GA-optimized feedforward-PID tracking control for a rugged electrohydraulic system design.

Rugged electrohydraulic systems are preferred for remote and harsh applications. Despite the low bandwidth, large deadband and flow nonlinearities in proportional valves valve and highly nonlinear friction in industry-grade cylinders that comprise rugged systems, their maintenance are much easier than very sophisticated and delicate servocontrol and servocylinder systems. With the target of making the easily maintainable system to perform comparably to a servosystem, a feedforward control has been designed here for compensating the nonlinearities. A PID feedback of the piston displacement has been employed in tandem for absorbing the unmodeled effects. All the controller parameters have been optimized by a real-coded genetic algorithm. The agreement between the achieved real-time responses for step and sinusoidal demands with those achieved by modern servosystems clearly establishes the acceptability of the controller design.

Mutagenesis of dihydrofolate reductase from Plasmodium falciparum: analysis in Saccharomyces cerevisiae of triple mutant alleles resistant to pyrimethamine or WR99210.

Inhibitors of dihydrofolate reductase (DHFR) have been a mainstay of chemotherapy of falciparum malaria for >50 years. Unfortunately, point mutations in DHFR are the major cause of resistance to drugs of this class and mutations have rapidly diminished the clinical effectiveness of these drugs. We designed a simple yeast-based system to produce and analyze point mutations in the Plasmodium falciparum DHFR domain of the DHFR-thymidylate synthase gene that confers resistance to pyrimethamine (PM), the major antifolate currently used in malaria treatment, or to WR99210, an experimental antifolate. We used PCR mutagenesis, screened >1000 DHFR alleles that encoded functional enzymes and studied approximately 100 that were more resistant than a naturally occurring resistant allele (N51I and S108N). The IC(50) values for both drugs were determined for a subset of 44 alleles that carried only a single new mutation. Mutations that increased resistance to PM 10-100 fold (to >10(-4) M) were identified in three regions of the DHFR domain - around amino acids 50, 188 and 213. In contrast, mutations that caused WR-resistance were far less common and only conferred approximately 10-fold resistance (to approximately 10(-7) M). Even more interesting, only the mutations at 188 increased resistance to WR and mutations in the 213 and other regions either had no effect or actually increased sensitivity to WR. This collateral hypersensitivity raises the possibility that opposing selection for resistance/sensitivity to PM and WR might be used to slow selection of populations of P. falciparum resistant to antifolate treatment.

Perspectives on isolated systolic hypertension in elderly patients.

Until the mid-20th century, clinicians' concern was directed mainly to the systolic component of blood pressure. Later, however, when systolic blood pressure was found to be elevated with advancing age and decreased compliance of the arterial wall, it began to be considered an inevitable consequence of aging. Based on this belief, physicians often concluded that only the diastolic blood pressure elevation, which reflected peripheral vascular resistance, was harmful, while systolic hypertension was innocuous. Therapeutic intervention was practiced mainly for diastolic hypertension, and research protocols were based on the levels of diastolic blood pressure alone. In the 1950s, even when life insurance companies' actuarial data revealed that systolic and diastolic blood pressure elevations were hazardous to health, few clinicians took heed. In 1962, the World Health Organization also defined hypertension as a blood pressure level of 165/95 mm Hg or higher for intervention purposes. However, until the 1991 Systolic Hypertension in the Elderly Program (SHEP) trial, many physicians were reluctant to pay credence to the need for therapy of elevated systolic blood pressure (vide infra).

Identification and analysis of dihydrofolate reductase alleles from Plasmodium falciparum present at low frequency in polyclonal patient samples.

As resistance to chloroquine spreads in sub-Saharan Africa, pyrimethamine plus sulfadoxine (PSD) is increasingly used as a first-line treatment for falciparum malaria. Populations of Plasmodium falciparum (Pf) resistant to PSD have been selected quickly in other regions. The resistance is strongly correlated with point mutations in dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS), the two targets of the drug. It is critical to identify drug-resistant Pf-DHFR alleles that are present at a low frequency in these populations since alleles that confer drug resistance will be quickly selected by PSD use. It is difficult to identify these rare alleles by standard molecular techniques. We have designed a yeast expression system that facilitates the identification and rapid analysis of Pf-DHFR alleles that confer PSD resistance, even when they are present at very low frequency in polyclonal patient samples. We analyzed samples from patients in Kilifi, Kenya collected between 1992 and 1995. We determined the prevalence of the drug-sensitive and drug-resistant alleles in patient samples analyzed in parallel by an allele-specific enzyme digestion (ASED) assay. We identified a pyrimethamine-resistant allele (S108N) present at a frequency of < 1% in a sample that was scored as only S108 by ASED. In addition, a novel pyrimethamine-resistant allele (1164M) was isolated twice, once each from two different patient samples. This approach will allow determination of the prevalence of Pf-DHFR alleles that confer pyrimethamine resistance in particular regions, and the rapid identification of novel alleles that confer drug resistance.

Prognostic significance of K-ras codon 12 mutations in patients with resected stage I and II non-small-cell lung cancer.

PURPOSE: The aim of this study was to investigate the prognostic importance of codon 12 K-ras mutations in patients with early-stage non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: We identified 260 patients with surgically resected stage I (n = 193) and stage II (n = 67) NSCLC with at least a 5-year follow-up. We performed polymerase chain reaction analysis of DNA obtained from paraffin-embedded NSCLC tissue, using mutation-specific probes for codon 12 K-ras. RESULTS: K-ras mutations were detected in 35 of 213 assessable specimens (16.4%). K-ras mutations were detected in 27 of 93 adenocarcinomas (29.0%), one of 61 squamous cell carcinomas (1.6%), five of 39 large-cell carcinomas (12.8%), and two of 20 adenosquamous carcinomas (10%) (P = .001). G to T transversions accounted for 71% of the mutations. There was no statistically significant difference in overall survival for all patients with K-ras mutations (median survival, 39 months) compared with patients without K-ras mutations (median survival, 53 months; P = .33). There was no statistically significant difference in overall or disease-free survival for subgroups with stage I disease, adenocarcinoma, or non-squamous cell carcinoma or for specific amino acid substitutions. The median survival time for stage II patients with K-ras mutations was 13 months, compared with 38 months for patients without K-ras mutations (P = .03). CONCLUSION: Codon 12 K-ras mutations were more common in adenocarcinomas than in squamous cell carcinomas. For the subgroup with stage II NSCLC, there was a statistically significant adverse effect on survival for the presence of K-ras mutations. However, when the entire group was considered, the presence of K-ras mutations was not of prognostic significance in this cohort of patients with resected early-stage NSCLC.

Hormonal response to orthostasis in elderly people with systemic systolic hypertension.

BACKGROUND: Orthostatic hypotension is a common phenomenon in the elderly. Hormonal changes during orthostatic stress have been described in elderly normotensive people and in those with essential hypertension. However, the hormonal response in elderly people who have systolic hypertension during orthostasis has not yet been quantified. METHODS: In this study we investigated 14 non-diabetic men, aged 60 to 75 years, with untreated systolic hypertension who were subjected to 45 degrees passive head-up incline on a tilt table for 15 min. Their hormonal profile and hemodynamic changes were analyzed before and after the stress. RESULTS: In the supine position, plasma levels of norepinephrine, atrial natriuretic peptide and aldosterone were in the normal range, while the plasma renin activity was low. Immediately upon tilt the systolic blood pressure fell but it reverted to baseline values after 15 min of orthostasis. At that time the cardiac output decreased while the systemic vascular resistance and the plasma norepinephrine concentration rose. The atrial natriuretic peptide appeared to fall, and the renin-aldosterone level did not change. CONCLUSION: The physiologic response to orthostatic stress in elderly people with systolic hypertension is comparable to that of elderly normotensive people and those with essential hypertension, i.e. a decrease in cardiac output and an increase in plasma norepinephrine levels. The atrial natriuretic peptide appeared to fall appropriately. The response of the renin-aldosterone system mimicked that in elderly patients with low renin essential isolated hypertension. These observations may have a bearing on the management of elderly people with systolic hypertension who also have orthostatic symptoms; they may not require a different approach from that needed for others of the same age group.

Clinical utility and the predictors of outcome of overdrive transesophageal atrial pacing in the treatment of atrial flutter.

Transesophageal atria pacing (TEAP) using a pill electrode was performed in 49 patients with atrial flutter. The responses observed were (1) immediate sinus rhythm in 17 (35%), (2) delayed sinus rhythm in 13 (27%), (3) atrial fibrillation in 11 (22%), and (4) no success in 8 (16%) patients. Sinus rhythm was thus restored in 30 patients (61%). In group A, 12 of 17 patients (p < 0.05) had coronary artery disease. The patients in group D had echocardiographic evidence of right atrial enlargement (2.56 +/- 0.29 cm, p = 0.007), left atrial enlargement (4.6 +/- 0.12 cm, p < 0.0001), right ventricular dilatation (3.41 +/- 0.45 cm, p < 0.05), left ventricular dilatation (6.39 +/- 0.66 cm, p < 0.05), and depressed left ventricular ejection fraction (32 +/- 7%, p < 0.05). Optimal pacing rate (375 +/- 54 beats/min) was 41% higher than the mean atrial flutter rate (266 +/- 37 beats/min) for cardioversion to immediate sinus rhythm. Pacing current strength and the pulse width had no influence on the final outcome. On the basis of the result of the initial attempt, patients undergoing TEAP repetitively had an almost predictably similar outcome on the subsequent attempts. Thus, normal sinus rhythm could be resumed in most patients with atrial flutter by TEAP. It does not require general anesthesia and can be performed even in patients who have undergone digitalization, when a direct-current countershock may be of some concern.

Special features of coronary heart disease in people of the Indian sub-continent.

Contrary to the popular belief, coronary heart disease (CHD) is indeed common in the Indian sub-continent. Expatriate Indians in their newly adopted countries have 3 to 5 times more chance of developing CHD than the native population or the other immigrant groups. The well-known risk factors such as hypercholesterolemia, hypertension and smoking do not appear to play a major role, while the syndrome of insulin resistance seems to be an important risk factor for CHD in people of this sub-continent. Abdominal obesity, hypertriglyceridemia, and low plasma HDL cholesterol are the markers of this syndrome. Increased plasma insulin levels or even better, the C-peptide measurement may help in identifying the abnormality early. As CHD among Indians has been found to be severe and more diffuse with serious complications and increased mortality at a younger age, preventive measures need to be instituted early. Low fat and complex carbohydrate diet along with regular aerobic exercise may help reduce abdominal obesity, improve insulin sensitivity and HDL cholesterol levels. Hypertriglyceridemia uncontrolled by above measures may require pharmacotherapy with agents such as gemfibrozil. Smoking must be stopped to help reduce insulin resistance and improve HDL levels and endothelial function. Those with hypertension should be considered for therapy with ACE inhibitors, which may improve insulin sensitivity. In patients with insulin resistance, therapy with metformin or troglitazone may be helpful.

Baroreflex function during 45-degree passive head-up tilt before and after long-term thiazide therapy in the elderly with systolic systemic hypertension.

The ratio of the 30th to the 15th cardiac cycle duration on an electrocardiogram (30:15 ratio) immediately after active standing from the supine position has been used as one of the markers of baroreflex function. A ratio of < or = 1.0 has been suggested to indicate baroreflex dysfunction. Blood pressure (BP) changes were measured and the 30:15 ratio was calculated after standing and during 45-degree passive head-up tilt from the supine position in 10 nondiabetic men (mean age +/- SE 70.1 +/- 1.05 years, and BP < 150/90 mm Hg). After tilt the decrease in systolic BP (from 132 +/- 4.8 to 117 +/- 6.3 mm Hg; p < 0.001) appeared to be larger than that after standing (from 132 +/- 4.6 to 123 +/- 5.8 mm Hg; p < 0.01), whereas the 30:15 ratios were 0.965 +/- 0.006 and 0.970 +/- 0.014, respectively, which suggested baroreflex dysfunction. Although the mean of the 2 ratios did not differ, the variance appeared to be less during tilting than after standing. Thus, the 45-degree passive head-up tilt appeared to be a better and more uniform inducer of orthostatic stress than active standing. Therefore, 45-degree head-up tilt was used in a group of 10 nondiabetic male patients (aged 70 +/- 1.46 years) with isolated systolic hypertension (systolic BP > 160 mm Hg, diastolic BP of < 90 mm Hg) to assess their baroreflex function. Upon tilting, their systolic BP decreased from 190 +/- 5.5 to 179 +/- 5.8 mm Hg (p < 0.05) and their 30:15 ratio was 0.985 +/- 0.011.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic response to orthostatic stress in the elderly with systolic systemic hypertension before and after long-term thiazide therapy.

The hemodynamic effects of orthostatic stress in elderly subjects with systolic hypertension were studied before and after long-term hydrochlorothiazide therapy (50 mg daily). Sixteen nondiabetic men aged 70 +/- 1 (SE) years participated in the study initially, and 12 completed 1 year of therapy. Patients underwent 45 degrees head-up incline on a tilt table before, after 1 month and after 1 year of therapy. Hemodynamic variables were measured in the following situations: (1) the supine position, (2) immediately after completion of passive 45 degrees head-up position at 0 minute, (3) at 15 minutes in the tilted state while patients performed intermittent foot movements to minimize gravitational pooling and simulate the standing position outside the laboratory, and (4) after returning to the supine position. Systolic and diastolic blood pressure (BP) decreased significantly after 1 month of therapy, and this reduction was maintained up to 1 year in all aforementioned body positions, with the exception of diastolic BP at 0 minute of tilt, which was significant at 1 year only. Before therapy was begun, there was a significant reduction in systolic BP immediately after completion of tilting; however, this was statistically insignificant both at 1 month and 1 year of therapy. Thus, the data may help dispel the concern of exacerbating the hypotensive response to orthostatic stress in patients with systolic hypertension after long-term thiazide diuretic therapy.

Captopril administered every three hours in difficult-to-control hypertension.

The renovascular hypertension of an elderly patient, which was controlled initially with standard-dose therapy with captopril, later responded only to 75 mg given every 3 h without side effects. Changeover to another class of antihypertensives, as is recommended in recalcitrant cases, was not needed. Convenient maintenance therapy with lisinopril (10 mg twice daily) has kept blood pressure under control for a year.

An analysis of symptoms in patients with permanent ventricular pacemakers.

The prevalence and severity of symptoms of the "pacemaker syndrome" were investigated in 64 patients with VVI pacemakers and compared, in the same patients, to a series of control symptoms, unrelated to pacemaker function. Symptoms were also compared in patient groups unlikely to have the "pacemaker syndrome" (atrial fibrillation), most likely to have such symptoms (retrograde atrial activation) and in an intermediate group (competitive paced and sinus rhythms). There was a linear relationship between the frequency and severity of "pacemaker" symptoms and control questions in all groups and no preponderance of "pacemaker" symptoms in any group. The study provides an estimate of the number and severity of symptoms in patients with VVI pacemakers, demonstrates the non-specificity of the "pacemaker syndrome" and shows no evidence of a sub-clinical "pacemaker syndrome" in the patients observed.

Atrial natriuretic peptide response to cardioversion of atrial flutter and fibrillation and role of associated heart failure.

Plasma atrial natriuretic peptide (ANP) concentrations were measured before and 1 hour after cardioversion in 40 patients (27 with atrial flutter and 13 with atrial fibrillation) admitted for elective cardioversion. Fourteen (11 with atrial flutter and 3 with atrial fibrillation) had clinical evidence of congestive heart failure (CHF). Conversion to sinus rhythm was successful in 39 patients. The mean ANP concentration in the entire group decreased after cardioversion from 38 +/- 4 to 17 +/- 2 pmol/liter (p less than 0.001). In the subgroup with CHF, the ANP level, which was not significantly higher than that in the group without CHF, decreased from 47 +/- 8 to 19 +/- 3 pmol/liter (p less than 0.01). Neither mode of cardioversion (spontaneous 1, pharmacologic 2 and direct-current countershock 36) nor associated CHF influenced ANP response to cardioversion. One patient with atrial flutter and "failed cardioversion" had unchanged ANP level. The decrease after cardioversion in ANP concentration correlated with its control level (r = 0.88, p less than 0.001) but not with the decrease in heart rate. The ANP level in patients with atrial fibrillation was 45 +/- 9 vs 38 +/- 5 pmol/liter in those with atrial flutter (difference not significant). Arrhythmia duration, left atrial size, and ventricular rate or arterial blood pressure did not correlate with ANP concentration in any subgroup. It is concluded that (1) the ANP level is elevated comparably in patients with both atrial flutter and fibrillation regardless of the presence or absence of CHF; and (2) the level decreases, independent of the mode of cardioversion or presence of CHF, promptly after successful cardioversion.

Factors encouraging research productivity in a division of general internal medicine.

The authors investigated two of the causes of and possible remedies for low research activity (as measured by rate of publication) of faculty members in a division of general internal medicine at a university hospital and its affiliated Veterans Administration medical center. They did this by analyzing information about the faculty in the health center's records spanning a 16-year period. This 1989 study suggests that the general medicine faculty members who are also involved in subspecialties and who have protected research time can improve their research productivity.

Use of hepatic vein catheterization in the evaluation of patients with anasarca.

In patients with anasarca, the relative importance of cardiac, pulmonary and/or hepatic dysfunction is often difficult to determine. Conventional use of the Swan-Ganz catheter helps to separate the contributions of right and left heart disease, but it is seldom used to evaluate liver dysfunction. This report describes passage of a Swan-Ganz catheter into the hepatic vein prior to pulmonary artery placement in 11 patients. Hepatic vein catheterization permitted wedged hepatic venography using contrast media and measurement of the wedged and free hepatic venous pressures. All 11 patients had pulmonary hypertension; three had cor pulmonale only, and the others had combinations of left and right heart failure. In addition, six patients had either a cirrhotic pattern on venography, or portal hypertension. Only three of these six patients had previous clinical evidence of liver disease. This study does not prove that identification of hepatic dysfunction by this method improves the outcome in such patients. However, this low risk modification of standard pulmonary artery catheterization provides additional information which is clinically useful in searching for and avoiding complications of cirrhosis, as well as offering a clearer understanding of pathophysiology in acute multisystem disease.

Nifedipine in chronic cor pulmonale: acute and relatively long-term effects.

After 20 mg sublingual nifedipine in 12 men with clinical stable chronic cor pulmonale the mean arterial pressure and systemic vascular resistance fell, cardiac index rose, and mean pulmonary arterial (Ppa) and wedge (Ppaw) pressures, right atrial pressure, and PaO2 remained unchanged. After 20 mg orally every 6 hours for 24 hours in 11 patients, the mean arterial pressure fell further, systemic vascular resistance remained low, and the cardiac index returned to baseline, whereas the Ppa and Ppaw decreased, but the pulmonary vascular driving pressure (Ppa-Ppaw), right atrial pressure, PaO2, and spirometry and ejection fractions remained unchanged. Of eight patients receiving maintenance therapy four developed untoward side effects in 1 to 3 weeks and one was noncompliant. The remaining three patients evaluated at 6 weeks failed to improve and had unchanged resting hemodynamics. Thus in the absence of a potentially reversible hypoxic pulmonary hypertension, nifedipine may not improve pulmonary arterial pressure and cardiac function in clinically stable patients with cor pulmonale.

Effect of inhalation of xylene on intracranial self-stimulation behavior in rat.

The effect of the inhalation of xylene on intracranial self-stimulation behavior was studied in rats in a flow-through (dynamic) inhalational behavioral chamber. Rats were exposed successively to four graded concentrations (102, 192, 419 and 623 ppm) of xylene vapor during 2-hr sessions on different days. The rate of lever-pressing showed a dose-dependent decrease during exposure to 192, 419 and 623 ppm of xylene. The 4-hr exposure to the smallest concentration (106 ppm) of xylene failed to show any effect on self-stimulation behavior. During a 5-day 2 hr/day exposure, the decrease in response observed on the 1st day was further accentuated with a nadir on the 3rd day; from the 4th day onwards, the depressant effect was attenuated showing the development of tolerance.

Effect of xylene inhalation on fixed-ratio responding in rats.

The effect of xylene inhalation was studied on operant behavior under a fixed-ratio (FR24) schedule in rats. Experiments were performed while rats were being exposed to xylene vapor in an inhalational (flow-through) behavioral chamber. Rats were exposed successively to three graded concentrations (113, 216 and 430 ppm) of xylene vapor each for 2 hr in range-finding studies during 6 1/4-hr sessions. The reinforcement rate which is correlated with FR responding was shown to be decreased at hr 1, hr 3 and hr 5. However at hr 2, hr 4 and hr 6 the reinforcement rate in rats increased approaching the control levels, thereby indicating development of tolerance. When rats were exposed to one of the three graded concentrations of xylene for 2 hr on separate days, they also showed a decrease in the reinforcement rate at hr 1; development of acute tolerance was also noted in this schedule. Exposure to the lowest (98.5 ppm) level of xylene used during 5-hr sessions caused no significant decrease in the reinforcement rate. This study thus attempts to identify a minimum effective concentration of xylene and indicates the development of acute tolerance to behavioral effect of xylene.