Computational approaches in cancer multidrug resistance research: Identification of potential biomarkers, drug targets and drug-target interactions.

Like physics in the 19th century, biology and molecular biology in particular, has been fertilized and enhanced like few other scientific fields, by the incorporation of mathematical methods. In the last decades, a whole new scientific field, bioinformatics, has developed with an output of over 30,000 papers a year (Pubmed search using the keyword "bioinformatics"). Huge databases of mass throughput data have been established, with ArrayExpress alone containing more than 2.7 million assays (October 2019). Computational methods have become indispensable tools in molecular biology, particularly in one of the most challenging areas of cancer research, multidrug resistance (MDR). However, confronted with a plethora of different algorithms, approaches, and methods, the average researcher faces key questions: Which methods do exist? Which methods can be used to tackle the aims of a given study? Or, more generally, how do I use computational biology/bioinformatics to bolster my research? The current review is aimed at providing guidance to existing methods with relevance to MDR research. In particular, we provide an overview on: a) the identification of potential biomarkers using expression data; b) the prediction of treatment response by machine learning methods; c) the employment of network approaches to identify gene/protein regulatory networks and potential key players; d) the identification of drug-target interactions; e) the use of bipartite networks to identify multidrug targets; f) the identification of cellular subpopulations with the MDR phenotype; and, finally, g) the use of molecular modeling methods to guide and enhance drug discovery. This review shall serve as a guide through some of the basic concepts useful in MDR research. It shall give the reader some ideas about the possibilities in MDR research by using computational tools, and, finally, it shall provide a short overview of relevant literature.

Loss of CUL4A expression is underlying cisplatin hypersensitivity in colorectal carcinoma cells with acquired trabectedin resistance.

BACKGROUND: Colorectal carcinoma (CRC) is the third most common cancer worldwide. Platinum-based anticancer compounds still constitute one mainstay of systemic CRC treatment despite limitations due to adverse effects and resistance development. Trabectedin has shown promising antitumor effects in CRC, however, again resistance development may occur. In this study, we aimed to develop strategies to circumvent or even exploit acquired trabectedin resistance in novel CRC treatment regimens. METHODS: Human HCT116 CRC cells were selected for acquired trabectedin resistance in vitro and characterised by cell biological as well as bioinformatic approaches. In vivo xenograft experiments were conducted. RESULTS: Selection of HCT116 cells for trabectedin resistance resulted in p53-independent hypersensitivity of the selected subline against cisplatin. Bioinformatic analyses of mRNA microarray data suggested deregulation of nucleotide excision repair and particularly loss of the ubiquitin ligase CUL4A in trabectedin-selected cells. Indeed, transient knockdown of CUL4A sensitised parental HCT116 cells towards cisplatin. Trabectedin selected but not parental HCT116 xenografts were significantly responsive towards cisplatin treatment. CONCLUSIONS: Trabectedin selection-mediated CUL4A loss generates an Achilles heel in CRC cancer cells enabling effective cisplatin treatment. Hence, inclusion of trabectedin in cisplatin-containing cancer treatment regimens might cause profound synergism based on reciprocal resistance prevention.

New cellular tools reveal complex epithelial-mesenchymal interactions in hepatocarcinogenesis.

To enable detailed analyses of cell interactions in tumour development, new epithelial and mesenchymal cell lines were established from human hepatocellular carcinoma by spontaneous outgrowth in culture. We obtained several hepatocarcinoma (HCC)-, B-lymphoblastoid (BLC)-, and myofibroblastoid (MF)-lines from seven cases. In-depth characterisation included cell kinetics, genotype, tumourigenicity, expression of cell-type specific markers, and proteome patterns. Many functions of the cells of origin were found to be preserved. We studied the impact of the mesenchymal lines on hepatocarcinogenesis by in vitro assays. BLC- and MF-supernatants strongly increased the DNA replication of premalignant hepatocytes. The stimulation by MF-lines was mainly attributed to HGF secretion. In HCC-cells, MF-supernatant had only minor effects on cell growth but enhanced migration. MF-lines also stimulated neoangiogenesis through vEGF release. BLC-supernatant dramatically induced death of HCC-cells, which could be largely abrogated by preincubating the supernatant with TNFbeta-antiserum. Thus, the new cell lines reveal stage-specific stimulatory and inhibitory interactions between mesenchymal and epithelial tumour cells. In conclusion, the new cell lines provide unique tools to analyse essential components of the complex interplay between the microenvironment and the developing liver cancer, and to identify factors affecting proliferation, migration and death of tumour cells, neoangiogenesis, and outgrowth of additional malignancy.

Results of Xpert® MTB/RIF implementation in Kyrgyzstan.

INTRODUCTION: In July 2012, the United States Agency for International Development (USAID) Quality Health Care Project introduced the Xpert® MTB/RIF assay at the facility level of the primary health care system in Kyrgyzstan. This study analysed the results of the implementation of Xpert. MATERIALS AND METHODS: Test results from 2734 patients from July 2012 to December 2014 were analysed. The sensitivity and specificity of Xpert in routine programme conditions were evaluated using culture and phenotypic drug susceptibility testing (DST) as gold standard. Contribution to early start of treatment for multidrug-resistant tuberculosis (MDR-TB) was expressed as the median time between availability of the test result and start of treatment. RESULTS: Compared to culture, the sensitivity and specificity of Xpert were respectively 92.7% and 90.4%. For the detection of rifampicin (RMP) resistance, Xpert sensitivity and specificity were respectively 90.1% and 90.7%. The median time to initiation of MDR-TB treatment decreased to 10 days (interquartile range [IQR] 6-16) in 2014 from 20 days (IQR 12-40, P < 0.001) in 2013. CONCLUSION: The Xpert assay demonstrated good agreement in the detection of both Mycobacterium tuberculosis and RMP-resistant pulmonary TB in routine clinical practice. Although Xpert improved the time to treatment initiation from 2013 to 2014, more efforts are needed to further reduce this delay.

Impact of insulin deficiency on glucose fluxes and muscle glucose metabolism during exercise.

Exercise in the insulin-deficient diabetic state is characterized by a further increase in elevated circulating glucose and NEFA levels and by excessive counterregulatory hormone levels. The aim of this study was to distinguish the direct glucoregulatory effects of insulinopenia during exercise from the indirect effects that result from the metabolic and hormonal environment that accompanies insulin deficiency. For this purpose, dogs underwent 90 min of treadmill exercise during SRIF infusion with (SRIF + INS, n = 8) or without (SRIF - INS, n = 6) intraportal insulin replacement. Glucagon was not replaced, thus allowing assessment of the direct effect of insulinopenia at the liver independent of the potentiation of glucagon action. Glucose was infused to maintain euglycemia. Hepatic glucose production (Ra); glucose utilization (Rd); and LGlcU, LGlcE, and LGlcO were assessed with tracers ([3H]glucose, [14C]glucose) and arteriovenous differences. With exercise, insulin fell from 66 +/- 6 to 42 +/- 6 pM in the SRIF + INS group, and was undetectable in the SRIF - INS group. Plasma glucose was 6.33 +/- 0.38 and 6.26 +/- 0.30 mM at rest in the SRIF + INS and SRIF - INS groups, respectively, and was unchanged with exercise. Ra rose from 7.5 +/- 2.3 to 16.5 +/- 2.2 mumol.kg-1.min-1 and 9.1 +/- 2.0 to 31.4 +/- 3.9 mumol.kg-1.min-1 with exercise in the SRIF + INS and SRIF - INS groups, whereas Rd rose from 19.5 +/- 2.0 to 46.8 +/- 3.9 mumol.kg-1.min-1 and 15.1 +/- 1.8 to 29.9 +/- 3.3 mumol.kg-1.min-1. LGlcU rose from 36 +/- 9 to 112 +/- 25 mumol/min and 15 +/- 4 to 59 +/- 13 mumol/min and LGlcO rose from 5 +/- 2 to 61 +/- 12 mumol/min and 5 +/- 3 to 32 +/- 9 mumol/min with exercise in the SRIF+INS and SRIF-INS groups, respectively. Arterial levels and limb balances of NEFAs and glycerol were similar in the two groups. In summary, during exercise: 1) marked insulinopenia attenuates the increases in muscle glucose uptake and oxidation by approximately 50%, independent of changes in circulating metabolic substrate levels; 2) substantial increases in muscle glucose uptake and oxidation are, however, still present even in the absence of detectable insulin levels; and 3) insulinopenia facilitates the increase in Ra, independent of the potentiation of basal glucagon action. In conclusion, marked insulinopenia contributes directly to the exacerbation of glucoregulation during exercise in the diabetic state by limiting the rises in glucose uptake and metabolism and by enhancing hepatic glucose production.

DFT and TD-DFT study on geometries, electronic structures and electronic absorption of some metal free dye sensitizers for dye sensitized solar cells.

The geometries, electronic structures, polarizabilities and hyperpolarizabilities of 2-hydroxynaphthalene-1,4-dione (henna1), 3-(5-((1E)-2-(1,4-dihydro-1,4-dioxonaphthalen-3-yloxy) vinyl) thiophen-2-yl)-2-isocyanoacrylic acid (henna2) and anthocyanin dye sensitizers were studied based on density functional theory (DFT) using the hybrid functional B3LYP. The Ultraviolet-Visible (UV-Vis) spectrum was investigated by using a hybrid method which combines the properties and dynamics of many-body in the presence of time-dependent (TD) potentials, i.e. TDSCF-DFT (B3LYP). Features of the electronic absorption spectrum in the visible and near-UV regions were plotted and assigned based on TD-DFT calculations. Due to the absorption, bands of the metal-organic compound are n→π(*) present. The calculated results suggest that the three lowest energy excited states of the investigated dye sensitizers are due to photoinduced electron transfer processes. The interfacial electron transfer between semiconductor TiO2 electrode and dye sensitizer is owing to an electron injection process from excited dye to the semiconductor's conduction band. The role of linking the henna1 dye with a carboxylic acid via a thiophene bridge was analyzed. The results are that using a stronger π-conjugate bridge as well as a strong donator and acceptor group enhances the efficiency.

Assessing the Performance of Clostridium perfringens Cooling Models for Cooked, Uncured Meat and Poultry Products.

Heat-resistant spores of Clostridium perfringens may germinate and multiply in cooked meat and poultry products when the rate and extent of cooling does not occur in a timely manner. Therefore, six cooling models (PMP 7.0 broth model; PMIP uncured beef, chicken, and pork models; Smith-Schaffner version 3; and UK IFR ComBase Perfringens Predictor) were evaluated for relative performance in predicting growth of C. perfringens under dynamic temperature conditions encountered during cooling of cooked, uncured meat and poultry products. The predicted growth responses from the models were extensively compared with those observed in food. Data from 188 time-temperature cooling profiles (176 for single-rate exponential cooling and 12 for dual-rate exponential cooling) were collected from 17 independent sources (16 peer-reviewed publications and one report) for model evaluation. Data were obtained for a variety of cooked products, including meat and poultry slurries, ground meat and poultry products with and without added ingredients (e.g., potato starch, sodium triphosphate, and potassium tetrapyrophosphate), and processed products such as ham and roast beef. Performance of the models was evaluated using three sets of criteria, and accuracy was defined within a 1- to 2-log range. The percentages of accurate, fail-safe, or fail-dangerous predictions for each cooling model differed depending on which criterion was used to evaluate the data set. Nevertheless, the combined percentages of accurate and fail-safe predictions based on the three performance criteria were 34.66 to 42.61% for the PMP 7.0 beef broth model, 100% for the PMIP cooling models for uncured beef, uncured pork and uncured chicken, 80.11 to 93.18% for the Smith-Schaffner cooling model, and 74.43 to 85.23% for the UK IFR ComBase Perfringens Predictor model during single-rate exponential chilling. Except for the PMP 7.0 broth model, the other five cooling models (PMIP, Smith-Schaffner, and UK IFR ComBase) are useful and reliable tools that food processors and regulatory agencies can use to evaluate the safety of cooked or heat-treated uncured meat and poultry products exposed to cooling deviations or to develop customized cooling schedules.

Acute effects of caffeine ingestion at rest in humans with impaired epinephrine responses.

Caffeine ingestion has been demonstrated to increase circulating epinephrine (Epi) and norepinephrine (NE), elevate free fatty acids (FFAs), and alter heart rate, blood pressure (BP), and ventilation in humans. Whether these physiological responses are a result of caffeine acting through direct stimulation of specific tissues via adenosine receptors or secondary to Epi increases is not known. In the present experiment, six tetraplegics (level of spinal cord lesions C4-C6) were tested at rest for 3 h to investigate the effects of 6 mg/kg caffeine in capsule form on subjects with impaired Epi responses. Ventilatory, cardiovascular, metabolic, and hormonal data were collected every 15-20 min after caffeine ingestion. There were no significant (P > 0.05) increases in plasma Epi after caffeine ingestion [0.19 +/- 0.04 (SE) nM (preingestion); 0.20 +/- 0.04 nM (80 min postingestion)] or in plasma NE [0.53 +/- 0.16 nM (preingestion); 0.49 +/- 0.09 nM (80 min postingestion; P > 0.05)]. However, significant increases were found in serum FFAs [0.53 +/- 0.08 nM (preingestion); 1.03 +/- 0.20 mM (40 min postingestion; P < 0.05] and in glycerol. These concentrations remained elevated throughout the experiment. BP increased in the first hour postingestion. These data demonstrate that caffeine in physiological doses directly stimulates specific tissues, i.e., adipose and peripheral vascular tissue, and these effects are not secondary to increases in Epi after caffeine ingestion.

Caffeine ingestion and metabolic responses of tetraplegic humans during electrical cycling.

Normally, caffeine ingestion results in a wide spectrum of neural and hormonal responses, making it difficult to evaluate which are critical regulatory factors. We examined the responses to caffeine (6 mg/kg) ingestion in a group of spinal cord-injured subjects [7 tetraplegic (C5-7) and 2 paraplegic (T4) subjects] at rest and during functional electrical stimulation of their paralyzed limbs to the point of fatigue. Plasma insulin did not change, caffeine had no effect on plasma epinephrine, and there was a slight increase (P < 0. 05) in norepinephrine after 15 min of exercise. Nevertheless, serum free fatty acids were increased (P < 0.05) after caffeine ingestion after 60 min of rest and throughout the first 15 min of exercise, but the respiratory exchange ratio was not affected. The exercise time was increased (P < 0.05) by 6% or 1.26 +/- 0.57 min. These data suggest that caffeine had direct effects on both the adipose tissue and the active muscle. It is proposed that the ergogenic action of caffeine is occurring, at least in part, by a direct action of the drug on muscle.

Hormonal and metabolic responses to electrically induced cycling during epidural anesthesia in humans.

Hormonal and metabolic responses to electrically induced dynamic exercise were investigated in eight healthy young men with afferent neural influence from the legs blocked by epidural anesthesia (25 ml of 2% lidocaine) at L3-L4. This caused cutaneous sensory anesthesia below T8-T9 and complete paralysis of the legs. Cycling increased oxygen uptake to 1.90 +/- 0.13 (SE) l/min, and fatigue developed after 22.7 +/- 2.7 min. Compared with voluntary exercise at the same oxygen uptake and heart rate, concentrations of blood and muscle lactate (musculus vastus lateralis) as well as plasma potassium increased more while muscle glycogen decreased more during electrically induced exercise. Hepatic glucose production always rose during exercise. However, during involuntary exercise with sensory blockade, it did not match the rise in peripheral glucose uptake and plasma glucose decreased (P < 0.05). Plasma glycerol increased less in electrically induced vs. voluntary exercise, and free fatty acids and beta-hydroxybutyrate decreased only during electrically induced exercise. Epinephrine, growth hormone, adrenocorticotropic hormone, and cortisol levels were higher during involuntary vs. voluntary exercise (P < 0.05). In conclusion, neural and humoral mechanisms exert redundant control with regard to responses of catecholamines and pituitary hormones (growth hormone and adrenocorticotropic hormone). In contrast, neural input from motor centers and feedback from working muscle are important for glucose production and lipolysis during exercise in humans. Humoral feedback is apparently not sufficient to trigger normal mobilization of extramuscular fuel stores.

Heart rate during exercise with leg vascular occlusion in spinal cord-injured humans.

Feed-forward and feedback mechanisms are both important for control of the heart rate response to muscular exercise, but their origin and relative importance remain inadequately understood. To evaluate whether humoral mechanisms are of importance, the heart rate response to electrically induced cycling was studied in participants with spinal cord injury (SCI) and compared with that elicited during volitional cycling in able-bodied persons (C). During voluntary exercise at an oxygen uptake of approximately 1 l/min, heart rate increased from 66 +/- 4 to 86 +/- 4 (SE) beats/min in seven C, and during electrically induced exercise at a similar oxygen uptake in SCI it increased from 73 +/- 3 to 110 +/- 8 beats/min. In contrast, blood pressure increased only in C (from 88 +/- 3 to 99 +/- 4 mmHg), confirming that, during exercise, blood pressure control is dominated by peripheral neural feedback mechanisms. With vascular occlusion of the legs, the exercise-induced increase in heart rate was reduced or even eliminated in the electrically stimulated SCI. For C, heart rate tended to be lower than during exercise with free circulation to the legs. Release of the cuff elevated heart rate only in SCI. These data suggest that humoral feedback is of importance for the heart rate response to exercise and especially so when influence from the central nervous system and peripheral neural feedback from the working muscles are impaired or eliminated during electrically induced exercise in individuals with SCI.

Oral therapy with proteolytic enzymes decreases excessive TGF-beta levels in human blood.

UNLABELLED: Therapy with oral proteolytic enzymes (OET) with combination drug products containing papain, bromelain, trypsin, and chymotrypsin has been shown to be beneficial in clinical settings such as radiotherapy-induced fibrosis, bleomycin pneumotoxicity and immunosuppression in cancer, all of which are nowadays known to be accompanied by excessive transforming growth factor-beta (TGF-beta) production. It has been demonstrated that proteolytic enzymes reduce TGF-beta levels in serum by converting the protease inhibitor alpha2 macroglobulin (alpha2M) from the "slow" form into the "fast" form, whereby the "fast" form binds and inactivates TGF-beta irreversibly. In this study we have investigated the effect of OET on the concentration of TGF-beta1 in serum of patients with rheumatoid arthritis (RA) (n = 38), osteomyelofibrosis (OMF) (n = 7) and herpes zoster (HZ) (n = 7). Seventy-eight healthy volunteers served as controls. TGF-beta1 levels in serum were assessed by enzyme-linked immunosorbent assay (ELISA). We have demonstrated that in healthy volunteers and in patients there exists a correlation between active and latent TGF-beta1 in serum (r=0.8021; P<0.0001). Treatment with OET had no significant effect on TGF-beta1 concentration in healthy volunteers or patients with a normal level of TGF-beta1. In patients with elevated TGF-beta1 concentration (> 50 ng/ml serum), OET reduced TGF-beta1 in RA (P < 0.005), in OMF (P < 0.05) and in HZ (P < 0.05). CONCLUSION: These results support the concept that OET is beneficial in diseases characterized in part by TGF-beta1 overproduction.

Assessing individual differences in constructive versus destructive responses to anger across the lifespan.

Scenario-based, self-report measures were developed to assess how people characteristically experience and manage anger from middle childhood through adulthood. The Anger Response Inventories (ARIs) for children, adolescents, and adults each assess (a) anger arousal, (b) intentions, (c) cognitive and behavioral responses, and (d) Long-term consequences. Several independent studies provide support for the reliability and validity of the ARIs. Theoretically consistent patterns of correlations were observed with (a) global self-report measures of hostility, aggression, and anger-management strategies (adult version); (b) teacher reports of behavioral and emotional adjustment (child and adolescent versions); and (c) self- and family-member reports of behaviors on specific anger episodes (adolescent and adult versions). Findings from additional personality and developmental studies are summarized, further supporting construct validity.

Temperature responses to electrically induced cycling in spinal cord injured persons.

PURPOSE: The purpose of the study was to investigate the core temperature responses to the induction of electrical exercise and to clarify whether an increase in temperature could be responsible for some of the observed reactions to acute and repeated exposure to electrical muscle stimulation. METHODS: The paralyzed thigh and gluteal muscles were stimulated electrically with surface electrodes in seven persons with transection of the spinal cord. By this means, they were able to pedal a lower extremity ergometer at 50 revolutions per minute for 30 min. Skin surface, esophageal (Tes), rectal (Tre), and muscle temperature in m. quadriceps were measured with thermocouples. RESULTS: The average rate of oxygen consumption was 0.91 +/- 0.16 L.min-1, and the heart rate after 20 min was 123 +/- 9 bpm during the electrically induced exercise. The involuntary, induced exercise led to increases in core temperature, whereas skin surface temperature was the same before and after exercise. Average Tes and Tre both rose 0.7 degrees C from, respectively, 36.6 +/- 0.2 and 36.9 +/- 0.1 degrees C, and muscle temperature increased even more: 2.9 degrees C from 33.9 +/- 0.3 degrees C. CONCLUSION: It is suggested that these increased temperatures may act as stimuli, directly or, through resulting release of humoral factors, and elicit the changes in heart rate, as well as the previously observed adaptive changes after electrically induced exercise, e.g., in muscle fiber size, and capillarization.

In vivo cell-mediated immunity and vaccination response following prolonged, intense exercise.

Epidemiological and experimental studies have shown increased frequency and severity of infections after intense, long-term exercise. This study examines whether an in vivo impairment of the cell-mediated immunity and antibody production can be demonstrated after intense, long-term exercise. Twenty-two male triathletes performed one-half an ironman (group A). Vaccinations with tetanus and diphtheritis toxoid and purified pneumococcal polysaccharide were given after the exercise. Furthermore, a skin test with seven different antigens was applied on the forearm. Antibody titers were measured before and 2 wk after the exercise. The skin test was read 48 h after the application. Eleven non-exercising triathletes (group B) and 22 moderately trained men (group C) were used as control groups. Group A revealed a significantly lower skin test response to the tetanus antigen than both groups B and C. In group A, a smaller cumulative response (sum of the diameters of indurations and number of positive skin test spots) was found than in both groups B and C. No differences in antibody titers were found among the three groups. Thus, the in vivo cell-mediated immunity was impaired in the first days after prolonged, high intensity exercise, whereas there was no impairment of the in vivo antibody production measured 2 wk after vaccination.

Insulin action and long-term electrically induced training in individuals with spinal cord injuries.

PURPOSE: Individuals with spinal cord injuries (SCI) have an increased prevalence of insulin resistance and type 2 diabetes mellitus. In able-bodied individuals, training with large muscle groups increases insulin sensitivity and may prevent type 2 diabetes mellitus. However, individuals with SCI cannot voluntarily recruit major muscle groups, but by functional electrical stimulation (FES) they can now perform ergometer bicycle training. METHODS: Ten subjects with SCI (35 +/- 2 yr (mean +/- SE), 73 +/- 5 kg, level of lesion C6--Th4, time since injury: 12 +/- 2 yr) performed 1 yr of FES cycling (30 min x d(-1), 3 d x wk(-1) (intensive training)). Seven subjects continued 6 months with reduced training (1 d x wk(-1) (reduced training)). A sequential, hyperinsulinemic (50 mU x min(-1) x m(-2) (step 1) and 480 mU x min(-1) x m(-2) (step 2)), euglycemic clamp, an oral glucose tolerance test (OGTT), and determination of GLUT 4 transporter protein in muscle biopsies were performed before and after training. RESULTS: Insulin-stimulated glucose uptake rates increased after intensive training (from 4.9 +/- 0.5 mg x min(-1) x kg(-1) to 6.2 +/- 0.6 mg x min(-1) x kg(-1) (P < 0.008) (step 1) and from 9.0 +/- 0.8 mg x min(-1) x kg(-1) to 10.6 +/- 0.8 mg x min(-1) x kg(-1) (P = 0.103) (step 2)). With the reduction in training, insulin sensitivity decreased to a similar level as before training (P > 0.05). GLUT 4 increased by 105% after intense training and decreased again with the training reduction. The subjects had impaired glucose tolerance before and after training, and neither glucose tolerance nor insulin responses to OGTT were significantly altered by training. CONCLUSIONS: Electrically induced bicycle training, performed three times per week increases insulin sensitivity and GLUT 4 content in skeletal muscle in subjects with SCI. A reduction in training to once per week is not sufficient to maintain these effects. FES training may have a role in the prevention of the insulin resistance syndrome in persons with SCI.

Do nonpatients underestimate the quality of life associated with chronic health conditions because of a focusing illusion?

BACKGROUND: A number of studies show that the general public often estimates that the quality of life (QOL) associated with various health conditions is worse than patients say it is. These studies raise the possibility that people overestimate the impact that unfamiliar health conditions will have on their quality of life. One possible reason people overestimate this is because they are susceptible to a focusing illusion--when asked to imagine themselves in unfamiliar circumstances, people overestimate the emotional impact of those features of their life that would change. METHODS: The authors surveyed members of the general public to test the hypothesis that their QOL ratings of hypothetical health conditions would be higher (indicating a better quality of life) after thinking about how the health condition would affect a broad range of life domains. Across 3 experiments, the authors varied the health conditions people were asked to consider (either paraplegia, below-the-knee amputation, or partial blindness), the life domains they were asked to consider, the response mode with which they evaluated how each health condition would affect each life domain, whether subjects rated the health condition before and after considering life domains or only after, and whether subjects rated their own current quality of life first. RESULTS: Across 3 experiments, using 10 different questionnaire versions, only 1 instance was found in which subjects' ratings were significantly higher after thinking about the effect of the health condition on life domains than before, and the magnitude of this increase was small. CONCLUSION: It could not be established that a focusing illusion contributes significantly to the discrepancy in QOL ratings of patients and nonpatients. Further research should explore other factors that could contribute to the discrepancy or other ways of testing for the influence of a focusing illusion.

Effect of high voltage stimulation on blood flow in the rat hind limb.

The purpose of this study was to test the effect of high voltage stimulation (HVS) on blood flow velocity (BFV) in the rat hind limb. A 20-MHz pulsed Doppler device was used to measure BFV changes in the femoral artery of 20 anesthetized rats after electrical stimulation. The animals were stimulated under the following conditions: four different pulse rates, changes in stimulus voltage, and changes in polarity. Blood flow velocity also was measured in the unstimulated hind limb. Although each of the four pulse rates caused significant increases in BFV, the 20-pulse-per-second rate produced BFV increases significantly greater than the other three pulse rates. The BFV changes, on the average, occurred less than 1 minute from the onset of stimulation and lasted up to 14 minutes after the cessation of the stimulation. The BFV increased with increases in voltage intensity. Both the positive and negative poles elicited significant increases in BFV, but the negative pole produced the greatest increases. Blood flow in the unstimulated hind limb was unchanged after stimulation. This study indicates that HVS of muscle does cause significant increases in blood flow to the stimulated rat hind limb.

Comparison of isometric exercise and high volt galvanic stimulation on quadriceps femoris muscle strength.

The purpose of this study was to compare the effectiveness of both high volt galvanic current (HVG) and isometric exercise to strengthen the quadriceps femoris muscles in 17 healthy subjects. The subjects were divided into three groups. The Control Group (n = 6) received no exercise or stimulation. The Isometric Exercise Group (n = 5) performed 15 sessions of maximum isometric contractions, and the Electrical Stimulation Group (n = 6) engaged in 15 sessions of electrically stimulated isometric contractions. The Isometric Exercise Group was found to have an increase in strength significantly greater (p less than .05) than either the Control or Electrical Stimulation Group. No increase in strength was observed in either the Control or Electrical Stimulation Group. This study indicates that HVG stimulation is not as effective as isometric exercise in increasing strength in muscle.

Effect of high voltage stimulation on edema reduction in the rat hind limb.

The purpose of this study was to test the effect of high voltage stimulation (HVS) on edema reduction in the rat hindpaw. The animals were divided into a control group (n = 20) and a treated group (n = 20). The right hindpaw volume was measured, and then the animal's paw was traumatized. The animals in the treated group were treated with HVS at 24, 48, and 72 hours posttrauma. Paw volume measurements were made on all animals at 0, 24, 48, 72, and 96 hours posttrauma. In addition, the paw volume was measured in the treated group both before and after HVS. The results showed that animals in both groups had a significant decrease in paw volume over the experimental period, but no significant difference was found between the two groups in the amount of edema reduction. The HVS treatment did not produce a significant change in paw volume immediately after treatment.