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PubMed2002

Global high-throughput screens for cellular function.

There is a critical need for global methods that allow for high-throughput assessment of cellular function for clinical and basic scientists working in both academia and the pharmaceutical industry. These methods typically couple systematic inactivation strategies with high-throughput cell-based assays that facilitate rapid target validation. We present here a survey of these technologies and their applications. We discuss their promise and limitations in addressing the vast number of candidate molecules of disease relevance that are emerging from genomics and proteomics.

Animals↗

PubMed1992

Computer simulation of the effects of ventricular interdependence on indices of left ventricular systolic function.

The influence of ventricular interdependence on cardiovascular function has been convincingly demonstrated. In the intact cardiovascular system ventricular interdependence is always present, and thus measures of cardiac function include the contribution of ventricular interdependence (VI). A cardiovascular system model is presented and used to discuss how VI affects selected indices of left ventricular (LV) systolic function. Indices of LV function studied were the ejection fraction, stroke work, peak time derivative of ventricular pressure (dP/dT) and the LV end-systolic pressure-volume relationship. The effects of right ventricular (RV) volume through systolic VI on these indices are conveniently studied by comparing the model responses to pulmonary artery (PA) and vena caval (VC) occlusions; both PA and VC occlusion reduce LV volume, but the RV volume is increased by PA but reduced by VC occlusions. Through systolic VI the increase in RV volume with PA occlusion shifted the LV end-systolic pressure-volume relationship to the left and thus affected measures of LV maximum elastance. The LV ejection fraction, peak dP/dT and stroke work were all augmented by the increase in RV volume associated with the PA occlusion. Experimental studies comparing the responses to PA and VC occlusions are in broad agreement with the results described here. Systolic VI also shifted the cardiac function curve, a global measure of cardiac function, to the left. The results thus suggest that commonly used indices of LV systolic function are dependent on RV function and do not solely reflect LV function.

Cardiac Volume↗

PubMed2004

Quantitative measures and indices to assess rheumatoid arthritis in clinical trials and clinical care.

Modern medical care has been advanced, in large part, by quantitative measures that provide single, easily-assessed end points for clinical trials, clinical research, or clinical care (eg, blood pressure, serum cholesterol). In rheumatoid arthritis, several types of quantitative measures are used to assess patient status, including formal joint counts; radiographic scores; laboratory tests; patient self-report questionnaire measures of physical function, pain, global status, morning stiffness, and fatigue; as well as physical measures of functional status. Each of these measures is effective to document changes of status with treatment in groups of patients; however, no single measure can serve as a "gold standard" to document changes in each individual patient. Therefore, the measures have been combined into pooled indices that can be applied to individual patients in clinical research and clinical care.

Arthritis, Rheumatoid↗

PubMed1987

Spatio-temporal characterization of intercostal activity during breathing in the cat.

It is envisaged that the motor control of the intercostal musculature--an assembly of mobile structures--can be characterized in terms of a conceptual spatially continuous control function, that underlies the discretely distributed muscular activity and reflects an inferred global dynamic control of the thoracic cage during breathing. The global control function is estimated by the spatio-temporal pattern obtained by averaging in time and space and interpolation of multichannel simultaneous intercostal EMG recording in the anaesthetized cat. Different examples of the experimental preparation in the presence of stimuli of different kinds are analysed. The resultant signal patterns are found to be self-consistent and capable of exhibiting systematically differing features in systematically differing experimental conditions, thus supporting the validity of the analysis and the choice of the estimator. It is concluded that a more detailed analysis of the requirements of this approach is then warranted. Such requirements are discussed, and, specifically, results that bear on the adequacy of spatial sampling rate are presented. It is suggested that such methods offer a promising approach in the study of motor control strategies of the respiratory apparatus.

Algorithms↗

PubMed1999

Adaptive internal state space construction method for reinforcement learning of a real-world agent.

One of the difficulties encountered in the application of the reinforcement learning to real-world problems is the construction of a discrete state space from a continuous sensory input signal. In the absence of a priori knowledge about the task, a straightforward approach to this problem is to discretize the input space into a grid, and to use a lookup table. However, this method suffers from the curse of dimensionality. Some studies use continuous function approximators such as neural networks instead of lookup tables. However, when global basis functions such as sigmoid functions are used, convergence cannot be guaranteed. To overcome this problem, we propose a method in which local basis functions are incrementally assigned depending on the task requirement. Initially, only one basis function is allocated over the entire space. The basis function is divided according to the statistical property of locally weighted temporal difference error (TD error) of the value function. We applied this method to an autonomous robot collision avoidance problem, and evaluated the validity of the algorithm in simulation. The proposed algorithm, which we call adaptive basis division (ABD) algorithm, achieved the task using a smaller number of basis functions than the conventional methods. Moreover, we applied the method to a goal-directed navigation problem of a real mobile robot. The action strategy was learned using a database of sensor data, and it was then used for navigation of a real machine. The robot reached the goal using a smaller number of internal states than with the conventional methods.

Journal Article↗

PubMed2003

Acute and maintenance ECT with flupenthixol in refractory schizophrenia: sustained improvements in psychopathology, quality of life, and social outcomes.

OBJECTIVE: To determine the effects of ECT combined with antipsychotic medication therapy on psychopathology, quality of life, and social functioning in patients with refractory schizophrenia. METHOD: An open acute (Phase I) and maintenance (Phase II) study of the combination of ECT and flupenthixol in the treatment of 46 schizophrenic patients who were nonresponsive to antipsychotic medication from at least two different classes. Scales used: the Brief Psychiatric Rating Scale (BPRS), the Quality of Life Scale (QLS), Social and Occupational Functioning Assessment Scale (SOFAS), Global Assessment of Functioning (GAF), and Mini-Mental State Exam (MMSE). The duration of Phase II was 1 year. RESULTS: In Phase I, there were marked reductions in the BPRS scores, and substantial increases in the QLS, SOFAS, GAF, and MMSE scores. During Phase II, the BPRS negative symptoms worsened but remained improved from baseline. Changes in other outcome measures were negligible. CONCLUSION: ECT and MECT combined with flupenthixol were effective in improving psychopathology in patients refractory to antipsychotic medication alone. Ratings of psychopathology, quality of life, and social functioning all improved in Phase I and were generally sustained during Phase II in patients who had remitted.

Acute Disease↗

PubMed2000

On the relationship of synaptic activity to macroscopic measurements: does co-registration of EEG with fMRI make sense?

A two-scale theoretical description outlines relationships between brain current sources and the resulting extracranial electric field, recorded as EEG. Finding unknown sources of EEG, the so-called "inverse problem", is discussed in general terms, with emphasis on the fundamental non-uniqueness of inverse solutions. Hemodynamic signatures, measured with fMRI, are expressed as voxel integrals to facilitate comparisons with EEG. Two generally distinct cell groups (1 and 2), generating EEG and fMRI signals respectively, are embedded within the much broader class of synaptic action fields. Cell groups 1 and 2 may or may not overlap in specific experiments. Implications of this incomplete overlap for co-registration studies are considered. Each experimental measure of brain function is generally sensitive to a different kind of source activity and to different spatial and temporal scales. Failure to appreciate such distinctions can exacerbate conflicting views of brain function that emphasize either global integration or functional localization.

Brain↗

PubMed1995

The failure of retrograde continuous warm-blood cardioplegia to resuscitate cardiac function in experimental acute coronary artery occlusion and reperfusion.

The effects of retrograde continuous warm-blood cardioplegia (RCWBC) on myocardial preservation during surgical revascularization for acute coronary artery occlusion were investigated using an isolated in-situ dog heart model. The left anterior descending artery (LAD) was occluded for 60 minutes followed by 60 minutes of cardioplegic arrest and reperfusion after release of the coronary artery occlusion. Thirty one animals were divided into 3 groups according to the manner of cardioplegic arrest. The first group of animals (n=10) received multiple doses of cold St. Thomas' Hospital solution delivered antegradely through the aortic root. The second group of animals (n=11) received the same dose of the crystalloid solution delivered retrogradely through the coronary sinus. The third group of animals (n=10) received RCWBC through the coronary sinus. In the animals which were capable of supporting the working mode after reperfusion (8 hearts in each group), regional myocardial function in the occluded LAD distribution measured by sonomicrometer as well as global myocardial function evaluated by left-ventricular stroke-work index were not significantly improved during reperfusion by RCWBC. Corresponding to the functional data, myocardial pH in the occluded LAD distribution was not significantly increased by RCWBC. Although RCWBC maintained myocardial pH in the circumflex artery distribution at a significantly higher level than the other two groups of hearts undergoing cold crystalloid cardioplegia, RCWBC resulted in a substantial decline of myocardial pH in the right-ventricular free wall. These results suggest that RCWBC after 60 minutes of LAD occlusion may not provide a significant benefit in myocardial preservation compared to cold crystalloid cardioplegia delivered through either an antegrade or retrograde manner.

Animals↗

PubMed2002

A longitudinal study of the Swedish Self-Evaluation of Communication Experiences after Laryngeal Cancer questionnaire in patients treated for laryngeal cancer.

A prospective longitudinal study was performed to investigate the sensitivity to change over time of the Swedish Self-Evaluation of Communication Experiences after Laryngeal Cancer questionnaire (S-SECEL), addressing communication dysfunction in patients with laryngeal cancer. Twenty-six consecutive patients attending a weekly tumour conference over a period of one year at Sahlgrenska University Hospital were included in the study prior to start of treatment. The patients answered four questionnaire repeatedly in the course of one year: the S-SECEL, the European Organization for Research and Treatment of Cancer (EORTC), the Core Quality of Life Core Questionnaire (QLQ-C30) supplemented by the Head and Neck cancer questionnaire module (QLQ-H&N35), and the Hospital Anxiety and Depression (HAD) scale. In addition, performance status was assessed. The S-SECEL questionnaire was well accepted by the patients, and compliance was satisfactory with a cumulative response rate of 88% at one year, supporting its feasibility in clinical settings. Repeated measures with the S-SECEL over one year demonstrated a significant decrease in voice and speech dysfunction. The correlation pattern over time between the S-SECEL and the EORTC and HAD questionnaires lent support to the construct validity of the S-SECEL and indicated that the questionnaire was sensitive to clinical change. The changes in S-SECEL correlated most strongly with changes in the EORTC QLQ-H&N35 speech scale, moderately with changes in the QLQ-C30 role and emotional functioning and global QoL scales, while the weakest correlations were with changes in physical functioning. The S-SECEL was sensitive to changes in communication dysfunction, with convergent and discriminant validity of longitudinal assessments, and with relevance for the quality of life of patients with laryngeal cancer receiving different treatment modalities.

Adult↗

PubMed2002

Social functioning and quality of life in the schizophrenic patient: advantages of amisulpride.

Schizophrenia is associated with significant social, psychological and occupational dysfunction. Not only is this distressing for the patients and their family and friends, but it also results in high indirect costs. Reintegration back into society, one of the most important aspects of quality life for schizophrenic patients and their physicians, must therefore take into account a patient's social functioning and employability, as well as improvement in symptoms. Although the typical antipsychotics are effective in managing the positive symptoms of schizophrenia, they may not alleviate other aspects of the disorder. They are also associated with extrapyramidal symptoms and other severe adverse events that have significant consequences for quality of life and compliance. The atypical antipsychotic, amisulpride, has an improved safety and tolerability profile and has been shown to be significantly more effective than placebo and haloperidol on a number of quality of life and social functioning scales, including the Global Assessment of Functioning, the Quality of Life Scale, the Functional Status Questionnaire and the Psychosocial Aptitude Rating Scale. In conclusion, amisulpride, in addition to its proven clinical efficacy, may help reintegration of the schizophrenic patient back into society.

Amisulpride↗

PubMed2004

Acute treatment of bipolar depression with adjunctive zonisamide: a retrospective chart review.

BACKGROUND: This retrospective chart review evaluated the use of zonisamide as adjunctive treatment in patients with bipolar depression. METHOD: The charts of outpatients with bipolar I or II disorder treated with adjunctive zonisamide were reviewed. The efficacy of zonisamide was assessed via comparison of physician-rated Global Assessment of Functioning (GAF) and Clinical Global Impression of Severity (CGI-S) Scale scores at baseline and after 6 weeks of therapy using paired t-tests. Patients who scored < or = 2 on the CGI-S after 6 weeks of zonisamide therapy were considered good responders to zonisamide. RESULTS: Charts for 12 patients (four men and eight women) with a mean (+/- SD) age of 39.6 (+/- 7.6) years were evaluated. Patients received a mean (+/- SD) zonisamide dosage of 236 (+/- 68) mg/day. Mean GAF scores significantly improved from 44.0 at baseline to 59.3 at week 6 (P = 0.05). Mean CGI-S scores improved from 4.54 at baseline to 3.42 at week 6, but the change was not statistically significant. Six patients (50.0%) were considered responders to zonisamide. Four patients discontinued zonisamide therapy, two for an adverse event (sedation) and two for lack of efficacy. CONCLUSIONS: Zonisamide may be a useful adjunctive treatment for some patients with bipolar depression. Conclusions from this study are limited due to its retrospective design. Further investigation of zonisamide in the treatment of bipolar depression is warranted.

Acute Disease↗

PubMed2006

Nurses' collaboration with physicians in managing medication improves patient outcome in acute psychiatric care.

The aim of the present paper was to examine the impact of nurses' collaboration with physicians in medication management on patient outcome in acute psychiatric care. Data for 143 patients with schizophrenia were assessed based on information given by nurses and physicians in charge. Twenty-two patients were defined as a collaborative group when physicians changed medication after receiving reports that nurses perceived the necessity to change. A control group was formed from the 50 patients when nurses perceived the necessity to change medication but did not tell physicians, or nurses advised of the necessity to physicians but medication was not changed. Physicians retrospectively evaluated patients' social functioning and acceptance of medication at admission and discharge. Social functioning was measured by Global Assessment of Functioning (GAF), and acceptance of medication by a single item using Japanese version of Schedule for Assessment of Insight (SAI-J). Changes in the scores from admission to discharge on GAF and acceptance of medication were defined as outcome measures. Nurses recognized the necessity to change medication for patients with frequent aggressive behavior and younger age. Compared with the control group, the collaborative group had less instruction for use of drugs, and more perceived necessity to decrease the current dose or the number of drugs because of stable symptoms. The collaborative group demonstrated significantly greater improvement in social functioning. The collaborative group improved acceptance of medication, although there were no significant differences between the two groups. Nurses' collaboration with physicians in medication management improved patient outcome in acute psychiatric care.

Acute Disease↗

PubMed1998

Factors predictive of referral to psychiatric hospital among general hospital psychiatric consultations.

The aim of this paper was to explore the factors necessitating psychiatric hospital care in a Finnish multi-centre study of general hospital in-patients referred for psychiatric consultation. The study group consisted of 1251 patients referred to psychiatric hospital (n = 181) and a comparison group (n = 1070) consisting of subjects who were not referred. Differences between groups were studied by univariate analysis. Logistic regression analysis was used both to assess the factors contributing to referral to psychiatric hospital and to create predictive models. The validity of the models was analysed by means of receiver operating characteristic (ROC) curves in an independent sample. Psychiatric hospital care during the previous 5 years was associated with a 3.7-fold (odds ratio) increased risk of hospitalization. A diagnosis of psychosis was associated with a 2.9-fold increased risk, and attempted suicide as a reason for consultation was associated with a 2.1-fold increased risk. Not being married doubled the risk, and the odds ratio was also high in cases of poor psychosocial functioning (as assessed by Global Assessment of Functioning (GAF) score). The predictive model differentiated reasonably well between those patients who were hospitalized and the other patients. In conclusion, this multi-centre study of factors predictive of referral to psychiatric hospital among general hospital patients revealed that the most important determinants were previous psychiatric care, diagnosis of psychosis or severe depression, attempted suicide, being unmarried, and poor psychosocial functioning as assessed by GAF score.

Adult↗

PubMed2004

Left atrial conduit volume is generated by deviation from the constant-volume state of the left heart: a combined MRI-echocardiographic study.

Although modeling the four-chambered heart as a constant-volume pump successfully predicts causal physiological relationships between cardiac indexes previously deemed unrelated, the real four-chambered heart slightly deviates from the constant-volume state by ventricular end systole. This deviation has consequences that affect chamber function, specifically, left atrial (LA) function. LA attributes have been characterized as booster pump, reservoir, and conduit functions, yet characterization of their temporal occurrence or their causal relationship to global heart function has been lacking. We investigated LA function in the context of the constant-volume attribute of the left heart in 10 normal subjects using cardiac magnetic resonance imaging (MRI) and contemporaneous Doppler echocardiography synchronized via ECG. Left ventricular (LV) and LA volumes as a function of time were determined via MRI. Transmitral flow, pulmonary vein (PV) flow, and lateral mitral annular velocity were recorded via echocardiography. The relationship between the MRI-determined diastolic LA conduit-volume (LACV) filling rate and systolic LA filling rate correlate well with the relationship between the echocardiographically determined average flow rate during the early portion of the PV D wave and the average flow rate during the PV S wave (r = 0.76). We conclude that the end-systolic deviation from constant volume for the left heart requires the generation of the LACV during diastole. Because early rapid filling of the left ventricle is the driving force for LACV generation while the left atrium remains passive, it may be more appropriate to consider LACV to be a property of ventricular diastolic rather than atrial function.

Atrial Function, Left↗

PubMed2004

Multiple versus single antipsychotic agents for hospitalized psychiatric patients: case-control study of risks versus benefits.

OBJECTIVE: Since use of multiple drugs to treat psychiatric patients is increasing, and research on this practice is rare, the authors carried out a retrospective case-control study of multiple versus single antipsychotic treatment in psychiatric inpatients. METHOD: Inpatient treatment groups receiving either antipsychotic monotherapy or polytherapy were matched in terms of age, sex, diagnostic category, and admission clinical ratings (Global Assessment of Functioning [GAF] and Clinical Global Impression [CGI]), which yielded 70 subject pairs. They were compared in terms of total chlorpromazine-equivalent daily dose, changes in total daily dose, length of hospitalization, incidence of adverse effects, and changes in clinical ratings (CGI, GAF, Positive and Negative Syndrome Scale score) between admission and discharge. RESULTS: Initial doses were closely similar at admission for both treatment groups, but the median total final antipsychotic dose was 78% higher for those receiving antipsychotic polytherapy versus monotherapy. Also, median length of stay in the hospital was 55% (8.5 days) longer, and risk of adverse effects was 56% higher with polytherapy, whereas clinical improvement scores were similar (within 11%) for both treatments. CONCLUSIONS: Short-term treatment with multiple antipsychotics was associated with major increases in drug exposure, adverse events, and time in the hospital but with no apparent gain in clinical benefit. These findings require further testing in controlled prospective studies.

Adult↗

PubMed1999

Parenting and adjustment in schizophrenia.

OBJECTIVE: Patients with schizophrenia who became parents and those who remained childless were compared on premorbid characteristics and current clinical and social adjustment. METHODS: Subjects were 400 men and women with a DSM-III-R diagnosis of chronic schizophrenia based on the Structured Clinical Interview for DSM-III-R (SCID). Assessments measured concurrent substance abuse and antisocial behavior, positive and negative symptoms using the Positive and Negative Syndrome Scale, functional status using the Global Assessment of Functioning scale, family support, and treatment compliance. A total of 158 patients were parents (47 men and 111 women), and 242 were childless (153 men and 89 women). RESULTS: Compared with childless subjects, parents were more likely to have had better premorbid social adjustment, to have ever been married or involved in a conjugal relationship, and to have become ill at a later age. More than two-thirds of parents entered parenthood before the onset of schizophrenia. More women than men were parents, and parents were more likely to be members of ethnic minority groups. No differences were found in current clinical and social adjustment of parents and childless subjects. CONCLUSIONS: Parenthood was associated with better premorbid social adjustment, but it conferred no advantage in the long-term course of schizophrenia. Patients who experience a later onset of schizophrenia or have better premorbid social skills may be more likely to undertake marriage and parenthood, but they will then also be more likely to need special support for the parenting role once the illness begins and takes its typical course.

Adult↗

PubMed2004

Perception of health and quality of life in minorities after mild-to-moderate traumatic brain injury.

Much has been reported of the influence of age, affective symptoms, and satisfaction on self-ratings of health functioning, but little is known about the extent that race-based perceptions may have on influencing behavior or adjustment after a mild-to-moderate traumatic brain injury (MTBI). We investigated differences in perception of health functioning by race for mental and physical functioning using a global measure of health functioning. MTBI (n = 135) and general trauma (GT, n = 83) patients recruited from an area Level-1 trauma center at 3 months after injury were administered the Medical Outcomes Study: Short Form (SF-36), Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders (4th ed.; American Psychiatric Association, 1994), Community Integration Questionnaire, Social Support Questionnaire (SSQ), Center for Epidemiological Studies-Depression, and the Visual Analogue Scale of Depression. A significant interaction for Race Group (p < .01) was found on the Physical Component Scale (PCS) of the SF-36. In the MTBI group, African Americans reported worse functioning (p < .04) on the PCS scale; they perceived functioning on subscales General Health Perception (p < .02) and Physical Functioning (p < .04) to be more limited. On the SSQ, Hispanic MTBI patients reported having fewer social supports available to them (p < .05), although the race groups were comparable for satisfaction with their support. Rate of depression across groups was comparable, although subjective reporting by minority MTBI patients indicated greater depressed feelings. Differences in perception of health functioning may be related to the unique interaction created between sustaining an MTBI and variations in cultural expression of disability. Manifestations of physical difficulties may be better accepted for some cultures than having mental illness.

Activities of Daily Living↗

PubMed1996

Superiority of lithium over verapamil in mania: a randomized, controlled, single-blind trial.

BACKGROUND: Both case reports and small controlled studies suggest the efficacy of verapamil in the treatment of mania. METHOD: Forty patients with DSM-IV mania were studied in a 28-day randomized, controlled, single-blind trial of either lithium or verapamil. RESULTS: The patients receiving lithium showed a significant improvement on all rating scales (Brief Psychiatric Rating Scale [BPRS], Mania Rating Scale [MRS], Global Assessment of Functioning [GAF], and Clinical Global Impression [CGI]) compared with those receiving verapamil. The mean MRS score at Day 28 in the lithium group was significantly lower than that in the verapamil group (17.47 vs. 24.43, respectively; F = 6.17, df = 1, p = .018). A similar pattern was seen with the BPRS (12.68 vs. 20.57; F = 10.69, df = 1, p = .002), CGI (2.31 vs. 3.33; F = 6.05, df = 1, p = .019), and GAF (43.52 vs. 52.31; F = 4.36, df = 1, p = .044) (ANCOVA). CONCLUSION: This study suggests that lithium is superior to verapamil in the management of acute mania.

Acute Disease↗