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Biomedical subjects

D L Kelly

Publications and source records attributed to D L Kelly.

At least 19 recordsLinked to original sources
PubMed2006

Characterization of a method for profiling gene expression in cells recovered from intact human prostate tissue using RNA linear amplification.

Coupling array technology to laser capture microdissection (LCM) has the potential to yield gene expression profiles of specific cell populations within tissue. However, remaining problems with linear amplification preclude accurate expression profiling when using the low nanogram amounts of RNA recovered after LCM of human tissue. We describe a novel robust method to reliably amplify RNA after LCM, allowing direct probing of 12K gene arrays. The fidelity of amplification was demonstrated by comparing the ability of amplified RNA (aRNA) versus that of native RNA to identify differentially expressed genes between two different cell lines, demonstrating a 99.3% concordance between observations. Array findings were validated by quantitative polymerase chain reaction analysis of a randomly selected subset of 32 genes. Using LCM to recover normal (N=5 subjects) or cancer (N=3) cell populations from intact human prostate tissue, three differentially expressed genes were identified. Independent investigators have previously identified differential expression of two of these three genes, hepsin and beta-microseminoprotein, in prostate cancer. Taken together, the current study demonstrates that accurate gene expression profiling can readily be performed on specific cell populations present within complex tissue. It also demonstrates that this approach efficiently identifies biologically relevant genes.

Cell Line, Tumor↗
PubMed2003

Measurement of antipsychotic-induced side effects: support for the validity of a self-report (LUNSERS) versus structured interview (UKU) approach to measurement.

A self-report measure of antipsychotic side effects (LUNSERS) was compared with that of an established semi-structured interview (UKU side effect rating scale). The validity and the ability of the LUNSERS to determine false positives by use of an internal 'red herring' subscale were assessed. 'Red herring' items are those which do not directly relate to known antipsychotic side effects. In an open study, 29 patients with schizophrenia and schizoaffective disorder from inpatient and outpatient settings within an Australian metropolitan mental health service were assessed for antipsychotic-induced side effects using both the LUNSERS and UKU. The LUNSERS and UKU were similar in their overall assessment of antipsychotic side effects (total score correlation of 0.58) and were correlated on a wide array of individual side effect items. Correlations between total scores and individual items were higher for those patients scoring low on the LUNSERS 'red herring' items compared with both those with high 'red herring' scores and the sample as a whole. Several LUNSERS items were identified as potentially problematic, requiring further explanation or supplementation with direct questioning. The 'red herring' scale appears to enable detection of patients that may be over-reporting symptomatology. The LUNSERS is a valuable self-report measure of antipsychotic side effects, particularly in cases where red herring scores are low.

Adolescent↗
PubMed2001

Management of treatment resistance in schizophrenia.

A systematic approach to the evaluation and characterization of treatment resistance in schizophrenia has become increasingly important since the introduction of the second-generation antipsychotics. The need for accurate evaluation will increase further as other new antipsychotic medications are developed. Patients with schizophrenia may manifest poor response to therapy because of intolerance to medication, poor adherence, inappropriate dosing, as well as true resistance of their illness to antipsychotic drug therapy. Criteria for treatment-resistance are presented to help in standardizing treatment and clinical trials. As clinicians face the decision of when to change or augment antipsychotic medications, a clear understanding of the appropriate length of a treatment trial and which target symptoms respond to antipsychotic therapy is critical for maximizing response in patients with treatment-resistant schizophrenia.

Adrenergic beta-Antagonists↗
PubMed2001

Predictors of successful extubation in neurosurgical patients.

A respiratory therapist-driven weaning protocol incorporating daily screens, spontaneous breathing trials (SBT), and prompts to caregivers has been associated with superior outcomes in mechanically ventilated medical patients. To determine the effectiveness of this approach in neurosurgical (NSY) patients, we conducted a randomized controlled trial involving 100 patients over a 14-mo period. All had daily screens of weaning parameters. If these were passed, a 2-h SBT was performed in the Intervention group. Study physicians communicated positive SBT results, and the decision to extubate was made by the primary NSY team. Patients in the Intervention (n = 49) and Control (n = 51) groups had similar demographic characteristics, illness severity, and neurologic injuries. Among all patients, 87 (45 in the Control and 42 in the Intervention group) passed at least one daily screen. Forty (82%) patients in the Intervention group passed SBT, but a median of 2 d passed before attempted extubation, primarily because of concerns about the patient's sensorium (84%). Of 167 successful SBT, 126 (75%) did not lead to attempted extubation on the same day. The median time of mechanical ventilation was 6 d in both study groups, and there were no differences in outcomes. Overall complications included death (36%), reintubation (16%), and pneumonia (9%). Tracheostomies were created in 29% of patients. Multivariate analysis showed that Glasgow Coma Scale (GCS) score (p < 0.0001) and partial pressure of arterial oxygen/fraction of inspired oxygen ratio (p < 0.0001) were associated with extubation success. The odds of successful extubation increased by 39% with each GCS score increment. A GCS score > or = 8 at extubation was associated with success in 75% of cases, versus 33% for a GCS score < 8 (p < 0.0001). Implementation of a weaning protocol based on traditional respiratory physiologic parameters had practical limitations in NSY patients, owing to concerns about neurologic impairment. Whether protocols combining respiratory parameters with neurologic measures lead to superior outcomes in this population requires further investigation.

Adolescent↗
PubMed2001

Comparison of discharge rates and drug costs for patients with schizophrenia treated with risperidone or olanzapine.

This study compared the discharge rates and drug costs of 789 patients with schizophrenia or schizoaffective disorder who began pharmacotherapy with olanzapine or risperidone between July 1997 and June 1998. Discharge rates 30 days after the start of treatment were 45 percent for the patients treated with risperidone and 32 percent for those treated with olanzapine (p=.001). Daily drug costs during the same period were $6.42 for risperidone and $12.29 for olanzapine (p<.001). For risperidone, lower dosages were associated with higher hospital discharge rates, whereas no significant association was observed for olanzapine. These data suggest that among inpatients with schizophrenia or schizoaffective disorder, use of risperidone results in a higher discharge rate and a lower drug cost than use of olanzapine.

Antipsychotic Agents↗
PubMed2001

Ziprasidone and the QTc interval: pharmacokinetic and pharmacodynamic considerations.

Many psychotropic medications might cause prolongation of the QTc interval; however, antipsychotics have recently come under increasing scrutiny in this regard. Ziprasidone, a newly marketed second-generation antipsychotic, was initially delayed in approval by the FDA due to its propensity to prolong the QTc interval in patients with schizophrenia. While ziprasidone does prolong the QTc interval, safety, concomitant medication, and overdose data present little reason to consider ziprasidone a major risk factor for Torsades de Pointes thus far. The paucity of data regarding this agent, however, and its use in those with additional risk factors for QTc-interval prolongation are striking. The risk for this phenomenon has not been studied in patients with concomitant disease states that might be associated with QTc-interval prolongation or in those taking metabolic inhibitors which might inhibit aldehyde oxidase. Little is known about a major metabolic route of ziprasidone, oxidation by aldehyde oxidase. Finally, experience with other agents associated with QTc-interval prolongation raises the possibility that both the type and number of individuals studied to date might not be sufficient to reveal problems with ziprasidone. This paper will review the literature concerning real and theoretical implications of pharmacokinetic and pharmacodynamic interactions with ziprasidone, particularly with regard to these effects on the QTc interval.

Animals↗
PubMed2000

DNA microarray analyses of genes regulated during the differentiation of embryonic stem cells.

Embryonic stem (ES) cells are derived from the inner cell mass of blastocysts, and in response to retinoic acid (RA) are induced to differentiate to form some of the first distinguishable cell types of early mammalian development. This makes ES cells an attractive model system for studying the initial developmental decisions that occur during embryogenesis and the molecular genetics and associated mechanisms underlying these decisions. Additionally, ES cells are of significant interest to those characterizing various gene functions utilizing transgenic and gene-targeting techniques. With the advent of DNA microarray technology, which allows for the study of expression patterns of a large number of genes simultaneously within a cell type, there is an efficient means of gaining critical insights to the expression, regulation, and function of genes involved in mammalian development for which information is not currently available. To this end, we have utilized Clontech's Atlas Mouse cDNA Expression Arrays to examine the expression of 588 known regulatory genes in D3 ES cells and their RA-induced differentiated progeny. We report that nearly 50% of the regulatory genes are expressed in D3 and/or D3-differentiated cells. Of these genes, the steady-state levels of 18 are down-regulated and 61 are up-regulated by a factor of 2.5-fold or greater. These changes in gene expression are highly reproducible and represent changes in the expression of a variety of molecular markers, including: transcription factors, growth factors and their receptors, cytoskeletal and extracellular matrix proteins, cell surface antigens, and intracellular signal transduction modulators and effectors.

Animals↗
PubMed1999

Differential olanzapine plasma concentrations by sex in a fixed-dose study.

This study examined plasma concentrations of olanzapine by sex (20 males and seven females) in an 8-week fixed-dose study. Dosing was 12.5 mg/day for the first week, then 25 mg/day. Trough plasma concentrations were drawn at weeks 1, 3, 5 and 8. Women volunteers were found to have significantly higher plasma concentrations than men. This difference was first evident at study week 5. Women have higher plasma concentrations of olanzapine, possibly due to differences in metabolism of the CYP450 isoenzyme system.

Adult↗
PubMed1999

Treatment-resistant schizophrenic patients respond to clozapine after olanzapine non-response.

BACKGROUND: Treatment-resistance in schizophrenia remains a public health problem. Clozapine has been shown to be effective in about one third of this population, but carries with it medical risks and weekly blood draws. As olanzapine is a drug with a very similar biochemical profile to clozapine, it is important to evaluate whether non-response to olanzapine predicts clozapine non-response. METHODS: Forty-four treatment-resistant patients received eight weeks of olanzapine, either in a double-blind trial or subsequent open treatment at a mean daily dose of 25 mg/day. Two of 44 patients (5%) responded to olanzapine treatment. Patients who did not respond could then receive clozapine. Twenty-seven subsequently received an 8-week open trial of clozapine. RESULTS: Patients who did and did not receive clozapine did not differ demographically or in psychopathology. Eleven of 27 (41%) met a priori response criteria during clozapine treatment (mean dose 693 mg/day) after failing to respond to olanzapine. CONCLUSIONS: This study demonstrates that failure to respond to olanzapine treatment does not predict failure to clozapine. Treatment-resistant patients who fail on olanzapine may benefit from a subsequent trial of clozapine.

Adult↗
PubMed1999

Rehospitalization rates of patients recently discharged on a regimen of risperidone or clozapine.

OBJECTIVE: The purpose of this study was to examine rehospitalization rates of people receiving risperidone or clozapine who had been discharged from state psychiatric hospitals in Maryland. METHOD: Rehospitalization status was monitored for all patients discharged from state psychiatric facilities on a regimen of either risperidone or clozapine between March 14, 1994, and Dec. 31, 1995. Patients were followed up with respect to readmission until Dec. 31, 1996. Time to readmission was measured by the product-limit (Kaplan-Meier) formula. Risk factors associated with rehospitalization were examined. RESULTS: One hundred sixty patients were discharged on risperidone, 75 having the diagnosis of schizophrenia. The patients with schizophrenia were more likely to be readmitted than the 85 patients with other mental disorders. Recidivism rates for schizophrenic patients discharged on risperidone versus those discharged on clozapine were not significantly different over the 24-month study period. However, no patient who received clozapine and remained discharged for more than 10 months (N = 49) was readmitted, while the readmission rate for risperidone-treated patients appeared to be steady up to 24 months. At 24 months 87% of the clozapine-treated patients and 66% of the risperidone-treated patients remained in the community. No clinical or demographic variables were found to predict rehospitalization. CONCLUSIONS: This study demonstrates that the rehospitalization rates of patients taking the second-generation antipsychotics risperidone and clozapine are lower than those in previously published reports of conventional antipsychotic treatment.

Adult↗
PubMed1999

A dose-outcome analysis of risperidone.

BACKGROUND: Although the establishment of appropriate dosage ranges for antipsychotics has important ramifications for both short-term treatment and long-term therapeutic outcomes, difficulties in dosing persist. Evidence exists that initial dosing recommendations for the titration of risperidone to 6 mg/day in 3 days are excessive. This study examines dosage trends of risperidone and further examines the relationship between dose and outcome by determination of discharge rates among individuals receiving varying doses of the drug. METHOD: Records of individuals receiving risperidone in Maryland state psychiatric facilities from March 1994 through February 1997 (N = 1056) were examined. Discharge rates and time to discharge were measured by Kaplan-Meier survival curve analysis. RESULTS: As risperidone use has risen each year since its introduction, mean doses in both inpatients and discharged patients have steadily declined. Additionally, risperidone doses for discharged patients were significantly lower than those for patients remaining in the hospital. Furthermore, patients receiving 2 and 4 mg/day were significantly more likely to be discharged than those receiving 6 mg/day (log-rank chi2 = 13.54, df = 2, p = .0011). This difference was seen in patients with similar diagnoses, ages, and racial status. CONCLUSION: Patients treated with doses less than the 6-mg/day initial dosing recommendations have better outcomes in terms of discharge. This finding should encourage clinicians to utilize adequate trials of risperidone aimed at stabilizing patients on doses in the 2- to 4-mg/day range before proceeding to higher doses.

Adolescent↗
PubMed1998

Olanzapine response in treatment-refractory schizophrenic patients with a history of substance abuse.

As many as half of all schizophrenic patients have abused alcohol or illicit drugs. This study determines the extent of substance abuse in a treatment-resistant population and assesses the response of this population to olanzapine treatment. Sixty patients with a DSM-III-R diagnosis of schizophrenia were included in an open 7-week trial of up to 25 mg/day of olanzapine. A history of substance abuse was present in 23 (38%) of the patients. At baseline evaluation, patients with a history of substance abuse had lower CGI scores and less negative symptomatology while having a higher rate of tardive dyskinesia. The overall group improved significantly over time. There were no differences in response between the substance-abusing (SA) and non-substance-abusing (NSA) patients as measured by the total BPRS, GGI and SANS ratings. The NSA group had significantly greater improvement in negative symptoms as measured by the BPRS negative symptom factor. Sixty-nine per cent (16/23) of the SA group and 60% (22/37) of the NSA were considered olanzapine responders by a priori criteria (p = NS). Extrapyramidal symptoms declined significantly in the overall group, but did not significantly differ between the SA and NSA groups. Treatment-refractory patients with prior substance abuse had a comparable outcome on olanzapine therapy to those with no history of abuse, as well as no increase in adverse effects. This suggests that olanzapine may be of benefit to SA patients who have a greater tendency for antipsychotic side effects and tardive dyskinesia.

Adult↗
PubMed1998

Reframing beliefs about work and change processes in redesigning laboratory services.

BACKGROUND: In 1996 a team started meeting to redesign care at Intermountain Health Care's (Salt Lake City) laboratory services on a fast track to dovetail with remodeling of the physical layout. The team reframed its current beliefs about using team processes--including use of a consultant/facilitator, team size, and decision making (by criteria instead of consensus). MEASUREMENT: Although the lab was strong in technical measurements, the sole management measurement before redesign was financial data generated by the accounting department. A comprehensive measurement system, which was required for the lab to evaluate the impact of the redesign efforts and manage its operations over time, constituted the team's first steps toward implementing the redesign effort. PROCESS REDESIGN: Once the team understood the purpose, customer expectations, desired outcomes of the specimen flow process, and the reasons for current breakdowns, it was able to design an ideal high-level process (with a floor plan to support it). Multiple subprocesses were redesigned and implemented on the basis of reframed beliefs--for example, that the process starts and ends with the customer (clinician or patient) and that there is one standardized entry point into the lab to reduce variability in processing and assign priority for analysis of specimens. For example, the team identified opportunities for improvements in the manner in which laboratory test results were communicated to physicians' offices. SUMMARY: The belief that appeared to have the most profound impact on the redesign effort was the clarification of the fundamental purpose of laboratory services and how it shapes every aspect of the business.

Attitude of Health Personnel↗
PubMed1998

Weight gain in adolescents treated with risperidone and conventional antipsychotics over six months.

Weight gain is a serious side effect of antipsychotic therapy. Potential consequences of obesity include noncompliance with medications as well as significant morbidity and mortality. Because atypical antipsychotic agents are increasingly being used in adolescents, it is important to determine and further characterize the rate of weight gain in this population. This study compares weight gain associated with the use of conventional antipsychotic agents with that seen with risperidone in adolescents. This retrospective study identified 60 adolescent inpatients who were taking risperidone (n = 18), conventional neuroleptics (n = 23), or no antipsychotic medication (n = 19). Monthly height and weight measurements were recorded over a 6-month period, allowing body mass index (BMI) values to be calculated. Subjects treated with risperidone gained a mean of 8.64 kg and increased in body mass by 3.67 kg/m2 over the 6-month observation period. Those taking conventional antipsychotics gained 3.03 kg or 0.31 kg/m2 in body mass, whereas the control group actually lost weight (-1.04 kg, or -1.01 kg/m2) in the same time frame. Although both antipsychotic groups gained in weight and BMI, the risperidone-treated group gained significantly more body mass than did the conventional antipsychotic group (p = 0.0011). Gains in body weight did not correlate with dose, and concomitant medications such as stimulants and lithium did not contribute to changes in BMI.

Adolescent↗
PubMed1998

Substitution of immediate-release valproic acid for divalproex sodium for adult psychiatric inpatients.

In a prospective open-label study, the substitution of immediate-release valproic acid for divalproex sodium was evaluated in the treatment of 47 adult psychiatric inpatients who had been stabilized on divalproex for at least one month. After two weeks, no significant change in Clinical Global Impressions scale (CGI) scores or in seizure frequency occurred, and serum valproate concentrations decreased by 14.4 percent (p=.001). One patient was restarted on divalproex because of gastrointestinal complaints. Among the 19 patients remaining hospitalized at six months, mean CGI scores did not significantly change. Costs were reduced 83 percent; annual savings per patient was approximately $905. These preliminary results suggest that many chronic psychiatric inpatients stabilized on divalproex may be safely switched to valproic acid.

Adult↗
PubMed1997

Reengineering a surgical service line: focusing on core process improvement.

Integrating principles from a variety of theory has led to the development of a conceptual framework for reengineering in a clinical care delivery setting to improve the value of services provided to the customer. A conceptual framework involving the identification of three high level core processes to reengineer can provide clarity and focus for clinicians to begin directing reengineering efforts. Those core processes are: clinical management of the patient's medical needs, patient operational processes to support the clinical processes, and administrative decision-making processes to support the implementation of the clinical and operational processes. Improvement in any one of these areas has the potential to increase value, but the concurrent targeting of these core processes for reengineering has provided a synergy that has accelerated the achievement of the desired outcomes in the area of surgical services.

Hospital Restructuring↗