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Biomedical subjects

Michael Linden

Publications and source records attributed to Michael Linden.

32 records · Page 2Linked to original sources
PubMed2004

Novel targeted deregulation of c-Myc cooperates with Bcl-X(L) to cause plasma cell neoplasms in mice.

Deregulated expression of both Myc and Bcl-X(L) are consistent features of human plasma cell neoplasms (PCNs). To investigate whether targeted expression of Myc and Bcl-X(L) in mouse plasma cells might lead to an improved model of human PCN, we generated Myc transgenics by inserting a single-copy histidine-tagged mouse Myc gene, Myc(His), into the mouse Ig heavy-chain Calpha locus. We also generated Bcl-X(L) transgenic mice that contain a multicopy Flag-tagged mouse Bcl-x(Flag) transgene driven by the mouse Ig kappa light-chain 3' enhancer. Single-transgenic Bcl-X(L) mice remained tumor free by 380 days of age, whereas single-transgenic Myc mice developed B cell tumors infrequently (4 of 43, 9.3%). In contrast, double-transgenic Myc/Bcl-X(L) mice developed plasma cell tumors with short onset (135 days on average) and full penetrance (100% tumor incidence). These tumors produced monoclonal Ig, infiltrated the bone marrow, and contained elevated amounts of Myc(His) and Bcl-X(L)(Flag) proteins compared with the plasma cells that accumulated in large numbers in young tumor-free Myc/Bcl-X(L) mice. Our findings demonstrate that the enforced expression of Myc and Bcl-X(L) by Ig enhancers with peak activity in plasma cells generates a mouse model of human PCN that recapitulates some features of human multiple myeloma.

Animals↗
PubMed2004

[The impact of guidelines, standards and economic restrictions on clinical decision-making processes].

Guidelines aim at improving clinical decision-making. Contrary to textbooks and reviews that want to improve medical knowledge, guidelines try to influence medical behaviour. Scientific models of clinical decision-making such as the action theory and empirical data on the effects of guidelines suggest that guidelines will not always reach their goals but can instead even lead to a deterioration in the quality of medical care. Therefore there is a need for controlled clinical trials to investigate whether guideline-exposed physicians yield better patient outcomes than guideline-naïve physicians. Guidelines should only be regarded as evidence-based if their positive effects have been empirically demonstrated.

Costs and Cost Analysis↗
PubMed2003

Targeted overexpression of Bcl-XL in B-lymphoid cells results in lymphoproliferative disease and plasma cell malignancies.

Multiple myeloma is an incurable malignancy, and there is currently no mouse model that fully recapitulates the development and progression of the disease. We now describe a transgenic mouse that expresses a Bcl-XL transgene under the control of the 3'kappa immunoglobulin light chain enhancer, which is most active in murine B cells in late developmental stages. These mice developed nonmalignant plasma cell foci in the bone marrow and soft tissues and hyaline tubular casts in the kidneys. Median survival of the 3'KE/Bcl-XL mice was similar to littermate controls. When the 3'KE/Bcl-XL mouse was crossed to an Emu/c-Myc transgenic mouse, median survival of double transgenic progeny was 5.5 weeks. Peripheral blood and soft tissues were infiltrated with immature/mature B cells, and plasma cell lesions were identified in the bone marrow of all mice coexpressing Bcl-XL and c-Myc. These B- and plasma cell lesions demonstrated features consistent with malignancy. These results indicate that the 3'kappa immunoglobulin light chain enhancer can effectively target expression of Bcl-XL to B cells in late developmental stages, and they provide direct evidence that Bcl-XL can contribute to plasmacytomagenesis. Furthermore, this murine model serves as an important step in developing a novel genetically induced mouse model of plasma cell malignancies exhibiting bone marrow involvement.

Animals↗
PubMed2003

Evidence for disturbed cortical signal processing and altered serotonergic neurotransmission in generalized anxiety disorder.

BACKGROUND: Current pathophysiological concepts of generalized anxiety disorder (GAD) assume a disturbed exteroceptive sensory system. Furthermore, central serotonergic neurotransmission has been shown to play an important role in anxiety disorder. Cortical signal processing as measured by auditory evoked potentials (AEPs) may reflect the integrity of the exteroceptive sensory system. Because a special aspect of AEP, the loudness dependence of the N1/P2-component (LD), has been related to central serotonergic activity, the LD may be useful for investigating serotonergic dysfunctions in GAD. METHODS: The LD was recorded in 31 medication-free patients with GAD without any psychiatric co-morbidity and in 31 matched control subjects. Dipole source analysis was performed to separate the LD of regions including the primary (LD-tangential dipole) and regions including the secondary auditory cortex (LD-radial dipole). RESULTS: A shallower LD-tangential was observed in patients with GAD as compared to healthy control subjects [F(1,60) = 6.727, p =.012; one-way analysis of variance]. The LD-radial showed no differences between groups. Severity of the anxiety symptoms was not related to the LDs. CONCLUSIONS: The results indicate an altered exteroceptive sensory system in GAD occurring at the level of the primary but not secondary auditory cortex. Because a shallow LD of the primary auditory cortex was related to a high firing rate of neurons in the dorsal raphe nucleus, the results may support evidence for an enhanced serotonergic activity in GAD.

Acoustic Stimulation↗
PubMed2003

[Epidemology and treatment of depressive disorders].

5-10% of the general population suffer from depressive disorders, one third of which are chronic. Depression impairs the quality of life, and 30.8% of patients show reduced working capacity. Patients are on average 10.9 days per month on sick leave. About half of the depressed patients undergo treatment, contacting general practitioners at an average of 14.5 times, psychotherapists 2 times and psychiatrists 1.4 times per year. Approximately 100 million daily doses of specific antidepressants are prescribed per year in Germany, an amount enough to treat 1% of the general population, which is indicative of an insufficient treatment rate. Pharmacotherapy has been found to be more effective than psychotherapy in acute episodes. However, psychotherapy patients show better long term results in respect to relapses and social adaptation. Due to the large number of depressed patients, general practitioners are the primary therapists. Referral to psychiatrists or psychotherapists is indicated in cases of chronic and complicated courses.

Absenteeism↗
PubMed2002

First vs multiple episode schizophrenia: two-year outcome of intermittent and maintenance medication strategies.

Results of studies on intermittent neuroleptic treatment strategies in first episode (FE) schizophrenia have not been published. Aims of the present study were to elucidate the comparative efficacy of prodrome-based neuroleptic intervention in first vs multiple episode (ME) schizophrenia. As to the methods, three randomly assigned open neuroleptic treatment strategies were compared over 2 years in 363 schizophrenic outpatients (115 FE, 248 ME; ICD-9, RDC): maintenance medication vs two intermittent medication strategies (prodrome-based intervention and crisis intervention). Concerning relapse prevention, the results demonstrate that ME patients seemed to profit most from maintenance medication compared to both intermittent treatments, whereas FE patients did equally well under maintenance medication and prodrome-based intervention treatment. Psychopathology, social adjustment, subjective well-being, and side-effects after two years did not differ significantly between the FE and ME patients irrespective of treatment strategy. Concerning treatment adherence, FE patients complied better with prodrome-based intervention than with maintenance medication. Cumulative neuroleptic dosage was lowest in FE patients under intermittent treatment. In conclusion, maintenance medication is the best strategy for relapse prevention in ME patients. In FE patients, prodrome-based intermittent intervention seems to be equivalent or even better with respect to compliance and dosage applied.

Adult↗
PubMed2002

The importance of psychosocial factors, gender, and severity of depression in distinguishing between adjustment and depressive disorders.

BACKGROUND: This study evaluated the severity of depressive symptomatology as it relates to: (a) sociodemographic factors and (b) the occurrence and type of acute and chronic psychosocial triggers or life events before admission. METHODS: In total, 718 psychiatric inpatients were assessed with the AMDP-system by the treating psychiatrist within the first 2 days after admission. RESULTS: In the females, sociodemographic factors (being married, children in the household, higher education and the quality of interactions) but not psychosocial stressors or life events were found to be related to severity of depression on admission. Females showed more severe depressive syndromes than males, however, depression severity in males was independent of sociodemographic factors, life events or psychosocial triggers. LIMITATIONS: Clinical assessment was based on retrospective history taking. The sample consisted of inpatients only, the results require replication using larger and more diverse samples. CONCLUSION: Gender differences and life conditions such as familial distress are related to severity of depression. The present criteria for the differentiation between depressive disorders and adjustment disorders are not independent and should be substituted by a multiaxial assessment.

Acute Disease↗
PubMed2002

Effectiveness and feasibility of a standardized stepwise drug treatment regimen algorithm for inpatients with depressive disorders: results of a 2-year observational algorithm study.

BACKGROUND: The goal of the Berlin Algorithm Project is to establish a standardized stepwise drug treatment regimen (SSTR) for the treatment of inpatients with depressive disorders. We are reporting on the first of 3 subsequent study phases evaluating effectiveness and feasibility of the SSTR in a naturalistic clinical setting. METHOD: Patients with depressive disorders (International Classification of Diseases, Ninth Revision criteria) admitted to an academic medical center for inpatient treatment were enrolled in the SSTR protocol that comprised an algorithm-guided sequential treatment process (including pharmacologic washout period, sleep deprivation, antidepressant monotherapy, lithium augmentation, monoamine oxidase inhibitor treatment, and electroconvulsive therapy) dependent on the scores of a standardized assessment of treatment outcome, the Bech Rafaelsen Melancholia Scale (BRMS). RESULTS: Of 248 patients with depression, 119 (48%) were enrolled in the SSTR protocol. One hundred twenty-nine patients (52%) were not included, mostly due to individualized treatment procedures. An intent-to-treat (ITT) analysis showed that 38% of enrolled patients achieved remission (BRMS score < or = 5), 34% achieved "classic" response (deltaBRMS score > or = 50%), 15% achieved "low" response (deltaBRMS score 26% to 49%), and 13% did not respond. The overall response rate (remitters and classic responders) of SSTR treatment was 72% of the ITT sample. Twenty-one patients (18%) dropped out from the SSTR as nonresponders and 19 patients (16%) dropped out as low responders due to protocol deviations. CONCLUSION: The acceptance of the antidepressive treatment algorithm among physicians not specifically trained was moderate, resulting in a relatively low enrollment rate. However, once patients were enrolled into the study, adherence to the algorithm-based rules resulted in a low dropout rate. Most importantly, algorithm-guided antidepressive treatment showed a favorable response in those depressed patients who were treated according to the SSTR protocol.

Algorithms↗
PubMed2002

Partial response and nonresponse to antidepressant therapy: current approaches and treatment options.

BACKGROUND: Response to antidepressant drug therapy is less than optimal for a considerable proportion of depressed patients; at present, however, few data exist to guide their rational therapeutic management. This review describes general principles for the management of such patients. This review is the result of an expert roundtable meeting convened to review published clinical data and clinical experience and provide clinicians with evidence-based principles on the management of patients who fail to respond optimally to initial antidepressant therapy. ROUNDTABLE FINDINGS: Failure to respond may be defined as a < 25% decrease on an accepted symptom rating scale such as the Montgomery-Asberg Depression Rating Scale (MADRS) or the Hamilton Rating Scale for Depression (HAM-D) in a patient who has received an adequate dosage for 4 weeks. In these patients, a neuropharmacologic rationale exists to switch to an agent with a different mode of action or a dual action. Partial response may be defined as 6 to 8 weeks at an adequate dosage and 25% to 50% decrease in MADRS or HAM-D score. In these patients, dose escalation should be considered, followed by augmentation and switching strategies. For augmentation, knowledge of neuropharmacology may allow prediction of which second agent will potentiate or complement the action of the first agent; it may also permit the prediction of potential safety concerns. CONCLUSIONS OF THE PANEL: On the basis of a review of the medical literature and clinical experience regarding patients with partial response or nonresponse to antidepressant drug therapy, it appears that simultaneous targeting of both the noradrenergic and serotonergic systems is one of the most effective augmentation strategies. Switching to an agent of a different class is probably optimal for those patients who fail to respond to first-line therapy.

Antidepressive Agents↗
PubMed1999

Assessing attention deficit hyperactivity disorder via quantitative electroencephalography: an initial validation study.

Spectral analysis of the electrophysiological output at a single, midline prefrontal location (the vertex) was conducted in 482 individuals, ages 6-30 years old, to test the hypothesis that cortical slowing in the prefrontal region can serve as a basis for differentiating patients with attention deficit hyperactivity disorder (ADHD) from nonclinical control groups. Participants were classified into 3 groups (ADHD, inattentive; ADHD, combined; and control) on the basis of the results of a standardized clinical interview, behavioral rating scales, and a continuous performance test. Quantitative electroencephalographic (QEEG) findings indicated significant maturational effects in cortical arousal in the prefrontal cortex as well as evidence of cortical slowing in both ADHD groups, regardless of age or sex. Sensitivity of the QEEG-derived attentional index was 86%; specificity was 98%. These findings constituted a positive initial test of a QEEG-based neurometric test for use in the assessment of ADHD.

Adolescent↗
PubMedDate not supplied

Concordance of the hormone receptors and correlation of HER-2/neu overexpression of the metachronous cancers of contralateral breasts.

The primary objective of this study was to evaluate the relative prevalence of estrogen receptor-negative contralateral breast cancer to the first primary cancer and to assess the correlation between the relative overexpression of HER-2/neu in the first primary cancer and contralateral breast cancer. A total of 144 women diagnosed with cancers in contralateral breasts were identified from the Henry Ford Health System tumor registry. Data were retrieved from electronic databases and medical records. Women were dichotomized into users and nonusers of tamoxifen. Hormone receptors were scored as positive or negative. HER-2/neu overexpression, assessed by immunohistochemistry, was scored as 0, 1(+), 2(+), or 3(+). Concordance between hormone receptors of the two cancers was low (kappa = 0.27, p = 0.06). Stratification of women by tamoxifen therapy yielded an almost fivefold increase in the proportion of estrogen receptor-negative cancers among the users, while the proportion of cancers expressing no estrogen receptor remained the same among the nonusers (39.6% versus 40.6%). Matched, archived, paraffin-embedded specimens of the first and contralateral breast cancers were available for 57 women. The correlation between the relative overexpression of HER-2/neu between the first primary and the contralateral breast cancer was 0.4 (p = 0.002). The higher prevalence of estrogen receptor-negative contralateral breast cancer among tamoxifen users concurs with previous reports. The biological mechanism for this observation is not understood; however, it has been proposed that tamoxifen inhibits the proliferation of estrogen receptor-positive breast cancer cells, while estrogen receptor-negative cells may continue to grow because of selective pressure. The correlation between HER-2/neu overexpression in the matched first primary and contralateral breast cancers was statistically significant, suggesting that the diagnosis of HER-2/neu overexpression in contralateral breast cancer is associated with HER-2/neu overexpression in the first primary cancer.

Breast Neoplasms↗
PubMedDate not supplied

Posttraumatic embitterment disorder.

BACKGROUND: Adjustment and reactive disorders are a heterogeneous group of mental disorders. Diagnostic criteria are vague and scientific research is limited despite the fact that these disorders play a major role in clinical practice. METHODS: The 'posttraumatic embitterment disorder' (PTED) is introduced as a new concept for a subgroup of adjustment disorders. A case vignette and diagnostic criteria are presented. RESULTS: Core criteria of PTED are: (1) a single exceptional negative life event precipitates the onset of the illness; (2) the present negative state developped in the direct context of this event; (3) the emotional response is embitterment and feelings of injustice; (4) repeated intrusive memories of the event; (5) emotional modulation is unimpaired, patients can even smile when engaged in thoughts of revenge, and (6) no obvious other mental disorder that can explain the reaction. Additional symptoms are feelings of helplessness, self-blame, rejection of help, suicidal ideation, dysphoria, aggression, down-heartedness, seemingly melancholic depression, unspecific somatic complaints, loss of appetite, sleep disturbances, pain, phobic symptoms in respect to the place or to persons related to the event, reduced drive. Duration is longer than 3 months. Performance in daily activities and roles is impaired. CONCLUSIONS: PTED is a frequent disorder. The diagnosis of PTED can lead to specific therapeutic interventions. PTED can be discriminated from PTSD, depression, anxiety disorders, and other adjustment disorders.

Adjustment Disorders↗
PubMedDate not supplied

Influence of age of patients who wish to die on treatment decisions by physicians and nurses.

OBJECTIVE: There is an ongoing debate on whether the wish to die in old age is a normal phenomenon and should be accepted as opposed to similar wishes in younger ages. The authors asked to what extent the age of a patient influences treatment decisions of physicians and nurses. METHODS: Real-life case vignettes of three persons ages 70 and over, with subthreshold depression and a wish to die, were presented to 19 physicians and 83 nurses, with the question of whether they would initiate psychopharmacological treatment or psychotherapy. For half of the participants, the real age of these persons was reduced by 20 years. Neither the participants nor the facilitators were aware of the focus of the study. RESULTS: The patient's age had a major influence on treatment decisions by physicians and nurses. The question of whether patients who expressed the wish to die should receive treatment, be it psychotherapy or intensive care, was answered with "yes" by both physicians and nurses significantly less frequently when the real age of the patient was known, whereas when a lower patient age (-20 years) was given, they more often saw the need for psychotherapy or other medical interventions. CONCLUSIONS: Age stereotypes have an influence on medical decision-making. Physicians and nurses must be trained in this respect in order to avoid maltreatment of elderly patients.

Adult↗