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J Gerlach

Publications and source records attributed to J Gerlach.

At least 19 recordsLinked to original sources
PubMed2002

Clinical issues related to depression in schizophrenia: an international survey of psychiatrists.

OBJECTIVE: Depressive symptoms in schizophrenia are associated with a substantial morbidity and mortality burden. The 'International Survey of Depression in Schizophrenia' was designed to evaluate current awareness and clinical approaches in this area. METHOD: A 48-item questionnaire was distributed to approximately 80 000 consultant psychiatrists world-wide. Responses were analysed using descriptive statistics. RESULTS: Respondents demonstrated considerable awareness of the prevalence and consequences of depression in schizophrenia. Although there was widespread adjunctive use of antidepressants, one-third of respondents indicated that they rarely or never prescribe these agents in combination with antipsychotic medication. There were considerable variations in opinions about the best approach to the treatment of depressive symptoms associated with schizophrenia. CONCLUSION: The considerable clinical burden of depressive symptomatology in schizophrenia was acknowledged by the majority of respondents to this survey. There was, however, little agreement on the best management strategy.

Adult↗
PubMed2001

Aberrant behavioral effects of a dopamine D1 receptor antagonist and agonist in monkeys: evidence of uncharted dopamine D1 receptor actions.

BACKGROUND: Basic research indicates a role for dopamine (DA) D1 antagonism in the treatment of schizophrenia. Clinical trials have not confirmed any role. Besides the defining second messenger (adenylyl cyclase [AC]), DA D1 receptors are linked to other effectors (e.g., phospholipase C [PLC]). Differing actions of DA D1 antagonists upon differing effectors could explain conflicting results between the lab/clinic. METHODS: In a monkey model in which behavioral effects of DA D1 antagonists/agonists have been well characterized we examined: 1) SKF 83959, biochemically, a DA D1 antagonist, behaviorally a DA D1 agonist, and 2) SKF 83822, biochemically, a DA D1 agonist, which, unlike all previously tested DA D1 agonists, does not also stimulate PLC. SKF 83959 and SKF 83822 were given alone and combined with DA D1 and D2 agonists, antagonists, and dextroamphetamine (AMP). RESULTS: SKF 83959 acted as a DA D1 agonist (induced oral dyskinesia given alone, counteracted DA D1 antagonist [NNC 756], induced dystonia, and did not inhibit AMP induced behaviors). SKF 83822, unlike previously studied DA D1 agonists, did not induce dyskinesia, but resulted in a state of extreme arousal and locomotor activation without stereotypy, effectively counteracted by NNC 756, but not by SKF 83959 nor raclopride (DA D2 antagonist). CONCLUSIONS: It is hypothesized that: 1) dyskinesia is linked to PLC stimulation; 2) DA D1 agonism can play a role in the induction of psychosis, via a mechanism linked neither to AC nor PLC, and 3) DA D1 antagonists differ in antipsychotic potential, possibly via this unidentified mechanism.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed2001

Depression in schizophrenia: recognition and management in the USA.

The recognition of depression as a distinct syndrome within schizophrenia is a relatively recent development. The International Survey of Depression in Schizophrenia was designed to evaluate current clinical practice and prescribing trends in the management of the depressive component of schizophrenia. A 48-item questionnaire, comprising fixed-response questions and questions stimulated by case scenarios, was distributed to 37513 psychiatrists in the USA. A total of 43484 psychiatrists in Canada, Australia and 21 European countries also received the questionnaire. A total of 1128 US psychiatrists responded. Analysis of the data revealed that US psychiatrists identify symptoms of depression in approximately one-third of patients with schizophrenia, and largely appreciate the magnitude of the resultant burden on patients and their families. Responses to questions regarding treatment approaches and case scenarios demonstrated that the level of adjunctive prescribing of antidepressants in the USA is often higher than in other regions. Levels of awareness of depression in patients with schizophrenia and recognition of the need for effective management appear to be high among US psychiatrists. However, more than a quarter of these specialists rarely or never prescribe adjunctive antidepressant medications. Disparities in treatment approaches varying from the existing scientific evidence base underscore the need for further investigation into ways of optimizing the management of this serious coexisting condition.

Antidepressive Agents↗
PubMed2001

Characterization of the distribution of matter in hybrid liver support devices where cells are cultured in a 3-D membrane network or on flat substrata.

Bioreactors for liver assist tested on small animal models are generally scaled-up to treat humans by increasing their size to host a given liver cell mass. In this process, liver cell function in different culture devices is often established based on the metabolite concentration difference between the bioreactor inlet and outlet irrespective of how matter distributes in the bioreactor. In this paper, we report our investigation aimed at establishing whether bioreactor design and operating conditions influence the distribution of matter in two bioreactors proposed for liver assist. We investigated a clinical-scale bioreactor where liver cells are cultured around a three-dimensional network of hollow fiber membranes and a laboratory-scale bioreactor with cells adherent on collagen-coated flat substrata. The distribution of matter was characterized under different operating modes and conditions in terms of the bioreactor residence time distribution evaluated by means of tracer experiments and modeled as a cascade of N stirred tanks with the same volume. Under conditions recommended by the manufacturers, matter distributed uniformly in the clinical-scale bioreactor as a result of the intense backmixing (N=1) whereas axial mixing was negligible in the laboratory-scale bioreactor (N=8). Switching from recycle to single-pass operation definitely reduced axial mixing in the clinical-scale bioreactor (N=2). Increasing feed flow rate significantly enhanced axial mixing in the laboratory-scale bioreactor (N=4). The effects of design, operating mode and conditions on matter distribution in bioreactors for liver cell culture suggest that characterization of the distribution of matter is a necessary step in the scale-up of bioreactors for liver assist and when function of liver cells cultured in different bioreactors is evaluated and compared.

Bioreactors↗
PubMed2001

Quantitative assessment of motion artifacts and validation of a new motion-correction program for myocardial perfusion SPECT.

UNLABELLED: Patient motion during myocardial perfusion SPECT can produce images that show artifactual perfusion defects. The relationship between the degree of motion and the extent of artifactual perfusion defects is not clear for either single- or double-head detectors. Using both single- and double-head detectors and quantitative perfusion SPECT (QPS) software, we studied the pattern and extent of defects induced by simulated motion and validated a new automatic motion-correction program for myocardial perfusion SPECT. METHODS: Vertical motion was simulated by upward shifting of the raw projection datasets in a returning pattern (bounce) and in a nonreturning pattern at 3 different phases of the SPECT acquisition (early, middle, and late), whereas upward creep was simulated by uniform shifting throughout the acquisition. Lateral motion was similarly simulated by left shifting of the raw projection datasets in a returning pattern and in a nonreturning pattern. Simulations were performed using single- and double-head detectors, and simulated motion was applied to projection images from 8 patients who had normal 99mTc-sestamibi SPECT findings. Additionally, images from 130 patients with actual clinical motion were assessed before and after motion correction. The extent of perfusion defects was assessed by QPS, and a 20-segment, 5-point scoring system was used to assess the effect of motion on the presence and extent of perfusion defects. RESULTS: Of 12 bounce simulations, the bouncing motion failed to produce significant (>3%) perfusion defects with either the single- or the double-head detector. With the single-head detector, early shifting created the largest defect, whereas with the double-head detector, shifting during the middle of the acquisition created the largest defect. With regard to upward creep, defects were of larger extent with the double- than the single-head detector. With the single-head detector, 8 of 20 simulated motion patterns yielded significant perfusion defects of the left ventricle, 7 (88%) of which were significantly improved after motion correction. With the double-head detector, 12 of 20 patterns yielded significant defects, all of which improved significantly after correction. Of 2,600 segments in the 130 patients with actual clinical motion, only 1.3% (30/2,259) of segments that were considered normal (score = 0 or 1) changed to abnormal (score = 2-4) after motion correction, whereas 27% (92/341) of abnormal segments were reclassified as normal after motion correction. CONCLUSION: Artifactual perfusion defects created by simulated motion are a function of the time, degree, and type of motion and the number of camera detectors. Application of an automatic motion-correction algorithm effectively decreases motion artifacts on myocardial perfusion SPECT images.

Aged↗
PubMed2001

The suitability of hepatocyte culture models to study various aspects of drug metabolism.

Since the liver is the main organ involved in the metabolism and the toxicity of xenobiotics, isolated rat hepatocytes have been increasingly used in recent years as a model to identify pharmacological and toxicological responses of drugs. However, it is generally recognised that isolated hepatocytes retain most of their functions only for a short period. For this reason, numerous models and techniques have been developed to study and improve the metabolic capacity of hepatocytes in vitro over an extended time period and in application for drug metabolism studies. In the present study, we compared four different cell culture models to fulfill these requirements and have therefore harvested hepatocytes and cultured them in different culture systems over two weeks. In order to prove certain advantages or disadvantages of each model, we compared the metabolic capacity, albumin secretion, the release of cytosolic and mitochondrial enzymes, as well as the capacity to metabolise diclofenac (DF). We found that rat hepatocytes in all studied culture models (except the Unisyn Bioreactor) were able to metabolise DF to the same extent as found in vivo. However, the concentration of metabolites was found to decrease with culture time using the monolayer although the DF metabolite level in the collagen Sandwich culture was higher than that of the monolayer culture. The 3D-membrane bioreactor preserved the metabolic capacity for a prolonged period of time. The concentrations of DF metabolites in the Unisyn hollow fiber bioreactor were below the detection limit, which corresponded to other parameters such as albumin secretion and cytochrome P450 activity, disqualifying this culture system clearly for the use of in vitro primary hepatocyte cultures. The other three systems all have their place in drug metabolism with different advantages. However, our studies clearly showed that hepatocytes cultured within a collagen sandwich or in the 3D-membrane bioreactor qualify to study various aspects of drug metabolisms over a long time period. Further studies are needed to prove if the later two culture models may really help to reduce animal testing.

Alanine Transaminase↗
PubMed2001

Quantitative analysis of regional motion and thickening by gated myocardial perfusion SPECT: normal heterogeneity and criteria for abnormality.

UNLABELLED: Quantitation of regional myocardial function is valuable in patients with coronary artery disease. This study assessed normal heterogeneity and developed and validated normal limits for quantitative regional motion and thickening by gated myocardial perfusion SPECT. METHODS: Patients underwent rest (201)Tl/exercise (99m)Tc-sestamibi gated SPECT. Reference values of motion and thickening for 20 myocardial segments were obtained in 105 patients with <5% likelihood of coronary disease (low-likelihood group). Criteria for abnormality of motion and thickening were defined for each segment, using receiver operator characteristic analysis, in 101 patients with coronary disease (training group). Semiquantitative visual interpretation was used as the gold standard. These criteria were prospectively validated in 100 patients (validation group). Criteria for grading motion and thickening abnormalities by severity levels were also defined and validated. RESULTS: Normal thickening decreased substantially along the longitudinal axis of the left ventricle, from 69% +/- 13% at the apex to 25% +/- 11% at the basal segments, whereas normal motion varied within the same ventricular plane. Validation of the criteria for abnormality yielded high accuracy in the detection of motion abnormalities (sensitivity, 88%; specificity, 92%) and thickening abnormalities (sensitivity, 87%; specificity, 89%). Quantitative motion and thickening segmental scores showed good agreement with visual scores. CONCLUSION: Normal regional myocardial contraction by gated myocardial perfusion SPECT is characterized by a substantial apex-to-base decline in thickening and by circumferential heterogeneity in endocardial motion. The assignment of segment-specific threshold values for defining motion and thickening abnormalities provided reasonably accurate identification and grading of regional myocardial dysfunction.

Aged↗
PubMed2000

Kaposi's sarcoma-associated herpesvirus open reading frame 50/Rta protein activates the entire viral lytic cycle in the HH-B2 primary effusion lymphoma cell line.

Rta, the gene product of Kaposi's sarcoma-associated herpesvirus (KSHV) encoded mainly in open reading frame 50 (ORF50), is capable of activating expression of viral lytic cycle genes. What was not demonstrated in previous studies was whether KSHV Rta was competent to initiate the entire viral lytic life cycle including lytic viral DNA replication, late-gene expression with appropriate kinetics, and virus release. In HH-B2, a newly established primary effusion lymphoma (PEL) cell line, KSHV ORF50 behaved as an immediate-early gene and autostimulated its own expression. Expression of late genes, ORF65, and K8.1 induced by KSHV Rta was eliminated by phosphonoacetic acid, an inhibitor of viral DNA polymerase. Transfection of KSHV Rta increased the production of encapsidated DNase-resistant viral DNA from HH-B2 cells. Thus, introduction of an ORF50 expression plasmid is sufficient to drive the lytic cycle to completion in cultured PEL cells.

DNA, Viral↗
PubMed2000

A new algorithm for the quantitation of myocardial perfusion SPECT. II: validation and diagnostic yield.

UNLABELLED: This study validates a new quantitative perfusion SPECT algorithm for the assessment of myocardial perfusion. The algorithm is not based on slices and provides fully 3-dimensional sampling and analysis independent of assumptions about the geometric shape of the left ventricle. METHODS: Radiopharmaceutical- and sex-specific normal limits and thresholds for perfusion abnormality in 20 segments of the left ventricle were developed for separate, dual-isotope rest 201Tl-exercise 99mTc-sestamibi SPECT in 36 patients with <5% before-scanning likelihood of coronary artery disease (CAD) (group 1) and 159 patients with perfusion abnormalities (group 2). These thresholds were validated in 131 patients (group 3) by comparison with expert visual interpretation. Thresholds for automatic segmental scores were developed and validated for groups 2 and 3, respectively. The accuracy of CAD detection was assessed in 94 patients, who underwent coronary angiography (group 4). RESULTS: Overall sensitivity for detection of stress and rest segmental perfusion abnormality was 91% and 96%, respectively, for men and 89% and 79%, respectively, for women. Overall specificity for stress and rest was 87% and 90%, respectively, for men and 88% and 90%, respectively, for women. Agreement between automatic and visual scores was good (weighted K of 0.71 and 0.60 for stress and rest images, respectively). Sensitivity and specificity were 88% for the detection of > or =70% stenosis. For the detection of left anterior descending, left circumflex, and right coronary artery stenosis, sensitivity was 84%, 86%, and 88%, respectively, and specificity was 84%, 88%, and 81%, respectively. CONCLUSION: The new quantitative perfusion SPECT approach is highly sensitive and specific for the detection and localization of CAD, provides accurate automatic scores for the assessment of regional perfusion, and overcomes the low-specificity limitations of previous quantitative algorithms.

Algorithms↗
PubMed2000

Regional differences in schizophrenia incidence in Denmark.

OBJECTIVE: To examine the regional distribution of schizophrenia incidence in Denmark. METHOD: A cohort consisting of 2441 Danish psychiatric patients, with first-time admissions between January 1, 1978 and December 31, 1982, and diagnosed as having schizophrenia (ICD-8) at least once in a 10-year period of observation was divided into three regional groups by degree of urbanization. RESULTS: Incidence increased for both sexes with increasing urbanization. A diagnostic delay was most pronounced in the least urbanized areas and was most pronounced for women. CONCLUSION: Our study confirms the existence of regional differences in schizophrenia incidence on a national basis. Marked regional differences in diagnostic delay were also demonstrated. A possible explanation could be regional differences in diagnostic procedures, underlining the importance of uniform diagnostic patterns as a means for reliable mapping of psychiatric morbidity and, hopefully, adequate treatment.

Adult↗
PubMed2000

[Liver cell culture in bioreactors for in vitro drug studies as an alternative to animal testing].

An important consideration for the utilisation of in vitro culture models for studies on drug metabolism as an alternative to animal testing is the maintenance of a defined degree of cell differentiation. Thus, in vitro conditions reflecting as near as possible the in vivo situation of the cells within the whole organ are required. A bioreactor was developed for the cultivation of liver cells which allows the reorganisation of hepatocytes and non-parenchymal cells of the liver in coculture to form three-dimensional, tissue-like structures including extracellular matrix components produced by the cells. In this study, the vitality and metabolic activity of isolated rat hepatocytes was investigated over a two week culture period in bioreactors. The results show that after a reorganisation phase, the cells preserve specific functions, such as protein and urea synthesis capacity and specific cytochrome P450 activities during the culture period, with maximal values during the first week. Possible applications of the model in pharmaceutical industry are studies on metabolite patterns, enzyme induction, drug-drug-interactions, first pass effects and long-term toxicity of drugs.

Animal Testing Alternatives↗
PubMed1999

Local liberation of cytokines during liver preservation.

In order to investigate locally produced mediators during the process of organ storage in liver transplantation, we collected the liver preservation solution effluent of 15 transplanted livers and compared it with serum samples taken preoperatively from donor and recipient, as well as 60 min after reperfusion. The mean ischemia time +/- SEM was 10 h 10 min +/- 53 min. Mean concentrations in University of Wisconsin preservation solution effluent were: interleukin-(IL-)1beta 154 +/- 77 pg/ml; IL-1 receptor antagonist (IL-1 ra) 1281 +/- 309 pg/ml; IL-6 412 +/- 90 pg/ml; and for tumor necrosis factor-(TNF-)alpha 74 +/- 21 pg/ml. Cytokine levels in the donors were lower than those detected in the effluent. All measured cytokines showed higher concentrations in the effluent compared to those of the recipient prior to the operation. With respect to a comparison of donor and recipient values, no correlation is evident. Likewise, the ischemic time does not correlate with effluent values. Further development of liver preservation concepts requires information about the state of the graft before reperfusion. Data on cytokine liberation may serve as a helpful tool for the further development of preservation concepts because they enable an estimation of cell activation during preservation.

Adenosine↗
PubMed1999

New and old antipsychotics versus clozapine in a monkey model: adverse effects and antiamphetamine effects.

RATIONALE: Neuroleptic primed Cebus apella monkeys have proven reliable in screening antipsychotics for extrapyramidal side effect (EPS) potential in humans, and the ratio EPS liability/antiamphetamine efficacy ["therapeutic index" (TI)] has fit well with clinical results. OBJECTIVES: 1) To find the TIs of one new (quetiapine), three potential [NNC 756 (dopamine (DA) D1 antagonist), NNC 22-0031 (alpha-1 adrenergic/5-HT2 serotonergic/DA D1 and D2 antagonist) and DOD 647 (DA D1 and D2 antagonist)] and three old antipsychotics (haloperidol, melperone and clozapine), 2) to test the model further and 3) to gain more insight as to clozapine's neuropharmacology. METHODS: Seven monkeys received haloperidol daily for 2 years; all were sensitized to dystonia. All drugs were given SC, in increasing doses until two animals had dystonia/other adverse effects (AE), and in decreasing doses with a fixed dose of dextroamphetamine producing motor unrest and stereotypies, to find the minimum significant antiamphetamine dose (AA). The ratio AE/AA = TI. RESULTS: Excepting clozapine and DOD 647, all drugs induced dystonia. At 2-4 mg/kg, clozapine caused uncoordinated movements, myoclonic jerks and rough tremor; unlike dystonia, the syndrome was not alleviated but worsened by the anticholinergic, biperiden. DOD 647 up to 2 mg/kg had no adverse effects. The TIs of the new and potential antipsychotics were 3-5 versus 4 for clozapine and 1 for haloperidol and melperone, suggesting that like clozapine, these new drugs will not produce EPS at antipsychotic doses.

Amphetamine↗
PubMed1999

Extrapyramidal side effects during chronic combined dopamine D1 and D2 antagonist treatment in Cebus apella monkeys.

Previous studies in non-human primates have shown that tolerance to dystonia occurs during chronic dopamine D1 (D1) but not D2 antagonism and induction/aggravation of oral dyskinesia (TD) during D2 but not D1 antagonism. We were therefore interested in determining the effects of combined chronic D1 + D2 antagonism on dystonia and dyskinesia. To this intent, 8 male Cebus apella monkeys were treated 10 weeks with gradually increasing doses of D1 antagonist (NNC 112) + a D2 antagonist (raclopride), followed by 2 weeks of treatment with the D2 antagonist alone. Due to previous neuroleptic exposure, 5 monkeys had TD and all were sensitized to dystonia. During the combined antagonist treatment, tolerance to dystonia occurred; the tolerance disappearing upon discontinuation of the D1 antagonist and continuation of the D2 antagonist alone. Parallel to these results, improvement of TD was seen during the combined antagonist treatment with worsening during the D2 antagonist alone. Both the combined antagonists and the D2 antagonist alone resulted in moderate/severe bradykinesia, with no tolerance. These findings indicate that supplementation of traditional D2 antagonism with a D1 antagonist would lessen the risk of dystonia and allow alleviation of preexisting TD, though parkinsonian side effects might still occur. The findings further indicate that separate dopaminergic mechanisms control dystonia/dyskinesia and parkinsonism.

Animals↗
PubMed1999

Chronic dopamine D1, dopamine D2 and combined dopamine D1 and D2 antagonist treatment in Cebus apella monkeys: antiamphetamine effects and extrapyramidal side effects.

To determine: (1) whether the apparent lack of efficacy of dopamine D1 (D1) antagonists in the clinic might be attributable to development of tolerance to antipsychotic effects; and (2) whether combined D1 and D2 antagonism might contribute to clozapine's clinical profile, eight Cebus apella monkeys were chronically treated with a D1 antagonist (NNC 756) ((+)-8-chloro-7-hydroxy-3-methyl-5-(7-(2,3- dihydrobenzofuranyl)-2,3,4,5-tetrahydro-1H-3-benzazepine), a D2 antagonist (raclopride) or a combination of the two antagonists. Prior neuroleptic exposure had resulted in oral dyskinesia in seven monkeys and sensitization to dystonia in all, yielding a model for acute and chronic extrapyramidal side effects (EPS). Dextroamphetamine-induced motoric unrest and stereotypies were used as a psychosis model. We found tolerance toward dystonic symptoms during D1 and D1 + D2 treatments but not during D2 treatment. D2 but not D1 or D1 + D2 antagonism caused exacerbation of dyskinesia. Both D1 and D1 + D2 antagonism were superior to D2 antagonism alone in counteracting the amphetamine-induced behaviors, with no tolerance to antiamphetamine effects. These findings suggest: (1) reasons other than tolerance (e.g., differences among antagonists) may explain the lack of efficacy in clinical trials with D1 antagonists; and (2) that D1 antagonism alone or combined and modest D1 and D2 antagonism offers the potential of antipsychotic efficacy with a lower risk of EPS than traditional D2 antagonism. Further clinical trials with D1 or combined D1 and D2 antagonists are, therefore, recommended.

Amphetamine↗
PubMed1999

Subjective experience and mental side-effects of antipsychotic treatment.

Many schizophrenic patients have a negative attitude towards antipsychotic drugs. This attitude is not only due to lack of insight into the disease, lack of recognition of the beneficial effects of the drugs, and to objective side-effects. The negative attitude is to a high degree due to mental side-effects and a sceptical opinion about antipsychotic medication in general. In a study of 53 chronic schizophrenic out-patients receiving maintenance depot antipsychotic treatment, we found that 60% were positive about the treatment, 32% were ambivalent and 8% had a negative attitude. Only 60% complained of side-effects, even though 94% had objective side-effects. Mental side-effects such as subjective akathisia, dysphoria and emotional indifference were most often observed by the patients, while hypokinesia and hyperkinesia were least noticed by them, but most often observed by the physician. No correlation was found between the patients' subjective assessment of their quality of life and the degree of psychosis and side-effects. With the new atypical antipsychotics this situation seems to be changing. These new drugs are primarily characterized by a lower level of motor extrapyramidal side-effects (EPS), and with fewer motor EPS, fewer mental EPS can be expected. In recent studies comparing the new antipsychotics with haloperidol, better effects have been observed with regard to negative symptoms and depression, and this may at least in part be a reflection of a lower level of mental side-effects of the atypical antipsychotics. This improved clinical profile of new antipsychotics is extremely valuable in the context of an integrated treatment in schizophrenia, consisting of early intervention, psychosocial rehabilitation and family/patient psycho-education.

Akathisia, Drug-Induced↗