Survival of patients with chronic-phase chronic myeloid leukaemia on imatinib after failure on interferon alfa

Until the recent introduction of imatinib, interferon alfa was the standard treatment for patients in the chronic phase of chronic myeloid leukaemia. We compared survival of 143 such patients, who did not respond to interferon alfa and were treated with imatinib, with that of 246 historical controls who received conventional treatment. Patients on imatinib showed an overall survival advantage (relative risk 0.54, 95% CI 0.31-0.93). However, although patients on imatinib who achieved at least some degree of cytogenetic response after 6 months had better survival than controls (0.13, 0.05-0.39), those with no cytogenetic response to imatinib had significantly worse survival (1.69, 1.09-2.64). Our findings suggest that cytogenetic responders obtain benefit from imatinib but patients who show no cytogenetic response should be given alternative treatment without delay. We confirmed these results in a case-matched analysis.     

Early proliferation of CCR5(+) CD38(+++) antigen-specific CD4(+) Th1 effector cells during primary HIV-1 infection

We investigated whether HIV-1 antigen-specific CD4(+) T cells expressed the viral coreceptor CCR5 during primary HIV-1 infection (PHI). In the peripheral blood of subjects with very early PHI (< 22 days after onset of symptoms), there was a 10- to 20-fold increase in the proportion of highly activated (CD38(+++)) and proliferating (Ki-67(+)) CD4(+) T cells that expressed CCR5(+), and were mostly T-cell intracellular antigen-1 (TIA-1)(+) perforin(+) granzyme B(+). Inthe same patient samples, CD4(+) T cells producing interferon (IFN)-gamma in response to HIV group-specific antigen (Gag) peptides were readily detected (median, 0.58%) by intracellular cytokine assay-these cells were again predominantly CD38(+++), Ki-67(+), and TIA-(++), as well as Bcl-2(low). On average, 20% of the Gag-specific CD4(+) T cells also expressed interleukin-2 (IL-2) and were CD127 (IL-7R)(+). Taken together, these results suggest that Gag-specific T-helper 1 (Th1) effector cells express CCR5 during the primary response and may include precursors of long-term self-renewing memory cells. However, in PHI subjects with later presentation, antigen-specific CD4(+) T cells could not be readily detected (median, 0.08%), coinciding with a 5-fold lower level of the CCR5(+)CD38(+++) CD4(+) T cells. These results suggest that the antiviral response to HIV-1 infection includes highly activated CCR5(+)CD4(+) cytotoxic effector cells, which are susceptible to both apoptosis and cytopathic infection with HIV-1, and rapidly decline.     

Autoimmune chronic active hepatitis in Down''s syndrome

Hashimoto's thyroiditis, autoimmune adrenalitis, pernicious anaemia, and diabetes mellitus are all recognised associations with Down's syndrome. In addition chronic active hepatitis (CAH) resulting from chronic hepatitis B antigenaemia is known to occur in these patients, but an association of autoimmune CAH and Down's syndrome has not previously been described. We report a case in which Down's syndrome was associated with autoimmune CAH, Hashimoto's thyroiditis, and alopecia areata.     

Enhancing employment services for people with severe mental illness: the challenge of the Australian service environment

OBJECTIVES: Comparatively few people with severe mental illness are employed despite evidence that many people within this group wish to obtain, can obtain and sustain employment, and that employment can contribute to recovery. This investigation aimed to: (i) describe the current policy and service environment within which people with severe mental illness receive employment services; (ii) identify evidence-based practices that improve employment outcomes for people with severe mental illness; (iii) determine the extent to which the current Australian policy environment is consistent with the implementation of evidence-based employment services for people with severe mental illness; and (iv) identify methods and priorities for enhancing employment services for Australians with severe mental illness through implementation of evidence-based practices. METHOD: Current Australian practices were identified, having reference to policy and legal documents, funding body requirements and anecdotal reports. Evidence-based employment services for people with severe mental illness were identified through examination of published reviews and the results of recent controlled trials. RESULTS: Current policy settings support the provision of employment services for people with severe mental illness separate from clinical services. Recent studies have identified integration of clinical and employment services as a major factor in the effectiveness of employment services. This is usually achieved through co-location of employment and mental health services. CONCLUSIONS: Optimal evidence-based employment services are needed by Australians with severe mental illness. Providing optimal services is a challenge in the current policy environment. Service integration may be achieved through enhanced intersectoral links between employment and mental health service providers as well as by co-locating employment specialists within a mental health care setting.     

Immunoelectron microscopic analysis of a novel carbohydrate differentiation antigen (CDA-3C2) in the developing rat olfactory and otic systems

A carbohydrate differentiation antigen (CDA-3C2) exhibits a highly specific and restricted pattern of expression during rat embryogenesis. In the periphery of the embryo, this antigen is associated transiently with the lateral ectoderm but is retained only in the olfactory and otic epithelium throughout morphogenesis. At the light microscopic level, CDA-3C2 immunoreactivity appears mostly along cell periphery and in the extracellular matrix. The aim of the present study was to determine the specific cellular and subcellular distribution of CDA-3C2 in vivo in order to identify potential sites of cellular and tissue function of the antigen during embryogenesis. There was a strikingly similar subcellular distribution of CDA-3C2 in the developing otic and olfactory systems, found mostly along cell membranes, microvillar projections and acellular secretions of the epithelium. Mature sensory components of the epithelia were not immunoreactive, whereas supportive cells and their secreted structures were densely stained. The highly coincident nature of CDA-3C2 in both sensory epithelia suggests that this carbohydrate epitope, and possibly its carrier macromolecule, participate in a morphogenetic function common to these two sensory epithelia. © Wiley-Liss, Inc.     

Cyclin E, a redundant cyclin in breast cancer

Cyclin E is an important regulator of cell cycle progression that together with cyclin-dependent kinase (cdk) 2 is crucial for the G₁/S transition during the mammalian cell cycle. Previously, we showed that severe overexpression of cyclin E protein in tumor cells and tissues results in the appearance of lower molecular weight isoforms of cyclin E, which together with cdk2 can form a kinase complex active throughout the cell cycle. In this study, we report that one of the substrates of this constitutively active cyclin E/cdk2 complex is retinoblastoma susceptibility gene product (pRb) in populations of breast cancer cells and tissues that also overexpress p16. In these tumor cells and tissues, we show that the expression of p16 and pRb is not mutually exclusive. Overexpression of p16 in these cells results in sequestering of cdk4 and cdk6, rendering cyclin D1/cdk complexes inactive. However, pRb appears to be phosphorylated throughout the cell cycle following an initial lag, revealing a time course similar to phosphorylation of glutathione S-transferase retinoblastoma by cyclin E immunoprecipitates prepared from these synchronized cells. Hence, cyclin E kinase complexes can function redundantly and replace the loss of cyclin D-dependent kinase complexes that functionally inactivate pRb. In addition, the constitutively overexpressed cyclin E is also the predominant cyclin found in p107/E2F complexes throughout the tumor, but not the normal, cell cycle. These observations suggest that overexpression of cyclin E in tumor cells, which also overexpress p16, can bypass the cyclin D/cdk4-cdk6/p16/pRb feedback loop, providing yet another mechanism by which tumors can gain a growth advantage.     

Improper positioning of the elevator lever of duodenoscopes may lead to sequestered bacteria that survive disinfection by automated endoscope reprocessors

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Single-cell analyses of CD4+ T cells from αβ T cell receptor-transgenic mice: a distinct mucosal cytokine phenotype in the absence of transgene-specific antigen

Development of distinct CD4⁺ T cell cytokine phenotypes may be conditioned by the anatomic site in which activation occurs. A double-label in situ hybridization technique was used to characterize co-expression of cytokine mRNA in antigen-specific responses of Peyer's patch (PP), lamina propria (LP), and splenic (SP) CD4⁺ T cells isolated from αβ T cell receptor-transgenic mice. Interleukin (IL)-2 was the dominant cytokine expressed by antigen-stimulated PP and SP populations, though it was expressed by a minority of the activated T cells. Cells that expressed interferon (IFN)-γ were less frequent, and IL-4, IL-5, and IL-10 were infrequent. In contrast, cells that expressed IFN-γ or IL-10 were most frequent in the LP population, with lower frequencies of IL-2, and few IL-4- and IL-5-positive cells. Co-expression of two cytokines by the same cell was the exception, regardless of the anatomic site from which the T cells were isolated. The surface phenotype of transgene-positive T cells isolated from each anatomic site was distinct, despite the absence of in vivo exposure to antigen for which the transgenic T cell receptor is specific. These data suggest that the cytokine responses of CD4⁺ T cells may be conditioned by the microenvironment, independently of specific antigen, and that the LP CD4⁺ T population has a distinct cytokine expression pattern with counter-regulatory properties that may be important for homeostasis in mucosal immune tissues.