Immediate-early gene expression in the brain of the thiamine-deficient rat.

Pyrithiamine-induced thiamine deficiency (PTD) in the rat is associated with neuronal loss in the thalamus and inferior colliculus. Recently, we were able to demonstrate the occurrence of apoptosis in the thalamus of these animals. Given that immediate-early genes (IEGs) participate in signal transduction pathways that mediate programmed cell death, the present study utilized in situ hybridization and immunohistochemistry to examine the expression of four IEGs (c-fos, c-jun, fos-B, and NGFI-A) during the progression of PTD. Elevated c-fos mRNA levels were initially observed in the posterior medial thalamus on d 12 of the deficiency. At the acute symptomatic stage (characterized by a loss of righting reflex on d 16-17), the posterior-medial thalamus exhibited increased mRNA for all genes examined, whereas the inferior colliculus demonstrated mRNA induction for c-fos, c-jun, and NGFI-A. Immunohistochemical analysis revealed that elevations of IEG mRNA associated with the acute symptomatic stage were consistently translated into protein in the thalamus. In contrast, whereas elevated Fos- and Jun-like immunoreactivity were detected in the inferior colliculus at this stage, NGFI-A-like immunoreactivity declined significantly below basal levels, suggesting a translational block. These results are consistent with our recent findings of apoptotic cell death, and indicate that differential patterns of IEG expression occur in the thalamus and inferior colliculus during PTD, which may contribute to the pathogenesis of this disorder.

Hippocampal Myc and p53 expression following transient global ischemia.

The proto-oncogene c-myc, and the tumor suppressor gene p53, encode proteins which function as transcriptional regulating factors governing cell proliferation, differentiation, and apoptosis. Recent evidence suggests that the delayed neuronal death which follows an episode of transient forebrain ischemia may involve apoptotic processes. We have therefore utilized immunohistochemistry to investigate the effects of transient global ischemia on neuronal expression of p53- and Myc-like immunoreactivities in the rodent forebrain 2, 12, 24, 48, and 72 h following reperfusion. Transient global ischemia (20 min), produced by four vessel occlusion (4-VO), initially elevated p53-like immunoreactivity in both CA1 and CA3 hippocampal subfields at 24 h of recirculation. However, distinct patterns of gene expression became evident in these regions at later time points. A pivotal difference was the persistence of ischemia-induced increases of p53- and Myc-like immunoreactivity in the CA1 region of the hippocampus. Unlike CA3 neurons where p53-like immunoreactivity subsided to basal levels by 48 h of survival, CA1 neurons continued to display increased p53-immunoreactivity 48 h post-ischemia, while Myc-like immunoreactivity was selectively elevated in CA1 neurons at this time point. Ischemia-induced increases in p53-like immunoreactivity were also detected in vulnerable regions of the amygdala, thalamus, and cortex 12 to 48 h after recirculation. Given that both p53 and Myc have been implicated in gene signalling pathways which mediate programmed cell death, our findings which demonstrate that 4-VO produces persistent elevations of p53- and Myc-like immunoreactivities in vulnerable neurons suggest that these proteins may also contribute to delayed neuronal death following an episode of transient forebrain ischemia.

Ischemia-induced CA1 neuronal death is preceded by elevated FosB and Jun expression and reduced NGFI-A and JunB levels.

Alterations in levels of the immediate-early gene (IEG) proteins Fos, FosB, DeltaFosB, Jun, JunB, JunD, and NGFI-A were investigated in rat hippocampus by immunohistochemistry 2, 12, 24, and 48 h after forebrain ischemia. Transient global ischemia of 20 min, produced by four vessel occlusion (4-VO), elicited different patterns of IEG expression in vulnerable CA1 and more resilient CA3 neurons. Cell counts revealed that except for JunD and NGFI-A, immunoreactivity for all examined IEGs was initially elevated by forebrain ischemia in both CA1 and CA3 hippocampal subfields. However, distinct patterns of IEG expression became evident in these regions at later time points. The pivotal difference was the persistence of ischemia-induced elevations of FosB and Jun expression in the CA1 region of the hippocampus. Unlike CA3 neurons, where IEG immunoreactivity had subsided to basal levels by 24-48 h, CA1 neurons continued to display increased FosB- and Jun-like immunoreactivity 48 h post-ischemia. Western blot analysis revealed that elevated expression of both FosB and DeltaFosB-like proteins were responsible for the immunohistochemical detection of enhanced FosB-like immunoreactivity in CA1 neurons at 48 h. These findings are consistent with recent in vitro studies that implicate FosB and Jun in gene signalling pathways responsible for programmed cell death. In contrast to FosB and Jun, JunB expression declined significantly below basal levels in CA1 neurons at 48 h, yet remained unaltered in CA3 neurons. Given that JunB can inhibit the transactivating properties of Jun, decreased JunB levels may contribute to the apoptotic death of CA1 neurons by enhancing the transcriptional regulating activity of Jun. Also notable at 48 h was the complete loss of constitutive NGFI-A expression from CA1 neurons of ischemic animals. These findings suggest that persistent elevations in FosB and Jun expression, concurrent with reductions in JunB and NGFI-A levels, contribute to the apoptotic death of CA1 neurons after forebrain ischemia.

Surveillance mammography after treatment of primary breast cancer: a systematic review.

As the prevalence of diagnosed breast cancer increases, it is important to define how best to provide long-term follow-up. Whereas many aspects of follow-up remain controversial, guidelines recommend surveillance mammograms as the only investigation to be performed routinely. We conducted a systematic review of the literature to elucidate the effect of routine surveillance mammograms on detecting ipsilateral recurrence (IR) and contralateral breast cancers (CBC). The systematic review yielded 15 articles. All were observational studies and ranked as level II-2 or III evidence. There were no randomized controlled trials identified. Most of the ten studies on detection of IR did not report on outcomes after detection. When reported, most studies found that the method of detection of IR did not influence overall survival or disease-free survival. Two of the nine studies on detection of CBC found that the CBC was detected at an earlier stage than the initial breast cancer, but did not report on long-term outcomes. This systematic review highlights the need for further research to help better define the optimum surveillance mammography regimen.

Continuous erythropoietin receptor activator (Mircera) for renal anemia.

(1) Continuous erythropoietin receptor activator (CERA) is a third-generation erythropoiesis stimulating agent (ESA). CERA is used to correct anemia and maintain hemoglobin levels in patients with renal (kidney) failure. CERA is administered either once every two weeks (to correct anemia) or once per month (to maintain hemoglobin levels). This offers a potential advantage over other ESAs that require more frequent administration. (2) Two phase 3 trials involving erythropoietin-naïve patients found no difference between correcting renal anemia with CERA once every two weeks compared to results with other ESAs that were administered up to three times weekly. Four phase 3 trials reported that maintenance of stable hemoglobin levels in dialysis patients with once-monthly CERA was comparable to other agents that were administered up to three times weekly. Further clinical trials are needed to examine other important outcomes, such as mortality and major adverse effects. (3) The most common adverse effects with CERA were hypertension, diarrhea, headache, and upper respiratory tract infection. There was a higher risk of procedural hypotension (low blood pressure during administration), gastrointestinal hemorrhage, and tachycardia with CERA compared to other ESAs. (4) Administration of CERA at extended intervals may simplify anemia management, reduce the burden on patients, and decrease health care staff time spent administering the treatment.

Rituximab for rheumatoid arthritis.

(1) Rituximab (RTX), a monoclonal antibody, selectively targets CD20+ B-cells that are implicated in the pathogenesis of rheumatoid arthritis (RA). (2) The use of RTX with methotrexate (MTX) results in statistically significant clinical improvements among RA patients who have an inadequate response to standard therapies, when compared to the use of MTX alone. (3) The optimal dose, duration of treatment or retreatment, long-term efficacy and safety, and placement of RTX in RA treatment algorithms need to be further investigated. (4) Health Canada has approved the combination of RTX with MTX for use in adult patients with moderate to severe active RA, who have had an inadequate response or intolerance to >1 tumour necrosis factor (TNF) inhibitor therapies.