Hedgehog pathway overexpression in pancreatic cancer is abrogated by new-generation taxoid SB-T-1216.

The Hedgehog pathway is one of the major driver pathways in pancreatic ductal adenocarcinoma. This study investigated prognostic importance of Hedgehog signaling pathway in pancreatic cancer patients who underwent a radical resection. Tumors and adjacent non-neoplastic pancreatic tissues were obtained from 45 patients with histologically verified pancreatic cancer. The effect of experimental taxane chemotherapy on the expression of Hedgehog pathway was evaluated in vivo using a mouse xenograft model prepared using pancreatic cancer cell line Paca-44. Mice were treated by experimental Stony Brook Taxane SB-T-1216. The transcript profile of 34 Hedgehog pathway genes in patients and xenografts was assessed using quantitative PCR. The Hedgehog pathway was strongly overexpressed in pancreatic tumors and upregulation of SHH, IHH, HHAT and PTCH1 was associated with a trend toward decreased patient survival. No association of Hedgehog pathway expression with KRAS mutation status was found in tumors. Sonic hedgehog ligand was overexpressed, but all other downstream genes were downregulated by SB-T-1216 treatment in vivo. Suppression of HH pathway expression in vivo by taxane-based chemotherapy suggests a new mechanism of action for treatment of this aggressive tumor.

Transforming rural health systems through clinical academic leadership: lessons from South Africa.

CONTEXT: Under-resourced and poorly managed rural health systems challenge the achievement of universal health coverage, and require innovative strategies worldwide to attract healthcare staff to rural areas. One such strategy is rural health training programs for health professionals. In addition, clinical leadership (for all categories of health professional) is a recognised prerequisite for substantial improvements in the quality of care in rural settings. ISSUE: Rural health training programs have been slow to develop in low- and middle-income countries (LMICs); and the impact of clinical leadership is under-researched in such settings. A 2012 conference in South Africa, with expert input from South Africa, Canada and Australia, discussed these issues and produced recommendations for change that will also be relevant in other LMICs. The two underpinning principles were that: rural clinical leadership (both academic and non-academic) is essential to developing and expanding rural training programs and improving care in LMICs; and leadership can be learned and should be taught. LESSONS LEARNED: The three main sets of recommendations focused on supporting local rural clinical academic leaders; training health professionals for leadership roles in rural settings; and advancing the clinical academic leadership agenda through advocacy and research. By adopting the detailed recommendations, South Africa and other LMICs could energise management strategies, improve quality of care in rural settings and impact positively on rural health outcomes.

Effect of digitalis on human ventricular refactoriness.

In order to evaluate the effect of digitalis on the effective refractory period of the human ventricle, 14 patients were studied with atrial or ventricular pacing and with the introduction of ventricular extra-stimuli. The ventricular effective refractory period (VERP) was recorded before and after 1.0 to 1.25 mg ouabain given intravenously and the results compared with similar changes in the Q-T interval. During atrial pacing (eight patients) at rates of 70 to 110 beats per minute, ouabain reduced the mean ventricular effective refractory period from 290 +/- 13 ms to 260 +/- 16 ms (P less than 0.01) and the mean Q-T interval was reduced from 372 +/- 18 ms to 359 +/- 19 ms (P less than 0.01); the mean VERP/Q-T ratio was 0.79 +/- 0.04 before ouabain and 0.73 +/- 0.04 after ouabain (P less than 0.01). Utilising ventricular drive pacing (six patients) the mean ventricular effective refractory period was reduced from 245 +/- 16 ms to 226 +/- 13 ms (P less than 0.01) and the mean Q-T interval reduced from 382 +/- 18 ms to 360 +/- 29 ms (P less than 0.01). There was no significant change in the mean VERP/Q-T ratio (0.63 +/- 0.04 before vs 0.63 +/- 0.04 after ouabain). The results demonstrate that clinically effective doses of ouabain produce a significant reduction of the effective refractory period of the human ventricle. This change is accompanied by a reduction in the VERP/Q-T ratio during atrial pacing.

Effect of cholestyramine on digoxin absorption and excretion in man.

Six subjects receiving digoxin therapy for heart disease were studied on two occasions with a single oral dose of 0.5 mg of tritiated digoxin. In every study, all stools and urine were saved for 1 week. Before the second study, treatment with cholestyramine, 4 g every 6 hours, was begun and continued throughout. In three patients, a third study was performed after cholestyramine treatment had been continued for 1 month. Results showed that after cholestyramine administration serum levels, stool output and urinary output of tritiated digoxin varied over a wider range, but cholestyramine had no net short-term effect of any of these variables. After 1 month of cholestyramine administration, there was a small statistically significant increase in stool output of tritiated digoxin and metabolites. In vitro studies suggested that cholestyramine is likely to be a weak digoxin binder in the gut and that changes induced by this resin in digoxin metabolism are not likely to be due to drug binding.

Comparison of the canine tissue distribution of digoxin after acute and chronic administration: implications for digitalis therapy.

Digoxin is often used as an antiarrhythmic and inotropic agent. It produces significant neuroexcitatory responses that influence both its therapeutic and toxic effects. Patients receiving digoxin can be separated into 2 groups: those who receive it acutely and those who receive it chronically. The therapeutic and toxic responses to digoxin vary between these groups. The neural tissue distribution of digoxin was compared in dogs after both acute and chronic injections. Acute administration of digitalis in this study was associated with preferential uptake of digoxin into peripheral sympathetic nerves. Chronic administration was associated with continued selective uptake into the central nervous system despite decreasing serum levels. Therefore, acute (experimental or suicidal) or chronic (maintenance) digoxin administration produces different neural responses. The peripheral sympathetic nervous system will be the primary area of interaction with acute digoxin administration and the central nervous system will have a greater involvement with chronic digoxin administration. Our results indicate that the uptake of digoxin into the peripheral nervous system and central nervous system depends upon the duration of digoxin administration. The time course of digoxin accumulation influences both its therapeutic and toxic actions.

Left atrial abnormality as an electrocardiographic criterion for the diagnosis of left ventricular hypertrophy in the presence of right bundle branch block.

Left atrial (LA) abnormality determined from precordial lead V1 was assessed by 2 observers as a criterion of left ventricular (LV) hypertrophy in the presence of right bundle branch block (BBB) in 23 patients. The presence of LV hypertrophy was confirmed from a postmortem cardiac partition technique and defined at 2 levels of confidence: probable and definite hypertrophy. Observers reliably differentiated between the hypertrophied and normal-sized ventricle in the presence of right BBB by using LA abnormality as an electrocardiographic criterion. When defined as definite hypertrophy, observer 1 correctly identified LV hypertrophy in 78% of the cases and observer 2 in 67% of the cases. False-positive results were present in 21% of cases by observer 1 and 14% by observer 2. Comparable results were achieved when a definition of probable hypertrophy was used. Observer performance of recognition of LA abnormality in this study was satisfactory with 91% agreement between observers. Our results are comparable and in some instances superior to conventional criteria commonly recommended to diagnose LV hypertrophy on the electrocardiogram without right BBB.

Digoxin-quinidine interaction. Changes in canine tissue concentration from steady state with quinidine.

Tissue concentrations of tritiated digoxin inthe dog are altered by simultaneous administration of quinidine. Serum levels rise as tissue concentration decreases significantly in all tissue except brain tissue, where an increase of 51 percent is noted over that of the control digitalized state. The digitalis toxicity associated with digoxin-quinidine interaction appears to be associated with rising brain levels of digoxin and falling levels in the myocardium. These findings suggest a neurally mediated form of toxicity with this interaction related to a change in the space of distribution. The question of possible loss of inotropic effect associated with diminished myocardial digoxin concentration requires further study.

Descriptive characteristics of the electrocardiogram from autopsied men free of cardiopulmonary disease--a basis for evaluating criteria for ventricular hypertrophy.

Most measurements establishing standard values for the normal electrocardiogram have been derived from a healthy population, whereas many electrocardiographic interpretations are necessary in hospitalized or seriously ill patients. Therefore, the characteristics of the electrocardiogram were described from 48 autopsied men known to be free of cardiopulmonary disease by clinical assessment and by a special cardiac examination using postmortem coronary angiography and a chamber partition technique. Highest values, mean and standard deviation, and the upper 97.5 percentile or lower 2.5 percentile when appropriate were noted for QRS voltage, QRS axis and duration, and intrinsicoid deflection in V5 or V6. Any ST-segment and T-wave changes were noted as well as left and right atrial abnormalities. Twenty-eight electrocardiographic criteria recommended to detect left ventricular hypertrophy and 10 recommended to detect right ventricular hypertrophy were evaluated for percentage of false-positive results and the 97.5 percentile value for each criterion was developed from the present data base. The data in this study can be used as a standard for comparing electrocardiographic variation in middle-aged men with specific relevance for electrocardiographic criteria of ventricular hypertrophy.

Sensitivity of electrocardiographic criteria for left ventricular hypertrophy according to type of cardiac disease.

The sensitivity of 30 electrocardiographic criteria for left ventricular (LV) hypertrophy, isolated or combined, was examined to determine the relation to the underlying disease. Patients with coronary artery disease (CAD), systemic hypertension, valvular heart disease and cardiomyopathy were evaluated. A cardiac partition technique was used to define ventricular hypertrophy. Single electrocardiographic criteria often showed high sensitivity for 1 disease state, but not for others. Precordial voltage criteria were most sensitive for those with hypertensive and valvular disease. A QRS axis of more than -30 degrees occurred most often in patients with CAD. Both left atrial abnormality and abnormal T-wave inversion of more than 1 mm in V6 occurred with a high sensitivity in general; however, T-wave inversion of more than 1 mm in V6 had a low sensitivity in cardiomyopathy. Methods using combinations of various electrocardiographic criteria improved sensitivity. Using these methods, sensitivity of the electrocardiogram for LV hypertrophy was excellent for patients with systemic hypertension and valvular heart disease and acceptable by usual standards for patients with CAD and cardiomyopathy. Because the use of a single criterion is often ineffective, methods using multiple electrocardiographic criteria to detect LV hypertrophy are recommended when the patients under study have diverse cardiac diseases.

Reevaluation of electrocardiographic criteria for left, right and combined cardiac ventricular hypertrophy.

Cardiac chamber weight was determined at necropsy in 323 men to develop correlative studies of electrocardiographic criteria for ventricular hypertrophy. Thirty recommended criteria for left ventricular (LV) hypertrophy, 10 for right ventricular (RV) hypertrophy, and combinations of both criteria for combined hypertrophy were evaluated. Four methods for electrocardiographic diagnosis of LV hypertrophy were derived: (1) a modification of the Romhilt-Estes point system; (2) the presence of any 1 of 3 criteria: (a) S V1 + R V5 or V6 greater than 35 mm, (b) left atrial abnormality, or (c) intrinsicoid deflection in lead V5 or V6 greater than or equal to 0.05 second; (3) a combination of any 2 criteria or of 1 criterion (above) plus at least 1 of the following 3 additional criteria: (a) left-axis deviation greater than -30 degrees, (b) QRS duration greater than 0.09 second, or (c) T-wave inversion in lead V6 of 1 mm or more; and (4) the use of a single criterion--left atrial abnormality. Sensitivity varied from 57 to 66% and specificity from 85 to 93% among these 4 methods. Myocardial infarction increased sensitivity of the foregoing methods, but the specificity was reduced. Method 2 is preferred for the electrocardiographic diagnosis of LV hypertrophy. Two methods were useful for right ventricular (RV) hypertrophy: (1) the use of any 1 of 4 criteria: (a) R/S ratio in lead V5 or V6 less than or equal to 1; (b) S V5 or V6 greater than or equal to 7 mm; (c) right-axis deviation of more than +90 degrees, or (d) P pulmonale; and (2) use of any 2 combinations of the foregoing criteria. Sensitivity ranged from 18 to 43% and specificity from 83 to 95%. Combined hypertrophy was best diagnosed using left atrial abnormality as the sole criteria of LV hypertrophy, plus any 1 of 3 criteria of RV hypertrophy: (a) R/S ratio in lead V5 or V6 less than or equal to 1, (b) S V5 or V6 greater than or equal to 7 mm, or (c) right axis deviation greater than +90 degrees.(ABSTRACT TRUNCATED AT 250 WORDS)

Mitochondrial function, oxygen extraction, epicardial S-T segment changes and tritiated digoxin distribution after reperfusion of ischemic myocardium.

This study examines the effect of 2 hours of reperfusion on transiently ischemic myocardium in pigs. Indexes of myocardial viability measured were mitochondrial function, oxygen extraction, epicardial S-T segment change and distribution of tritiated digoxin. Results were as follows: (1) Mitochondrial function was markedly impaired in the reperfused area after 60 minutes or more of coronary occlusion. The defect would seem to be a block in electron flow near site I, which can be partially bypassed with succinate. (2) An apparent inability of the reperfused myocardium to extract oxygen did not improve with 2 hours of reperfusion. (3) Epicardial S-T segment mapping suggested that necrosis occurred during reperfusion. (4) There was an altered distribution of tritiated digoxin in the reperfused area. The results show that reperfusion for 2 hours did not improve myocardial viability after 60 minutes or more of ischemia.

Digitalis in pulmonary heart disease (cor pulmonale).

The use of digitalis in pulmonary heart disease has been a topic of great interest for a number of years. The physician's decision to use or not to use digitalis in pulmonary disease has often been an emotional rather than a reasoned one. The diagnostic difficulties from a clinical point of view in separation of pulmonary from cardiac symptoms and findings have also been confusing. The fact that small doses of digitalis may have an inotropic effect on the cardiac muscle has been a difficult concept for many physicians to adopt. On the other hand, the larger doses of digitalis that are often necessary to control the ventricular response in supraventricular arrhythmias sometimes gives rise to confusion. We shall attempt to review the subject in detail and examine indications, contraindications, toxicity, dosage, assessment of benefit, and role of digitalis serum levels in patient management.

Hemodynamic effects of combined digoxin and dopamine administration in postoperative patients with cardiac dysfunction.

In 10 patients with postoperative cardiac dysfunction which required dopamine for inotropic and hemodynamic support, we observed the cardiovascular effects of short-term digoxin administration. The average dosage of dopamine was 7.45 micrograms/kg per minute and was maintained while the patients were given 1 mg of digoxin over 8 hours. The dosage of dopamine was then tapered over the next 4 hours. We observed a significant increase in the cardiac index (4 hours) and a reduction in the heart rate (8 hours) before the dopamine dosage was reduced. After a reduction in dopamine dosage to 2.28 micrograms/kg per minute, these effects persisted. No significant changes were noted in systemic vascular resistance or pulmonary artery diastolic pressure during digoxin administration. These results indicate that the inotropic effects of dopamine and digoxin are additive when given in combination and that digoxin can be used to significantly reduce the dopamine dosage in patients with postoperative cardiac failure. Thus, the combination of an acute inotropic agent, dopamine, and a chronic inotropic agent, digoxin, appears to be clinically useful in postoperative cardiac dysfunction.

Ventricular arrhythmia before and after aorto-coronary bypass surgery.

The influence of aorto-coronary bypass surgery (ACBS) on ventricular arrhythmia was examined in 57 patients. Six-hour Holter monitoring was done on the day prior to and 3 mth after ACBS. None of the patients were on any antiarrhythmic drugs during these recordings. Ventricular arrhythmia was classified into three groups: Group I (45 patients) had an average of less than 10 premature ventricular contractions (PVCs) per hour, Group II (7 patients), 11-30 PVCs per hour and Group III (5 patients), greater than 30 PVCs per hour. There was no significant change in the number of patients in each group after ACBS. Complex PVCs were present in 8 patients preoperatively and in 9 patients after ACBS. The number of diseased vessels and the extent of left ventricular wall motion abnormality noted preoperatively, had no effect on ventricular arrhythmia following surgery. These data show that ACBS, when performed to relieve angina, does not have a significant effect on the prevalence of PVCs and does not prevent or reduce the occurrence of complex PVCs.

Correlation of left ventricular wall motion abnormalities with ventricular arrhythmias in patients with coronary artery disease.

We studied 71 patients with 12-hour Holter monitoring to determine if the incidence and complexity of ventricular arrhythmias in symptomatic coronary artery disease patients were related to the extent of left ventricular dysfunction. Their average age was 51 years, and each had cardiac catheterization within 3 months of study. Thirty-six patients had left ventricular aneurysms, 10 had normal left ventricular angiograms and 25 had left ventricular hypokinesis or akinesis without dyskinesis. The patients with aneurysms had significantly more heart failure, prior infarction, cardiomegaly and impaired ejection fractions. The mean premature ventricular contractions per hour for the aneurysm patients was 34 +/- 52, 3 +/- 5 for those with normal left ventricles, and 11 +/- 24 in the remainder. Complex premature ventricular contraction were noted in 50% of the aneurysm patients, in 10% of the patients with normal left ventricles and in 23% of the patients with hypokinesis or akinesis. Ventricular arrhythmias increase with greater left ventricular wall motion abnormality in patients with symptomatic coronary artery disease.

Coronary artery atherosclerosis observed in men over 14 consecutive years.

The incidence of cardiovascular death and myocardial infarction associated with ischemic heart disease has declined over the past 15 years. Whether this is associated with a decrease in the severity of coronary atherosclerosis is unknown. The extent of coronary atherosclerosis in men was determined by postmortem coronary angiography in 505 patients over an observation period of 14 years. Patients were divided into those with ischemic heart disease (42%) and those without (58%). Mean coronary scores showed no significant trends over the 14-year period in those without ischemic heart disease and for the last 10 years in those with ischemic heart disease. In those few patients evaluated early in the study with ischemic heart disease, a significantly lower coronary score was found compared to subsequent years. This study was performed during an era of declining cardiovascular death rates and a declining incidence of myocardial infarction, and suggests that this decline may relate to favorable changes in pathogenesis rather than to a decrease in extent of coronary atherosclerosis.