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PubMed2004

Pathobiology of hemophilic synovitis I: overexpression of mdm2 oncogene.

Hemophilia is a genetic disease caused by a deficiency of blood coagulation factor VIII or IX. Bleeding into joints is the most frequent manifestation of hemophilia. Hemarthrosis results in an inflammatory and proliferative disorder termed hemophilic synovitis (HS). In time, a debilitating, crippling arthritis, hemophilic arthropathy, develops. Although the clinical sequence of events from joint bleeding to synovitis to arthropathy is well documented, the component or components in blood and the molecular changes responsible for hemophilic synovitis are not known. Iron has long been suspected to be the culprit but direct evidence has been lacking. Previously, we showed that iron increased human synovial cell proliferation and induced c-myc expression. Here we show that bleeding into a joint in vivo and iron in vitro result in increased expression of the p53-binding protein, mdm2. Iron induced the expression of mdm2 by normal human synovial cells approximately 8-fold. In a murine model of human hemophilia A, hemarthrosis resulted in pathologic changes observed in human hemophilic synovitis and a marked increase in synovial cell proliferation. Iron, in vitro, induced the expression of mdm2. The molecular changes induced by iron in the blood may be the basis of the increase in cell proliferation and the development of hemophilic synovitis.

Animals↗
PubMed2001

Down-regulation of BOB.1/OBF.1 and Oct2 in classical Hodgkin disease but not in lymphocyte predominant Hodgkin disease correlates with immunoglobulin transcription.

In contrast to the tumor cells (L&H cells) of lymphocyte predominant Hodgkin disease (LPHD), Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin disease (cHD) are unable to transcribe immunoglobulin, despite the presence of rearranged immunoglobulin genes. Although initial studies have suggested crippling immunoglobulin gene mutations to be the cause of absent immunoglobulin expression in cHD, recent work of our group has demonstrated an impaired activation of the immunoglobulin promoter as a superior mechanism. As immunoglobulin transcription is mainly regulated by the B-cell transcription factors Oct2 and BOB.1/OBF.1, we analyzed 35 cases of LPHD, 32 cases of cHD, and 2 Hodgkin disease cell lines for the expression of these transcription factors and also in parallel for immunoglobulin expression. Our results demonstrate an absence of Oct2 and/or BOB.1/OBF.1 in cHD and a striking overexpression of Oct2 in LPHD. Immunoglobulin expression was lacking in cHD but present in LPHD. Furthermore, the reintroduction of BOB.1/OBF.1 and Oct2 into cultured HRS cells restored the activity of cotransduced immunoglobulin promoter constructs. Our findings dismiss the concept that the different immunoglobulin expression in cHD and LPHD is due to disrupting mutations of immunoglobulin V genes in cHD but is most likely due to a down-regulation of Oct2 and/or BOB.1/OBF.1. This study further revealed Oct2 as a new and valuable marker for the identification of L&H cells and their distinction from HRS cells. The impairment of immunoglobulin transcription with a down-regulated synthesis of Oct2 and BOB.1/OBF.1 is the first established general recurrent defect found in HRS cells.

Cell Line↗
PubMed2003

State of the art: why do the lungs of patients with cystic fibrosis become infected and why can't they clear the infection?

Cystic Fibrosis (CF) lung disease, which is characterized by airway obstruction, chronic bacterial infection, and an excessive inflammatory response, is responsible for most of the morbidity and mortality. Early in life, CF patients become infected with a limited spectrum of bacteria, especially P. aeruginosa. New data now indicate that decreased depth of periciliary fluid and abnormal hydration of mucus, which impede mucociliary clearance, contribute to initial infection. Diminished production of the antibacterial molecule nitric oxide, increased bacterial binding sites (e.g., asialo GM-1) on CF airway epithelial cells, and adaptations made by the bacteria to the airway microenvironment, including the production of virulence factors and the ability to organize into a biofilm, contribute to susceptibility to initial bacterial infection. Once the patient is infected, an overzealous inflammatory response in the CF lung likely contributes to the host's inability to eradicate infection. In response to increased IL-8 and leukotriene B4 production, neutrophils infiltrate the lung where they release mediators, such as elastase, that further inhibit host defenses, cripple opsonophagocytosis, impair mucociliary clearance, and damage airway wall architecture. The combination of these events favors the persistence of bacteria in the airway. Until a cure is discovered, further investigations into therapies that relieve obstruction, control infection, and attenuate inflammation offer the best hope of limiting damage to host tissues and prolonging survival.

Bacterial Infections↗
PubMed2005

Osteoclasts; culprits in inflammatory osteolysis.

Periarticular osteolysis, a crippling complication of rheumatoid arthritis, is the product of enhanced osteoclast recruitment and activation. The osteoclast, which is a member of the monocyte/macrophage family, is the exclusive bone resorptive cell, and its differentiation and activation are under the aegis of a variety of cytokines. Receptor activator of NF-kappaB ligand (RANKL) and macrophage colony-stimulating factor are the essential osteoclastogenic cytokines and are increased in inflammatory joint disease. Tumor necrosis factor-alpha, which perpetrates arthritic bone loss, exerts its osteoclastogenic effect in the context of RANKL with which it synergizes. Achieving an understanding of the mechanisms by which the three cytokines affect the osteoclast has resulted in a number of active and candidate therapeutic targets.

Animals↗
PubMed2001

Clues to the etiology of autoimmune diseases through analysis of immunoglobulin genes.

The role of autoantibodies in the etiology of autoimmune diseases remains unclear. However, an examination of the sequences of these autoantibodies can be informative. Antibody sequences that violate constraints normally imposed during ontogeny and during development point to a failure of regulation. The existence of clonally related sequences indicates that production of these antibodies may frequently be driven by self-antigen. A better understanding of the mechanisms that normally constrain the composition of the antibody repertoire and of the nature of the inciting and/or driving antigens may yield new insights into both the pathogenesis and potential treatment of these crippling diseases.

Animals↗
PubMed2005

HIV-1 Nef mediates post-translational down-regulation and redistribution of the mannose receptor.

Human immunodeficiency virus (HIV) has derived a variety of means to evade the host immune response. HIV-derived proteins, including Tat, Nef, and Env, have all been reported to decrease expression of host molecules such as CD4 and major histocompatibility complex I, which would assist in limiting viral replication. The mannose receptor (MR) on the surface of macrophages and dendritic cells (DC) has been proposed to function as an effective antigen-capture molecule, as well as a receptor for entering pathogens such as Mycobacterium tuberculosis and Pneumocystis carinii. Regulation of this receptor would therefore benefit HIV in removing an additional arm of the innate immune system. Previous work has shown that MR function is reduced in alveolar macrophages from HIV-infected patients and that surface MR levels are decreased by the HIV-derived protein Nef in DC. In addition, several laboratories have shown that CD4 is removed from the surface of T cells in a manner that might be applicable to decreased MR surface expression in macrophages. In the current study, we have investigated the role of Nef in removing MR from the cell surface. We have used a human macrophage cell line stably expressing the MR as well as human epithelial cells transiently expressing CD4 and a unique CD4/MR chimeric molecule constructed from the extracellular and transmembrane domains of CD4 and the cytoplasmic tail portion of the MR. We show that the MR is reduced on the cell surface by approximately 50% in the presence of Nef and that the MR cytoplasmic tail can confer susceptibility to Nef in the CD4/MR chimera. These data suggest that the MR is a potential intracellular target of Nef and that this regulation may represent a mechanism to further cripple the host innate immune system.

Amino Acid Sequence↗
PubMed2005

Escherichia coli K1 inhibits proinflammatory cytokine induction in monocytes by preventing NF-kappaB activation.

Phagocytes are well-known effectors of the innate immune system to produce proinflammatory cytokines and chemokines such as tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-1beta, and IL-8 during infections. Here, we show that infection of monocytes with wild-type Escherichia coli K1, which causes meningitis in neonates, suppresses the production of cytokines and chemokines (TNF-alpha, regulated on activation, normal T expressed and secreted, macrophage-inflammatory protein-1beta, IL-1beta, and IL-8). In contrast, infection of monocytes with a mutant E. coli, which lacks outer membrane protein A (OmpA- E. coli) resulted in robust production of cytokines and chemokines. Wild-type E. coli K1 (OmpA+ E. coli) prevented the phosphorylation and its degradation of inhibitor of kappaB, thereby blocking the translocation of nuclear factor (NF)-kappaB to the nucleus. OmpA+ E. coli-infected cells, subsequently subjected to lipopolysaccharide challenge, were crippled severely in their ability to activate NF-kappaB to induce cytokine/chemokine production. Selective inhibitors of the extracellular signal-regulated kinase (ERK) 1/2 pathway and p38 mitogen-activated protein kinase (MAPK), but not Jun N-terminal kinase, significantly reduced the activation of NF-kappaB and the production of cytokines and chemokines induced by OmpA- E. coli, indicating a role for these kinases in the NF-kappaB/cytokine pathway. It is interesting that the phosphorylation of ERK 1/2 and p38 MAPK was notably reduced in monocytes infected with OmpA+ E. coli when compared with monocytes infected with OmpA- E. coli, suggesting that the modulation of upstream events common for NF-kappaB and MAPKs by the bacterium is possible. The ability of OmpA+ E. coli K1 to inhibit the macrophage response temporarily may enable bacterial survival and growth within the host for the onset of meningitis by E. coli K1.

Bacterial Outer Membrane Proteins↗
PubMed2005

Factors influencing osteoporosis knowledge: a community study.

According to the 2004 Surgeon General's report, more than 10 million people in the United States have osteoporosis, and another 34 million are at risk of developing this crippling disease that affects the quality of life. Efforts must be made to stem this disease that may be largely prevented with lifestyle changes. To engage in self-care to prevent osteoporosis, people need to have knowledge of risks and preventive behaviors. The purpose of this study was to examine factors influencing osteoporosis knowledge in 255 people in a university community. The Facts on Osteoporosis Quiz (Ailinger, Lasus, & Braun, 2003) was used to measure osteoporosis knowledge. Findings indicated that respondents had inadequate knowledge about osteoporosis. Age was positively correlated with knowledge (r = .27, p < .000), but education was not. There were marked differences in mean scores among ethnic groups. The findings suggest topics that community health nurses need to focus on in their osteoporosis educational interventions.

Adolescent↗
PubMed2005

Exploring the hand test with medically ill children and adolescents.

Pediatric psychologists use the tools of assessment to evaluate the psychological functioning of youth with chronic and acute medical illnesses. This study is an exploration of the use of a performance-based measure, the Hand Test (HT; Wagner, 1983), with pediatric medical patients. A sample of medical inpatients (n = 27) and psychiatric outpatients (n = 24) were administered the HT, a self-report measure, and a parent-report behavior rating scale. Results indicate that the psychiatric group scored higher than the medical group on HT Aggression, Withdrawal, and Pathological scores. The Aggression (d = 0.90) and Pathological (d = 0.80) variables were particularly robust in differentiating between groups, but the Crippled variable did not differ between groups. Hierarchical logistic regression demonstrated the incremental validity of the HT over behavior ratings alone in the classification of clinical groups. Analyses indicated that the HT can add important information in the differentiation of medically ill children from those with psychological disturbance.

Acute Disease↗
PubMed1986

Does strict phosphorus control precipitate renal osteomalacia?

Hyperphosphatemia leads to the development of osteitis fibrosa in patients with chronic renal failure. In contrast, crippling osteomalacia may appear in uremic patients who are hypophosphatemic or aluminum intoxicated or who undergo total or subtotal parathyroidectomy. Thus, strict phosphorus control by use of aluminum-containing gels may ameliorate renal osteitis fibrosa, but may potentiate the development of osteomalacia. To evaluate this possibility, we compared the bone histologies of 10 chronic renal hemodialysis patients who consistently maintained predialysis phosphorus levels between 4-5 mg/dl (Strict-P) to those of 46 randomly selected dialysis patients (Random-P). We found that the Strict-P group had lower circulating immunoreactive PTH (P less than 0.02) and alkaline phosphatase (P less than 0.05) levels and, as expected, less evidence of hyperparathyroid bone disease. On the other hand, the Strict-P patients had osteomalacia, as evidenced by moderate osteoid accumulation and reduced capacity of bone to assume a fluorescent tetracycline label. Furthermore, all Strict-P patients had histological evidence of bone aluminum accumulation. We conclude that maintenance of normal serum P levels with aluminum-containing gels in hemodialysis patients prevents severe hyperparathyroid bone disease. Such treatment, however, is also attended by a moderate degree of aluminum-associated osteomalacia.

Adult↗
PubMed1997

Cdc6p establishes and maintains a state of replication competence during G1 phase.

CDC6 is essential for the initiation of DNA replication in the budding yeast Saccharomyces cerevisiae. Here we examine the timing of Cdc6p expression and function during the cell cycle. Cdc6p is expressed primarily between mitosis and Start. This pattern of expression is due in part to posttranscriptional controls, since it is maintained when CDC6 is driven by a constitutively induced promoter. Transcriptional repression of CDC6 or exposure of cdc6-1(ts) cells to the restrictive temperature at mitosis blocks subsequent S phase, demonstrating that the activity of newly synthesized Cdc6p is required each cell cycle for DNA replication. In contrast, similar perturbations imposed on cells arrested in G(1) before Start have moderate or no effects on DNA replication. This suggests that, between mitosis and Start, Cdc6p functions in an early step of initiation, effectively making cells competent for replication. Prolonged exposure of cdc6-1(ts) cells to the restrictive temperature at the pre-Start arrest eventually does cripple S phase, indicating that Cdc6p also functions to maintain this initiation competence during G(1). The requirement for Cdc6p to establish and maintain initiation competence tightly correlates with the requirement for Cdc6p to establish and maintain the pre-replicative complex at a replication origin, strongly suggesting that the pre-replicative complex is an important intermediate for the initiation of DNA replication. Confining assembly of the complex to G(1) by restricting expression of Cdc6p to this period may be one way of ensuring precisely one round of replication per cell cycle.

Cell Cycle Proteins↗
PubMed2002

Telehealth policy: looking for global complementarity.

Telehealth is gaining acceptance as a tool for bridging the local and global health-care divides. However, integrating telehealth into existing health infrastructures presents a daunting challenge for governments, policy makers, telehealth advocates and health-care workers. The development of specific inter-jurisdictional telehealth policies will significantly improve the ability to meet this challenge. In the policy context, one 'success' is the increasing number of jurisdictions addressing policy issues. However, policy decisions have largely been taken in isolation, within individual health institutions, regions, provinces/states or countries. This represents a failure of the current approach. Telehealth, by its very nature, has the ability to transgress existing geo-political boundaries. As a consequence, policy in any single jurisdiction may hamper or even cripple the ability of telehealth to fulfil its potential. Commonality - or at least complementarity - of approach to telehealth policy must be encouraged. To achieve this, it is essential to understand the current or anticipated regulatory constraints that may affect telehealth. We have begun a preliminary study of country-specific policy issues.

Journal Article↗
PubMed2005

Limited ARSAC licence acquisition for radionuclide radiology.

Radionuclide radiology faces a potentially crippling future manpower shortage. A combination of future retirement, few trainees and many currently unfilled posts threatens to limit future service delivery. The case is made for in-house modular training of existing consultants as the way forward for radionuclide radiology, allowing limited ARSAC licence acquisition. We propose this as a viable solution to the manpower problem in radionuclide radiology.

Consultants↗
PubMed2003

Chronic Lyme disease: it's not all in our heads.

Those of us with chronic Lyme disease are not at all confused, as suggested by Sigal and Hassett (2002). We know from years of experience that we have real, specific symptoms that are usually painful and disabling and include severe headaches, crippling arthritis, and heart palpitations, which lead to serious heart disease. Many of us know that our symptoms are kept in check while we are on antibiotics, but they painfully reappear when the antibiotics are withdrawn. Just because the medical community cannot detect a specific causative bacterium and managed health care companies want to maximize profits doesn't mean that those of us afflicted with this terrible condition are delusional and not truly benefiting from antibiotic treatment. We are not all crazy; we are sick and we should not be required to prove it to get medical care.

Anti-Bacterial Agents↗
PubMedDate not supplied

Transition management as an intervention for survivor syndrome.

In today's health care environment of merged organizations, downsizing and restructuring, employees can be experiencing a debilitating syndrome called "layoff survivor syndrome." This syndrome can have a crippling effect on workers and organizations as employees struggle to adapt to the changed working environment. This article represents my self-reflection as a nursing unit manager who personally experienced survivor sickness and witnessed its impact on the unit staff that I was leading at the time. The work of Noer (1993) is explored to clarify the syndrome and describe how the nursing staff and I manifested the syndrome. The writings of Bridges (1991), Brockner (1992) and Noer (1993) provide timely and relevant insights into managing the impact of layoffs and downsizing on those left behind to carry on. Noer (1993) sees the adaptation to the change as the ability to make the psychological shift from the old business paradigm that perpetuated codependency to the new business paradigm of fostering empowered employees. Bridges (1991) takes us a step further in making this psychological shift to adapt to the new work environment by providing a three phase process he calls transitions. The works of these three authors hold an important message for organizations and employees working in environments that abound with constant change.

Adaptation, Psychological↗
PubMed1981

Home parenteral nutrition: the "costs" of patient and family participation.

The continued advancements in technology and medicine now make it possible for patients who are nutritional "cripples" to thrive on an outpatient basis through home parenteral nutrition (HPN). Since the social and psychological literature does not yet reflect extensive information on this type of program, this article outlines in detail a successful HPN program and explores the personal factors and needed resources involved in participation in such a program, including the perils of third party reimbursement. Based on experience in evaluating 36 HPN candidates and working with 26 HPN participants, the salient problems and concerns patients and families encounter with HPN therapy are discussed along with suggestions for constructively addressing such issues.

Adaptation, Psychological↗
PubMed1977

Crawling patterns in neglected poliomyelitis in the Solomon Islands.

Two hundred and twenty-two adult crawling poliomyelitic cripples were investigated. Analysis showed that bilateral lower limb paralysis with or without trunk involvement was the most common residual lesion. Remarkably paralysis was confined to a single lower limb in six cases. The various crawling patterns can be classified into six broad groups which are described and illustrated. It is suggested that in a developing country this classification has a practical application in the assessment of patients for rehabilitation to crutch walking. Subjects in the "true quandruped progression" and "squatting gait" categories generally have an excellent potential for rehabilitation, as often do those in the "infant-like crawl" group. Caution should be exercised in attempting crutch walking for those in the "body-dragging" group, and there seems little indication for attempting to establish upright walking for those in the "buttock pivoting" and "minimal movement" groups.

Adult↗
PubMed1983

A long-term review of children with congenital and acquired upper limb deficiency.

A long-term review of 131 children fitted with upper limb prostheses at the Ontario Crippled Children's Centre between 1965 and 1975 is reported. There were 116 children with congenital deficiencies and 15 who had had amputations. Follow-up ranged from 7 to 17 years. A total of 42 children had abandoned their prostheses, 37 of whom had congenital deformities and five were amputees. The level of deficiency was of fundamental importance in determining whether the prosthesis would be accepted; in the forearm, the longer the stump, the more likely it was that the child would discard the prosthesis. Overall, 50 per cent of children fitted over the age of two years abandoned their prostheses compared with only 22 per cent of patients who had been fitted before the age of two years. The highest drop-out rate was at the age of 13 years when the children became more conscious of their cosmetic appearance. Suggestions for reducing the high drop-out rate in the early teens are put forward.

Adolescent↗