Abstract

The adipose tissue produces and secretes many bioactive substances, which we conceptualized as adipocytokines (Nature Medicine 1996). Adiponectin is a novel adipocytokine, which we identified by screening the adipose-specific genes from human fat. Adiponectin is a secreted protein, the concentration of which reaches as high as 5–15 μg/ml in human plasma. Adiponectin mRNA is expressed exclusively in adipose tissues. The adiponectin mRNAs and its plasma levels are reduced in obesity, type 2 diabetes and atherosclerosis. Hyperinsulinemic euglycemic clamp studies in humans and monkeys, and several recent studies from others revealed that adiponectin is an insulin-sensitizing hormone. Furthermore, adiponectin exhibited the antiatherogenic moieties, decreasing the attachment of monocytes to endothelial cells through inhibiting the expressions of adhesion molecules, the lipid accumulation in macrophage through reducing the expression of scavenger receptor, and the cytokine-stimulated proliferation of smooth muscle cells. The genetic mutation of the adiponectin gene accompanying hypoadiponectinemia was strongly associated with the incidence of type 2 diabetes and atherosclerosis in Japanese subjects. Hypoadiponectinemia was the strongest predictor for the development of type 2 diabetes in humans. Adiponectin knockout mice exhibited dietinduced diabetes and a more severe atherosclerotic response by vascular injury. Adiponectin supplement reversed the insulin resistance syndrome including diabetes and atherosclerotic change in the knockout mice. We conclude the "hypoadiponectinemia" stands upstream of the pathophysiology of the metabolic syndrome, hence it can be a direct target of drug intervention to tackle the life style-related disease rampant in the developed countries. (Presented at the 1276th Meeting, September 17, 2002.)

In spite of the rapid increase of the number of Korean centenarians over the last two decades, little has been known about their family life. Therefore, this study aims to explore the nature of the family life and the family relationships of the Korean centenarians. To achieve this purpose, 49 Korean centenarians and their families were interviewed. Qualitative, in-depth data regarding the family structure, family history and relationship with primary caregiver were gathered from the centenarians and their family members. All the interviews were tape recorded and transcribed verbatim for the analysis. Three researchers read each transcript a number of times to elicit some emerging themes. The major findings were: Family was the most important determinant of the quality of life of Korean centenarians, even though there existed much heterogeneity in terms of the nature of their family life and the quality of family relationships. While most of the Korean centenarians lived with an adult child's family and were looked after by their daughter-in-laws, some lived with married daughters or lived by themselves. The life course of Korean centenarians was the one filled with many wars, poverty and negative life events such as the death of children and spouse. Their life was very much based on son-centered (especially the eldest son) expectations and norms, reflecting the traditional Korean family norm. Negative aspects of the eldest son-centered life, such as caregiving burden of the primary caregiver, conflict among siblings, and negative view toward a residence with a married daughter were found among the centenarians. Theoretical and policy implications of the results to improve the quality of life of centenarians are discussed. (Presented at the 1277th Meeting, September 21, 2002.)

In the mammalian brain, fast excitatory neurotransmission is mediated by ionotropic glutamate receptors (iGluR), which play crucial roles in learning and memory. iGluRs are classified into four subfamilies: AMPA, kainate, NMDA, and δ receptors. An understanding of their basic functions is essential for appreciation of the mechanisms by which iGluRs serve as mnemonic devices. We are approaching this issue by characterizing ataxic mice that have spontaneous mutations in the δ2 subtype of iGluRs. δ2 receptors are predominantly expressed in cerebellar Purkinje cells and are essential for long-term depression, a form of memory storage in the cerebellum. However, the mechanisms by which δ2 receptors participate in cerebellar functions are largely unknown, because δ2 receptors do not bind glutamate analogs. We found that a point mutation of δ2, which was identified in lurcher ataxic mice, caused channel activation in the absence of ligand binding and displayed distinct properties similar to those of AMPA receptors. In addition, we found that a point mutation in the corresponding regions of other iGluRs also resulted in channel activation in the absence of ligands, indicating that this region may be a part of the channel gate of iGluRs. Similarly, by analyzing the mutation in hotfoot ataxic mice, we demonstrated that the N-terminal region of δ2 receptors and other iGluRs was essential for channel assembly and subsequent transport to the cell surface. Therefore, characterization of naturally occurring mutants has provided valuable clues not only about how δ2 receptors function but also about the general functional structure of iGluRs. (Presented at the 1280th Meeting, October 16, 2002.)

The concept of combining living cells with appropriate templates was initially developed in the late 1980s at MIT and Mass General as it related to burn injury and skin replacement. The concept to grow new tissue was developed by applying the principles of engineering with the biologic sciences. The problem was to deliver a sufficient number of cells in a configuration that would allow cell survival and dictate tissue development. In our combined labs at MIT, MGH and Children's hospital, cartilage was harvested from a cow and seeded onto a synthetic polymer scaffolding. The cell polymer constructs were then implanted into a nude mouse. Specimens were evaluated over a period of time. Progressive development of cartilage tissue was seen in association with the breakdown of the polymer fiber. Different polymers proved to have different efficacies. Every cell type appeared to function differently, that is; each chemical polymer reacted differently to different cell types in each species studied. Later hydrogels were employed as vehicles for cell transplantation. The first were derivatives of seaweed, alginic acid. When calcium is added, they become ionically cross linked, and gel to retain specific shapes. Reverse thermally sensitive polymers were then explored. They are liquid at room temperature but when put into the body, as the temperature increases, they gel. Cells suspended in this gel remain viable, and can be used to generate specific shapes or be injected into a recipient. Several studies were undertaken to determine the optimal cell concentrations for various tissues. Dr. Joseph Upton, of the Beth Israel Hospital, proposed that cartilage be generated in the shape of a human ear. A synthetic biodegradable polymer mold was synthesized. The implant, in the shape of the ear, was seeded with auricular chondrocytes and implanted onto the back of a mouse. Hyaline cartilage in the shape of the human ear was generated. The tissue consisted of mature hyaline cartilage having the convolutions of the human ear. The experiments were then repeated using autologous cells by implanting the cell polymer constructs into the animals from which the cells had been isolated. Experiments were then focused on bone. The periosteal lining of bone is torn when it is broken. Cells shed by the torn periosteum are responsible for the repair of bone. When those cells were seeded onto the polymer fibers and implanted into animals, initially the implants develop cartilage. At four weeks, tissue which grossly and histologically appeared to be immature cartilage, was generated. After more than 4 months however, the tissue progressed to become bone. Composites of bone lined with cartilage were then developed. Based on these and other studies, new materials, such as sea coral, which is very porous, has interconnecting channels, and is very compatible with bone, have been explored. Human applications: A patient presented to the emergency room, having cut off his distal thumb. Although the bone had been avulsed, the volar skin pad was left intact. Dr. John Shufflebarger (a plastic surgeon with UMass Memorial Health Care) transplanted skin from the patient's chest to repair the skin damage. A block of coral, cut into the shape of the missing bone, was injected with cells isolated from the patient's own periosteum, and prepared for implantation. The coral/cell complex was then implanted in a pocket under his skin, where the missing distal phalanx had been avulsed. Eighteen months after the injury, the patient possessed a stable, sensate thumb, without pain and was able to do the overwhelming majority of daily activities. His interphalangeal joint became encased within a stable fibrous capsule, resulting in reasonable strength on opposition. Follow up MRI and serial x-ray examinations demonstrated vascular perfusion of the graft with no evidence of volume loss or fragmentation. Light microscopy of specimens obtained one year later demonstrated the development of lamellar bone within the coral. Immature vs. mature cells: Yet another critical factor, which is now receiving much attention, is the source of the cells to be utilized for tissue engineering. Several studies have suggested that the use of immature cells, rather than fully differentiated cells of specialized tissues, are able to multiply to a higher degree in vitro. Immature cells can be induced to differentiate after several divisions. Also, the implantation of the immature cells may be advantageous in that they require less oxygen, as their metabolic rate is much lower than their fully differentiated counterpart. Hence, they are more likely to survive implantation into areas where a vascular bed is not yet fully developed. Efforts by other groups have focused on the use of embryonic stem cells. Those cells will not only be recognized as foreign, but must also be stimulated to differentiate into the appropriate, tissue specific progenitor cell. In our laboratories, we have discovered a new, previously undescribed, adult progenitor cell, which we have named, a "spore-like" cell. It is very small (less than 5 microns in diameter) and has the ability to survive very hostile environments, including extremes of temperature, and low oxygen environments. It appears to lie dormant in all tissues of the body, and is stimulated to proliferate and mature after an insult or injury to the tissue. We have characterized these cells in many tissues including liver, brain, kidney and pancreas. We believe that they are responsible for the natural repair of injured tissue, and that the development of their use will replace the need for fetal cells, and move tissue engineering toward human applications. Repair of spinal cord injury: We have studied the potential to use these immature "spore-like" cells found in the central nervous system, i.e., the brain and spinal cord. Historically, when you remove the spinal cord from an animal, all of the cells are reportedly dead within about five minutes, as soon as they lose their oxygen source. However, about an hour after you harvest gray matter from the brain or spinal cord and filter the "debris", small, undifferentiated cells can be seen. In a three-dimensional culture, they start to multiply, and in the right conditions, some start to form branches. Using various markers for neurons, oligodendrocytes, and astrocytes, we have observed that these "spore-like" cells have the ability to mature into the different cellular elements of central nervous system tissue. Based on this, we explored the potential of the central nervous system to repair itself. We concluded that there is a potential to combine neural stem cells from a rat spinal cord with polymer components and various growth factors and reintroduce them into a spinal cord injured animal. We think this will be a viable approach to repair spinal cord injury or damage done to the central nervous system by stroke. Finally, several studies are now underway to apply these technologies to the development of many tissues. We believe that these techniques will ultimately lead to widespread approaches to replace non-functional tissue in humans. (Presented at the 1282nd Meeting, October 17, 2002.)

Skin aging can be divided into intrinsic aging and photoaging. Intrinsic aging is characterized by smooth, dry, pale and finely wrinkled skin. On the other hand, photoaging is characterized by severe wrinkling and irregular pigmentation. The people of Japan, Korea, and China look very similar and it is very hard to differentiate them from each other. Although the population of Asia is more than half of the total population of Earth, the inherent characteristics of Asian skin have not been well investigated as compared with Caucasian white skin. The characteristics of photoaging of Asian skin such as pigmentary changes and wrinkle patterns differ from those of Caucasian skin. There are racial and ethnic differences in the genetic background, as well as skin structure and function, between the brown skin of Asians and the white skin of Caucasians. As Asian skin is more pigmented, the acute and chronic cutaneous responses to UV irradiation in brown skin differ from those seen in white skin. Various factors such as age, sun-exposure, gender and smoking are considered to be independent risk factors for wrinkles in the white skin of Caucasians. However, the relative risks of each factor on wrinkles in the brown skin of Asians have not yet been investigated, but could differ from those in Caucasians. We have investigated the clinical manifestation of aged skin in Korean people. We also have studied causative factors of skin wrinkling and its relative risk, and molecular mechanisms of wrinkle development. (Presented at the 1284th Meeting, October 29, 2002.)

Interest in psoriasis presently concentrates on clinical epidemiology, genetics as well as on immune pathology in addition to newly developed treatment modalities. In these principal areas of psoriasis research progress has been significant during the last years. In genetics a total of 16 susceptibility loci have been detected seven of which were designated PSORS 1–7. Regions of greatest interest now include PSORS 1 located in close vicinity of the HLA-C locus as well as PSORS 7 which localizes within the terminal differentiation complex on chromosome 1. So far our epidemiologic data revealed that compared to other skin diseases psoriasis appears to be more often associated with diabetes, hypertension, cardiac diseases and Crohn's disease. On the other hand atopic disorders (e.g., atopic dermatitis, pollen allergies or asthma) are underrepresented. This phenomenon may be explained by the Th 1/Th 2 dichotomy of immunity which in skin appears to be reflected in two of the most common inflammatory disorders, psoriasis and atopy. The relative lack of infections seen in psoriatic skin (despite heavy pathogen colonization) represents another puzzle. However our recent observations on the presence of antimicrobial factors being produced by keratinocytes in psoriasis but also in normal epidermis appear interesting. These peptides represent potent human antibiotics and belong to the b-defensin family. Whereas b-defensin 1 is constitutively expressed, upregulation of b-defensin 2, 3 and recently detected b-defensin 4 takes place by contact with bacterial membranes or supernatants from bacterial cultures. There appear to be a variety of pathogen associated molecular structures that have not been deciphered up to now. These data show that keratinocytes in human skin actively participate in the regulation of innate immune responses not only by producing potent antibiotics but also by recognition of pathogens and production of proinflammatory cytokines/chemokines. (Presented at the 1288th Meeting, November 5, 2002.)

BETA2/NeuroD, a basic helix-loop-helix transcription factor isolated in our laboratory, has been shown to regulate the insulin gene transcription by binding to enhancer elements, RIPE3a, Nir and Far boxes. BETA2 is expressed in the pancreatic islet, enteroendocrine and neuronal cells. The timing of expression indicates that it plays an important role in the development of these cells and tissues. In order to support this hypothesis and dissect its physiological function, we have deleted this gene in mice. Phenotypic analysis of these mice showed defects in all these three cell types. Due to excess apoptosis, the endocrine cell population is decreased and the resulting islet cells are not able to form a proper islet structure. Therefore, KO animals develop diabetes and die at P3–5. In the intestine, CCK and secretin producing cells, but not other cells, are missing. Without CCK and secretin, pancreatic exocrine cells are not able to polarize and secret the zymogen granules. The lack of digestive enzymes may also contribute to the early death of these mice. Fortuitously, by crossing our animals into a different genetic background, we found that 40% of our animals survive for several months although they are hyperglycemic and have a reduced number of β cells than those in the original genetic background. The survival of these animals is due to the lack of ketoneacidosis. The number of β cells of these animals increases in the first two weeks of life and reaches 95% of their wild type littermates at the end of one month. At the same time, the level of circulated glucose level in the serum decreases. Using these animals we have carried out studies on the origin of these new β cells. We found that they were derived from the large pancreatic ducts and proliferation of pre-exiting islet cells. In brain, granule cells of hippocampus and cerebellum, ganglia of vestibule and cochlea and photoreceptor cells of retina are either missing or drastically decreased. These defects cause animal to develop ataxia, imbalance, deafness, blindness and epilepsy. Therefore, BETA2/NeuroD is essential for proper cell differentiation in these organs. Without proper differentiation, these cells go through apoptosis. (Presented at the 1295th Meeting, November 25, 2002.)

What is common in aggression and in abusive/neglectful parenting is low levels of empathy. Fostering empathy – the ability to identify with another person's feelings – can serve as an antidote to aggression and is crucial to good parenting. Poor parenting and aggression cut across all socio-economic levels of the community and, as such, empathy needs to be fostered in all children. During the period of rapid brain development, adversity has a devastating impact on the baby's developing brain. Repeated experiences of stress are hardwired into the brain, creating damaging pathways. Risk factors such as domestic violence, child abuse and neglect, maternal depression, maternal addictions, and poverty are not just additive to the vulnerable developing brain; they are multiplicative in their impact. The parent is the baby's lifeline, mitigating stress for them and helping them to learn to regulate their emotions. The impact of poor parenting on a child's life is profound, resulting in insecure attachments which lead to a spectrum of inadequate coping mechanisms, poor emotional regulation, diminished learning potential and low competence. Responsive and nurturing parenting is the key to optimal early childhood development; it allows the young brain to develop in a way that is less aggressive and more emotionally stable, social and empathic. Good early childhood development leads to good human development. We must match our investment where the opportunity is most ripe – building parenting capacity. The 'Roots of Empathy' program offers real hope in breaking the intergenerational transference of poor parenting and violence. (Presented at the 1296th Meeting, November 26, 2002.)

The expectations of our patients for functional and aesthetic prosthodontic solutions obviously become higher and higher. In many cases the implantologicalprosthodontic treatment has proven to be the best of all treatment possibilities, because this modern treatment modality can offer our patients options and solutions that were not available to them before. This is primarily based on facts that with implants we are able to avoid the preparation of healthy teeth, we can avoid removable dentures and we can care for better stabilization and retention of removable superstructures. Thus creating successful functional and aesthetic results is a primary challenge for the dental implant treatment team. That's why it is so important that the restorative dentist is familiar with the latest surgical and prosthodontic techniques as well as with the different components of a modern implant system to achieve the best possible result for his patients. Also very important are the latest developments in the field of dental technology, for example full ceramic systems or spark erosion technology. These new techniques will help clinicians create better functional and aesthetic results and increase the patient's satisfaction. Former frequently occuring functional and aesthetic problems can get managed by thorough planning and conscientious treatment. Thorough planning is the base for every successful implant treatment. During the planning phase the optimal number, distribution and position of the implants should be determined from the prosthodontic point of view. Therefore to know the modern implant prosthetic concepts is most important. Moreover knowledge about the conventional prosthodontic treatments is very helpful, because the condition and distribution of the natural teeth, the dentition of the opposite jaw, the occlusion, the relation of the jaws, the muscular activity and the functional and aesthetic expectations of our patients must be considered in an implant treatment planning, too. With regard to this, the lecture will explain the possibilities of the Ankylos^®-Implant-System and present successfully treated patients with different indications (edentulous jaw, reduced dentition and single tooth loss) but also show some failures due to improper implant prosthodontic planning. The conclusion is that implant prosthetic solutions are superior to conventional prosthetic treatments in nearly all cases. Therefore implantology should get a firm part in the therapy modalities of the restorative dentist and will be in my opinion the prosthetics of the future. (Presented at the 1299th Meeting, November 27, 2002.)

Anxiety reactions are emotional signals of danger, deeply rooted in the phylogenesis of the neurobiological fight-flight system: The higher the reactions are, the higher is the probability of flight and a subsequent avoidance of the dangerous situation. The intensity does, however, not only depend on the objective dangerousness of the situations by which the reactions have been elicited but likewise on the individual's anxietyproneness. This trait originates from genetic as well as experiencial factors, in man as in other species. An extremely high degree of anxiety-proneness is often found as a trait underlying inadequately strong, long-lasting and sometimes even permanent anxiety reactions as mental state disorders. On the other side, an extremely low degree of anxiety-proneness may result in an inappropriate lack of anxiety reactions with a tendecy to a neglect instead of an avoidance of even very dangerous situations as often found in childrens' conduct disorder and juvenile delinquency. The trait pattern of anxietyproneness in man can be elucidated by means of personality questionnaires. Described in different terms, e.g., as trait anxiety or harm avoidance, it appears as a central feature of the broad personality dimension of so-called neuroticism. We detected it retrospectively as a premorbid characteristic in case records and – by means of a biograpical interview – in self-desciptions of psychiatric patients with various "neurotic", in paticular anxiety disorders or schizophrenia. Probably, it reflects a vulnerability to these disorders as similar findings were reported from prospective longitudinal studies. Abnormally high degrees of anxiety-proneness characterize avoidant personality disorder. The reverse is observed – usually in combination with a strong tendency to novelty seeking – in antisocial personality disorder, particularly so in its psychopathic variant according to Hare. Because of the likelihood of criminal behavior, the indolence with respect to legal punishment and a low motivation and ability to change the inappopriate attitude towards social norms and other peoples' demands, these subjects are usually resistant to therapeutic interventions. Yet even habitually highly anxious individuals are not easily treatable with longlasting success. Nonetheless, some empirically founded suggestions can be formulated how to at least diminish the negative consequences of extremely high or low anxiety-proneness. (Presented at the 1301st Meeting, December 5, 2002.)

The nuclear receptors (NRs) play central roles in development, metabolism and energy homeostasis through their ability to transduce hormonal signals into modulation of gene activity. The ligands of NRs are classical hormones (steroid and thyroid hormones, etc), vitamin and dietary nutrient fatty acids derivatives. The mouse is an excellent animal model for defining the human diseases. The null allele mutations (knockouts) already obtained for some NRs have provided valuable information about their functions, but have also revealed major complications and difficulties: (1) an early embryonic lethality, (2) temporal effect (developmental stage or adult stage), (3) functional redundancy and (4) spatio-effect (cell-autonomous or non-autonomous). To overcome these limitations, spatio- temporally controlled somatic mutagenesis, Cre-ER^T/LoxP system, was established. Obesity, excess energy storage in adipose tissue, is a major health problem linking to diabetes, hyperlipidemia and hypertension. Among NRs, retinoid X receptor α (RXRα)-peroxisome proliferator-activated receptor γ (PPARγ) heterodimers could mediate adipocyte differentiation and obesity as has been demonstrated with in vitro cell culture system and RXRα- and PPARγ-specific ligand studies. Therefore an adipocyte-specific temporally controlled somatic mutagenesis system was established. Using this system RXRα as well as PPARγ were selectively ablated in adipocytes of adult mice which were obtained and analysed. Interestingly, both mice were hyperglycemic, indicating that RXRα-PPARγ heterodimers in adipocyte regulated glucose homeostasis and were possible new drug target for diabetes. Furthermore, using temporally controlled mutagenesis system in hepatocytes, the NR function were also studied to identify a new signaling molecule to control liver regeneration. (Presented at the 1302nd Meeting, December 9, 2002.)

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