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PubMed1993

Neuropathologic analysis of postmortal brain samples of HIV-seropositive and -seronegative i.v. drug addicts.

Between 1987 and 1992 we performed forensic-pathologic and neuropathologic examinations on 70 cases of i.v. drug addicts who died of an overdose. In almost 25% of the cases HIV-positivity was revealed by serological examinations. In all the cases, irrespective of the result of the serological examination, a diffuse, reactive astrocytosis was the most prominent histologic alteration, accompanied by more or less pronounced regressive changes of this cell type in the deep layers of the white matter. Furthermore, also in all the cases, a slight to moderate, reactive proliferation of microglia could be assessed. In a few cases of the HIV-seropositive group a lymphocytic meningitis, viz. meningoencephalitis was found; these changes may indicate an early invasion of the central nervous system (CNS) by the HIV. In spite of these inflammatory alterations, in the latter cases no HIV-specific antigens (p24 and gp41) could be demonstrated in the brain, most probably because of the small number of infectious particles. In order to reveal the earliest phase of invasion of the CNS by the HIV, we performed a search for HIV-specific nucleic acid sequences by the aid of the polymerase chain reaction (PCR) in 8 HIV-seronegative and 8 normal control cases. Although, most probably due to contamination, also the control cases exhibited some PCR-signals, these were more pronounced and appeared with more primer-pairs within the group of HIV-seronegative drug addicts. It is conceivable that HIV penetrates the CNS and is harboured in it in latent form shortly after the primary infection.(ABSTRACT TRUNCATED AT 250 WORDS)

Brain Diseases↗

PubMed1992

Modification in penicillin-binding proteins during in vivo development of genetic competence of Haemophilus influenzae is associated with a rapid change in the physiological state of cells.

By using whole-cell labeling assay with 125I-penicillin V, we observed a reduction in the binding of the radiolabeled beta-lactam to four or five penicillin-binding proteins (PBPs) in Haemophilus influenzae cells cultivated under specific conditions. PBPs 3A, 3B, 4, and 6 were altered after the growth of bacteria in diffusion chambers implanted in the peritoneal cavity of rats. PBP 2 was also modified when cells were cultivated in human cerebrospinal fluids. Because this observation may have important consequences on the efficacy of beta-lactams during antibiotic therapy, we characterized the physiological state of bacteria cultivated in animals in the hope of explaining how such important changes in cell properties develop in vivo. Since the development of natural genetic competence occurs at the stationary phase of growth in H. influenzae, we used a DNA transformation assay to evaluate the physiological state of bacteria grown in diffusion chambers implanted in rats. Chromosomal DNA isolated from an antibiotic-resistant donor strain was mixed with bacteria in diffusion chambers. At different times during a 5-h incubation period, recipient bacteria were collected from the chambers, CFU were determined by plate counting, and antibiotic-resistant transformants were isolated on selective plates. Genetic competence rapidly developed in cells grown in rats, and the frequency of transformation by test DNA was elevated. Electron microscopy revealed an irregular cell shape and blebs at the surface of bacteria cultivated in animals and in cerebrospinal fluids. In an attempt to induce a similar physiological state in vitro, we supplemented broth cultures with cyclic AMP or synchronized cultures by a nutritional upshift. No changes in PBPs were observed with supplemental cyclic AMP or during a single cell cycle. Finally, a reduction in the affinity of PBPs for 125I-penicillin V identical to that observed in bacteria grown in rats was observed in cells isolated from the stationary phase of growth in vitro. These results clearly indicate that H. influenzae cells grown in animals undergo a rapid change to a physiological state similar to that found in late-stationary-phase cultures in vitro. This observation indicates that the rational design of future and improved antibiotic therapy of H. influenzae infections should consider cell properties of slow-growing or latent bacteria.

Animals↗

PubMed1975

EB virus: malignant lymphoma in cottontop marmosets following inoculation and recovery of the virus from cells of an experimental tumor maintained in organ culture.

The oncogenic potential of Epstein-Barr virus (EBV) was investigated in cottontop marmosets. Neoplasia resembling human malignant lymphomas, reticulum cell sarcoma type, occurred following inoculation of materials containing EBV. One of 4 monkeys that received autologous cells transformed in vitro by EBV developed lymphoma in mesenteric lymph nodes seven and one-half months after inoculation. Three of 4 marmosets inoculated with cell-free EBV developed lymphoma. The latent period for given with EBV accelerated the course of disease. Nevertheless malignant lymphoma occurred in an animal given only cell-free virus. Six of 8 marmosets inoculated with EBV demonstrated antibodies to the virus. Four marmosets not exposed to the virus, of which 2 received immunosuppressive drugs, have not developed tumors, nor EBV antibodies. EBV antigen detectable by immunofluorescences has been found in 2% of cells shed from one tumor maintained in organ culture. These results imply that EBV is capable of inducing malignant lymphoma in at least one primate species. Additional experimental evidence is required, however, before its oncogenic capacity in this host can be accepted without reservation.

Animals↗

PubMed2004

Epstein-Barr virus nuclear antigen 2 induces interleukin-18 receptor expression in B cells.

Epstein-Barr virus (EBV) latently infects and immortalizes B lymphocytes and causes lymphoproliferative malignancies. We show here that the EBV nuclear antigen EBNA2 induces expression of the 2 chains of the interleukin-18 receptor (IL-18R) in Burkitt lymphoma (BL) cell lines and in nontransformed B cells. Activation of IL-18R expression by EBNA2 is independent of its interaction with the transcriptional repressor RBPJ kappa. It occurs in the absence of any other viral protein but requires de novo synthesis of cellular proteins. IL-18R induction is a highly specific function of EBNA2, because neither other EBV latent proteins nor the cellular proteins c-myc or Notch can exert this effect. Using cDNA microarray expression profiling, we find that the IL-18 receptor expressed in EBV-infected BL cells has signaling capacity, because IL-18 significantly modified gene expression. We report that EBNA2 expression is associated with IL-18R expression in vivo in EBV-positive B-lymphomas from AIDS patients.

B-Lymphocytes↗

PubMed1977

Gastrointestinal cancer studies in the human to nude mouse heterotransplant system.

Human gastrointestinal cancer xenografts were established in the nude mouse. Grafts were accomplished with gastric adenocarcinomas, gastric leiomyosarcoma, histiocytic lymphoma of the stomach and gallbladder, pancreatic tumors, colonic cancers and cell lines of duodenal (HUTU-80) and pancreatic (HS-766-T) cancers, melanoma (SK-Mel-5), and murine metastasizing Lewis lung carcinoma. The rate of successful xenografting of these tumors varied from virtually 100% with colon and duodenal cancer, 50% for a pancreatic cancer (P-1), to only 17% for gastric adenocarcinoma. Pancreas and colon adenocarcinomas have been maintained by successive xenotransplantation over 16 and 19 months, respectively. Human xenografts retained morphological identity with tissues of origin through several transplant generations and shared some of their ultrastructural characteristics but did not metastasize. Rodent xenografts, of heterogenous origin were characterized by differences in the duration of the latent period and in the rate of their initial development as described by the average doubling times and average slopes (B) of their growth curves. Differences between B of the Lewis lung carcinoma and all of the human xenografts and between B of a pancreatic adenocarcinoma and three other neoplasms were significant (P less than 0.05 to 0.04). Labeling indices determined for 14 cancer transplants were in the range of previously reported data for similar neoplasms in patients or other xenograft systems. These findings suggest that the nude mouse model can be used to evaluate endogenous properties of gastrointestinal cancers and their responses to exogenous agents.

Adenocarcinoma↗

PubMed2000

Human herpesvirus 8 virology, epidemiology and related diseases.

Human herpesvirus 8 ([HHV-8], Kaposi's sarcoma-associated herpesvirus [KSHV]) is a novel human oncovirus classified as a gamma-herpesvirus. HHV-8 is associated with Kaposi's sarcoma (KS), primary effusion lymphoma (PEL) and some cases of multicentric Castleman's disease (MCD). Antibodies against HHV-8 are detected in the sera of almost all KS patients, about 30% of HIV-infected homosexual males in the world and 1.4% of the Japanese population. In HHV-8-associated malignancies such as KS and PEL, HHV-8 latently infects these tumor cells. Unlike other viruses, HHV-8 encodes several human homologues including cytokines (IL-6, MIPs, IRFs) and regulatory proteins (cyclin D, G-protein coupled receptor [GPCR]). These proteins may play significant roles in the pathogenesis of HHV-8-associated diseases. It has been demonstrated in vitro that the functions of retinoblastoma and p53 proteins were inhibited by viral cyclin D and latency-associated nuclear antigen, respectively. Mice transgenic for GPCR have a KS-like region in the skin. These data suggest the full oncogenecity of HHV-8. On the other hand, many cells expressing lytic proteins are found in MCD tissues, suggesting that the pathogenesis of MCD is different from that of HHV-8-associated malignancies.

Castleman Disease↗

PubMed2002

Lymphomas of the oral cavity: histology, immunologic type, and incidence of Epstein-Barr virus infection.

The purpose of this study was to determine the histologic class and immunologic phenotype of lymphomas presenting initially in the oral cavity and whether this correlated to a high incidence of Epstein-Barr virus (EBV) infection as has been reported with lymphomas in the nasal cavity. Seventy-one cases of oral lymphomas from the oral pathology referral service were analyzed retrospectively. They were classified according to the Revised European American Lymphoma (REAL) classification system using routine immunohistochemistry. EBV infection was determined by detection of early viral RNA sequences (EBER) and latent membrane protein (LMP-1) expression. Only non-Hodgkin's lymphomas were observed, with a female predominance of 2:1. They were primarily of B-cell origin and histologically classified mainly as large B-cell type (68%); T-cell lymphomas were rare (8%). EBV infection was observed in 14% of the B-cell lymphomas, an incidence rate higher than that reported in studies of B-cell lymphomas not located in the oral cavity but not as high as that observed in pleomorphic T-cell lymphomas (all sites, 36%) or nasal cavity T-cell lymphomas (nearly 100%). Interestingly, EBV proliferation did not correlate with expression of either Bcl-2 or p53.

Epstein-Barr Virus Infections↗

PubMed1972

Rapid viral induction of murine lymphomas in the graft-versus-host reaction.

When weanling (SJL/J x C57BL/1)F(1) hybrid mice were given five weekly-injections of small doses of viable SJL/J spleen cells, so as to induce a graft-versus-host reaction (GVHR), reticulum cell sarcomas were induced in all of the host mice by the 40th day after the first cell injection. Such tumors, on transplantation, were accepted by syngeneic (SJL/J x C57BL/1)F(1) and C57BL/1 hosts, but not by SJL/J or NZB mice. Cell-free extracts of SJL/J spleens injected into similar hybrids resulted in identical tumors in all hosts within the same period; the transplantation characteristics were also similar. Normal (SJL/J x C57BL/1)F(1) hybrids as well as similar hybrids injected with SJL/J liver or syngeneic F(1) spleen cells did not develop tumors. Cell-free preparations of eight tumors induced in F(1)'s by viable SLJ/J spleen cells were injected into newborn (C57BL/1 x A)F(1) and C57BL/1 mice: tumors were induced, with seven of eight tumor preparations, with a latent period of 33-49 days. Such tumors were lymphosarcomas, and, in the case of (C57BL/1 x A)F(1) hosts, further transplantation revealed that they were antigenically C57BL/1 tumors. These experiments provide conclusive evidence for a viral etiology of GVHR-induced tumors. Furthermore, tumor induction in the GVHR does not appear to depend specifically on an immunological mechanism but is most probably due to release or activation of a sufficient quantity of oncogenic virus within a certain time period in a highly susceptible host. Comparison with radiation induction of viral leukemia in mice revealed similarities in regard to optimal host age and the spacing of administration of the tumor-inducing agent. SJL/J mice carry a type C virus which causes a high incidence of spontaneous Hodgkin-like tumors by 1 yr of age; C57BL/1 mice do not develop lymphomas spontaneously but carry a latent leukemogenic virus. Their hybrid also has a low incidence of spontaneous lymphomas. Based on the results of these and previous experiments, the viruses of these strains of mice appear to be highly synergistic in tumor induction in the GVHR. The SJL/J virus is a powerful oncogenic agent. The C57BL/1 virus may be a helper virus to the SJL/J, but is a more powerful determinant of the antigenic composition of the induced tumors. This suggests that the virus of C57BL/1 mice, when activated, is capable of controlling the C57BL/1 genome. Because of the ease and rapidity of viral tumor induction, the SJL/J and C57BL/1 strains of mice, with their F(1) hybrid, should be useful for further study of the mechanisms controlling induction of such tumors.

Animals↗

PubMed2002

Accelerated progression of asbestos-induced mesotheliomas in heterozygous p53+/- mice.

Asbestos fibers produce diffuse malignant mesotheliomas in chronic rodent inhalation assays or after direct intrapleural or intraperitoneal injection. In vitro models have provided evidence that asbestos fibers are genotoxic carcinogens that can directly or indirectly generate reactive oxygen- and nitrogen-derived species that cause DNA damage. Heterozygous p53+/- mice show an increased incidence and reduced latency of malignant mesotheliomas induced by weekly intraperitoneal injections of crocidolite asbestos fibers. In this study, we investigated whether loss of heterozygosity (LOH) at the p53 tumor-suppressor gene locus contributes to accelerated tumor progression. LOH was found in 50% of the tumors produced in heterozygous p53+/- mice. In contrast to tumors that arise in p53+/+ mice or those that retained one p53 allele, LOH was associated with large tumor masses with central areas of necrosis, local invasion, and penetration of lymphatics. Increased tumor size was not associated with increased levels of cell proliferation as determined by BrdU incorporation, but it was correlated with a reduction in apoptosis as determined morphologically and by the TUNEL assay. Wild-type p53 protein is essential for cell cycle arrest in response to DNA damage and in maintenance of genomic stability. Cell lines established from tumors that showed LOH at the p53 tumor-suppressor gene locus were nearly tetraploid. These results suggest that p53 haplo-insufficiency sensitizes mice to the clastogenic or aneuploidogenic effects of crocidolite asbestos fibers, resulting in a shorter latent period. As solid tumors develop, spontaneous loss of the wild-type allele accompanied by decreased apoptosis and genetic instability is associated with accelerated tumor growth, invasion, and lymphatic dissemination.

Animals↗

PubMed1998

Theoretical calculation and prediction of brain-blood partitioning of organic solutes using MolSurf parametrization and PLS statistics.

Sixty-three structurally diverse compounds were investigated to statistically model the brain-blood partitioning of organic solutes using theoretically computed molecular descriptors and multivariate statistics. The program MolSurf was used to compute theoretical molecular descriptors related to physicochemical properties such as lipophilicity, polarity, polarizability, and hydrogen bonding. The multivariate Partial Least Squares Projections to Latent Structures (PLS) method was used to delineate the relationship between the brain-blood partitioning of organic solutes and the theoretically computed molecular descriptors. Good statistical models were derived. Properties associated with polarity and Lewis base strength had the largest impact on the blood-brain partitioning and should be kept to a minimum to promote high partitioning. The absence of atoms capable of hydrogen bonding interactions as well as high lipophilicity and the presence of polarizable surface electrons, i.e., valence electrons, were also found to promote high brain-blood partitioning. The results indicate that theoretically computed molecular MolSurf descriptors in conjunction with multivariate statistics of PLS type can be used to successfully model the brain-blood partitioning of organic solutes and hence differentiate drugs with poor partitioning from those with acceptable partitioning at an early stage of the preclinical drug-discovery process.

Blood-Brain Barrier↗

PubMedDate not supplied

HIV infection and rheumatic diseases--autoimmune mechanisms in immunodeficient hosts.

The recognition of a newly acquired immunodeficiency syndrome (AIDS) in 1981 has had dramatic social and economic implications. Eventually, an epidemic of the viral infection developed with a potential to spread globally. The extraordinary breadth of AIDS research lead to the early identification of the causative agent: The human immunodeficiency virus (HIV) is a member of the lentivirus family and is characterized by its ability to remain latent within the genome of the infected host. The primary targets for the HIV are helper T-lymphocytes and monocytes/macrophages, which results in the progressive destruction of immune functions in the infected hosts. Binding to and entry into the cells is facilitated by a high-affinity interaction of a viral glycoprotein and the CD4 molecule. Signs of the immunodeficient state, manifested as a broad spectrum of opportunistic infections initially dominated the clinical presentations of HIV infected patients. Over the last decade, however, the manifestations of HIV infection have steadily grown and, surprisingly, include many rheumatic syndromes and autoimmune phenomena. The finding that HIV-infected individuals present with a highly progressive form of Reiter's syndrome and psoriasis has challenged our understanding of immune functions in HLA-B27 associated disorders. Obviously, CD8+ T-cells can maintain function despite the depletion of CD4+ helper T-cells. Consistent with the current model of the pathogenesis of rheumatoid arthritis and systemic lupus erythematosus, patients with these syndromes were described to go into remission when CD4+ T-cells were selectively depleted in active HIV infection. There is growing evidence that complex mechanisms arise from the interaction of the HIV and the human host which extend beyond the initial expectation that the virus only kills CD4+ helper T-cells. Indicating yet another aspect of HIV disease, a new syndrome mimicking Sjögren's syndrome has been encountered in HIV-infected patients and has been named the diffuse infiltrative lymphocytosis syndrome. Dense infiltrates of CD8+, potentially antiviral killer cells, are characteristically found in the salivary glands of patients who express a certain HLA genotype and who are, typically, long-term survivors of the disease. Recent reports have stressed a new mechanism of disease induction in HIV infected patients. Inappropriate induction of potentially destructive cytokines appears to be initiated by the viral infection and the expression of the viral genome seems to be effectively modulated by cytokines. In summary, HIV infection may provide important insights in the pathogenesis of rheumatic diseases co-occurring with HIV infections.(ABSTRACT TRUNCATED AT 400 WORDS)

Arthritis, Rheumatoid↗

PubMed2002

Antigen-induced production of interferon-gamma in samples of peripheral lymph nodes from sheep experimentally inoculated with Mycobacterium avium subsp. paratuberculosis.

The production of interferon-gamma (IFN-gamma) in response to Johnin purified protein derivate was measured in samples of the prescapular lymph node (PLN) from 10 sheep, aged 2 years, and nine sheep, aged 1 year that had been inoculated orally with Mycobacterium avium subsp. paratuberculosis within their first month of life. Ten non-inoculated sheep, aged 1 year, constituted the negative control group. The results obtained in the PLN IFN-gamma assay were compared with those derived from serological tests: a complement fixation test (CFT), agar gel diffusion test (AGID) and enzyme-linked immunosorbent assay (ELISA), as well as an IFN-gamma test on samples of blood. Among the 19 inoculated sheep, 16 gave positive reactions in the PLN IFN-gamma assay on samples incubated overnight, and 18 tested positive when the assay was applied to PLN samples incubated for 48h. In comparison, three, four and seven inoculated sheep gave positive reactions in the ELISA, CFT and in the blood IFN-gamma assay on samples incubated overnight, respectively. The AGID and IFN-gamma assay on blood samples incubated for 48h detected eight inoculated animals. Twelve inoculated sheep, that tested positive in the PLN IFN-gamma assay were clinically normal, gave negative results in an IS900-based polymerase chain reaction (PCR) assay on samples of ileum and ileocaecal lymph node and had no histological evidence of paratuberculosis, but tested positive on more than two occasions in sequential serological testing before necropsy. None of the 10 non-inoculated sheep tested positive in the AGID, CFT, ELISA, blood IFN-gamma assay on samples incubated overnight and for 48h or the PLN IFN-gamma assay on samples incubated overnight, but one gave a positive result in the PLN IFN-gamma assay on samples stimulated for 48h. It is likely that the positive reactions obtained by the PLN IFN-gamma assay in the 12 inoculated sheep that tested negative in the PCR assay and histopathological examination represents immunological evidence of latent infection or previous exposure to M. paratuberculosis rather than active infection.

Animals↗

PubMed2005

Exploratory factor analysis of the Research and Development Culture Index among qualified nurses.

AIMS AND OBJECTIVES: This paper presents the exploratory factor analysis of a rating instrument for assessing the strength of organizational Research and Development (R&D) culture. BACKGROUND: Despite nursing's limited research capacity, the discipline is capitalizing upon opportunities to become involved in research and is making strong progress. Within the context of the debate on nursing research capacity, the R&D Culture Index was developed as a means of appraising R&D culture within health care organizations. DESIGN: Factor analysis was carried out on data collected from 485 nursing staff. The method of extraction was Principal Components Analysis with oblique rotation. METHODS: The Index was developed from the findings of qualitative research conducted with NHS staff. Eighteen items, encompassing the main themes from the data, were initially included in the Index. This pilot instrument was distributed to nursing staff within three different types of NHS Trust. Factor analysis resulted in rejection of two items and the analysis was repeated using the remaining 16 items. RESULTS: Three latent factors were extracted accounting for 58.0% of the variance in the data. The factors were: R&D Support, describing the perceived support within the working environment for R&D activity; Personal R&D Skills and Aptitude, describing an individual's perception of their ability towards R&D activity; and Personal R&D Intention, describing an individual's willingness to engage in R&D activity. Each factor had good internal reliability, as did the overall index. CONCLUSION: The R&D Culture Index provides an efficient means of assessing the strength of an organization's R&D culture in a way that captures the role of the individual practitioner and the organizational environment. RELEVANCE TO PRACTICE: These findings suggest that the continuing promotion of R&D within health care organizations is dependent upon a multi-faceted approach that addresses the learning needs of the organization as well as those of the individual practitioners.

Adult↗

PubMed1997

Color flow Doppler sonography rapidly differentiates type I and type II amiodarone-induced thyrotoxicosis.

Amiodarone-induced thyrotoxicosis (AIT) occurs both in abnormal thyroid glands (nodular goiter, latent Graves' disease) (type I AIT) or in apparently normal thyroid glands (type II AIT). Differentiation of the two forms is crucial, because type I AIT responds well to methimazole and potassium perchlorate combined treatment, whereas type II AIT is effectively managed by glucocorticoids. Differential diagnosis is often difficult, although thyroid radioactive iodine uptake is usually low-to-normal in type I and low-suppressed in type II, and serum interleukin-6 levels are normal/slightly elevated in type I, markedly elevated in type II. Color flow Doppler sonography (CFDS) is a technique that shows intrathyroidal blood flow and provides real-time information on thyroid morphology and hyperfunction. To investigate the usefulness of CFDS in differentiating the two types of AIT, 27 consecutive AIT patients, 11 type I and 16 type II, were evaluated by CFDS before starting antithyroid treatment. Gender, age, severity of thyrotoxicosis, and cumulative amiodarone dose were similar in the two groups. All type II AIT patients had a CFDS pattern 0 (ie, absent vascularity), in agreement with the pathogenesis of the disease, due to thyroid damage. Likewise, nine patients with subacute thyroiditis, another destructive process of the thyroid gland, also had a CFDS pattern 0. Eleven patients with type I AIT had a CFDS pattern ranging from pattern I (presence of parenchymal blood flow with patchy uneven distribution) (7 patients, 64%) to pattern II (ie, mild increase of color flow Doppler signal with patchy distribution) (1 patient, 9%) and pattern III (markedly increased color flow Doppler signal with diffuse homogeneous distribution)(3 patients, 27%), similar to that found in patients with untreated Graves' disease patients, thus indicating a hyper-functioning gland. Control subjects and euthyroid patients under long-term amiodarone treatment had absent thyroid hypervascularity and a CFDS pattern 0. These findings demonstrate that CFDS distinguishes type I and II AIT. Because of its rapidity and noninvasive features, CFDS represents a valuable tool for a quick differentiation between the two types of AIT. This can avoid any delay in initiating the appropriate treatment for a rapid control of thyrotoxicosis in patients whose tachyarrhythmias or other cardiac disorders make thyroid hormone excess extremely deleterious.

Adult↗

PubMed1981

Activation delays in frog twitch muscle fibres.

1. The length dependence of the mechanical latent period and early tension development, uncomplicated by latency relaxation, was determined from responses of single muscle fibres to restimulation at the peak of the isometric twitch at 15 degrees C. 2. The onset of the reactivation response showed little (less than 1.5 X 10(-7) N) or no latency relaxation. 3. Reactivation latency was minimal (2.8 msec) and constant at 1.9-2.1 micrometers sarcomere length and it increased by about 3 msec with sarcomere extension to 3.2 micrometers. 4. Reactivation responses showed two stages of early tension development, an initial phase in which tension acceleration increased, and a phase of maximum responsiveness in which tension acceleration was constant; the transition between the two phases occurred about 4.5 msec after the start of the stimulus at 2.2 micrometers sarcomere length and was delayed about 4 msec with increase in sarcomere length to 3.2 micrometers. 5. The square root of the maximum tension acceleration was directly proportional to the degree of overlap of thick and thin filaments in the sarcomere length range 2.3-3.2 micrometers. 6. It is proposed that the onset of the phase of constant tension acceleration marks the end of the period during which the activator, calcium, is distributed throughout the sarcomere. 7. Analysis of early tension transients in relation to myofibril structure showed that length-dependent changes in reactivation latency and time of onset of constant tension acceleration were probably brought about mainly by alteration of the kinetics of distribution of activator within the myofibril and by changes in the diffusion distance between activator-release sites ner the end of the sarcomere and the tension-generating sites. 8. There was a 2 msec myofibril priming delay in the rise of tension in twitch responses that was not seen in reactivation responses; the possible origin of that delay is discussed in relation to structural changes accompanying activation and to competition between calcium-binding structures. 9. The onset of twitch latency relaxation occurred within about 250 microseconds after the time corresponding to latency of the earliest reactivation responses and appeared to signal the start of a process that took place after the arrival of calcium among the myofilaments. The origin of latency relaxation is discussed.

Animals↗

PubMed1999

Hodgkin disease with subsequent transformation to CD30 positive non-hodgkin lymphoma in six patients.

BACKGROUND: Previous studies have indicated that some patients with Hodgkin disease have an aggressive clinical course. However, their characteristics have not been elucidated. METHODS: Six patients initially diagnosed as having Hodgkin disease with subsequent transformation to CD30 positive non-Hodgkin lymphoma were clinically and immunohistochemically studied. Ten patients with classic anaplastic large cell lymphoma (ALCL) and 19 patients with classic Hodgkin disease were studied for comparison by immunohistochemistry. RESULTS: Five patients, excluding one whom the authors recently encountered, had an aggressive clinical course and died within approximately 1 year after diagnosis; four of them were autopsied. Common histologic findings in the six patients included sheets of atypical mononuclear cells and sinusoidal infiltration of small numbers of these cells, as well as Reed-Sternberg cells or lacunar cells. Follow-up biopsies revealed histologic progression to ALCL in which sheets of atypical mononuclear or multinucleated cells spread throughout the lymph nodes. Immunohistochemically, epithelial membrane antigen, granzyme B, perforin, and pancadherin were expressed frequently in the six patients and in ALCL but were not expressed in Hodgkin disease. Latent membrane protein-1 (LMP-1) and Epstein-Barr virus-encoded RNA (EBER-1) were totally negative in the six patients and in ALCL but were expressed frequently in Hodgkin disease. In contrast, LeuM1 (CD15) was expressed frequently in the six patients and in Hodgkin disease, whereas it was not expressed in ALCL. MT1 (CD43), UCHL-1 (CD45RO), and P80 were totally negative in the six patients and in Hodgkin disease, whereas they were expressed variably in ALCL. CONCLUSIONS: These results suggest that the six patients studied had intermediate phenotypes between ALCL and Hodgkin disease. The authors also suggest that patients with sheets of atypical mononuclear cells and sinusoidal infiltration of atypical mononuclear and multinucleated cells have an aggressive clinical course and should be treated with intensive chemotherapy.

Adult↗

PubMed1977

[Epileptic manifestations following head injury (author's transl)].

An analysis is presented of the findings in a group of 300 patients with head injury, aged 15 years or over at the time of the accident, who subsequently developed epileptic manifestations. Early fits (including one case of immediate onset) were found in 33% of the cases (99 patients). In contrast to post-traumatic late epilepsy (PTE), which is a manifestation of a static process, early fits are triggered off by a dynamic process (brain oedema, haemorrhage) and are a sign of cerebral irritation, but do not represent a true form of epilepsy. Early fits are related to the acute traumatic state; the time limit is flexible, but lies in the region of 4 weeks following injury. Conversion of early fits to PTE (with or without a latent interval) occurred in 72% of the cases. This percentage is higher than the average incidence quoted in the literature and presumably arises partly from the selection criteria applied in this study. The time of appearance of early fits following injury is one factor which determines the prognosis. Fits appearing on the first day carry a relatively favourable prognosis and do not proceed to PTE in 41% of the cases, whereas this percentage shrinks to 15% in the case of fits appearing from the second week onwards. Early fits are an isolated occurrence in one third of the cases; progression to PTE is less frequent in these patients than following frequent, repeated convulsions. Furthermore, the incidence of early fits is dependent, to a large extent, on traumatological and clinical factors: the combination of unconsciousness of over three hours' duration, neurological signs referable to the central nervous system, persistent organic psychotic syndrome and intracranial bleeding leads to a significantly higher incidence of early fits than unconsciousness of less than three hours' duration and absence of neurological signs in patients who, moreover, do not display features of the psychotic syndrome, and shows a greater tendency to early fits even than the combination of depressed fracture of the skull with penetration of the dura. Should, however, early fits occur in spite of a favourable assessment of the traumatological factors involved, then progression to PTE occurs in a higher percentage of such cases than in patients displaying signs of a serious import following injury. The transition to PTE is markedly higher following diffuse cerebral contusion (75% of cases) than in cases displaying signs of local contusion....

Adult↗

PubMed2001

Evaluation of interactions of human cytomegalovirus immediate-early IE2 regulatory protein with small ubiquitin-like modifiers and their conjugation enzyme Ubc9.

The human cytomegalovirus (HCMV) major immediate-early protein IE2 is a nuclear phosphoprotein that is believed to be a key regulator in both lytic and latent infections. Using yeast two-hybrid screening, small ubiquitin-like modifiers (SUMO-1, SUMO-2, and SUMO-3) and a SUMO-conjugating enzyme (Ubc9) were isolated as IE2-interacting proteins. In vitro binding assays with glutathione S-transferase (GST) fusion proteins provided evidence for direct protein-protein interaction. Mapping data showed that the C-terminal end of SUMO-1 is critical for interaction with IE2 in both yeast and in vitro binding assays. IE2 was efficiently modified by SUMO-1 or SUMO-2 in cotransfected cells and in cells infected with a recombinant adenovirus expressing HCMV IE2, although the level of modification was much lower in HCMV-infected cells. Two lysine residues at positions 175 and 180 were mapped as major alternative SUMO-1 conjugation sites in both cotransfected cells and an in vitro sumoylation assay and could be conjugated by SUMO-1 simultaneously. Although mutations of these lysine residues did not interfere with the POD (or ND10) targeting of IE2, overexpression of SUMO-1 enhanced IE2-mediated transactivation in a promoter-dependent manner in reporter assays. Interestingly, many other cellular proteins identified as IE2 interaction partners in yeast two-hybrid assays also interact with SUMO-1, suggesting that either directly bound or covalently conjugated SUMO moieties may act as a bridge for interactions between IE2 and other SUMO-1-modified or SUMO-1-interacting proteins. When we investigated the intracellular localization of SUMO-1 in HCMV-infected cells, the pattern changed from nuclear punctate to predominantly nuclear diffuse in an IE1-dependent manner at very early times after infection, but with some SUMO-1 protein now associated with IE2 punctate domains. However, at late times after infection, SUMO-1 was predominantly detected within viral DNA replication compartments containing IE2. Taken together, these results show that HCMV infection causes the redistribution of SUMO-1 and that IE2 both physically binds to and is covalently modified by SUMO moieties, suggesting possible modulation of both the function of SUMO-1 and protein-protein interactions of IE2 during HCMV infection.

Amino Acid Sequence↗