Thyrotropin receptor expression in adrenal, kidney, and thymus

Inflammatory conditions characterized by neutrophil activation are associated with a variety of chronic diseases. Reactive oxygen species are produced by activated neutrophils and produce DNA damage which may lead to tissue damage. Previous studies have shown that activated murine neutrophils induce DNA strand breaks in a target plasmacytoma cell, RIMPC 2394. We studied the effect of a water soluble nitroxide anti-oxidant, Tempol, on murine neutrophil induction of DNA strand breaks in this system. Murine neutrophils were isolated from the peritoneal cavity of BALB/cAn mice after an i.p. injection of pristane oil. Neutrophils were activated by the phorbol ester PMA and co-incubated with RIMPC 2394 cells. Control alkaline elution studies revealed progressive DNA strand breaks in RIMPC cells with time. The addition of Tempol to the incubation mixture prevented DNA damage in a dose dependent fashion. Five mM Tempol provided complete protection. Tempol protection against DNA strand breaks was similar for both stimulated neutrophils and exogenously added hydrogen peroxide. Measurement of hydrogen peroxide produced by stimulated neutrophils demonstrated that Tempol did not decrease hydrogen peroxide concentration. Oxidation of reduced metals, thereby interfering with the production of hydroxyl radical, is the most likely mechanism of nitroxide protection, although superoxide dismutase (SOD) like activity and scavenging of carbon-based free radicals may also account for a portion of the observed protection. The anti-oxidant activity of Tempol inhibited DNA damage by activated neutrophils. The nitroxides as a class of compounds may have a role in the investigation and modification of inflammatory conditions.     

Transcriptional regulation of metabolic processes: implications for cardiac metabolism

Developmental delay is frequently used to identify children with delay in meeting developmental milestones in one or more streams of development. There is no consensus on the specific definition. Developmental delay is best viewed generically as a chief complaint rather than a diagnosis. A child suspected to have delays should always be assessed in each of the major streams of development: expressive and receptive language, including social communication; visual problem solving (nonverbal cognition); motor development; neurobehavioral development; and social-emotional development. A model developed by the National Center for Medical Rehabilitation Research is used to compare existing classifications of developmental delays. This model defines the five domains in the disability process: pathophysiology, impairment, functional limitation, disability, and societal limitation. An etiology domain is added. This model is used to illustrate how existing classification systems of cerebral palsy, mental retardation, autism, and language delay draw on information from one or more domains. The model illustrates some of the conflicts between different systems. For example, most classification systems for cerebral palsy emphasize only impairment (spasticity, dyskinesias, and topography). The current definition and classification system for mental retardation focuses on functional limitations (IQ), disability, and societal limitations, ignoring pathophysiology and details of impairment. Given the complexity of neurodevelopmental disabilities, it is unlikely that a single classification system will fit all needs.     

Human and nonhuman primate lymphocytes engrafted into SCID mice reside in unique mesenteric lymphoid structures

The present study compares the location and phenotype of B lineage lymphocytes in tissues from SCID mice engrafted with PBMC of human, chimpanzee, and pig-tailed macaque origin. In mice repopulated with both human and nonhuman primate lymphocytes, plasma cells were found in the peritoneal cavity in vascularized structures located in the mesentery near the pancreas, intestines, and spleen. The predominant isotype of the plasma cells was IgG; IgM and IgA cells were also present. Kappa and lambda light chains were expressed by 62% and 38% of the Ig-containing cells, respectively. J chain expression occurred in most cells irrespective of the Ig isotype. In the SCID mice engrafted with human lymphocytes, a few IgM-containing cells were found in the spleen; plasma cells were not found in other tissues, including the intestine. The aggregation of plasma cells did not appear to be a result of infection with EBV. T cells were rarely found in the lymphoid aggregates but were recovered from the spleen and peritoneal lavage. Human Ig levels in the serum of engrafted mice reflected the isotype distribution of the cells with IgG > IgM > or = IgA.     

Quantitative risk assessment for Escherichia coli O157:H7 in ground beef hamburgers

Quantitative Risk Assessment (QRA) is a methodology used to organize and analyze scientific information to estimate the probability and severity of an adverse event. Applied to microbial food safety, the methodology can also help to identify those stages in the manufacture, distribution, handling, and consumption of foods that contribute to an increased risk of foodborne illness, and help focus resources and efforts to most effectively reduce the risk of foodborne pathogens. The term Process Risk Model (PRM) is introduced in this paper to describe the integration and application of QRA methodology with scenario analysis and predictive microbiology to provide an objective assessment of the hygienic characteristics of a manufacturing process. The methodology was applied to model the human health risk associated with Escherichia coli O157:H7 in ground beef hamburgers. The PRM incorporated two mathematical submodels; the first was intended to described the behaviour of the pathogen from the production of the food through processing, handling, and consumption to predict human exposure. The exposure estimate was then used as input to a dose-response model to estimate the health risk associated with consuming food from the process. Monte Carlo simulation was used to assess the effect of the uncertainty and variability in the model parameters on the predicted human health risk. The model predicted a probability of Hemolytic Uremic Syndrome of 3.7 x 10(-6) and a probability of mortality of 1.9 x 10(-7) per meal for the very young. These estimates are likely high for all hamburger meals, but may be reasonable for the home-prepared hamburgers described by this model. The efficacy of three risk mitigation strategies were evaluated by modifying the values of the predictive factors and comparing the new predicted risk. The average probability of illness was predicted to be reduced by 80% under a hypothetical mitigation strategy directed at reducing microbial growth during retail storage through a reduction in storage temperature. This strategy was predicted to be more effective than a hypothetical intervention which estimated a plausible reduction in the concentration of E. coli O157:H7 in the feces of cattle shedding the pathogen and one aimed at convincing consumers to cook hamburgers more thoroughly. The conclusions of this approach are only accurate to the extent that the model accurately represents the process. Currently, uncertainty and ignorance about the hygienic effects of the individual operations during production, processing, and handling limit the applicability of a PRM to specify HACCP criteria in a quantitative manner. However, with continuous improvement through stimulated research, a PRM should encompass all available information about the process, food, and pathogen and should be the most appropriate decision-support tool since it represents current knowledge.     

Marked granulocytic proliferation induced by granulocyte colony-stimulating factor in the spleen simulating a myeloid leukemic infiltrate

The authors describe a patient with a long-standing history of systemic lupus erythematosus and leukopenia who received multiple intermittent doses of recombinant granulocyte colony-stimulating factor (G-CSF) and who underwent splenectomy because of a clinical impression of sequestration of granulocytes by the spleen. Histologic evaluation of the spleen revealed marked granulocytic hyperplasia with an increase in immature myeloid precursors, morphologically indistinguishable from a myeloid leukemic infiltrate. A postsplenectomy bone marrow aspirate and biopsy revealed a normocellular bone marrow with active hematopoiesis and trilineage maturation. The bone marrow aspirate cultured cells showed no numeric or structural chromosomal abnormality. Extramedullary hematopoiesis after receipt of G-CSF was previously reported, but, to our knowledge, ours is the first report of morphologic changes virtually identical to a leukemic infiltrate in spleen after G-CSF treatment. We describe the histologic and immunohistochemical findings in the spleen, compare our observations with those of others reported in the literature, and postulate a possible mechanism for this phenomenon.     

Interaction of the hemochromatosis gene product HFE with transferrin receptor modulates cellular iron metabolism

Mutations of a novel MHC class I-like protein, termed HFE, have been found in the vast majority of patients with the iron overload disease heredity hemochromatosis. Identification of HFE is likely to shed light on one of the major enigmas of mammalian iron homeostasis: How is intestinal iron absorption regulated?     

Expanding role of alpha adrenoceptor blockade in the treatment of benign prostatic hyperplasia

PURPOSE: To evaluate the efficacy and safety of timolol hemihydrate once daily versus timolol maleate gel forming solution once daily in patients with primary open-angle glaucoma or ocular hypertension. METHODS: We prospectively randomized patients with primary open-angle glaucoma or ocular hypertension to receive either timolol hemihydrate 0.5% solution or timolol maleate gel forming solution 0.5% every morning. The primary efficacy variable was the 8:00 AM trough intraocular pressure (IOP) 24 hours after administration. RESULTS: Three months after initiation of therapy, baseline IOP had decreased from 23.6 +/- 1.9 mmHg to 18.3 +/- 2.8 mmHg in the group taking timolol hemihydrate (n = 22) and from 23.7 +/- 2.2 mmHg to 18.4 +/- 3.1 mmHg in the group receiving timolol maleate gel (n = 21) at the 24-hour trough level. This was not a significant difference between groups at 3 months. Also, no difference was observed between groups in the 2-hour post instillation IOP. Visual acuity was decreased in the group receiving timolol maleate gel compared with those receiving timolol hemihydrate one minute after instillation of study medicine at month 3. Otherwise, ocular and systemic safety were similar between groups. No differences between groups in cardiac pulse or systolic and diastolic blood pressure were observed. CONCLUSION: Timolol hemihydrate 0.5% solution given once a day appears to be as efficacious and safe in decreasing IOP as timolol maleate gel 0.5% given once a day.     

Expression of the CD8alpha beta-heterodimer on CD8(+) T lymphocytes in peripheral blood lymphocytes of human immunodeficiency virus- and human immunodeficiency virus+ individuals

CD8(+) T lymphocytes play a pivotal role in controlling human immunodeficiency virus (HIV)-1 replication in vivo. We have performed four-color flow cytometric analysis of CD8(+) peripheral blood lymphocytes (PBL) from 21 HIV-1 seronegative and 103 seropositive individuals to explore the phenotypic heterogeneity of CD8beta-chain expression on CD8(+) T lymphocytes and to clarify how its expression on CD8(+) T lymphocytes may relate to acquired immunodeficiency syndrome (AIDS) clinical progression. We showed that the single monoclonal antibody (MoAb) 2ST8-5H7, directed against the CD8alpha beta-heterodimer, identifies CD8(+) T lymphocytes as effectively as the conventional combination of anti-CD3 and anti-CD8alpha antibodies. However, we detected a significantly lower mean fluorescence (MF) of anti-CD8alpha beta staining on PBL from HIV-1 seropositive donors as compared with seronegative donors. In fact, CD8(+) T lymphocytes from HIV-1-infected individuals with the lowest CD4 counts showed the lowest levels of CD8alpha beta MF. To explore further this change in CD8alpha beta expression, we assessed the expression of 14 different cell surface molecules on CD8alpha beta+ T lymphocytes of PBL from 11 HIV-1 seronegative and 22 HIV-1 seropositive individuals. The MF of anti-CD8alpha beta staining was significantly reduced on CD8(+) T lymphocyte subsets that showed immunophenotypic evidence of activation. The subset of lymphocytes expressing low levels of CD8alpha beta expressed higher levels of activation, adhesion, and cytotoxic-associated molecules and was predominantly CD45RO+ and CD28(-). Finally, we monitored the expression of the CD8alpha beta-heterodimer on PBL of eight HIV-1-infected individuals over a 16-week period after the initiation of highly active antiretroviral therapy (HAART), including zidovudine (ZDV), lamivudine (3TC), and indinavir (IDV), and found a significant increase in the expression of the CD8alpha beta-heterodimer. These results suggest that antibodies recognizing the CD8alpha beta-heterodimer are useful tools to specifically identify CD8(+) T lymphocytes. Moreover, the quantitative monitoring of CD8alpha beta expression allows the detection of discrete CD8(+) T lymphocyte subsets and may be useful for assessing the immune status of individuals infected with HIV-1.     

Neoplastic fixation to the prevertebral compartment by squamous cell carcinoma of the head and neck

OBJECTIVE: The purpose of this study was to determine the accuracy of MR imaging in determining fixation of squamous cell carcinomas to the prevertebral space. MATERIALS AND METHODS: MR images of 15 patients with large pharyngeal carcinoma (n = 13) or laryngeal carcinomas with pharyngeal extension (n = 2) were retrospectively reviewed independently by two head and neck radiologists who were unaware of the surgical findings. MR images were evaluated for four criteria in the prevertebral longus muscle complex: muscle concavity, irregular tumor-muscle interface, T2 hyperintensity, and enhancement. All patients underwent panendoscopy where fixation or mobility of the tumor relative to the prevertebral fascia was assessed by manual manipulation. Tumors in six patients were fixed to the prevertebral space and inoperable. In nine patients whose tumors were not fixed, open neck explorations were performed and tumors were resected in seven patients. MR findings were compared with panendoscopy in all patients and with intraoperative assessment in nine patients. RESULTS: Eleven of 15 patients had at least two of the MR imaging criteria present. None of the MR findings were both sensitive and specific for tumor fixation. Although muscle concavity and enhancement each had a sensitivity of 88%, both criteria suffered from low specificity (14% and 29%, respectively). An irregular tumor-muscle interface and muscle T2 hyperintensity were criteria that suffered from both low sensitivity and specificity. Accuracy of the imaging criteria independently ranged from 53% to 60%. CONCLUSION: Although abnormal muscle contour, T2 hyperintensity, and enhancement are frequently present in neck carcinomas that are fixed to the prevertebral space, these findings may also be present in patients in whom the tumor is mobile and resectable. MR imaging may not be able to differentiate between neoplastic fixation and nonneoplastic changes in the prevertebral space.