Polo-like kinase 1 inhibitors in mono- and combination therapies: a new strategy for treating malignancies

Polo-like kinase 1 (Plk1) inhibitors belong to a new class of drugs for the treatment of malignant diseases. They selectively act against a target (Plk1) which is involved in different stages of mitosis such as centrosome maturation, spindle formation, chromosome separation and cytokinesis. Because Plk1 is mainly expressed in proliferating tissues and overexpressed in cancers, its inhibition is potentially less prone to toxicities associated with current antimitotic agents, which also act on nondividing cells. Several Plk1 inhibitors are being evaluated as cancer treatment drugs. Based on the essential role of Plk1 during mitosis, Plk1 inhibitors target all rapidly dividing cells irrespective of their tumor suppressor or oncogene mutations. In this article, their mechanisms of action, efficacy and toxicity profile are discussed.     

Dental caries experience and related factors among a clustered random sample of students in occupied Palestinian territory: a cross-sectional study

Background

Dental caries is still the most prevalent chronic disease worldwide. In the occupied Palestinian territory, data about oral health status and its determinants are scarce. This study aimed to assess the prevalence of dental caries and associated factors among schoolchildren in a random sample of marginalised schools in the West Bank.

Clinical implications of increased lung uptake of thallium-201 during exercise scintigraphy 2 weeks after myocardial infarction

To determine the prevalence and clinical significance of increased lung thallium-201 uptake during submaximal exercise myocardial scintigraphy performed 2 weeks after acute myocardial infarction, 61 patients underwent submaximal exercise testing (target heart rate, 120 beats/min), multigated blood pool imaging at rest and coronary angiography before hospital discharge. Thallium lung uptake on the initial anterior projection image was graded qualitatively by comparing the intensity of thallium-201 activity in the lungs with that in the mediastinum. In 39 patients (64 percent), it was normal (equal to mediastinal activity) and in 22 (36 percent), it was increased (greater than mediastinal activity). Compared with patients with normal lung uptake, those with increased uptake had a greater prevalence of prior infarction (13 versus 36 percent, probability [p] < 0.05), less global cardiac reserve as assessed by the four level New York Heart Association classification (p < 0.05), more advanced Killip class in the coronary care unit (p < 0.05), a higher Norris coronary prognostic index (2.6 ± 1.9 versus 4.6 ± 2.3 [mean ± standard deviation], p <0.01), failure to achieve the target heart rate because of dyspnea, fatigue or angina (36 versus 86 percent, p < 0.01), a greater prevalence of exercise-induced S-T segment depression (18 versus 45 percent, p < 0.05), a greater number of anterior thallium-201 myocardlal defects (p < 0.05); a lower radionuclide ejection fraction at rest (50.4 ± 6.1 versus 39.6 ± 9.3 percent, p < 0.01) and a greater number of asynergic left ventricular segments (p < 0.05).Thus, the occurrence of increased lung thallium-201 uptake during submaximal exercise scintigraphy in the early postinfarction period is frequent and appears to be a marker of severe and functionally more important coronary artery disease associated with left ventricular dysfunction.     

Dichloroacetate: Effects on exercise endurance in untrained rats

The effect of dichloroacetate (DCA), an activator of pyruvate dehydrogenase, on the performance of fed, untrained rats was evaluated while swimming for different durations. DCA-treated rats were able to swim almost 40% longer than controls (354 ± 18 versus 255 ± 18 sec, p < .001). This was associated with lower levels of blood and muscle lactate at rest and after 210 and 240 sec of swimming. At exhaustion, blood lactate was the same in the two groups even though the DCA rats had worked for an additional 99 sec (16.9 ± 1.2 versus 15.8 ± 1.2 mM/L NS). Pretreatment with DCA did not alter the usual exercise-induced decreases in muscle ATP and creatine phosphate or liver glycogen. After 210 sec of exercise, plasma FFA and blood glucose and acetoacetate were also the same in the two groups; however, β-hydroxybutyrate was somewhat higher, and there was a small but significant sparing of muscle glycogen in the DCA group. The data indicate that DCA enhances the ability of rats to exercise at near maximal work loads. They are consistent with the notion that improved endurance is a consequence of a decreased rate of lactate accumulation; however, the possibility that it is secondary to some other action of DCA cannot be excluded.     

Electrophysiologic effects of atropine on human sinus node and atrium.

Electrophysiologic studies were conducted in 17 patients without apparent sinus node disease before and after intravenous administration of 1 to 2 mg of atropine. Mean values in milliseconds (+/- standard error of the mean) before and after administration of atropine were as follows: sinus cycle length 846 +/- 26.4 versus 647 +/- 20.0 (P less than 0.001); sinus nodal recovery time 1,029 +/- 37 versus 774 +/- 36 (P less than 0.001); mean calculated sinoatrial (S-A) conduction time 103 +/- 5.7 versus 58 +/- 3.9 (P less than 0.001); mean P-A interval 34 +/- 1.5 msec versus 31 +/- 1.5 (P less than 0.05); mean atrial effective and functional refractory periods during sinus rhythm 285 +/- 11.3 versus 238 +/- 7.9 and 331 +/0 11.6 versus 280 +/- 8.6, respectively (P less than 0.001 for both); mean atrial effective and functional refractory periods measured at equivalent driven cycle length 239 +/- 7.7 versus 213 +/- 7.4 and 277 +/- 11.4 versus 245 +/- 9.5, respectively (P less than 0.001 for both). In conclusion, atropine shortened sinus cycle length, sinus nodal recovery time and calculated S-A conduction time. The shortening of atrial refractory periods with atropine implies that vagotonia prolongs atrial refractoriness in man.     

Evaluation of a QRS scoring system for estimating myocardial infarct size. II. Correlation with quantitative anatomic findings for anterior infarcts

The ability of an independently developed QRS point score to estimate the size of infarcts predominantly within the anterior third of the left ventricle was evaluated by quantitative pathologic-electrocardiographic correlation. The study was limited to 21 patients with a single infarct documented by postmortem examination, for whom an appropriately timed standard 12 lead electrocardiogram was available that did not exhibit signs of left or right ventricular hypertrophy, left or right bundle branch block or anterior or posterior fascicular block. At necropsy the heart was cut into five to seven slices. The location and size of the infarct was quantitated by computer-assisted planimetry of the slices.The electrocardiogram of 19 (90 percent) of the patients exhibited either a Q wave or an R wave of no more than 20 ms in lead V₂. The infarct in the two patients without this electrocardiographic finding was small, occupying 2 and 3 percent of the left ventricle, respectively. The percent infarction of the left ventricle correlated with the QRS point score (r = 0.80). Thus in patients without complicating factors in the electrocardiogram and with a single infarct, the electrocardiogram provides a marker for infarction in the anterior third of the left ventricle and permits estimation of infarct size.     

Platelet function studies in coronary artery disease. X. Effect of dipyridamole

To evaluate the effects of dipyridamole on blood platelet function in patients with coronary artery disease, platelet counts and aggregation were examined in aortic and coronary venous blood. Before administration of dipyridamole, platelet counts and aggregation in response to adenosine diphosphate were less (p <0.02) in coronary venous than in aortic blood. Dipyridamole administration (100 mg) resulted in an increase in platelet counts and platelet aggregation in coronary venous blood so that the differences in aortic and coronary venous blood values were eliminated. These phenomena were probably related to inhibitory actions of dipyridamole. on platelet adhesion to atherosclerotic vessels. To further study the mechanism of action, the direct effects of dipyridamole on in vitro platelet aggregation were evaluated. Although dipyridamole, in the concentrations used, had no effect on in vitro platelet aggregation, it greatly potentiated the aggregation inhibitory actions of exogenous prostacyclin. In vivo potentiation of endogenous prostacyclin and inhibitory actions on platelet adhesion are the most likely mechanisms of the potentially beneficial actions of dipyridamole.