A Mechanically Resilient Soft Hydrogel Improves Drug Delivery for Treating Post-Traumatic Osteoarthritis in Physically Active Joints.

Intra-articular delivery of disease-modifying osteoarthritis drugs (DMOADs) is likely to be most effective in early post-traumatic osteoarthritis (PTOA) when symptoms are minimal and patients are physically active. DMOAD delivery systems therefore must withstand repeated mechanical loading without affecting the drug release kinetics. Although soft materials are preferred for DMOAD delivery, mechanical loading can compromise their structural integrity and disrupt drug release. Here, we report a mechanically resilient soft hydrogel that rapidly self-heals under conditions resembling human running while maintaining sustained release of the cathepsin-K inhibitor L-006235 used as a proof-of-concept DMOAD. Notably, this hydrogel outperformed a previously reported hydrogel designed for intra-articular drug delivery, used as a control in our study, which neither recovered nor maintained drug release under mechanical loading. Upon injection into mouse knee joints, the hydrogel showed consistent release kinetics of the encapsulated agent in both treadmill-running and non-running mice. In a mouse model of aggressive PTOA exacerbated by treadmill running, L-006235 hydrogel markedly reduced cartilage degeneration. To our knowledge, this is the first hydrogel proven to withstand human running conditions and enable sustained DMOAD delivery in physically active joints, and the first study demonstrating reduced disease progression in a severe PTOA model under rigorous physical activity, highlighting the hydrogel's potential for PTOA treatment in active patients.

Evaluation of efficacy and safety in the use of cytarabine for mobilization of hematopoietic stem cells in a reference hospital in northeastern Brazil.

Autologous hematopoietic stem cell transplantation (Auto-HSCT) is widely used in the treatment of patients with hematological neoplasms. Since these cells circulate in small quantities in the periphery, the use of regimens that promote their mobilization is essential. In this study, we retrospectively evaluated the efficacy and safety of using intermediate doses of cytarabine (1.6 g/m²) + filgrastim (10 mcg/kg/day) in the mobilization of stem cells in 157 patients treated by the Unified Health System at the Hematology and Bone Marrow Transplant Service of the Hospital Real Português de Beneficência, in Recife, Pernambuco. The sample included patients with multiple myeloma (MM) (58.6 %), lymphomas (29.9 %), and other neoplasms (11.5 %). The target of 2.0 × 10 6 CD34+ cells/kg was achieved by 148 (94.3 %) patients, in most cases (84.1 %) in a single apheresis and the median number of cells collected was 9.5 × 10 6 CD34+ cells/kg. No episode of febrile neutropenia was observed, however, 79 patients (50.3 %) required platelet transfusion (no cases attributed to bleeding). The median engraftment time was 11 days. Given these results, we suggest that the use of intermediate doses of cytarabine, combined with filgrastim, is safe and effective in mobilizing hematopoietic stem cells (HSCs).

Morphological and functional cardiac alterations in children with congenital Zika syndrome and severe neurological deficits.

INTRODUCTION: Zika virus infection during pregnancy causes fetal microcephaly and brain damage. Congenital Zika syndrome (CZS) is characterized by systemic involvement with diffuse muscle impairment, a high frequency of arthrogryposis, and microphthalmia. Cardiac impairment in CZS has rarely been evaluated. Our study assessed morphology and biventricular cardiac function in children with CZS and advanced neurological dysfunction. METHODS: This cross-sectional study was conducted on 52 children with CZS (Zika group; ZG) and 25 healthy children (control group; CG) in Paraiba, Brazil. Clinical evaluation, electrocardiogram (EKG), and transthoracic echocardiogram (TTE) were performed on all children. Additionally, troponin I and natriuretic peptide type B (BNP) levels, the degree of cerebral palsy, and neuroimaging findings were assessed in the ZG group. RESULTS: The median age of the study population was 5 years in both groups, and 40.4% (ZG) and 60% (CG) were female. The most prevalent electrocardiographic alteration was sinus arrhythmia in both the ZG (n = 9, 17.3%) and CG (n = 4, 16%). The morphological parameters adjusted for Z score were as follows: left ventricular (LV) end-diastolic diameter in ZG: -2.36 [-5.10, 2.63] vs. CG: -1.07 [-3.43, 0.61], p<0.001); ascending aorta (ZG: -0.09 [-2.08, 1.60] vs. CG: 0.43 [-1.47, 2.2], p = 0.021); basal diameter of the right ventricle (RV) (ZG: -2.34 [-4.90, 0.97] vs. CG: -0.96 [-2.21, 0.40], p<0.01); and pulmonary artery dimension (ZG: -2.13 [-5.99, 0.98] vs. CG: -0.24 [-2.53, 0.59], p<0.01). The ejection fractions (%) were 65.7 and 65.6 in the ZG and CG, respectively (p = 0.968). The left atrium volume indices (mL/m2) in the ZG and CG were 13.15 [6.80, 18.00] and 18.80 [5.90, 25.30] (p<0.01), respectively, and the right atrium volume indices (mL/m2) were 10.10 [4.90, 15.30] and 15.80 [4.10, 24.80] (p<0.01). The functional findings adjusted for Z score were as follows: lateral systolic excursion of the mitral annular plane (MAPSE) (ZG: 0.36 [-2.79, 4.71] vs. CG: 1.79 [-0.93, 4.5], p = 0.001); tricuspid annular plane systolic excursion (TAPSE) (ZG: -2.43 [-5.47, 5.09] vs. CG: 0.07 [-1.98, 3.64], p<0.001); and the S' of the RV (ZG: 1.20 [3.35, 2.90] vs. CG: -0.20 [-2.15, 1.50], p = 0.0121). No differences in biventricular strain measurements were observed between the groups. Troponin I and BNP levels were normal in in the ZG. Grade V cerebral palsy and subcortical calcification were found in 88.6% and 97.22% of children in the ZG group, respectively. CONCLUSION: A reduction in cardiac dimensions and functional changes were found in CZS patients, based on the TAPSE, S' of the RV, and MAPSE, suggesting the importance of cardiac evaluation and follow-up in this group of patients.

The Role of AKT3 Copy Number Changes in Brain Abnormalities and Neurodevelopmental Disorders: Four New Cases and Literature Review.

Microdeletions at 1q43-q44 have been described as resulting in a clinically recognizable phenotype of intellectual disability (ID), facial dysmorphisms and microcephaly (MIC). In contrast, the reciprocal microduplications of 1q43-q44 region have been less frequently reported and patients showed a variable phenotype, including macrocephaly. Reports of a large number of patients with copy number variations involving this region highlighted the AKT3 gene as a likely key player in head size anomalies. We report four novel patients with copy number variations in the 1q43-q44 region: one with a larger deletion (3.7Mb), two with smaller deletions affecting AKT3 and SDCCAG8 genes (0.16 and 0.18Mb) and one with a quadruplication (1Mb) that affects the entire AKT3 gene. All patients with deletions presented MIC without structural brain abnormalities, whereas the patient with quadruplication had macrocephaly, but his carrier father had normal head circumference. Our report also includes a comparison of phenotypes in cases with 1q43-q44 duplications to assist future genotype-phenotype correlations. Our observations implicate AKT3 as a contributor to ID/development delay (DD) and head size but raise doubts about its straightforward impact on the latter aspect of the phenotype in patients with 1q43-q44 deletion/duplication syndrome.

In Situ Leukemia as Manifestation of Relapse After Allogeneic Transplantation of Bone Marrow of ALL B: A Case Report.

Acute lymphoid leukemia (ALL) is a malignant proliferation of abnormal lymphoid precursors in the bone marrow. It is the most common acute leukemia in childhood, accounting for only 20% of acute leukemia in adults. The clinical presentation is heterogeneous including pallor, fatigue and weakness. Diagnosis is performed through myelogram, bone marrow biopsy and immunophenotyping. Chemotherapy and, in some cases, bone marrow transplantation (BMT) are used to treat the disease. However, the efficacy of treatment in adult patients is still below expected and therapeutic innovations have not increased disease-free survival. In addition, about 20% of patients have relapse, usually generalized, of the disease. This article aims to report the case of a patient previously treated for ALL B presenting localized medullar relapse or in situ leukemia.

Improvement of thrombocytopenia after treatment for Helicobacter pylori in a patient with immunologic thrombocytopenic purpura.

Immune thrombocytopenic purpura is the most common autoimmune hematologic disease, affecting individuals of different ages. Recently, the bacterium Helicobacter pylori entered the list of causes of immune thrombocytopenic purpura. Here we present the case of a 55-year-old female patient with low platelet counts initially attributed to chronic vaginal bleeding. As corticosteroid therapy was ineffective she was treated for H. pylori infection. Within four weeks the patient had a platelet count of 87.17 ×10(9)/L accompanied by clinical improvement of the symptoms.

Improvement of thrombocytopenia after treatment for Helicobacter pylori in a patient with immunologic thrombocytopenic purpura

Immune thrombocytopenic purpura is the most common autoimmune hematologic disease, affecting individuals of different ages. Recently, the bacterium Helicobacter pylori entered the list of causes of immune thrombocytopenic purpura. Here we present the case of a 55-year-old female patient with low platelet counts initially attributed to chronic vaginal bleeding. As corticosteroid therapy was ineffective she was treated for H. pylori infection. Within four weeks the patient had a platelet count of 87.17 ×109/L accompanied by clinical improvement of the symptoms.

Distributed coordination of heterogeneous agents using a semantic overlay network and a goal-directed graphplan planner.

In this paper, we describe a distributed coordination system that allows agents to seamlessly cooperate in problem solving by partially contributing to a problem solution and delegating the subproblems for which they do not have the required skills or knowledge to appropriate agents. The coordination mechanism relies on a dynamically built semantic overlay network that allows the agents to efficiently locate, even in very large unstructured networks, the necessary skills for a specific problem. Each agent performs partial contributions to the problem solution using a new distributed goal-directed version of the Graphplan algorithm. This new goal-directed version of the original Graphplan algorithm provides an efficient solution to the problem of "distraction", which most forward-chaining algorithms suffer from. We also discuss a set of heuristics to be used in the backward-search process of the planning algorithm in order to distribute this process amongst idle agents in an attempt to find a solution in less time. The evaluation results show that our approach is effective in building a scalable and efficient agent society capable of solving complex distributable problems.

Estudo longitudinal dos sinais e sintomas de disfunção temporomandibular frente a tratamento conservador com placa estabilizadora em clínica de graduação / Longitudinal study of signs and symptoms of temporomandibular dysfunction aftre conservative tretment with stabilizing splints by undergraduate students

Objetivo: Avaliar longitudinal a eficácia da terapia oclusal em pacientes com Disfunção Temporomandibular (DTM) atendidos em clínica de graduação de curso de Odontologia. Materiais e Métodos: Os indivíduos foram examinados clinicamente utilizando-se o índice internacional Research DiagnosticCriteria for Temporomandibular Disorders (RDC/TMD) na época de seu atendimento (T0) e reavaliados 6meses após o início do tratamento com placas estabilizadoras (T1). Dezesseis pacientes participaram das duasavaliações. Oitenta e oito por cento dos pacientes examinados eram do sexo feminino. Foram avaliados os seguintes parâmetros: 1) Dor: através de Escala VAS (dor no momento da avaliação, dor média nos últimos 6 meses e pior dor nos últimos 6 meses), 2) Amplitude dos movimentos mandibulares (abertura bucal, protrusão e lateralidade); 3) Sons articulares (clique, crepitação) e 4) Sensibilidade à palpação dos músculos mastigatórios e da articulação temporomandibular. Os dados foram comparados entre os dois momentos utilizando-se o teste “t” pareado ou Wilcoxon. Correlação de Pearson foi realizada entre as variáveis dor e amplitude dos movimentos mandibulares. O índice de significância foi ajustado em p<0,05. Resultados: Houve melhora significativa entre as duas sessões para as variáveis relacionadas à dor e amplitude dos movimentos mandibulares (p<0,05), exceto protrusão (p=0,438). Houve correlação negativa significativa somente entre a dor média e aamplitude da abertura bucal antes do tratamento (p<0,05). Após o tratamento, essa correlação não persistiu (p>0,05). Conclusões: As placas oclusais lisas planas mostraram melhora significativa para a dor e amplitude dos movimentos mandibulares, mostrando ser um tratamento eficiente a ser realizado em clínicas de graduação para pacientes com dor miofascial e deslocamento de disco.

Dispositivo intra-uterino ectópico intra-vesical / Intrauterine device in the vesical bladder

Paciente com colocação de dispositivo intra- uterino há quatro anos, relata há dois anos episódios de dores abdominais e hematúria macroscópica. Ao ultra-som transvaginal verificou-se bexiga urinária contendo material fixo à parede durante as manobras de mudança de decúbito. Realizou-se cirurgia para retirada do material que ao exame anatomo-patológico confirmou-se ser dispositivo intra-uterino ectópico.

Patient placement of intra-uterine device four years ago, reported two years ago episodes of abdominal pain and blood in their urine. To the transvaginal ultrasound urinary bladder was found containing some fixed to the wall during the shunting of a change of position. There was surgery to remove the foreign body that the anatomical and pathological examination confirmed to be the intrauterine device ectopic.

Intermittent ureterovesical junction obstruction in children.

While intermittent ureteropelvic junction obstruction is well recognized clinically, intermittent obstruction at the ureterovesical junction has not been previously described. We herein present a case report of intermittent ureterovesical junction obstruction, characterized by intermittent hydroureteronephrosis on ultrasonography and symptoms of flank/abdominal pain, nausea and vomiting.

Morphology of mitochondrial permeability transition: morphometric volumetry in apoptotic cells.

Here we report on the mitochondrial permeability transition (MPT), which refers to the morphology of mitochondria whose inner membrane has lost its selective permeability. In all types of apoptotic cells so far examined, we found outer mitochondrial membranes that had been ruptured. These mitochondria present a swollen matrix covered by an inner membrane herniating into the cytoplasm through the breached outer membrane. Similarly ruptured outer mitochondrial membranes have been reported in studies on mitochondrial fractions induced to undergo MPT, carried out by others. Our observations were made on five types of rat tissue cells and six different cultured cell lines in the early stages of apoptosis. Samples from the cell lines HL-60, HeLa, WEHI-164, and a special batch of PC-12 cells were subjected to various apoptogenic agents and analyzed morphometrically. Nonapoptotic companion cells with unaltered nuclear structure (CUNS) were also analyzed. The mitochondrial volume in microm(3) and the volume fraction of the cytoplasm occupied by mitochondria in cells with typical nuclear signs of apoptosis and also in CUNS were evaluated. The volume of the mitochondria with ruptured membrane represents at least 69% (47-89%) of the total mitochondrial volume of the apoptotic cells. Thus, a considerable fraction of the cellular mitochondrial mass is or was in the state of permeability transition and probably involved in enhancement of the apoptotic program. In all samples, a fraction of the cells with normal nuclei possessed mitochondria with breached outer membranes as described above. In these cells, MPT occurred before the appearance of the typical nuclear phenotype of the apoptotic cells.

[Choroidal type aneurysmal malformation of the vein of Galen associated with Dandy-Walker malformation in an adult]. / Malformação aneurismática da veia de Galeno do tipo coroidal num adulto associada a malformação de Dandy-Walker.

Lasjaunias differentiated true vein of Galen aneurysmal malformations (MAVG), which drain to the median prosencephalic vein of Markowski, the embryonic precursor of the vein of Galen, from the aneurysmal dilatations of vein of Galen (VGDA), which reveal venous drainage into a dilated vein of Galen, but already formed. In angioarchitectural terms, MAVG can still be divided in two subtypes: the mural form and the choroidal form, the most common. The authors describe the clinical case of a 18 years-old female, without symptoms until July 2001, who presented an episode of impaired equilibrium associated with vomits and non-specific vision disturbances. This episode had an approximate duration of 6-8 hours with complete recovery. Neuroimaging studies were performed including CT, MRI and digital angiography, disclosed an aneurysmal vein of Galen malformation of choroidal type and Dandy-Walker malformation, association that the authors couldn't found so far described in the literature.