Mdmx promotes genomic instability independent of p53 and Mdm2.

The oncogene Mdmx is overexpressed in many human malignancies, and together with Mdm2, negatively regulates the p53 tumor suppressor. However, a p53-independent function of Mdmx that impacts genome stability has been described, but this function is not well understood. In the present study, we determined that of the 13 different cancer types evaluated, 6-90% of those that had elevated levels of Mdmx had concurrent inactivation (mutated or deleted) of p53. We show elevated levels of Mdmx-inhibited double-strand DNA break repair and induced chromosome and chromatid breaks independent of p53, leading to genome instability. Mdmx impaired early DNA damage-response signaling, such as phosphorylation of the serine/threonine-glutamine motif, mediated by the ATM kinase. Moreover, we identified Mdmx associated with Nbs1 of the Mre11-Rad50-Nbs1 (MRN) DNA repair complex, and this association increased upon DNA damage and was detected at chromatin. Elevated Mdmx levels also increased cellular transformation in a p53-independent manner. Unexpectedly, all Mdmx-mediated phenotypes also occurred in cells lacking Mdm2 and were independent of the Mdm2-binding domain (RING) of Mdmx. Therefore, Mdmx-mediated inhibition of the DNA damage response resulted in delayed DNA repair and increased genome instability and transformation independent of p53 and Mdm2. Our results reveal a novel p53- and Mdm2-independent oncogenic function of Mdmx that provides new insight into the many cancers that overexpress Mdmx.

[Physicians facing the first antituberculosis campaign in Mexico]. / Los médicos ante la primera campaña antituberculosa en México.

In the paper entitled "Physicians Face the First Antituberculosis Campaign in Mexico", tuberculosis is focused on as an important cause of death and disability in many parts of Mexico in the last quarter of the ninetieth century and the first decade of the twentieth century. The first measures taken are described, along with the formal proposal that attempted to include institutions as well as individuals. The manner in which tuberculosis was associated with nutrition, with alcoholism and with work and life conditions is studied. As a last point, the debate among medical professionals that was provoked by the campaign against tuberculosis is analyzed.

[Low-molecular-weight heparin in unstable angina pectoris]. / La heparina de bajo peso molecular en la angina de pecho inestable.

We studied the therapeutic effect of standard heparin (HS) compared with low-molecular-weight (HBPM) in two homogeneous groups of 14 patients heparin selected at random, with clinical history and electrocardiographic signs of unstable angina pectoris. Patients received the conventional treatment with platelets' inhibitors, nitrates, adrenergic beta-blockers or calcium antagonists. Both heparins, separately, showed statistical therapeutic effect on the symptoms and signs of unstable angina pectoris. They decreased to zero the number and duration of symptomatic myocardial ischemic events observed by ambulatory electrocardiogram (EKG-Holter). The symptoms of the angina pectoris disappeared at the same elapsed time: in 51.9 +/- 20.2 min. for the HS, and in 48.14 +/- 20.7 min. for the HBPM. They decreased the frequency of the silent myocardial ischemia observed at the EKG-Holter: 9 events decreased to 4 with the HS, and 8 events decreased to 3 with the HBPM. They decreased the total elapsed time of the silent ischemia from 52 min. to 15 min., and the mean elapsed time of the silent ischemia decreased from 3.71 +/- 3.29 min. to 1.07 +/- 1.81 min. with the HS (P < 0.001). With HBPM it decreased the total elapsed time of the silent ischemia from 60 min to 10 min, and the mean elapsed time of the silent ischemia decreased from 4.28 +/- 4.49 min. to 0.71 +/- 1.43 min. (P < 0.02). Both heparins considerably decreased the frequency of the lethal arrhythmias. Although in this study we did not find statistical differences in the therapeutic action of either heparins, HBPM reduced rapidly angina symptoms and the events associated to angina pectoris, cardiac arrhythmias, specially lethal extrasystolia, conduction defects and atrial paroxysmal tachycardia. Compared to HS, HBPM is easily applied, does not produce side effects on coagulation or bleeding time.

[Effectiveness of anticoagulant oral treatment in patients with thrombus in left ventricle after acute myocardial infarction]. / Eficacia del tratamiento anticoagulante oral en pacientes con trombo en ventrículo izquierdo después de un infarto agudo del miocardio.

Left ventricular mural thrombi (LVMT) is a complication of acute myocardial infarction (AMI), that may produce peripheral embolism which could be fatal. In order to establish an adequate time of oral anticoagulant (OA) therapy, we undertook a prospective study that included 45 patients with AMI and left ventricular thrombi detected by echocardiographic study, in the first 5 to 10 days postinfarction, the study was repeated, in 3 and 6 months. Treatment with oral anticoagulant was initiated at the point of the detection of thrombi maintaining an INR of 1.5 to 2. Thirty nine patients (79%) were males and 6 (11%) were females, with an age of 29 to 85 years and a range of 62 +/- 11 years. Forty four patients (98%) presented anterior wall infarction and 1 (2%) posteroinferior infarction. In patients with anterior infarction, in 38 (85%) the thrombi was located at the apical wall (p < 0.05), 5 (11%) in the septal wall and other (2%) in anterior and apical walls. The patient with the posteroinferior infarction presented extension to the right ventricle, where the thrombus was located (2%). The contractility alterations related with thrombi were diskinesia, followed by hipokinesia and finally akinesia. The ejection fraction had not relationship with thrombi formation. LVMT dissolved in 32 patients (71%) at 3 months (p < 0.05), in 8 (18%) in 6 months and in 5 (11%) it was maintained for more than 6 months. None of the patients presented complications of OA. We conclude that the LVMT are more frequent in anterior infarctions, essentially in those that present diskinesia. The majority of LVMT are resolved in 6 months with OA therapy.

[Limitation of myocardial expansion in late thrombolysis evaluated by two-dimensional echocardiography]. / Limitación de la expansión miocárdica con trombolisis tardía evaluada por ecocardiografía bidimensional.

Myocardial expansion in acute myocardial infarction (AMI) is present in about 45% of the patients within the first 72 hours. This is associated with ventricular aneurysm formation, myocardial rupture, heart failure and early death. Experimental studies in animals with AMI have used late reperfusion to decrease the incidence of expansion with success. The present is a prospective, longitudinal, open and randomized study in 21 patients with anterior AMI, to evaluate if the late reperfusion (6 to 12 hours) can decrease the incidence of myocardial expansion graded quantitatively with bidimensional echocardiography. Two groups were made: group A (n = 12) who received thrombolysis with streptokinase 1.5 mill. IU plus oral aspirin 150 mg OD (n = 9). Both groups had the same characteristics of AMI and functional class of Killip and Kimball (I-II class). Intrahospital treatment was given freely in both groups. The expansion was evaluated with bidimensional echocardiography used Jugdutt's method. In group A, expansion was present in 25% of the cases, while in group B was 66.6% (p < 0.0005). The distortion area, distortion peak, septal thickness and large asynergic segment were more sensitive parameters to identify myocardial expansion. Our results are similar to some experimental studies. We conclude that late thrombolysis can be useful in decreasing the incidence of myocardial expansion. Bidimensional echocardiography is a useful, fast and safe method to identify myocardial expansion.