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.

Strengthening Rural Health Placements for Medical Students: Lessons for South Africa from International Experience

BACKGROUND:This article derives lessons from international experience of innovative rural health placements for medical students. It provides pointers for strengthening South African undergraduate rural health programmes in support of the government's rural health; primary healthcare and National Health Insurance strategies.METHODS:The article draws on a review of the literature on 39 training programmes around the world; and the experiential knowledge of 28 local and international experts consulted through a structured workshop.RESULTS:There is a range of models for rural health placements: some offer only limited exposure to rural settings; while others offer immersion experiences to students. Factors facilitating successful rural health placements include faculty champions who drive rural programmes and persuade faculties to embrace a rural mission; preferential selection of students with a rural background; positioning rural placements within a broader rural curriculum; creating rural training centres; the active nurturing of rural service staff; assigning students to mentors; the involvement of communities; and adapting rural programmes to the local context. Common obstacles include difficulties with student selection; negative social attitudes towards rural health; shortages of teaching staff; a sense of isolation experienced by rural students and staff; and difficulties with programme evaluation.CONCLUSIONS:Faculties seeking to expand rural placements should locate their vision within new health system developments; start off small and create voluntary rural tracks; apply preferential admission for rural students; set up a rural training centre; find practical ways of working with communities; and evaluate the educational and clinical achievements of rural health placements

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.

Digestive disease resources on the Internet.

The aim of this study is to help digestive disease professionals fully utilize the resources available on the Internet for patient care, education, and research. The following search resources were employed to locate websites: general search engines--Lycos, Metacrawler, Webcrawler, and Yahoo!; medical search engines--HealthWeb, MedMatrix, MedWeb, and MedWebPlus; website links; and publications. The inclusion of web sites was based on their content. Each site was evaluated with respect to its authorship, attribution, currency, and disclosure. All digestive disease professional organizations and academic centers that met the above criteria were included. Only nutrition sites with relevance to digestive diseases were included. A variety of very useful web sites related to digestive diseases exist on the Internet, and their numbers are growing. Many of these sites have valuable information that can be used to improve patient care, promote medical education, and facilitate research. Digestive disease professionals should adopt the Internet and address the many issues raised by this technology.

Cardiovascular effects of atropine in postoperative cardiac patients receiving digoxin for ventricular dysfunction.

Digoxin is clinically useful as a cardiac antiarrhythmic and inotropic agent. Its antiarrhythmic actions are mediated through the cholinergic nervous system. The cholinergic system, when activated, can depress ventricular function. We have sought to further increase the cardiovascular effects of digoxin by blocking its cholinergic effects with atropine. Atropine, 1 mg intravenously, was given to 10 postoperative cardiac patients. The cardiovascular time course was monitored by an ECG, radial arterial line, and pulmonary artery thermodilution catheter for 8 hours. A significant increase (p less than 0.05) in the cardiac output (CO), from 5.98 +/- 0.24 L/min to 6.60 +/- 0.34 L/min, was evident within 2 hours after atropine administration. The CO returned to control levels by 6 hours. There were no significant changes in heart rate, systemic vascular resistance, pulmonary artery wedge pressure, or systemic blood pressure. The results indicate that the cholinergic blockade of digoxin with atropine will acutely increase the cardiac output in postoperative cardiac patients.

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.

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.

Clinical use of digitalis glycosides. An update.

Digitalis glycosides continue to place high on the list of prescribed drugs. Digoxin is 8th on prescriptions written in the United States in 1980, digitoxin 16th, and digitalis leaf 23rd. There is little doubt that most physicians continue to believe these drugs are useful. The application of more definite indications, smaller doses, and the recognition of the role of pharmacokinetics and drug interactions make use of the glycosides more challenging than ever before in 1985.

Effect of propafenone in patients with stable ventricular arrhythmias.

Thirty patients with clinically significant ventricular ectopy were treated with propafenone, a new potent antiarrhythmic agent with membrane stabilizing action. Patients had a minimum mean of greater than 30 ventricular premature beats per hour documented by continuous 48-hour ambulatory ECG recording. Twenty-five patients qualified as responders, defined as greater than 85% reduction of ventricular ectopy compared to baseline, and completed a double-blind placebo-crossover phase. Significant reduction in single ventricular ectopy per hour, paired ventricular ectopy per hour, and ventricular tachycardia beats per hour were observed. Almost total abolition of ventricular tachycardia and paired ventricular ectopy was achieved. Side effects were minimal and well tolerated. A significant prolongation of the PR interval occurred. QRS prolongation and prolongation of the corrected QT interval was observed in some patients, with new left bundle branch block developing in two patients. Long-term efficacy and safety studies will be necessary to determine the ultimate role of this new agent in the selection of antiarrhythmic therapy, but these initial results are encouraging.

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.

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)

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.

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.

The influence of production mode on the recall of signs in normal adult subjects.

Preliminary evidence has suggested that signs produced with contact between the two hands or between the hand and body are learned more readily than signs produced without such contact. Using a paradigm that eliminated the possibly confounding variables of previous studies, the effect of production mode on sign acquisition and recall was investigated with normal young adults. Results indicated that contact signs were acquired more readily than noncontact signs by one of two subject groups. More contact than noncontact signs were produced correctly during recall. Recall at 1 week was equivalent to that at same day for contact signs, but same-day recall was greater than 1-week recall for noncontact signs. Examination of responses that were correct except for a contact/noncontact discrepancy suggested that contact was added more often than it was deleted from signs during recall. These findings are discussed in terms of the role of tactile feedback in learning and memory and their potential application to teaching signs to nonverbal children.

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.

Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. Results of a Veterans Administration Cooperative Study.

We conducted a multicenter, double-blind, placebo-controlled randomized trial of aspirin treatment (324 mg in buffered solution daily) for 12 weeks in 1266 men with unstable angina (625 taking aspirin and 641 placebo). The principal end points were death and acute myocardial infarction diagnosed by the presence of creatine kinase MB or pathologic Q-wave changes on electrocardiograms. The incidence of death or acute myocardial infarction was 51 per cent lower in the aspirin group than in the placebo group: 31 patients (5.0 per cent) as compared with 65 (10.1 per cent); P = 0.0005. Nonfatal acute myocardial infarction was 51 per cent lower in the aspirin group: 21 patients (3.4 per cent) as compared with 44 (6.9 per cent); P = 0.005. The reduction in mortality in the aspirin group was also 51 per cent--10 patients (1.6 per cent) as compared with 21 (3.3 per cent)--although it was not statistically significant; P = 0.054. There was no difference in gastrointestinal symptoms or evidence of blood loss between the treatment and control groups. Our data show that aspirin has a protective effect against acute myocardial infarction in men with unstable angina, and they suggest a similar effect on mortality.

Digitalis-sensitive Na+, K+-ATPase: lack of a direct catecholamine-mediated stimulation in bovine myocardial tissue.

It has been documented that biogenic amines can stimulate Na+, K+-ATPase from various tissue preparations. However, it is unclear whether or not this stimulation occurs in myocardial tissues. We have evaluated possible catecholamine stimulation of purified Na+, K+- ATPase preparations utilizing a bovine ventricular microsomal preparation. We have studied the dose response of the enzyme to ouabain and digitoxigenin in the presence and absence of propranolol and norepinephrine. Our results indicate that propranolol increases the sensitivity of Na+, K+-ATPase to inhibition by digitalis, and that stimulation of Na+, K+-ATPase in bovine myocardium is not mediated via an adrenergic mechanism. In addition, our results indicate that in myocardial tissue, both stereoisomers of propranolol produce a direct nonspecific membrane effect which can modify Na+, K+-ATPase activity.