bcl-2 overexpression promotes myocyte proliferation

To determine the influence of Bcl-2 on the developmental biology of myocytes, we analyzed the population dynamics of this cell type in the heart of transgenic (TG) mice overexpressing Bcl-2 under the control of the alpha-myosin heavy chain promoter. TG mice and non-TG (wild type, WT) mice were studied at 24 days, 2 months, and 4 months after birth. Bcl-2 overexpression produced a significant increase in the percentage of cycling myocytes and their mitotic index. These effects were strictly connected to the expression of the transgene, as demonstrated in isolated myocytes. The formation of mitotic spindle and contractile ring was identified in replicating cells. These typical aspects of mitosis were complemented with the demonstration of karyokinesis and cytokinesis to provide structural evidence of cell division. Apoptosis was low at all ages and was not affected by Bcl-2. The higher cell replication rate in TG was conditioned by a decrease in the expression of the cell-cycle inhibitors, p21(WAF1) and p16(INK4a), and by an increase in Mdm2-p53 complexes. In comparison with WT, TG had 0.4 x 10(6), 0.74 x 10(6), and 1.2 x 10(6) more myocytes in the left ventricle at 24 days, 2 months, and 4 months, respectively. Binucleated myocytes were 12% and 25% larger in WT than in TG mice at 2 and 4 months of age. Taken together, these observations reveal a previously uncharacterized replication-enhancing function of Bcl-2 in myocytes in vivo in the absence of stressful conditions.     

Intense myocyte formation from cardiac stem cells in human cardiac hypertrophy

It is generally believed that increase in adult contractile cardiac mass can be accomplished only by hypertrophy of existing myocytes. Documentation of myocardial regeneration in acute stress has challenged this dogma and led to the proposition that myocyte renewal is fundamental to cardiac homeostasis. Here we report that in human aortic stenosis, increased cardiac mass results from a combination of myocyte hypertrophy and hyperplasia. Intense new myocyte formation results from the differentiation of stem-like cells committed to the myocyte lineage. These cells express stem cell markers and telomerase. Their number increased >13-fold in aortic stenosis. The finding of cell clusters with stem cells making the transition to cardiogenic and myocyte precursors, as well as very primitive myocytes that turn into terminally differentiated myocytes, provides a link between cardiac stem cells and myocyte differentiation. Growth and differentiation of these primitive cells was markedly enhanced in hypertrophy, consistent with activation of a restricted number of stem cells that, through symmetrical cell division, generate asynchronously differentiating progeny. These clusters strongly support the existence of cardiac stem cells that amplify and commit to the myocyte lineage in response to increased workload. Their presence is consistent with the notion that myocyte hyperplasia significantly contributes to cardiac hypertrophy and accounts for the subpopulation of cycling myocytes.     

Successful RF ablation of permanent VT in a patient with acute coronary syndrome treated by complex angioplasty and stent implantation

We describe a case of a 59-year-old male with permanent VT in the course of an acute coronary syndrome. Coronary angiography revealed acute occlusion of the right coronary artery. Although the underlying condition was treated by implantation of 4 stents with excellent haemodynamic effect (TIMI 3), the tachycardia continued, being refractory to drugs (amiodarone). The attempts to restore sinus rhythm by DC electrical cardioversion or transvenous pacing were unsuccessful. The patient was referred to the EP lab. A critical isthmus localised at the paraseptal region of the LV and parallel to the mitral annulus was identified. The isthmus was closed by linear RF application, resulting in VT termination. Due to impaired LV ejection fraction (<30%) the patient was scheduled for ICD implantation. During 6-week follow-up the patient remained free of arrhythmia.     

Docetaxel and bortezomib downregulate <Emphasis Type="Italic">Bcl-2</Emphasis> and sensitize PC-3-<Emphasis Type="Italic">Bcl-2</Emphasis> expressing prostate cancer cells to irradiation

Background  Currently, docetaxel is used to treat hormone-refractory metastatic prostate cancer. Docetaxel not only inhibits microtubule formation but can also downregulate expression of Bcl-2, a known antiapoptotic oncogene. Furthermore, the 26S proteasome inhibitor bortezomib can downregulate Bcl-2 expression. Previously, we demonstrated that overexpression of Bcl-2 renders cells resistant to radiation therapy. In this study, we investigated whether treating human prostate cancer cells with docetaxel, bortezomib, or both could modulate Bcl-2 expression and whether such modulation could render Bcl-2-overexpressing cells more susceptible to radiation. Methods  PC-3-Bcl-2 and PC-3-Neo human prostate cancer cells treated with docetaxel and/or bortezomib in addition to irradiation were analyzed in vitro for proliferation, clonogenic survival, cell cycle phase distribution, and expression of Bcl-2 and Bcl-xL proteins. Results  Docetaxel and bortezomib alone had significant cytotoxic effects. In addition, docetaxel, bortezomib, or radiation resulted in a G2M phase arrest in PC-3-Bcl-2, whereas only docetaxel or radiation did so in PC-3-Neo cells. Both cell lines were more sensitized to radiation’s killing effects when treated with the combination of docetaxel and bortezomib than when treated with either agent alone. Furthermore, docetaxel and bortezomib-treated cells exhibited marked changes in the expression of Bcl-2 and Bcl-xL. Conclusions  This is the first study to demonstrate that docetaxel and bortezomib in combination can effectively sensitize Bcl-2-overexpressing human prostate cancer cells to radiation effects by modulating the expression of key members of the Bcl-2 family. Together, these findings warrant further evaluation of the combination of docetaxel and bortezomib in prostate cancer.     

Maternal smoking in early childhood: a risk factor for bronchial responsiveness to exercise in primary-school children.

The relationship between maternal smoking and bronchial hyperresponsiveness as assessed by a standardized free running test was investigated in a cohort of 1812 primary-school children in first grade. A child's exposure to maternal smoking during pregnancy, the first year of life, and the study year was recorded. Current exposure was not positively associated with bronchial hyperresponsiveness. The prevalence of this disorder was higher when maternal smoking during the child's first year of life was reported (9%) than when it was not (5.9%). The odds of being hyperresponsive were significantly higher in children exposed to maternal smoking in their first year of life (odds ratio, 2.82; 95% confidence interval, 1.25 to 6.34; p less than 0.01), especially in children with asthma (odds ratio, 20.55; 95% confidence interval, 2.5 to 168.9; p less than 0.01). Current exposure to maternal smoking was associated with less hyperresponsiveness. The effect of current maternal smoking might reflect changes in smoking habits by mothers of children with symptoms, whereas exposure to tobacco smoke in early life might be causally related to bronchial hyperresponsiveness. Our findings support the general hypothesis that early lung injuries have an impact on the later respiratory health of children.     

Diagnostic procedures in abnormal reactions to foods and food additives

Allergic and intolerance reactions to food and food additives may occur as a result of antibody-mediated or non-immunological mechanisms. Histories of adverse reactions to food must be confirmed and clarified by means of in-vivo and in-vitro tests. Offending substances and clinical manifestations are enumerated. The predictive value and the diagnostic or the threshold sensitivity in provocation tests are demonstrated. There are useful laboratory techniques as the detection of specific antibodies or the estimation of involved mediators. Further procedures for the identification and confirmation of the diagnosis of adverse reactions to food and food additives are suggested.     

Endovascular stent repair for a dissecting thoracoabdominal aneurysm is feasible in the setting of a district general hospital: a multidisciplinary approach

A patient presented to a district general hospital with a type B dissection of the aorta. He was deemed too unwell for surgical intervention. An endovascular stent repair was successfully carried out. The case shows that such a procedure can be safely performed by a multidisciplinary team within a district general hospital.