme and in vitro anti-proliferative activities with IC(50) values below micromolar range. Some of these compounds can also significantly reduce tumor growth in human tumor xenograft models in mice.

Functionalized glycomers as growth inhibitors and inducers of apoptosis in human glioblastoma cells.

The effects of functionalized aryl beta-D-glycopyranosides (glycomers) on the proliferation, survival, and apoptosis of human glioblastoma cells in culture were evaluated as a way to control tumor progression. The results showed that inhibition of growth and/or induction of apoptosis can be achieved by these molecules in human glioblastoma cells. Inhibition of DNA synthesis precedes induction of apoptosis and growth inhibition. The substituents at C-1, C-2, C-3,C-4, and C-6 on the pyranosidic scaffold are important to modulate the action and the efficacy of these molecules. Human fibroblasts and brain-derived endothelial cells were less sensitive to glycomers than tumor cells. Thus, functionalized aryl beta-D-glycopyranosides represent a new class of molecules potentially able to control the progression of brain tumors.