Empathy plays a crucial role in our relationships with others and enhances personal well-being. The brain areas that are critical for the experience of on-line empathy and empathic behavior are not known. The current study investigated the neural substrates of empathy through the examination of whether the ventromedial prefrontal cortex (VMPC) is critical for empathy. For the first time, on-line empathic experience and behavior were measured in patients with brain damage to the VMPC. Six patients with bilateral damage to the VMPC were case-matched on specific demographic and neuropsychological criteria to two comparison groups: a brain damage group and a healthy adult group. On-line empathy was induced in an ecologically-valid manner in which the participant experienced live the sorrow of another person. The participant thought they would be playing an economic game against two opponents. However, during the study the participant overheard their game opponent experience deep sadness, revealing that it was the anniversary of their son's death (empathic induction.) A comparison neutral induction involved the participant overhearing their opponent converse with the research assistant about a neutral topic. On-line empathic experience was measured by a questionnaire completed before and after the inductions. Empathic behavior was measured implicitly through an economic game. It was defined as the degree of behavioral change on the game as a result of the empathic induction (after accounting for baseline behavior.) The economic game used to measure empathic behavior was the Repeated Fixed Opponent variant of the well-validated Ultimatum Game. This particular variant had not been studied in participants of a similar age range to the patient sample (younger and older adults). Furthermore, there is evidence for some aging-related differences in behavior on economic games, providing additional rationale to examine the behavior of healthy younger and older adults on the game. Consequently, game behavior of younger and older adults was measured and then used to implement a model of healthy game behavior in the experiment that investigated empathy in patients with damage to the VMPC. Patients with damage to the VMPC experienced poor on-line empathy and showed poor empathic behavior. Patients with brain damage to the VMPC reported significantly less on-line empathy than patients with brain damage to other regions. Empathic behavior was not shown by patients with damage to the VMPC as a result of the empathic induction and their behavior was significantly different from both the healthy and the brain damage comparison groups which showed increased empathic behavior due to the empathic induction. A specific role for the VMPC region in empathy was demonstrated by the finding that patients with damage to this region had less on-line empathy and empathic behavior than patients with brain damage to other regions. This study showed that the VMPC region of the brain is critical for empathy. Further research is needed to elucidate whether patients with brain damage to the VMPC show decreased empathic behavior in all domains or whether it is specific to monetary decision-making.

To transfer the information in the genome from mother cell to daughter cell, the DNA replication must be carried out only once and with very high fidelity prior to every cell division. In yeast there are several different DNA polymerases involved in DNA replication and/or DNA repair. The two replicative DNA polymerases, DNA polymerase delta (Pol delta) and DNA polymerase epsilon (Pol epsilon), which both include a proofreading 3´→5´exonuclease activity, can replicate and proofread the genome with a very high degree of accuracy. The aim of this thesis was to gain a better understanding of how the enigmatic DNA polymerase epsilon participates in DNA transactions. To investigate whether Pol epsilon or Pol delta is responsible for the synthesis of DNA on the lagging strand, the processing and assembly of Okazaki fragments was studied. Pol delta was found to have a unique property called “idling” which, together with the flap-endonuclease (FEN1), maintained a ligatable nick for DNA ligase I. In contrast, Pol epsilon was found to lack the ability to “idle” and interact functionally with FEN-1, indicating that Pol epsilon is not involved in processing Okazaki fragments. Together with previous genetic studies, it was concluded that Pol delta is the preferred lagging strand polymerase, leaving Pol epsilon to carry out some other function. The structure of Pol epsilon was determined by cryo-electron microscopy, to a resolution of ~20 Å. Pol epsilon is composed of a globular “head” domain consisting of the large catalytic subunit Pol2p, and a “tail” domain, consisting of the small subunits Dpb2p, Dpb3p, and Dpb4p. The two separable domains were found to be connected by a flexible hinge. Interestingly, the high intrinsic processivity of Pol epsilon depends on the interaction between the tail domain and double-stranded DNA. As a replicative DNA polymerase, Pol epsilon encounters different lesions in DNA. It was shown that Pol epsilon can perform translesion synthesis (TLS) through a model abasic site in the absence of external processivity clamps under single-hit conditions. The lesion bypass was dependent of the sequence on the template and also on a proper interaction of the “tail”domain with the primer-template. Yeast cells treated with a DNA damaging agent and devoid of all TLS polymerases showed improved survival rates in the presence of elevated levels of dNTPs. These genetic results suggested that replicative polymerases may be engaged in the bypass of some DNA lesions. In vitro, Pol epsilon was found to bypass 8-OxoG at elevated dNTP levels. Together, the in vitro and in vivo results suggest that the replicative polymerases may be engaged in bypass of less bulky DNA lesions at elevated dNTP levels. In conclusion, the low-resolution structure presented represents the first structural characterization of a eukaryotic multi-subunit DNA polymerase. The replicative DNA polymerase Pol epsilon can perform translesion synthesis due to an interaction between the tail domain and double-stranded DNA. Pol epsilon may also bypass less bulky DNA lesions when there are elevated dNTP concentrations in vivo.

DNA-damage tolerance (DDT) in yeast is composed of two parallel pathways and mediated by sequential ubiquitination of proliferating cell nuclear antigen (PCNA). While monoubiquitination of PCNA promotes translesion synthesis (TLS), which is dependent on low fidelity polymerase ζ (Pol ζ) composed of a catalytic subunit Rev3 and a regulatory subunit Rev7, polyubiquitination of PCNA by Mms2-Ubc13-Rad5 promotes error-free lesion bypass. Inactivation of these two pathways results in a synergistic effect on DNA-damage responses; however, this two-branch DDT model has not been reported in any multicellular organisms. In order to examine whether Arabidopsis thaliana possesses a two-branch DDT system, rad5a rev3 double mutant plants were created and compared with the corresponding single mutants. Arabidopsis rad5a and rev3 mutations are indeed synergistic with respect to growth inhibition induced by replication-blocking lesions, suggesting that AtRAD5a and AtREV3 are required for error-free and TLS branches of DDT, respectively. Unexpectedly this study reveals three modes of genetic interactions in response to different types of DNA damage, indicating that plant RAD5 and REV3are also involved in DNA damage responses independent of DDT. By comparing with yeast cells, it is apparent that plant TLS is a more frequently utilized means of lesion bypass than error-free DDT. In addition, it was also observed that treatments with the DNA damaging agent methylmethanesulfonate increased the nuclear ploidy level in the double mutant plants.

Kawasaki disease (KD) is characterized by a systemic vasculitis of unknown etiology. More research indicates that KD is related to genetic. In 2003, Sekiya et al. studied the correlation of Th2-related genes and the KD in Japan. They found out that -431T allele would increase the concentration of Thymus and activation-regulated chemokine (TARC)/ CCL17 protein in serum by single nucleotide polymorphism (SNP) -431 C>T of chemokine TARC/ CCL17 operon 5¡¦-flanking region , which suggests that SNP has functionality. Therefore, this study explored the polymorphism and relationship between the regulation of chemokine of TARC/ CCL17 and KD. Firstly, we performed polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) to detect TARC/CCL17 -431 C>T genotype. Then enzyme immunoassay was used to detect TARC/CCL17 chemokine¡¦s expression. The results showed that the performance of TARC -431 C/T SNP, the alleles from KD patients with -431 T, were significantly less than the non-KD control group. It was observed that the -431 T alleles had a lower chance to occur in KD with aneurysms, but independent with coronary artery lesions (CAL). In addition, the acute stage of KD has a higher TARC protein expression, which gradually decreases during IVIG treatment period. However, the up-regulation of TARC protein may not be the direct consequence caused by the single nucleotide polymorphism of TARC -431 C>T.

Background: Kawasaki disease (KD) affects mainly children younger than five years of age, leading to coronary artery lesions, and even to life-threatening myocardial infarctions. Since 1976, Kawasaki disease has occurred among thousands of children in Taiwan. Evidence suggests that inflammation plays a key role in the pathogenesis of atherosclerosis. Significant determinants of high sensitivity C-reactive protein (hs-CRP), which is a sensitive indicator of inflammation, as well as white blood cell (WBC) count, and high-density lipoprotein cholesterol (HDLc) and coronary artery lesion were identified. The relationships between these factors¡¦ concentration and arterial lesion were likewise investigated and had reported. The aim of this study was to determine the serum levels of the hs-CRP, WBC count, and plasma HDLc levels in patients with later phase of KD. Methods and Materials: From July 2005 to June 2006, 97 children with Kawasaki disease at least 1 year after diagnosis were recruited in this study. These participated children had been diagnosed as KD and collected at the interval of 2001 to 2004. Diagnosis was based on the 1984 revised by the KD Research Committee in Japan. The participants were grouped into 45 patients with KD and coronary aneurysms (Group I), 52 patients with KD and normal coronary arteries (Group II), and 50 healthy age-matched children (Control Group III). Their WBC count, systemic and diastolic blood pressures, body mass index, age, sex, fasting total cholesterol concentrations, triglyceride, high-density lipoprotein cholesterol (HDLc), low-density lipoprotein cholesterol, serum hs-CRP levels, and coronary artery lesion by cardioechography were recorded and compared. The analytical differences between hs-CRP, WBC count, and plasma HDLc levels and the coronary artery events in KD were examined. Results: Serum hs-CRP levels of Group I patients (mean 0.264 mg/dl) was significantly greater than that of Group II (mean 0.155 mg/dl, p=0.006) and Group III patients (mean 0.116 mg/dl, p =0.017). Similarly, the WBC count of Group I patients (mean 6,543.11/mm3) was significantly greater than that of Group II (mean 5,720.19/mm3, p=0.029), and Group III patients (mean 5,611.27/mm3, p =0.012). However, plasma HDLc levels of Group I patients (mean 41.42 mg/dl) was significantly lesser than that of Group II (mean 44.79 mg/dl, p=0.035), and Control Group III patients (mean 46.58 mg/dl, p=0.027). There was a positive association between hs-CRP and WBC count levels (r = 0.641, p < 0.05), but none between hs-CRP and plasma HDLc levels. Conclusions: There is the possibility of ongoing low-grade inflammation late after the convalescent phase of Kawasaki disease in children with coronary aneurysms, which may have a role in increasing coronary artery dysfunction. These results also suggest that hs-CRP, WBC count, and plasma HDLc levels are useful parameters for predicting formation of coronary artery lesion even in children after onset of KD.

The purpose of work is to determine the character and frequency of traumas encountered in different events of track-and-field athletics, and the influence of physical therapy on decrease of traumas. In order to achieve the goal, we have implemented the tasks, i.e. we determined the character of traumas usually encountered in track-and-field athletics, as well as the traumas suffered by men and women. We determined the frequency of sport traumas, according to the sport experience. We determined the character and localization of traumas, according to the events of track-and-field athletics, as well as the most common treatment methods in case of sport traumas. We learnt whether the physical therapy has the influence on the rise of repeated traumas. While writing the work, we referred to the hypothesis that the character and frequency of traumas depends on the specificity of events of track-and-field athletics, and studied whether the number of traumas decreases if the physical therapy is applied. The work used the following research methods: analysis of scientific literature, oral questionnaires-interview, analysis of the content of documents (data of medical cards). After the research had been made and the results compared to the other authors, we reached the conclusion that the character and localization of the traumas depends on the event of track-and-field event. The lesion encountered the most often is the strain, and the rarest one is abrasion and fatigue fractures... [to full text]

This thesis is focused on automatic detection of white matter lesions (WML) in Fluid Attenuation Inversion Recovery (FLAIR) Magnetic Resonance Images (MRI) of the brain. There is growing interest within the medical community regarding WML, since the total WML volume per patient (lesion load) was shown to be related to future stroke as well as carotid disease. Manual segmentation of WML is time consuming, labourious, observer-dependent and error prone. Automatic WML segmentation algorithms can be used instead since they give way to lesion load computation in a quantitative, efficient, reproducible and reliable manner. FLAIR MRI are affected by at least two types of degradations, including additive noise and the partial volume averaging (PVA) artifact, which affect the accuracy of automated algorithms. Model-based methods that rely on Gaussian distributions have been extensively used to handle these two distortions, but are not applicable to FLAIR with WML. The distribution of noise in multicoil FLAIR MRI is non-Gaussian and the presence of WML modifies tissue distributions in a manner that is difficult to model. To this end, the current thesis presents a novel way to model PVA artifacts in the presence of noise. The method is a generalized and adaptive approach, that was applied to a variety of MRI weightings (with and without pathology) for robust PVA quantification and tissue segmentation. No a priori assumptions are needed regarding class distributions and no training samples or initialization parameters are required. Segmentation experiments were completed using simulated and real FLAIR MRI. Simulated images were generated with noise and PVA distortions using realistic brain and pathology models. Real images were obtained from Sunnybrook Health Sciences Centre and WML ground truth was generated through a manual segmentation experiment. The average DSC was found to be 0.99 and 0.83 for simulated and real images, respectively. A lesion load study was performed that examined interhemispheric WML volume for each patient. To show the generalized nature of the approach, the proposed technique was also employed on pathology-free T1 and T2 MRI. Validation studies show the proposed framework is classifying PVA robustly and tissue classes are segmented with good results.

This thesis is focused on automatic detection of white matter lesions (WML) in Fluid Attenuation Inversion Recovery (FLAIR) Magnetic Resonance Images (MRI) of the brain. There is growing interest within the medical community regarding WML, since the total WML volume per patient (lesion load) was shown to be related to future stroke as well as carotid disease. Manual segmentation of WML is time consuming, labourious, observer-dependent and error prone. Automatic WML segmentation algorithms can be used instead since they give way to lesion load computation in a quantitative, efficient, reproducible and reliable manner. FLAIR MRI are affected by at least two types of degradations, including additive noise and the partial volume averaging (PVA) artifact, which affect the accuracy of automated algorithms. Model-based methods that rely on Gaussian distributions have been extensively used to handle these two distortions, but are not applicable to FLAIR with WML. The distribution of noise in multicoil FLAIR MRI is non-Gaussian and the presence of WML modifies tissue distributions in a manner that is difficult to model. To this end, the current thesis presents a novel way to model PVA artifacts in the presence of noise. The method is a generalized and adaptive approach, that was applied to a variety of MRI weightings (with and without pathology) for robust PVA quantification and tissue segmentation. No a priori assumptions are needed regarding class distributions and no training samples or initialization parameters are required. Segmentation experiments were completed using simulated and real FLAIR MRI. Simulated images were generated with noise and PVA distortions using realistic brain and pathology models. Real images were obtained from Sunnybrook Health Sciences Centre and WML ground truth was generated through a manual segmentation experiment. The average DSC was found to be 0.99 and 0.83 for simulated and real images, respectively. A lesion load study was performed that examined interhemispheric WML volume for each patient. To show the generalized nature of the approach, the proposed technique was also employed on pathology-free T1 and T2 MRI. Validation studies show the proposed framework is classifying PVA robustly and tissue classes are segmented with good results.

The purpose of this dissertation was to evaluate outcomes associated with blood component (BC) transfusion in adult trauma patients. Specific aims were to: 1) explore the relationship between traumatic injury, hemorrhage, and BC transfusion, focusing on consequences of the component storage lesion through presentation of a conceptual model; 2) systematically review research literature comparing outcomes of massively transfused major trauma patients based on ratios of BCs received; 3) evaluating the relationship between type of blood transfusion trauma patients received (whole blood versus BCs) and mortality likelihood after controlling for demographic and clinical variables; 4) evaluating the relationship between volume and ratio of BCs transfused to trauma patients and development of inflammatory complications (ICs) after controlling for demographic and clinical variables. Specific aim one was addressed through the development of a conceptual model, depicting the current state of knowledge regarding the storage lesion, and short-/long-term outcomes of traumatic injury, hemorrhage, and blood transfusion. The second specific aim was addressed through a systematic review of studies that grouped critically injured, massively transfused patients based on ratios of BCs they received, and compared clinical outcomes among groups. Findings from this analysis revealed increased survival likelihood with massive transfusion of BCs in a 1:1:1 (packed red blood cells [PRBCs], fresh frozen plasma [FFP], platelets [PLTs]) fashion. The third specific aim involved a secondary analysis of the National Trauma Data Bank to evaluate the relationship between type of transfusion trauma patients received (whole blood versus BCs) and mortality. Patients who received BCs experienced a higher mortality likelihood compared with those who received whole blood. The fourth specific aim was addressed through a secondary analysis of the Inflammation and Host Response to Injury Trauma-Related Data Base, to evaluate the relationship between volume and ratio of BCs transfused and development of ICs in patients with major trauma. Findings revealed that total transfused volume of PRBCs, injury severity, and comorbidities were associated with development of ICs. There were no differences in time to complication between PRBCs:FFP or PRBCs:PLTs ratio groups.

In Syrian hamsters, social behavior is mediated exclusively by chemosensory cues and circulating gonadal steroid hormones. Where these two signals are processed in the brain is unknown, but the posterior bed nucleus of the stria terminalis (pBNST) has been suggested as a candidate site. Therefore, we tested male hamsters’ preference for opposite-sex odors following excitotoxic lesions of the pBNST. Lesions of the pBNST (pBNST-X) eliminated male hamsters’ preference for opposite-sex odors. Furthermore, pBNST-X males spent significantly less time investigating female odors than clean odors and significantly less time investigating female odors than control males did. Lesions of the pBNST did not change male hamsters’ investigation of male odors. The deficits observed in pBNST-X males were not due to a failure to discriminate between odors, as pBNST-X males were able to distinguish between odors. Together, these data suggest the pBNST is critical for opposite-sex odor preference in male hamsters.