Chromatin and transcriptional regulators act in a cascade to establish a bilateral asymmetry of the C. elegans nervous system

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, February 2011.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections."October 2010." Student received a Ph. D. per February 2011 MIT Degree List, Office of the Registrar. Cataloged from student-submitted PDF version of thesis.Includes bibliographical references.Neuroanatomical bilateral asymmetry is a widespread feature in both vertebrates and invertebrates. Although mostly bilaterally symmetric, the nervous system of Caenorhabditis elegans displays bilateral asymmetry. Bilateral asymmetry in C. elegans arises in part from left-right asymmetric cell lineages. The single left-right unpaired MI neuron is normally generated from the right side of an otherwise left-right symmetric cell lineage that on the left gives rise to the e3D epithelial cell. We performed genetic screens and isolated mutants that displayed symmetry in this normally asymmetric cell lineage, with the MI neuron transformed into an e3D-like cell. We identified that a C. elegans Otx homeodomain protein CEH-36 and two basic helix-loop-helix proteins NGN-1 and HLH-2 promote the generation of the MI neuron and are required to establish the bilateral asymmetry in this cell lineage. We found that CEH-36 is asymmetrically expressed and is present in an MI precursor cell on the right but not in an e3D precursor cell on the left. This bilaterally asymmetric CEH-36 expression in turn promotes asymmetric NGN-1 and HLH-2 expression, leading to the generation of the MI neuron on the right side of the cell lineage. The Otx/bHLH transcriptional cascade is evolutionarily conserved, and our results suggest that this transcriptional cascade plays a role in establishing neuroanatomical bilateral asymmetry in other animals. We also discovered that a mutation in a replication-dependent histone H3 gene his-9 transforms the MI neuron into an e3D-like cell. This mutant allele of his-9 causes an altered-function activity that is predicted to impair the interaction of the mutant HIS-9 protein with another histone H3 molecule and inhibit the formation of a histone H3-H4 tetramer. Replication-dependent histones H3-H4 are deposited onto replicating DNA by the heterotrimeric protein complex CAF-1. We observed that loss of function of each of three genes encoding members of the C. elegans CAF-1 complex transformed MI into an e3D-like cell. We propose that CAF-1-mediated nucleosome formation is impaired by the presence of mutant HIS-9 proteins that are unable to form the histone H3-H4 heterotetramer. We also found that two histone-modifying enzymes SET-16 and UTX-1 are required to establish the bilateral asymmetry in this cell lineage. set-16 encodes a protein homologous to the human MLL protein, a histone methyltransferase specific for histone H3 lysine 4, and utx-1 encodes a protein homologous to human UTX protein, a histone demethylase specific for histone H3 lysine 27. Our results reveal a novel mechanism of establishing neuroanatomical bilateral asymmetry and suggest that nucleosome formation and histone H3 modification are required to establish this bilateral asymmetry.by Shunji Nakano.Ph.D

Clinical outcome of tapered wedge stem

The purpose of this study is to evaluate the results and intraoperative or postoperative complications of primary total hip arthroplasty (THA) using a contemporary tapered wedge titanium femoral component. A total of 213 THAs in 187 patients were followed up more than 5 years (mean, 102 months ; range, 60-150). The mean age at surgery was 64.2 years (range, 20–89 years). These patients were clinically evaluated using the JOA scoring system and radiographically host bone reactions around the implants, as well as femoral loosening. The mean JOA score improved from 49 (range, 21–75) to 92 (range, 59–100). All 12 patients with poor results (JOA < 75) coexisted with cerebral, spinal, joint, and musculoskeletal disorders. At the final follow-up, implant survival was 100%. Complications occurred in 23 hips. They consisted of 12 hips with intra-operative fractures, 2 hips with sciatic nerve palsy, one hip with infections, 3 hips with recurrent dislocations, and 8 hips with aseptic cup loosening. In conclusion, we have shown excellent survival rate of the contemporary tapered wedge stem in primary THA ; however, patients with coexisting diseases could not acquire sufficient improvement in hip function and ambulatory ability

Efectos de la edad y el sexo sobre la memoria espacial de ratas Wistar en el laberinto radial de 8 brazos

Trabajo de InvestigaciónEl presente estudio tuvo como objetivo evaluar el desempeño de 24 ratas Wistar en una tarea de memoria espacial, según las características de sexo y edad (ratas jóvenes y ratas adultas). Para este fin, se llevó a cabo una fase inicial de habituación de 10 minuto diarios en el laberinto radial de Olton, y una fase de entrenamiento de una tarea de memoria espacial durante 27 sesiones.INTRODUCCIÓN Y ASPECTOS GENERALES 1. RESUMEN 2. JUSTIFICACIÓN 3. MARCO TEÓRICO 4. MÉTODO 5. RESULTADOS 6. DISCUSIÓN Y CONCLUSIONES BIBLIOGRAFÍA ANEXOSPregradoPsicólog

Cathepsins B and L in synovial fluids from patients with rheumatoid arthritis and the effect of cathepsin B on the activation of pro-urokinase

To clarify the pathophysiological role of cathepsins in rheumatoid arthritis (RA), we investigated whether cathepsin B or cathepsin L was increased in synovial fluid (SF) of RA joints, and whether the cathepsin isolated from SF of RA patients activated pro-urokinase or not. Thus, we estimated the content of cathepsins in SF of RA patients by measuring their activities by fluorospectrometry, using Z-Phe-Arg-MCA as the substrate. Cathepsin activity was approxymately 4-fold higher in the SF of RA patients than in those of patients with osteoarthritis. Cathepsin B and cathepsin L were separated by cation-exchange column chromatography. As a result, a large peak corresponding to cathepsin B and a very small peak correponding to cathepsin L were detected. Biochemical sequential fractionation of the cathepsin purified from the SF showed that the large peak was mainly composed of cathepsin B. This purified enzyme induced conversion of pro-urokinase to urokinase, and the Km for pro-urokinase was approximately 8.27μM. These findings indicated that an imbalance between cathepsin B and its inhibitors occurred due to increased concentrations of active cathepsin B in RA articular lesions, and that cathepsin B might be related to the degradation of cartilage in RA by activating the fibrinolytic cascade

Natural history of extruded lumbar intervertebral disc herniation

We studied the natural history of extruded lumbar intervertebral discs using MRI. Forty-nine patients with lumbar disc herniation were included in this study. Ages ranged from 19 to 57. On the T2-weighted sagittal MR image, the signal intensity in the herniated mass was measured and the ratio to that in the original nucleus (i.e, nucleus pulposus from which they extruded) was calculated (signal intensity ratio ; SIR). The relationship with SIR and duration of illness was evaluated. In ten patients who were re-examined by MRI after conservative treatment, the size of the herniation measured by T1-weighted axial MR image was compared before and after treatment. The signal intensity of HNP became higher than that of the original nucleus immediately following herniation and thereafter decreased with time, suggesting that initial hydration of the HNP occurred shortly after herniation followed by dehydration of the HNP. The size of the HNP with a SIR value of 1.2 and higher on T2-weighted MR images decrease with time, however, the HNP with a SIR below 1.2 did not show any size reduction. The SIR of 1.2 and higher is a good indicator predicting spontaneous reduction of the HNP. Dehydration in the HNP may play an important role in the reduction of the lumbar disc herniation

Early ambulation after total knee arthroplasty prevents patients with osteoarthritis and rheumatoid arthritis from developing postoperative higher levels of D-dimer

This study aimed to clarify the therapeutic effects of postoperative ambulation after total knee arthroplasty (TKA) on deep venous thrombosis (DVT) in patients with osteoarthritis (OA) and rheumatoid arthritis (RA) after TKA. Subjects of this study were thirty-seven inpatients (21 inpatients : OA, 16 inpatients : RA) undergoing TKA (32 female and 5 male). Subjects were divided into two groups, deep venous thrombosis (DVT) group (n=25) and non-DVT group (N group, n=12). The cutoff value was 10.0 g/ml plasma D-dimer level measured on 7th postoperative day. The N group was below the cutoff value. Another cutoff value divided into two groups, ambulatory group (n=26) and non-ambulatory group (n=11). Ambulatory group was the date of ambulation beginning below 7th day. Statistical analysis confirmed that all subjects showed a significant correlation to the date of ambulation. Postoperative ambulation beginning had strong association with the level of D-dimer (r=0.71). Group comparison showed that the non-ambulatory group had significant higher values of D-dimer than ambulatory group (P=0.022). Typical case supported these results. Postoperative early ambulation within a week after TKA kept patients with OA and RA after TKA lower level of D-dimer

整形外科予定手術患者における鼻腔黄色ブドウ球菌保菌調査 : 保菌者と非保菌者間で手術部位感染発生を比較

Background: Staphylococcus aureus (S. aureus), including MRSA, is considered to be the leading cause of surgical site infection (SSI) after orthopedic surgery. We screened for nasal carriers of S. aureus among patients who were scheduled to undergo orthopedic surgery at our hospital to reveal the effect of nasal S. aureus carriage on SSI. Our study design clearly has the intent of finding S. aureus nasal carriage and eradicating MRSA when found, and this strategy is to verify whether it's effective for preventing orthopedic surgical infections. Methods: Subjects were 4148 patients who underwent preoperative screening for nasal carrier and subsequently underwent orthopedic surgery during a 7-year period between April 2007 and March 2014. The incidence of SSI among patients who were operated in our department was investigated, and the rates were compared between patients with and without nasal carriage to reveal the effect of preoperative nasal carriage on SSI. Results: In total, 1036 patients were nasal carriers of S. aureus (carriage rate, 25.0%), whereas 140 patients carried MRSA (carriage rate, 3.4%). SSI developed in 24 patients [incidence, 0.58% (24/4148)] consisting of 12 non-carriers [0.39% (12/3112)] and 12 carriers [1.16% (12/1036)] with a significant difference in the incidence between the groups. Among 24 cases of SSI, more than half (13 cases) were caused by bacterial species other than S. aureus or those that could not be detected by the tests used. Only 7 patients out of 24 SSI patients, S. aureus was the bacterium detected in preoperative nasal cultures and the causal bacterium for SSI (concordance rate of 29.2%) Conclusions: It was difficult to reduce the incidence rate of SSI in eradication group to the same level as nasal culture negative group. However, nasal carriage of S. aureus or MRSA may be a risk factor for SSI in orthopedic surgery

Lenvatinib for Anaplastic Thyroid Cancer

Background: Lenvatinib has been approved by regulatory agencies in Japan, the United States, and the European Union for treatment of radioiodine-refractory differentiated thyroid cancer (RR-DTC). Thyroid cancer, however, is a clinically diverse disease that includes anaplastic thyroid cancer (ATC), the subtype associated with the highest lethality. Effective therapy for ATC is an unmet need. Patients and methods: This phase 2, single-arm, open-label study in patients with thyroid cancer, including ATC, RR-DTC, and medullary thyroid cancer was conducted from 3 September 2012 to 9 July 2015. Patients received lenvatinib 24 mg daily until disease progression or development of unacceptable toxicity. The primary endpoint was safety, and the secondary endpoint was efficacy, as assessed by progression-free survival (PFS), overall survival (OS), and objective response rate. Results: At data cutoff, 17 patients with ATC were enrolled. All experienced >= 1 treatment-emergent adverse event (TEAE). The most frequent TEAEs were decreased appetite (82%), hypertension (82%), fatigue (59%), nausea (59%), and proteinuria (59%). Of note, only one patient required lenvatinib withdrawal because of a TEAE, and this TEAE was considered unrelated to lenvatinib. The median PFS was 7.4 months [95% confidence interval (CI): 1.7-12.9], the median OS was 10.6 months (95% CI: 3.8-19.8), and the objective response rate was 24%. Conclusion: In this study, lenvatinib demonstrated manageable toxicities with dose adjustments and clinical activity in patients with ATC. This clinical activity of lenvatinib warrants further investigation in ATC