Reconstituted ovaries self-assemble without an ovarian surface epithelium.

Three-dimensional (3D) stem cell models of the ovary have the potential to benefit women's reproductive health research. One such model, the reconstituted ovary (rOvary) self-assembles with pluripotent stem cell-derived germ cells creating a 3D ovarian mimic competent to support the differentiation of functional oocytes inside follicles. In this study, we evaluated the cellular composition of the rOvary revealing the capacity to generate multiple follicles surrounded by NR2F2+ stroma cells. However, the rOvary does not develop a surface epithelium, the source of second-wave pre-granulosa cells, or steroidogenic theca. Therefore, the rOvary models represent the self-assembly of activated follicles in a pre-pubertal ovary poised but not yet competent for hormone production.

Innate and adaptive AAV-mediated immune responses in a mouse model of Duchenne muscular dystrophy.

High systemic doses of adeno-associated viruses (AAVs) have been associated with immune-related serious adverse events (SAEs). Although AAV was well tolerated in preclinical models, SAEs were observed in clinical trials, indicating the need for improved preclinical models to understand AAV-induced immune responses. Here, we show that mice dual-dosed with AAV9 at 4-week intervals better recapitulate aspects of human immunity to AAV. In the model, anti-AAV9 immunoglobulin G (IgGs) increased in a linear fashion between the first and second AAV administrations. Complement activation was only observed in the presence of high levels of both AAV and anti-AAV IgG. Myeloid-derived pro-inflammatory cytokines were significantly induced in the same pattern as complement activation, suggesting that myeloid cell activation to AAV may rely on the presence of both AAV and anti-AAV IgG complexes. Single-cell RNA sequencing of peripheral blood mononuclear cells confirmed that activated monocytes were a primary source of pro-inflammatory cytokines and chemokines, which were significantly increased after a second AAV9 exposure. The same activated monocyte clusters expressed both Fcγ and complement receptors, suggesting that anti-AAV-mediated activation of myeloid cells through Fcγ receptors and/or complement receptors is one mechanism by which anti-AAV antigen complexes may prime antigen-presenting cells and amplify downstream immunity.

Fibroblasts in heart scar tissue directly regulate cardiac excitability and arrhythmogenesis.

After heart injury, dead heart muscle is replaced by scar tissue. Fibroblasts can electrically couple with myocytes, and changes in fibroblast membrane potential can lead to myocyte excitability, which suggests that fibroblast-myocyte coupling in scar tissue may be responsible for arrhythmogenesis. However, the physiologic relevance of electrical coupling of myocytes and fibroblasts and its impact on cardiac excitability in vivo have never been demonstrated. We genetically engineered a mouse that expresses the optogenetic cationic channel ChR2 (H134R) exclusively in cardiac fibroblasts. After myocardial infarction, optical stimulation of scar tissue elicited organ-wide cardiac excitation and induced arrhythmias in these animals. Complementing computational modeling with experimental approaches, we showed that gap junctional and ephaptic coupling, in a synergistic yet functionally redundant manner, excited myocytes coupled to fibroblasts.

Nebulized glycyrrhizin/enoxolone drug modulates IL-17A in COVID-19 patients: a randomized clinical trial.

Introduction: Glycyrrhizin (GA) and its derivative Enoxolone (18ß), isolated from the Glycyrrhiza glabra plant, are two potential molecules for treating viral diseases. Both demonstrate to regulate immune system with antiviral and anti-inflammatory activities, with the latter mainly due to modulation of inflammatory cytokines. The aim of this clinical trial was to evaluate the safety and efficacy of a nebulized GA/18ß drug for treating COVID-19 patients. Methods: An open label, randomized, placebo-controlled clinical trial was conducted in Mexico City from January-August 2022 (Registration No. PROTAP-CLI-00). Clinical and biochemical parameters were recorded. Blood samples from patients were regularly collected to evaluate interleukins IL-4, IL-2, IL-1b, TNF-α, IL-17A, IL-6, IL-10,IFN-γ, IL-12, IL-8 and TGF-ß1, as well as IgM and IgG against SARS-CoV-2. Two doses of the drug were used - 30/2 mg (dose A) and 90/4 mg (dose B). Results and discussion: Both GA/18ß doses modulated inflammatory response by reducing mainly IL-17A expression, which in turn kept IL-1ß, IL-6, IL-8 and TNF-α interleukins unchanged, indicating significant modulation of key interleukin levels to prevent exacerbation of the immune response in COVID-19 patients. Early on, dose A increased IgM, while dose B induced expression of the antiviral IFN-γ. No severe side effects were seen with either dose, indicating nebulized GA/18ß is a safe treatment that could be used for COVID-19 and potentially other viral infections involving inflammatory response.

Assessment of a Decision Support System for Adults with Type 1 Diabetes on Multiple Daily Insulin Injections.

Introduction: DailyDose is a decision support system designed to provide real-time dosing advice and weekly insulin dose adjustments for adults living with type 1 diabetes using multiple daily insulin injections. Materials and Methods: Twenty-five adults were enrolled in this single-arm study. All participants used Dexcom G6 for continuous glucose monitoring, InPen for short-acting insulin doses, and Clipsulin to track long-acting insulin doses. Participants used DailyDose on an iPhone for 8 weeks. The primary endpoint was % time in range (TIR) comparing the 2-week baseline to the final 2-week period of DailyDose use. Results: There were no significant differences between TIR or other glycemic metrics between the baseline period compared to final 2-week period of DailyDose use. TIR significantly improved by 6.3% when more than half of recommendations were accepted and followed compared with 50% or fewer recommendations (95% CI 2.5%-10.1%, P = 0.001). Conclusions: Use of DailyDose did not improve glycemic outcomes compared to the baseline period. In a post hoc analysis, accepting and following recommendations from DailyDose was associated with improved TIR. Clinical Trial Registration Number: NCT04428645.

TREM2 macrophages induced by human lipids drive inflammation in acne lesions.

Acne affects 1 in 10 people globally, often resulting in disfigurement. The disease involves excess production of lipids, particularly squalene, increased growth of Cutibacterium acnes, and a host inflammatory response with foamy macrophages. By combining single-cell and spatial RNA sequencing as well as ultrahigh-resolution Seq-Scope analyses of early acne lesions on back skin, we identified TREM2 macrophages expressing lipid metabolism and proinflammatory gene programs in proximity to hair follicle epithelium expressing squalene epoxidase. We established that the addition of squalene induced differentiation of TREM2 macrophages in vitro, which were unable to kill C. acnes. The addition of squalene to macrophages inhibited induction of oxidative enzymes and scavenged oxygen free radicals, providing an explanation for the efficacy of topical benzoyl peroxide in the clinical treatment of acne. The present work has elucidated the mechanisms by which TREM2 macrophages and unsaturated lipids, similar to their involvement in atherosclerosis, may contribute to the pathogenesis of acne.

Three-Dimensional Quantification of Cam Resection Using MRI Bone Models: A Comparison of 2 Techniques.

Background: The current clinical standard for the evaluation of cam deformity in femoroacetabular impingement syndrome is based on radiographic measurements, which limit the ability to quantify the complex 3-dimensional (3D) morphology of the proximal femur. Purpose: To compare magnetic resonance imaging (MRI)-based metrics for the quantification of cam resection as derived using a best-fit sphere alpha angle (BFS-AA) method and using 3D preoperative-postoperative surface model subtraction (PP-SMS). Study Design: Descriptive laboratory study. Methods: Seven cadaveric hemipelvises underwent 1.5-T MRI before and after arthroscopic femoral osteochondroplasty, and 3D bone models of the proximal femur were reconstructed from the MRI scans. The alpha angles were measured radially along clockfaces using a BFS-AA method from the literature and plotted as continuous curves for the pre- and postoperative models. The difference between the areas under the curve for the pre- and postoperative models was then introduced in the current study as the BFS-AA-based metric to quantify the cam resection. The cam resection was also quantified using a 3D PP-SMS method, previously described in the literature using the metrics of surface area (FSA), volume (FV), and height (maximum [FHmax] and mean [FHmean]). Bivariate correlation analyses were performed to compare the metrics quantifying the cam resection as derived from the BFS-AA and PP-SMS methods. Results: The mean ± standard deviation maximum pre- and postoperative alpha angle measurements were 59.73° ± 15.38° and 48.02° ± 13.14°, respectively. The mean for each metric quantifying the cam resection with the PP-SMS method was as follows: FSA, 540.9 ± 150.7 mm2; FV, 1019.2 ± 486.2 mm3; FHmax , 3.6 ± 1.0 mm; and FHmean, 1.8 ± 0.5 mm. Bivariate correlations between the BFS-AA-based and PP-SMS-based metrics were strong: FSA (r = 0.817, P = .012), FV (r = 0.888, P = .004), FHmax (r = 0.786, P = .018), and FHmean (r = 0.679, P = .047). Conclusion: Strong positive correlations were appreciated between the BFS-AA and PP-SMS methods quantifying the cam resection. Clinical Relevance: The utility of the BFS-AA technique is primarily during preoperative planning. The utility of the PP-SMS technique is in the postoperative setting when evaluating the adequacy of resection or in patients with persistent hip pain with suspected residual impingement. In combination, the techniques allow surgeons to develop a planned resection while providing a means to evaluate the depth of resection postoperatively.

Trasplante de microbiota fecal para el tratamiento de la obesidad y de sus comorbilidades asociadas: Revisión

RESUMEN La obesidad es un problema de salud pública a nivel mundial. Existen evidencias sobre la interacción entre la microbiota intestinal, la regulación metabólica y la obesidad. El problema mundial de la obesidad impulsa el estudio de nuevas propuestas preventivas y/o terapéuticas. El trasplante de microbiota fecal (TMF) se proyecta como un posible tratamiento para la obesidad y sus comorbilidades asociadas. El objetivo de este estudio es sintetizar la documentación actual que existe sobre el efecto en parámetros metabólicos y clínicos que produce el TMF en humanos con obesidad, así como evidenciar la metodología empleada en el TMF. En los resultados primarios se señaló la existencia de cambios significativos en la composición de la microbiota intestinal (MI) y mejoría en marcadores metabólicos como disminución de la resistencia a la insulina (RI) y de la hemoglobina glicada (HbA1c), así como aumento de colesterol de alta densidad (HDL). Además, en marcadores clínicos como la disminución del índice de masa corporal y de la circunferencia de cintura. En los resultados secundarios se sustentó la necesidad de estandarizar el diseño experimental del TMF, iniciando con establecer la correcta selección de donantes hasta determinar el seguimiento del TMF a largo plazo. En conclusión, a pesar de que hay un número limitado de estudios y una falta de estandarización de las metodologías para llevar a cabo TMF, se han podido evidenciar algunas asociaciones metabólicas positivas, por lo que el TMF sigue siendo una opción potencialmente prometedora para el tratamiento coadyuvante de la obesidad.

ABSTRACT Obesity is a worldwide health problem. There is evidence of the interaction between the gut microbiota metabolic regulation, and obesity. The global problem of obesity has prompted the study of new preventive and/or therapeutic proposals. Fecal Microbiota Transplantation (FMT) is projected as a possible treatment for obesity and its associated comorbidities. The objective of this study is to synthesize the current documentation that exists on the effect in metabolic and clinical parameters produced by FMT in humans with obesity, as well as to make evident the methodology used in FMT. Primary results indicated the existence of significant changes in the composition of gut microbiota and improvement in some metabolic markers such as a decrease in insulin resistance (IR) and glycated hemoglobin (HbA1c), as well as an increase in high-density cholesterol (HDL). Further changed were noted in clinical markers such as the decrease in body mass index and waist circumference. Secondary results supported the need to standardize the experimental design of FMT, starting with establishing the correct selection of donors to determine the long-term follow-up of FMT. In conclusion, even though there is a limited number of studies and a lack of standardization on the methodology to carry out FMT, some positive metabolic associations have been shown, which is why FMT remains a potentially promising option for treatment adjuvant of obesity.

Acute Promyelocytic Leukemia: A Long-Term Retrospective Study in Mexico.

BACKGROUND: The present retrospective study reviewed acute promyelocytic leukemia (APL) cases recorded in Mexico between January 2007 and January 2017. The primary objective of the study was to evaluate overall survival (OS) in Mexican patients with APL. Secondary objective was to evaluate the impact of induction treatment with different anthracyclines on OS, event-free survival (EFS) and complications in this patient population. METHODS: The medical charts of patients referred to medical institutions in Mexico from January 2007 through January 2017 for the treatment of suspected APL were reviewed retrospectively. Patients aged 15 - 75 years, in whom the diagnosis of APL was confirmed, who had an Eastern Cooperative Group performance status of 0 - 2, and who were eligible for combined treatment with intensive chemotherapy and all-trans retinoic acid (ATRA), were included in the study. Study participants received induction and consolidation treatment with ATRA plus either daunorubicin or idarubicin, followed by 2 years of single-agent ATRA as maintenance therapy. Patients who were unable to pay for ATRA treatment received anthracycline-based induction and consolidation, with methotrexate plus mercaptopurine as maintenance therapy. RESULTS: A total of 360 patients from 21 public and private hospitals were included in the study. The median age of the population was 37 years, and 51% were male. Of the 360 patients, 205 (57%) vs. 155 (43%) received daunorubicin vs. idarubicin as induction treatment for APL. ATRA was administered to 201 (98%) patients in the daunorubicin group vs. 138 (89%) in the idarubicin group (P = 0.001), and was initiated at diagnosis in 92% vs. 73% of recipients, respectively (P = 0.0001). At 150 months, OS and EFS for the entire population were 84% and 79%, respectively. Both OS (90% vs. 76%, P = 0.003) and EFS (85% vs. 72%, P = 0.001) were significantly prolonged in daunorubicin vs. idarubicin recipients. Rates of complications were similar in the two groups. CONCLUSIONS: As arsenic trioxide (ATO) is not currently available in Mexico, anthracycline plus ATRA is the mainstay of treatment for APL here. Our results confirm the efficacy of this strategy, with high OS and EFS rates being observed 12.5 years after diagnosis.

CowN sustains nitrogenase turnover in the presence of the inhibitor carbon monoxide.

Nitrogenase is the only enzyme capable of catalyzing nitrogen fixation, the reduction of dinitrogen gas (N2) to ammonia (NH3). Nitrogenase is tightly inhibited by the environmental gas carbon monoxide (CO). Nitrogen-fixing bacteria rely on the protein CowN to grow in the presence of CO. However, the mechanism by which CowN operates is unknown. Here, we present the biochemical characterization of CowN and examine how CowN protects nitrogenase from CO. We determine that CowN interacts directly with nitrogenase and that CowN protection observes hyperbolic kinetics with respect to CowN concentration. At a CO concentration of 0.001 atm, CowN restores nearly full nitrogenase activity. Our results further indicate that CowN's protection mechanism involves decreasing the binding affinity of CO to nitrogenase's active site approximately tenfold without interrupting substrate turnover. Taken together, our work suggests CowN is an important auxiliary protein in nitrogen fixation that engenders CO tolerance to nitrogenase.

Long-term Survival After Heart Transplantation: A Population-based Nested Case-Control Study.

BACKGROUND: Heart transplantation is the mainstay of treatment for patients in end-stage heart failure. This study sought to contrast survival after transplantation with that of the general population to quantify standardized mortality rates using a nested case-control study design. METHODS: Control subjects were noninstitutionalized inhabitants of the United States identified through the National Longitudinal Mortality study. Case subjects were adults who underwent heart transplantation between 1990 and 2007 and identified through the Organ Procurement and Transplantation Network. Propensity-matching (5:1, nearest neighbor, caliper = 0.1) was utilized to identify suitable control subjects based on age, sex, race, and state of permanent residency. The primary study endpoint was 10-year survival. RESULTS: In all, 31,883 heart transplant recipients were matched to 159,415 noninstitutionalized residents of the United States. The 10-year survival of heart transplant recipients was 53%. The population expected mortality rate was 15.9 deaths per 100 person-years with an observed rate of 45.1 deaths per 100 person-years (standardized mortality rate [SMR] 2.84; 95% confidence interval, 2.82 to 2.87). The broadest gaps between observed and expected survival were evident in female (SMR 3.63), black (SMR 3.67), and Hispanic (SMR 4.12) recipients. Standardized mortality ratios declined over time (1990 to 1995, 3.09; 1996 to 2000, 2.90; 2001 to 2007, 2.58). The long-term standardized survival of older recipients was closest to that expected for their age. CONCLUSIONS: Heart transplant recipients have considerable long-term survival and have a threefold higher standardized long-term mortality rate than that of the noninstitutionalized population. Long-term mortality rates have consistently declined over time and will likely continue to decrease.

Treatment-Related Mortality From Infectious Complications in an Acute Leukemia Clinic.

BACKGROUND: The main causes of mortality in patients with acute leukemia are the infectious complications. The author wanted to know the induction-related mortality and treatment-related mortality in the acute leukemia patients at the Instituto Nacional de Cancerologia (INCan), Mexico. Also the author is interested in finding out the micro-organism and the main site of infection to make some changes in the management of patients in these clinics. Primary objective was induction chemotherapy-related mortality and treatment-related mortality. Secondary objective was to determine the site of infection, micro-organism, type of chemotherapy related with more mortality and relapse mortality. METHODS: This was a retrospective case-series analysis of all patients who were admitted to the INCan Acute Leukemia Clinic between January 2012 and December 2015 with febrile neutropenic complications. We reviewed the case histories of all patients, including those with acute lymphoblastic leukemia (ALL), acute myeloblastic leukemia (AML), acute biphenotypic leukemia and acute promyelocytic leukemia, regardless of disease status (newly diagnosed or relapsed) at the time of clinic attendance. Patients who died as the result of an infectious complication during the analysis window were identified, and their demographics, disease characteristics, treatment history (chemotherapy within 45 days of date of death) and details of the infectious complication resulting in death were collected. RESULTS: Of the 313 patients studied during that time period, 84 (27%) died as a result of infectious complications. Lung infections were the most common, accounting for 67% of all deaths from infectious complications. Escherichia coli producing extended-spectrum beta-lactamases was the most frequently isolated infectious organism (12 patients; 14%). The majority of deaths occurred during either induction therapy (27 patients; 32%) or treatment for a first relapse (25 patients; 30%). Hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone (hyper-CVAD) was the chemotherapy regimen most commonly received within 45 days prior to death (17 patients; 20%). CONCLUSIONS: Our findings suggest a need for long-term management and supportive care to prevent infectious complication-associated fatalities during both initial chemotherapy and subsequent disease relapse in patients with acute leukemia. The use of prophylaxis will help patients to prevent complications.

Lower Urinary Tract and Gastrointestinal Dysfunction Are Common in Early Parkinson's Disease.

PURPOSE: Autonomic dysfunction is a common nonmotor feature and early manifestation of Parkinsons disease (PD). Autonomic dysfunction in PD is associated with a worse prognosis. We sought to characterize autonomic dysfunction and identify associated factors in patients with early PD. METHODS: An observational, cross-sectional, descriptive, and analytical study was conducted to evaluate patients with early PD from the Parkinsons Progression Markers Initiative. We utilized the Scales for Outcomes in Parkinsons Disease-Autonomic dysfunction questionnaire to determine the prevalence and frequencies of autonomic symptomatology. The cohort was grouped into high and low dysautonomic scores. A regression model identified variables that independently explained dysautonomic scores in our early PD cohort. RESULTS: 414 PD patients had a mean age of 61.1 (SD 9.7) years at diagnosis and mean disease duration of 6.7 (SD 6.6) months. Among all patients, 43.7% (181/414) had high dysautonomic scores. Urinary and gastrointestinal symptoms were the most prevalent and frequently reported dysautonomic symptoms. Patients with fatigue (beta = 4.28, p < 0.001), probable rapid eye movement sleep behavior disorder (beta = 2.71, p < 0.001), excessive daytime sleepiness (beta = 1.88,p=0.039), impulsivity and compulsivity (beta = 2.42, p < 0.001), and increasing age (beta = 1.05, p < 0.001) were more likely to have high dysautonomic scores. CONCLUSION: Lower urinary tract and gastrointestinal symptoms are prevalent and frequent in early PD patients. Fatigue, sleep disorders, impulsivity and compulsivity, and age are predictors of autonomic dysfunction. Autonomic symptoms predominated in this group of early PD patients in the disease course and were associated with more severe disease.

DNA methylation changes in clonally propagated oil palm.

KEY MESSAGE: Several hypomethylated sites within the Karma region of EgDEF1 and hotspot regions in chromosomes 1, 2, 3, and 5 may be associated with mantling. One of the main challenges faced by the oil palm industry is fruit abnormalities, such as the "mantled" phenotype that can lead to reduced yields. This clonal abnormality is an epigenetic phenomenon and has been linked to the hypomethylation of a transposable element within the EgDEF1 gene. To understand the epigenome changes in clones, methylomes of clonal oil palms were compared to methylomes of seedling-derived oil palms. Whole-genome bisulfite sequencing data from seedlings, normal, and mantled clones were analyzed to determine and compare the context-specific DNA methylomes. In seedlings, coding and regulatory regions are generally hypomethylated while introns and repeats are extensively methylated. Genes with a low number of guanines and cytosines in the third position of codons (GC3-poor genes) were increasingly methylated towards their 3' region, while GC3-rich genes remain demethylated, similar to patterns in other eukaryotic species. Predicted promoter regions were generally hypomethylated in seedlings. In clones, CG, CHG, and CHH methylation levels generally decreased in functionally important regions, such as promoters, 5' UTRs, and coding regions. Although random regions were found to be hypomethylated in clonal genomes, hypomethylation of certain hotspot regions may be associated with the clonal mantling phenotype. Our findings, therefore, suggest other hypomethylated CHG sites within the Karma of EgDEF1 and hypomethylated hotspot regions in chromosomes 1, 2, 3 and 5, are associated with mantling.

Effect of Patella Alta on the Native Anatomometricity of the Medial Patellofemoral Complex: A Cadaveric Study.

BACKGROUND: Patella alta has been identified as an important risk factor for lateral patellar instability and medial patellofemoral complex (MPFC) reconstruction failure. PURPOSE: To evaluate the length changes of the MPFC at multiple possible reconstruction locations along the extensor mechanism in varying degrees of patella alta throughout knee motion. STUDY DESIGN: Controlled laboratory study. METHODS: Eight fresh-frozen cadaveric knees were used in this study. The MPFC was identified and dissected with the patellar tendon and quadriceps tendon. A custom-made jig was utilized to evaluate lengths from 0° to 90° of flexion with physiological quadriceps loading. Length was measured with a 3-dimensional robotic arm at 4 possible reconstruction locations along the extensor mechanism: the midpoint patella (MP), the MPFC osseous center (FC), the superior medial pole of the patella (SM) at the level of the quadriceps insertion, and 1 cm proximal to the SM point along the quadriceps tendon (QT). These measurements were repeated at 0°, 20°, 40°, 60° and 90° of flexion. Degrees of increasing severity of patella alta at Caton-Deschamps index (CDI) ratios of 1.0, 1.2, 1.4, and 1.6 were then investigated. RESULTS: Patella alta and MPFC attachment site location significantly affected changes in MPFC length from 0° to 90° of flexion (P< .0005). Length changes at attachment MP showed no difference when CDI 1.0 was compared with all patella alta values (CDI 1.2, 1.4, 1.6; P > .05). Similarly, FC showed no difference in length change from 0° to 90° until CDI 1.6, in contrast to proximal attachments (SM, QT), which demonstrated significant changes at CDI 1.4 and 1.6. When length changes were analyzed at each degree of flexion (0°, 20°, 40°, 60°, 90°), Spearman correlation analysis showed a moderate negative linear correlation for QT at CDI 1.0 (r= -0.484; P = .002) and 1.6 (r = -0.692; P < .0005), demonstrating constant loosening at the QT point at normal and elevated patellar height. In contrast, no differences in length were observed for MP at CDI 1.0 throughout flexion, and at CDI 1.6, there was a difference only at 0° (P < .05). Points FC and MP at CDI 1.6 had similar length change properties to points SM and QT at CDI 1.0 (P > .05), suggesting that distal attachments in the setting of patella alta may provide similar length changes to proximal attachmentswith normal height. CONCLUSION: Anisometry of the MPFC varies not only with attachment location on the extensor mechanism but also with patellar height. Increased patellar height leads to more significant changes in anisometry in the proximal MPFC attachment point as compared with the distal component. In the setting of patella alta, including a CD ratio of 1.6, the osseous attachments of the MPFC remain nearly isometric wheras the proximal half length changes increase significantly. CLINICAL SIGNIFICANCE: The results of this study support the idea that the MPFC should be considered as 2 separate entities (proximal medial quadriceps tendon femoral ligament and distal medial patellofemoral ligament) owing to their unique length change properties.

Effect of Vertical or Beveled Chondral Defect Creation on Rim Deformation and Contact.

OBJECTIVE: To determine biomechanical effects of knee cartilage defect perimeter morphology based on cartilage strain and opposing subchondral bone contact. DESIGN: Articular cartilage defects were created in 5 bovine femoral condyles: group 1, 45° inner bevel with 8-mm rim; group 2, vertical with 8-mm rim; and group 3, 45° outer bevel with 8-mm base. Samples were placed into a custom-machined micro-computed tomography tube and subjected to 800 N of axial loading. DICOM data were used to calculate cartilage thickness 4 and 6 mm from the center, distance between tibial cartilage surface and femoral subchondral bone, and contact width between tibial cartilage and subchondral bone. Strain 4 mm from the center and both absolute and change in distance (mm) to subchondral bone were compared between groups 1 and 2 using paired t tests. Strain at 6 mm and distance changed, loaded distance, and contact width (mm) were compared between groups using the Friedman test with post hoc analysis using Wilcoxon signed rank test. RESULTS: No significant differences in rim strain were noted between groups 1 and 2 at 4 mm ( P = 0.10) and between groups 1, 2, and 3 at 6 mm ( P = 0.247) from the defect center. The loaded distance was significantly different between groups 1 and 3 ( P = 0.013). No significant change in distance to the subchondral bone was found between groups ( P = 0.156). The difference in subchondral bone contact area approached but did not reach significance ( P = 0.074). CONCLUSION: When debriding focal articular cartilage defects, establishment of an inner bevel decreases tissue deformation and contact with opposing subchondral bone.

El concepto dialéctico de internalización en Vygotski: aproximaciones a un debate / O conceito dialético de internalização em Vygotsky: aproxima-se de um debate / Vygotski's dialectic concept of internalization: approaches to an debate

Resumen El artículo presenta algunos aspectos centrales del debate contemporáneo en torno a la noción de internalización de L. S. Vygotski, intentando una lectura coherente con las premisas teóricas y epistemológicas de la tradición histórico-cultural. Se argumenta que en el corazón de la crítica a la noción de internalización -basada en señalar su dualismo- subyacen supuestos igualmente dualistas, que determinan interpretaciones alejadas de la noción de internalización genuinamente vygotskiana, arraigada ésta en la filosofía de tradición dialéctica. Se defiende que es necesario reconocer esta dimensión filosófico-epistemológica para llegar a una noción de internalización que permita tanto superar el dualismo, como constituirse en herramienta útil para el tratamiento de diversos problemas en psicología.

Abstract The article presents some central aspects of the contemporary debate on the L.S. Vygotski's notion of internalization, attempting a coherent reading with the theoretical and epistemological premises of the historical-cultural tradition. It is argued that at the heart of the critique of the notion of internalization - based on its dualism - underlies equally dualistic assumptions, which determine interpretations that are far from the genuinely vygotskian notion of internalization, rooted in the dialectical philosophy. It is proposed that it is necessary to recognize this philosophical-epistemological dimension to arrive at a notion of internalization that allows both to overcome the dualism, and to become a useful tool for the treatment of several problems in psychology.

Resumo O artigo apresenta alguns aspectos centrais do debate contemporâneo em torno da noção de internalização de L. S. Vygotsky, tentando ler coerentemente as premissas teóricas e epistemológicas da tradição histórico-cultural. Argumenta-se que, no centro da crítica da noção de internalização, baseada em apontar seu dualismo - subjacente a pressupostos igualmente dualistas, que determinam as interpretações para longe da noção de internalização genuinamente vygotskana, enraizada na filosofia da tradição dialética. Defende-se que é necessário reconhecer essa dimensão filosófico-epistemológica para chegar a uma noção de internalização que permita tanto superar o dualismo como se tornar uma ferramenta útil para o tratamento de vários problemas na psicologia.

Efficacy of hydralazine and valproate in cutaneous T-cell lymphoma, a phase II study.

OBJECTIVES: To evaluate the activity and safety of hydralazine and valproate (Transkrip) in cutaneous T-cell lymphoma (CTCL). METHODS: Previously untreated and progressive/refractory CTCL patients received hydralazine at 83 mg or 182 mg/day for slow and rapid acetylators respectively plus magnesium valproate at a total dose of 30 mg/Kg t.i.d daily in continuous 28-day cycles in this phase II study. The primary objective was overall response rate (ORR) measured by the modified severity weighted assessment tool (m-SWAT), secondary end-points were time to response (TTR), time to progression (TTP), duration of response (DOR), progression-free survival (PFS), overall survival (OS) and safety. RESULTS: Fourteen patients were enrolled (7 untreated and 7 pretreated). ORR was 71% with 50% complete and 21% partial. Two had stable disease and two progressed. At a median follow-up of 36 months (5-52), median TTR was 2 months (1-4); median DOR was 28 months (5-45); median PFS 36 and not reached for OS. There were no differences in median TTR, DOR, and PFS between treated and pretreated patients. Pruritus relieve was complete in 13 out of 14 patients. No grade 3 or 4 toxicities were observed. CONCLUSION: The combination of hydralazine and valproate is safe, very well tolerated and effective in CTCL.

Tratamiento prostodóntico de pacientes con displasia ectodérmica hipohidrótica: reporte de dos casos / Prosthodontic treatment of patients aflicted with hypohidrotic ectodermal dysplasia: Report of two cases

Resumen: La displasia ectodérmica es un desorden hereditario caracterizado por un desarrollo anormal de ciertos tejidos y estructuras de origen ectodérmico. La forma más comúnmente observada de displasia ectodérmica es del tipo hipohidrótica. El diagnóstico se basa en la ausencia o disminución de glándulas sudoríparas. Comúnmente es una condición complicada en cuanto al tratamiento odontológico de las deficiencias orales características de este síndrome. Es importante que estas personas reciban atención dental a temprana edad por razones fisiológicas y psicosociales. Este reporte clínico describe las características y el tratamiento prostodóntico de dos hermanos con displasia ectodérmica hipohidrótica.

Abstract: Ectodermal dysplasia is a hereditary disorder characterized by the abnormal development of certain ectodermal-origin tissues and structures. Hypohidrotic type is the most commonly observed form of ectodermal dysplasia. Diagnosis is based on the absence or decrease of sweat glands. Dental treatment of oral deficiencies characteristic of this syndrome is commonly quite complex. Physiological and psychosocial reasons dictate the importance for these patients to receive dental treatment at early ages. The present clinical report describes characteristics and prosthodontics treatment of two siblings afflicted with hypohidrotic ectodermal dysplasia.