CYTOLOGICAL, ULTRASTRUCTURAL, AND BIOCHEMICAL STUDIES OF THE STRUCTURE OF PREMATURELY CONDENSED CHROMOSOMES

The phenomenon of premature chromosome condensation, resulting from fusion between mitotic and interphase cells, includes dissolution of the interphase nuclear framework, thus allowing a direct visualization of interphase chromosomes. Light microscope morphology of prematurely condensed chromosomes (PCC) from synchronized HeLa cells supports the model of an interphase "chromosome condensation cycle". PCC are increasingly attenuated as cells progress through G(,1). A maximum degree of decondensation is observed at active sites of DNA replication during S phase, and a condensed morphology is rapidly resumed following completion of replication of a chromosome segment.^ To permit ultrastructural and biochemical studies of PCC, a procedure was developed to induce premature chromosome condensation at high frequency. This was achieved by polyethylene glycol (PEG)-mediated fusion of a dense monolayer of mitotic and interphase cells induced by centrifugation onto lectin-coated culture dishes. Using this method, PCC induction frequencies of 60-90% are routinely obtained.^ Scanning electron microscope analysis of PCC spreads revealed that the extension of PCC during progression through G(,1) is accompanied by a transition of the basic 30 nm chromatin fiber from tightly packed looping fibers to extended longitudinal fibers. Sites of active DNA replication is S-PCC were indicated to be organized a single longitudinal fibers. Following replication of a chromosome segment, a rapid reorganization from the extended longitudinal fiber to packed looping fibers occurs. The postreplication maturation process appears to include the assembly of a chromosome core consisting of multiple longitudinal fibers.^ The role of histone H1 phosphorylation in PCC formation was investigated by acidurea polyacrylamide gel electrophoresis of total histone extracted from metaphase chromosomes and PCC following high frequency fusion. This investigation failed to demonstrate an extensive phosphorylation of H1 associated with PCC formation. However, significant dephosphorylation of superphosphorylated metaphase chromosome H1 was observed, indicating that interphase H1-phosphatase activity is dominant over metaphase H1 kinase activity. These observations provide evidence against models suggesting a role for H1 superphosphorylation in triggering mitotic condensation of chromosomes. ^

DETERMINANTS OF THE SELECTIVE PHAGOCYTOSIS OF CARCINOGENIC PARTICULATE NICKEL COMPOUNDS

Certain inorganic nickel compounds such as crystalline NiS and Ni(,3)S(,2) are potent inducers of carcinogenesis and in vitro cell transformation, while several closely-related compounds such as amorphous NiS are essentially devoid of genotoxic activity. The phenomenon of selectivity of phagocytosis among such particulate nickel compounds has been hypothesized to account for their widely varying toxicological potency, yet the determinants of this selectivity have not been well characterized. Extracellular medium composition, particle dissolution, and particle surface charge were examined as potential determinants of selective phagocytosis for the carcinogenic crystalline and noncarcinogenic amorphous modifications of NiS. Selectivity and avidity of uptake of crystalline NiS by CHO cells was not dependent upon serum: phagocytosis of crystalline, but not amorphous NiS proceeded readily in a minimal salts/glucose medium at 37(DEGREES)C. The evolution of phagocytosis-inhibiting Ni(II) from the surface of amorphous NiS particles did not demonstrably contribute to the lower uptake of these noncarcinogenic particles despite their somewhat greater dissolution rate than the readily phagocytosed crystalline NiS particles. Significant differences in surface charge were noted between crystalline and amorphous NiS, the former being more negative in charge in distilled water suspension. Exposure of amorphous NiS particles to the vigorously reducing environment of a LiAlH(,4) solution under an inert atmosphere resulted in the particles' acquisition of a more negative surface charge. Amorphous NiS particles thus treated were phagocytosed by CHO cells to an extent similar to that of untreated crystalline NiS particles and likewise were shown to induce morphological transformation of primary Syrian hamster embryo cells with a similar potency. The potentiation of uptake characteristic of LiAlH(,4)-treated amorphous NiS was lost gradually upon storage of particles in ambient oxygenated atmosphere and was lost rapidly by apparent particle surface oxidation in aerated distilled water suspensions aged for up to 7 days. Concomitant with this loss of uptake there occurred a loss of negative surface charge. These results suggest the predominant role of particle surface charge rather than adsorbed serum components or particle dissolution as a determinant of selective phagocytosis among particulate nickel compounds. ^

Alexander’s Dictum and the Reality of Familiar Objects

Alexander's Dictum--"to be is to have causal powers"--appears to furnish an argument against the reality of familiar medium-sized objects. For every time a familiar object appears to cause a familiar macro-event, it sets up a rival claim by its component microparticles to have caused the complex swarm of microphysical events that composes into that macro-event. But this argument, argues this paper, wrongly assumes that even after familiar objects are removed from the picture, there is a phenomenon of joint causation which unites all and only the microparticles within each familiar object.

Effects of the microenvironment on Fas/Fas ligand interactions and their implications for UV-induced immune suppression

Skin cancer is the most common malignancy in humans. Although highly treatable, non-melanoma skin cancer is commonly followed by other non-cutaneous malignancies. Ultraviolet radiation (UVR) acts as both tumor initiator and promoter, and also results in the suppression of specific immune responses. The systemic suppression of immune responses is initiated by DNA damage, which promotes IL-10 production, an important cytokine as anti-IL-10 can abrogate the suppression, and upregulates the pro-apoptotic proteins Fas and Fas ligand (FasL). FasL is a critical factor for UV-induced immune suppression, and the suppressor cell induced by UV expresses FasL. ^ We hypothesized that the microenvironment affects Fas/FasL interactions, and that these interactions are important to the phenomenon of UV induced immune suppression. To determine the effects of the interaction of FasL and IL-10, splenocytes isolated from C57Bl/6 mice were cultured in the presence or absence of IL-10 post-mitogenic activation. We determined that IL-10 protects from Fas-mediated apoptosis by lowering Fas sensitivity and lowering the levels of either Fas or FasL. This protection is stronger when IL-10 is given immediately after mitogenic activation, and does not increase any of the inhibitors of apoptosis studied. In vivo, splenocytes from UV-irradiated mice are resistant to Fas-mediated apoptosis and present very high levels of IL-10, lowered Fas sensitivity and lowered caspase cleavage despite higher expression of Fas and FasL than non-irradiated mice. ^ UV-induced immune suppression affects female mice preferentially, which led us to look at prolactin as a possible component of this suppression since this hormone has also been associated with increased skin carcinogenesis. The interaction of FasL and prolactin results in suppression of the delayed type hypersensitivity response to Candida albicans. This lack of response depends on FasL as is not seen in gld mice. Similar to UV-induced immune suppression, the suppression is caused by a Th2 deviation, and correlates with a significant increase in Fas expression. In the presence of UV, the effects of prolactin seemed to be protective, and UV actually restores the DTH response.^ Taken together, these observations suggest that the microenvironment dictates the outcome of the interaction of FasL with Fas going from promoting apoptosis to preventing apoptosis or mediating a Th2 deviation and suppression of a Th1 response. ^

DNA damage-induced Fas ligand expression by epidermal dendritic cells mediates UV-induced immune suppression of contact hypersensitivity

Exposure to UVB radiation induces local and systemic immune suppression, evidenced by inhibition of the contact hypersensitivity response (CHS). Epidermal dendritic cells, the primary antigen presenting cells responsible for the induction of CHS, are profoundly altered in phenotype and function by UVB exposure and possess UV-specific DNA damage upon migrating to skin-draining lymph nodes. Expression of the proapoptotic protein FasL has been demonstrated in both skin and lymph node cells following UVB exposure. Additionally, functional FasL expression has recently been demonstrated to be required in the phenomenon of UV-induced immune suppression. To test the hypothesis that FasL expression by DNA-damaged Langerhans cells migrating to the skin-draining lymph nodes is a crucial event in the generation of this phenomenon, mice were given a single 5KJ/m2 UV-B exposure and sensitized to 0.5% FITC through the exposed area. Dendritic cells (DC) harvested from skin-draining lymph nodes (DLN) 18 hours following sensitization by magnetic CD11c-conjugated microbeads expressed high levels of Iab, CD80 and CD86, DEC-205 and bore the FITC hapten, suggesting epidermal origin. Radioimmunoassay of UV-specific DNA damage showed that DC contained the vast majority of cyclobutane pyrimidine dimers (CPDs) found in the DLN after UVB and exhibited increased FasL mRNA expression, a result which correlated with greatly increased FasL-mediated cytotoxicity. The ability of DCs to transfer sensitization to naïve hosts was lost following UVB exposure, a phenomenon which required DC FasL expression, and was completely reversed by cutaneous DNA repair. Collectively, these results demonstrate the central importance of DNA damage-induced FasL expression on migrating dendritic cells in mediating UV-induced suppression of contact hypersensitivity. ^

Long-term hyperexcitability of sensory and motor axons in Aplysia californica: Induction by axotomy, serotonin, and transient depolarization

Neuropathic pain is a debilitating neurological disorder that may appear after peripheral nerve trauma and is characterized by persistent, intractable pain. The well-studied phenomenon of long-term hyperexcitability (LTH), in which sensory somata become hyperexcitable following peripheral nerve injury may be important for both chronic pain and long-lasting memory formation, since similar cellular alterations take place after both injury and learning. Though axons have previously been considered simple conducting cables, spontaneous afferent signals develop from some neuromas that form at severed nerve tips, indicating intrinsic changes in sensory axonal excitability may contribute to this intractable pain. Here we show that nerve transection, exposure to serotonin, and transient depolarization induce long-lasting sensory axonal hyperexcitability that is localized to the treated nerve segment and requires local translation of new proteins. Long-lasting functional plasticity may be a general property of axons, since both injured and transiently depolarized motor axons display LTH as well. Axonal hyperexcitability may represent an adaptive mechanism to overcome conduction failure after peripheral injury, but also displays key features shared with cellular analogues of memory including: site-specific changes in neuronal function, dependence on transient, focal depolarization for induction, and requirement for synthesis of new proteins for expression of long-lasting effects. The finding of axonal hyperexcitability after nerve injury sheds new light on the clinical problem of chronic neuropathic pain, and provides more support for the hypothesis that mechanisms of long-term memory storage evolved from primitive adaptive responses to injury. ^

Modeling survival and the development of second primary tumors among Hodgkin's disease patients

Hodgkin's disease (HD) is a cancer of the lymphatic system. Survivors of HD face varieties of consequent adverse effects, in which secondary primary tumors (SPT) is one of the most serious consequences. This dissertation is aimed to model time-to-SPT in the presence of death and HD relapses during follow-up.^ The model is designed to handle a mixture phenomenon of SPT and the influence of death. Relapses of HD are adjusted as a covariate. Proportional hazards framework is used to define SPT intensity function, which includes an exponential term to estimate explanatory variables. Death as a competing risk is considered according to different scenarios, depending on which terminal event comes first. Newton-Raphson method is used to estimate the parameter estimates in the end.^ The proposed method is applied to a real data set containing a group of HD patients. Several risk factors for the development of SPT are identified and the findings are noteworthy in the development of healthcare guidelines that may lead to the early detection or prevention of SPT.^

Identifying characteristics of mentally ill homeless individuals who are successfully linked to health and social services post-incarceration via the jail inreach project

Healthcare for the Homeless—Houston (HHH) received a research grant from The Medallion Foundation, Inc. in March 2006 to pilot The Jail Inreach Project, an intensive “inreach” initiative to assess the impact of providing continuity of mental and primary health care services for homeless individuals who suffer from mental illness and/or substance abuse being released from jail. This pilot project was initiated by HHH, in collaboration with the Harris County Sheriff’s Office and the Mental Health Mental Retardation Authority of Harris County (MHMRA). Those who are flagged as “frequent flyers” and who are diagnosed with a mental illness are referred to the Jail Inreach Project. In order to maximize the effectiveness of the discharge plan, case managers offer the option of meeting the client at the time of release and bring them to the HHH clinic located four blocks from the jail. Participation in both the program and the option for direct release to the care of a case manager are voluntary.^ The purpose of this study is to determine the outcomes of the Jail Inreach Project and addresses the following objectives: (1) to evaluate the characteristics of inmates that chose to be released from jail to the direct care of an HHH case manager versus those who opt for self release and (2) to determine the number and percent of inmates that are linked to services and relationship with type of release (direct versus indirect), (3) to determine if there is a relationship between outcomes and characteristics and (4) to determine what outcomes are a function of release, controlling for characteristics. Statistical analysis, including frequencies, cross tabulations, chi-square and logistical regression, found that those who opt for self release are six times less likely to be successfully linked to services and that gender is the most significant predictor of choosing self release. Men are far more likely to opt for self release than women engaged in this program. These findings help inform policy and program design and development that addresses the difference in service utilization and successful linkage to services post-incarceration. Successful linkage to services, thus continuity of and access to care, further impact the effects of the revolving door phenomenon of mentally ill homeless individuals cycling between the streets, jails and hospital emergency centers.^

Commercial Sexual Exploitation and Missing Children in the Coastal Region of Sao Paulo State, Brazil

The commercial sexual exploitation of children (CSEC) has emerged as one of the world’s most heinous crimes. The problem affects millions of children worldwide and no country or community is fully immune from its effects. This paper reports first generation research of the relationship that exists between CSEC and the phenomenon of missing children living in and around the coastal regions of the state of Sao Paulo, Brazil, the country’s richest State. Data are reported from interviews and case records of 64 children and adolescents, who were receiving care through a major youth serving non-governmental organization (NGO) located in the coastal city of Sao Vicente. Also, data about missing children and adolescents were collected from Police Reports – a total of 858 Police Reports. In Brazil, prostitution is not a crime itself, however, the exploitation of prostitution is a crime. Therefore, the police have no information about children or adolescents in this situation, they only have information about the clients and exploiters. Thus, this investigation sought to accomplish two objectives: 1) to establish the relationship between missing and sexual exploited children; and 2) to sensitize police and child-serving authorities in both the governmental and nongovernmental sectors to the nature, extent, and seriousness of many unrecognized cases of CSEC and missing children that come to their attention. The observed results indicated that the missing children police report are significantly underestimated. They do not represent the number of children that run away and/or are involved in commercial sexual exploitation.

Addressing the Challenges of Child and Family Homelessness

Homeless children in families comprise the fastest-growing group of homeless persons in the United States. Indeed, the American Academy of Pediatrics considers homelessness to be an issue with which pediatricians should be concerned. In this article, we review existing literature to provide a background for researchers, policymakers, and social service providers hoping to understand the phenomenon of child and family homelessness and various strategies used to address it. We begin with a definition and description of the population of homeless families with children. We then offer a broad consideration of the effects of child and family homelessness, from physical health problems like malnutrition and increased incidence of infection to emotional and academic impacts. We end with a platform of policies and other action steps for addressing the problems of homelessness for children and their families.

Towards a new concept of leadership

In the present work we have posited some necessary guidelines to reformulate an essential pillar of leadership: the relationship group-leader. The set of enunciations that are developed are meant to establish the basic principles of the theoretical interpretation of this essential phenomenon of social life. In most works dealing with leadership we usually find that texts are centred on the leader. However, the process possesses another member of even greater importance embodied in the social group that forms around him or her. Thus, social actors need to reach a higher degree of sociability and to express, amongst other things, needs and goals, and they look for them openly in a chosen representative. And he or she, in turn, must fulfil the expectations of the group. In other words, the asymmetry of said relationship is inverted. Moreover, at the leader's end, we must discern between the person and the 'character'. This is how the particular game of leadership unfolds. The resulting construct accounts for the construction of a significant social feat.

Towards a new concept of leadership

In the present work we have posited some necessary guidelines to reformulate an essential pillar of leadership: the relationship group-leader. The set of enunciations that are developed are meant to establish the basic principles of the theoretical interpretation of this essential phenomenon of social life. In most works dealing with leadership we usually find that texts are centred on the leader. However, the process possesses another member of even greater importance embodied in the social group that forms around him or her. Thus, social actors need to reach a higher degree of sociability and to express, amongst other things, needs and goals, and they look for them openly in a chosen representative. And he or she, in turn, must fulfil the expectations of the group. In other words, the asymmetry of said relationship is inverted. Moreover, at the leader's end, we must discern between the person and the 'character'. This is how the particular game of leadership unfolds. The resulting construct accounts for the construction of a significant social feat.

Towards a new concept of leadership

In the present work we have posited some necessary guidelines to reformulate an essential pillar of leadership: the relationship group-leader. The set of enunciations that are developed are meant to establish the basic principles of the theoretical interpretation of this essential phenomenon of social life. In most works dealing with leadership we usually find that texts are centred on the leader. However, the process possesses another member of even greater importance embodied in the social group that forms around him or her. Thus, social actors need to reach a higher degree of sociability and to express, amongst other things, needs and goals, and they look for them openly in a chosen representative. And he or she, in turn, must fulfil the expectations of the group. In other words, the asymmetry of said relationship is inverted. Moreover, at the leader's end, we must discern between the person and the 'character'. This is how the particular game of leadership unfolds. The resulting construct accounts for the construction of a significant social feat.

Chronology and petrology in MIS4-2 of DSDP Site 94-609

Ice-rafting evidence for a '1500-year cycle' sparked considerable debate on millennial-scale climate change and the role of solar variability. Here, we reinterpret the last 70,000 years of the subpolar North Atlantic record, focusing on classic DSDP Site 609, in the context of newly available raw data, the latest radiocarbon calibration (Marine09) and ice core chronology (GICC05), and a wider range of statistical methodologies. A ~1500-year oscillation is primarily limited to the short glacial Stage 4, the age of which is derived solely from an ice flow model (ss09sea), subject to uncertainty, and offset most from the original chronology. Results from the most well-dated, younger interval suggest that the original 1500 ± 500 year cycle may actually be an admixture of the ~1000 and ~2000 cycles that are observed within the Holocene at multiple locations. In Holocene sections these variations are coherent with 14C and 10Be estimates of solar variability. Our new results suggest that the '1500-year cycle' may be a transient phenomenon whose origin could be due, for example, to ice sheet boundary conditions for the interval in which it is observed. We therefore question whether it is necessary to invoke such exotic explanations as heterodyne frequencies or combination tones to explain a phenomenon of such fleeting occurrence that is potentially an artifact of arithmetic averaging.

Chemical composition of minerals from rocks of the Utashud Island, off the Southeast Kamchatka

A brief review of various relationships connecting seismofocal zone and volcanic belts within the Kurile island-arc system is represented. Possibilities of manifestation of the submarine volcanic activity and associated relief of the hydrothermal systems on the Pacific shelf of the South Kamchatka are considered. We propose to consider Malko-Petropavlovsk zone of transverse dislocations as seismogenerating one. The phenomenon of ultrafast deformations.