Subthreshold depression and subjective cognitive complaints in Parkinson's disease.

BACKGROUND AND PURPOSE: Subthreshold depression (SubD) is characterized by clinically relevant depressive symptoms not meeting criteria for major depression. The possible association of SubD with subjective cognitive complaints and/or objective cognitive impairments was investigated in a sample of consecutive, non-demented Parkinson's disease (PD) outpatients. METHODS: Amongst 115 patients, SubD was identified in 30 patients, major depression in 33; 36 patients were classified as non-depressed. Enrolled patients were administered tests and questionnaires validated in PD for assessing objective and subjective cognitive dysfunctions. RESULTS: On objective cognitive measures SubD patients did not differ from non-depressed patients, whereas depressed patients achieved significantly lower scores than the other two groups. SubD and depressed patients reported more cognitive complaints than non-depressed patients. CONCLUSIONS: SubD is a non-motor aspect of PD that is not related to objective cognitive deficits but is associated with subjective cognitive complaints, thus impacting on patients' well-being.

Sgk1 enhances RANBP1 transcript levels and decreases taxol sensitivity in RKO colon carcinoma cells.

The serum- and glucocorticoid-regulated kinase (Sgk1) is essential for hormonal regulation of epithelial sodium channel-mediated sodium transport and is involved in the transduction of growth factor-dependent cell survival and proliferation signals. Growing evidence now points to Sgk1 as a key element in the development and/or progression of human cancer. To gain insight into the mechanisms through which Sgk1 regulates cell proliferation, we adopted a proteomic approach to identify up- or downregulated proteins after Sgk1-specific RNA silencing. Among several proteins, the abundance of which was found to be up- or downregulated upon Sgk1 silencing, we focused our attention of RAN-binding protein 1 (RANBP1), a major effector of the GTPase RAN. We report that Sgk1-dependent regulation of RANBP1 has functional consequences on both mitotic microtubule activity and taxol sensitivity of cancer cells.

miR-29b sensitizes multiple myeloma cells to bortezomib-induced apoptosis through the activation of a feedback loop with the transcription factor Sp1.

MicroRNAs (miRNAs) with tumor-suppressor potential might have therapeutic applications in multiple myeloma (MM) through the modulation of still undiscovered molecular pathways. Here, we investigated the effects of enforced expression of miR-29b on the apoptotic occurrence in MM and highlighted its role in the context of a new transcriptional loop that is finely tuned by the proteasome inhibitor bortezomib. In details, in vitro growth inhibition and apoptosis of MM cells was induced by either transient expression of synthetic miR-29b or its stable lentivirus-enforced expression. We identified Sp1, a transcription factor endowed with oncogenic activity, as a negative regulator of miR-29b expression in MM cells. Since Sp1 expression and functions are regulated via the 26S proteasome, we investigated the effects of bortezomib on miR-29b-Sp1 loop, showing that miR-29b levels were indeed upregulated by the drug. At the same time, the bortezomib/miR-29b combination produced significant pro-apoptotic effects. We also demonstrated that the PI3K/AKT pathway plays a major role in the regulation of miR-29b-Sp1 loop and induction of apoptosis in MM cells. Finally, MM xenografts constitutively expressing miR-29b showed significant reduction of their tumorigenic potential. Our findings indicate that miR-29b is involved in a regulatory loop amenable of pharmacologic intervention and modulates the anti-MM activity of bortezomib in MM cells.

Biological mechanisms of stroke prevention by physical activity in type 2 diabetes.

The principal modifiable risk factors for stroke are hypertension, diabetes mellitus, hypercholesterolaemia, hyperhomocysteinaemia, smoking and limited physical activity. However, it is not clear whether physical inactivity is a risk factor per se, or because it predisposes to pathological conditions that are risk factors for stroke. The limited availability of effective therapeutic approaches for stroke emphasizes the crucial role of prevention of risk factors. The global burden associated with type 2 diabetes is large and continues to grow. Convincing epidemiologic data support the role of physical activity in preventing type 2 diabetes. The increasing evidence of physical activity in preventing diabetic complications, including stroke, has generated interest in the molecular basis underlying these beneficial effects. The aim of the present review is to discuss the biological mechanisms underlying the effect of physical activity in preventing stroke in type 2 diabetes.

Somatization as a predictor of medication discontinuation due to adverse events.

Medication discontinuation due to intolerable side-effects remains a significant clinical problem in the treatment of depression. We were unable to locate studies which found predictors of medication cessation due to side-effects. We posited that an identifiable subgroup of medically healthy, depressed adults who discontinued medication because of adverse events would have higher pre-treatment somatic symptoms than patients who completed a course of treatment. The sample (n =940) was drawn from a series of double-blind, placebo-controlled studies of antidepressants (imipramine, phenelelzine, L-deprenyl, mianserin and desipramine). Within the medication group, side-effect dropouts had more somatic symptoms than study completers and those who discontinued treatment for miscellaneous reasons. Within the placebo-treated group, the small number of subject who discontinued treated because of side-effects precluded valid statistical analyses, but the findings were in the same direction as those in the medication group. Clearly, further research is required to determine whether these results, obtained from a series of university-based clinical trials with healthy subjects, are generalizable to patients with significant comorbid medical and/or psychiatric disorders, treated with newer antidepressants agents in a general clinical practice setting.

Atypical and non-atypical subtypes of depression: comparison of social functioning, symptoms, course of illness, co-morbidity and demographic features.

BACKGROUND: There are scant data regarding the demographic and psychosocial characteristics of outpatients with Atypical Depression (AD). METHODS: The demographic characteristics, rates of chronic dysphoria, baseline Symptom Check List Revised, and Social Adjustment Scale scores of 320 moderately depressed patients with and without AD were compared. RESULTS: ADs had a higher number of self-reported symptoms, greater impairments in functioning, and higher rates of chronic dysphoria and bipolar II than patients without Atypical Depression (NAD). LIMITATIONS: Variables used in this study were mostly cross-sectional, and the analyses were performed post-hoc. CONCLUSIONS: These data suggest ADs had a more pernicious course of illness than NADs, and that patients with AD were more symptomatic and dysfunctional at admission.

One year clinical and psychosocial outcomes of early-onset chronic depression.

BACKGROUND: Results from short-term treatment studies have demonstrated the efficacy of antidepressant medications for outpatients with early-onset chronic depression. However, scant data exists regarding the long-term outcome of these patients treated for this disorder. METHODS: The author conducted a one-year naturalistic follow-up study of 50 outpatients with early-onset, chronic depression, who were treated in a university-based psychopharmacology research clinic. Assessments were conducted blind to the patients' histories. RESULTS: Forty-eight percent of the total sample reported 9-12 months of sustained euthymia (Months Well). Among the patients who recovered, 50% relapsed. LIMITATIONS: The major limitations of this study were its small sample size and lack of a comparison group. CONCLUSIONS: These results data demonstrate that despite initial response, many outpatients with chronic depression seem to relapse after leaving university-based psychopharmacology centers.

Residual symptoms and social functioning over six-months in recovered outpatients with chronic depression.

BACKGROUND: Scant data exists regarding the global mental health of recovered chronically depressed outpatients. The purpose of this study was to compare the symptoms and functioning of these patients to those found in a normal control group (NCG). METHODS: Social functioning was assessed by the Social Adjustment Scale interview. Symptoms were measured with the Symptom Check List-90. RESULTS: The overall social functioning of recovered females was more impaired than a NCG. Recovered males and females had more psychiatric symptoms than a NCG. LIMITATIONS: The two samples were not demographically similar. CONCLUSIONS: Though the differences in social functioning and symptoms between the recovered patients and NCG's were statistically significant, they were not clinically meaningful. In general, recovered females had a relatively robust level of mental health.

Predictors of persistent social impairment among recovered depressed outpatients.

BACKGROUND: Though the social functioning of most depressed outpatients improves with effective treatment, a subgroup may remain impaired after recovering from depression. The purpose of this study was to identify predictors of residual social impairment among patients who recovered from depression. METHODS: These data were obtained from the Treatment of Depression Collaborative Research Program (TDCPR) public access tape. The TDCPR tested the relative efficacy of two psychotehrapies, imipramine, and placebo in major depression. Patients received follow-up assessments after completing the clinical trial. The following assessment instruments were used to assess predictor variables: Social Adjustment Scale II, Personality Assessment Form (PAF), Longitudinal Interval Follow-up Events (LIFE), and the Schedule for Affective Disorders (SADS). RESULTS: Recovered patients who were socially impaired at the end of treatment and six months later, had a higher rate of Intermittent Depression, and reported greater malfunctioning during adolescence than recovered patients whose functioning was unimpaired after treatment and at follow-up. The rates of personality disorders were not significantly different between these groups. LIMITATIONS: These analyses were performed post-hoc and the sample size was small. CONCLUSIONS: A chronic course of depression predicted persistent social maladjustment among patients who recovered from depression for 6 months.

Regulation of cell survival in CD95-induced T cell apoptosis: role of NF-kappa B/Rel transcription factors.

The activity of NF-kappa B/Rel transcription factors can inhibit the apoptosis induced by TNF, UV or cancer therapy drugs in a number of cell types, including human T lymphocytes. Furthermore, the NF-kappa B/Rel inducer, phorbol-12-myristate-13-acetate (PMA), has been reported to suppress the CD95-induced apoptosis of human T lymphocytes. To verify whether the survival-enhancing effect of PMA required NF-kappa B/Rel activity, we generated two Jurkat cell sublines (AL.7 and AL.8) transfected with a pCMV4-I kappa B alpha construct, and two (AL.3 and AL.5) with the void pCMV4 vector. Compared to wild type, AL.3 and AL.5 cells, the AL.7 and AL.8 sublines displayed markedly lower amounts of NF-kappa B/Rel nuclear complexes and a reduced expression of a kappa B-controlled CAT reporter gene after 1 and 4 h of incubation with PMA, respectively. All the five cell types displayed negligible levels of apoptosis when cultured with medium or PMA alone; when stimulated with the mAb CH-11, the AL.7 and AL.8 sublines displayed apoptotic responses only slightly (<0.5 fold) higher than control cells. On the other hand, the salvage activity of PMA was partially impaired in the AL.7 and AL.8 sublines. PMA inhibited apoptosis by >85% in wild type, AL.3 and AL.5 cells and by <60% in the AL.7 and AL.8 sublines; the apoptosis percentages in the mAb CH-11 + PMA cultures of the I kappa B alpha-transfected cells were >4-fold higher than in control cells. We conclude that the inhibition of the CD95-induced apoptosis by PMA relies on both NF-kappa B/Rel-dependent and -independent mechanisms. The partial contribution of these nuclear factors to the suppression of apoptosis indicates that the NF-kappa B/Rel activity can influence the extent of the CD95-induced T cell death.

A 5' regulatory sequence containing two Ets motifs controls the expression of the Wiskott-Aldrich syndrome protein (WASP) gene in human hematopoietic cells.

The recently-identified Wiskott-Aldrich syndrome protein gene (WASP) is responsible for the Wiskott-Aldrich X-linked immunodeficiency as well as for isolated X-linked thrombocytopenia (XLT). To characterize the regulatory sequences of the WASP gene, we have isolated, sequenced and functionally analyzed a 1.6-Kb DNA fragment upstream of the WASP coding sequence. Transfection experiments showed that this fragment is capable of directing efficient expression of the reporter chloramphenicol acetyltransferase (CAT) gene in all human hematopoietic cell lines tested. Progressive 5' deletions showed that the minimal sequence required for hematopoietic-specific expression consists of 137 bp upstream of the transcription start site. This contains potential binding sites for several hematopoietic transcription factors and, in particular, two Ets-1 consensus that proved able to specifically bind to proteins present in nuclear extracts of Jurkat cells. Overexpression of Ets-1 in HeLa resulted in transactivation of the CAT reporter gene under the control of WASP regulatory sequences. Disruption of the Ets-binding sequences by side-directed mutagenesis abolished CAT expression in Jurkat cells, indicating that transcription factors of the Ets family play a key role in the control of WASP transcription.

Identification by differential display of transcripts regulated during hematopoietic differentiation.

The polymerase chain reaction-based differential display method (DDRT-PCR) was used to identify mRNAs differentially expressed during the maturation of human CD34+ progenitor cells stimulated to differentiate in vitro towards granulomonocytic or erythroid lineages with a mixture of hemopoietins (kit ligand + interleukin 3 + GM-CSF in the absence or presence of erythropoietin, respectively). Three cDNA transcripts (B32, B41, and B56) display differential expression during cytokine-induced maturation of CD34+ cells. These clones have no homology with already-described sequences. Primer extension cofirmed the presence of the corresponding mRNA. The levels of mRNA corresponding to B32 are enhanced in the later phases of the granulomonocytic as well as in the erythroid differentiation of CD34+ cells. The mRNA identified by B41 was induced by a late stage in only granulomonocytic differentiation of CD34+ cells. The mRNA corresponding to B56 was instead present in nonstimulated CD34+ cells, declined in the early stages of differentiation, and reappeared at later stages in cells treated with both combinations of cytokines. Expression of these genes was detected in a number of acute myelogenous leukemias, as well as in some leukemic cell lines. B32 and B41 were downregulated in KG-1 cells induced to differentiate towards the monocytic lineage, whereas the levels of B56 were unchanged. In K562 cells, clones B41 and B56 were downregulated only in the late phases of PMA-induced megakaryocytic differentiation and during erythroid differentiation. B32 was rapidly downregulated when K562 cells were induced to differentiate towards either megakaryocytic or erythroid phenotypes. These transcripts represent novel hematopoietic cDNAs that should prove of value for the study of human blood cells and their disorders.

Social functioning and residual symptomatology among outpatients who responded to treatment and recovered from major depression.

It is unclear whether depressed patients who respond to treatment, and subsequently recover, manifest a significant degree of residual symptomatology and enduring psychosocial impairment. The purpose of this study was to compare the social functioning and symptoms of depressed outpatients who responded to acute treatment, and had a sustained recovery from major depression for 6 months, with psychiatrically normal community samples. The sample (n = 48) was drawn from the NIMH Treatment of Depression Collaborative Research Program. The Social Adjustment Scale scores and the Symptom Check List of recovered patients were clinically indistinguishable from the community sample scores. These data suggest that patients who benefit from acute treatment and recover from major depression can expect to achieve a normal level of functioning and symptomatology.

Placebo run-in period in studies of depressive disorders. Clinical, heuristic and research implications.

BACKGROUND: In spite of the virtually ubiquitous nature of the initial 10-day placebo run-in period (IPR) in drug trials, there is little empirical data establishing its relevance. METHOD: Data from 593 subjects were examined retrospectively to determine whether or not the prognosis of subjects minimally improved during the IPR was different to those who were unimproved. The IPR period was single-blind and was followed by a six-week double-blind phase in all studies. RESULTS: Twenty-six per cent of the subjects were minimally improved and 74% were unimproved. Approximately 10% of the subjects who were much improved were not followed systematically. Across a range of diagnosis, severity and chronicity subjects minimally improved (versus unimproved) after IPR had a more favourable prognosis whether assigned to drug or placebo. CONCLUSIONS: Change during IPR appears to be a meaningful predictor. Stratification should be considered in future antidepressant studies.

The efficacy of imipramine and psychotherapy in early-onset chronic depression: a reanalysis of the National Institute of Mental health Treatment of Depression Collaborative Research Program.

The authors compared the effectiveness of Cognitive Behavioral Therapy (CBT), Interpersonal Psychotherapy (IPT), Imipramine Clinical Management (ICM) to Placebo Clinical Management (PCM) for outpatients with early-onset chronic depression (N = 65) in the National Institute of Mental Health (NIMH) Treatment of Depression Collaborative Research Program (TDRP). The post-treatment depression scores of the CBT. IPT, and ICM groups were not significantly different from the PCM group. We did not find a relationship between the duration of Major Depression and response to a specific treatment. Studies are needed to determine if combining psychotherapy with medication improves social functioning and enhances the quality of life for patients with chronic depression.

Expression of the RET receptor tyrosine kinase and GDNFR-alpha in normal and leukemic human hematopoietic cells and stromal cells of the bone marrow microenvironment.

The RET proto-oncogene product is a receptor tyrosine kinase representing the signal-transducing molecule of a multisubunit surface receptor complex for the glial cell line-derived neurotrophic factor (GDNF), in which a novel glycosyl-phosphatidylinositol (PI)-linked protein (termed GDNFR-alpha) acts as the ligand-binding component. We have analyzed expression of RET and GDNFR-alpha in purified normal hematolymphopoietic cells, leukemia/lymphoma cell lines, and 154 primary samples from patients with hematopoietic malignancies encompassing different lineages and differentiation stages. Relatively low amounts of RET mRNA were found in early CD34+ hematopoietic progenitors, but RET transcripts appeared to increase after myelomonocytic maturation. No expression of RET was found in peripheral blood and tissue B and T lymphocytes. Analysis of human myelomonocytic cell lines was overall consistent with results obtained on purified normal cells. Accordingly, RET expression was mainly confined to acute myeloid leukemias (AMLs) displaying either monocytic (French-American-British M4 and M5) or intermediate-mature myeloid (M2 and M3) phenotypes, being less frequently detected in early myeloid (M0 and M1) AMLs. In contrast, RET mRNA was sporadically detected in B-cell tumors, whereas, among T-cell malignancies, RET transcripts were mainly detected in cells of postthymic and mature T-cell phenotype. RET broad detection in primary tumors was not paralleled by the mutual expression of GDNFR-alpha, which was detected only in 2 isolated primary samples and in 3 leukemia/lymphoma cell lines. However, GDNFR-alpha transcripts, in the absence of RET mRNA, were found in normal bone marrow stromal cells (BMSC), in BM fibroblasts, and in two osteoblast cell lines previously described to support normal hematopoiesis. In the presence of GDNF-receptors derived from BMSC by PI-specific phospholipase C cleavage, GDNF efficiently bound RET-expressing AML blasts and was functionally active by reducing their clonogenic growth and triggering the monocytic maturation of leukemic cells.

Outcome of cognitive-behavioral therapy for depression: relation to hemispheric dominance for verbal processing.

Unmedicated depressed outpatients were tested on dichotic syllable and complex tone tests prior to receiving 16 weekly sessions of cognitive therapy (n = 31) or 6-12 weeks of placebo treatment (n = 45). Cognitive-therapy responders had twice the right-ear (left hemisphere) advantage for syllables when compared with nonresponders but did not differ from nonresponders on the nonverbal task. The larger right-ear advantage in cognitive-therapy responders was due to better right-ear accuracy; they did not differ from nonresponders in left-ear accuracy. No differences in perceptual asymmetry or accuracy were found between placebo responders and nonresponders. Right-ear accuracy for syllables was the best predictor of response to cognitive therapy in a logistic regression analysis. The findings suggest that greater left-hemisphere advantage for verbal processing is associated with more favorable outcome of cognitive therapy for depression.

Chronological milestones to guide drug change. When should clinicians switch antidepressants?

BACKGROUND: We attempt to identify the time when patients whose conditions are unimproved while receiving antidepressants are unlikely to respond and should have their treatment changed. METHODS: A total of 593 patients were studied. The course of treatment for patients was examined to determine the weeks at which patients who received drug therapy had a better chance of being rated as responders at the study end (week 6) vs patients who received placebo. RESULTS: At the end of week 3, 19 (32%) of the 59 patients who received drug therapy and 6 (10%) of the 57 patients who received placebo and who never minimally improved were rated as responders at week 6. For those who showed no improvement by week 4, the effects of drug therapy and the placebo were equal. Patients who received drug therapy and whose conditions were unimproved but who had been minimally improved at some point had a superior prognosis with drug therapy vs placebo until week 4. Of those unimproved at week 4 but minimally improved at some point previously, 20 (39%) of the 51 patients who received drug therapy vs 3 (8%) of the 36 patients who received placebo were rated as responders at week 6. Of the 75 patients who minimally improved while receiving drug therapy at the end of week 5, 33 (44%) had a chance of being rated a responder at the end of week 6 vs 9 (26%) of the 35 patients receiving placebo. CONCLUSIONS: Patients tolerant of an adequate dose, whose conditions have never been at least minimally improved by the end of week 4, should have their treatment regimen altered. These patients represented a minority of drug-treated patients in the sample studied (ie, 39/392 [10%]). Patients whose conditions minimally improve at some prior week but not after week 5 should have their treatment changed. Patients whose conditions minimally improve in week 5 should continue treatment until week 6.

Imipramine treatment of alcoholics with primary depression: A placebo-controlled clinical trial.

BACKGROUND: Depressive disorders are commonly comorbid with alcoholism, particularly in treatment-seeking samples. If antidepressant treatment were safe and improved the treatment outcome in the subset of actively drinking alcoholics with depression, this would be of clinical importance. METHODS: We conducted a randomized, 12-week placebo-controlled trial of imipramine hydrochloride combined with weekly relapse prevention psychotherapy. The subjects were 69 actively drinking alcoholic outpatients with current depressive disorders. The first onset of depression was either antecedent to the abuse of alcohol or occurred during prolonged periods of sobriety. Depression and drinking outcomes at 12 weeks, as well as their relationship, were measured. RESULTS: Imipramine treatment was safe and associated with improvement in depression in both adequately treated and intention-to-treat samples. While there was no overall effect on drinking outcome, patients whose mood improved showed decreased alcohol consumption that was more marked in those treated with imipramine. CONCLUSIONS: Imipramine treatment is effective for primary depression among actively drinking alcoholic outpatients, and may improve alcoholic outcome for those whose depression responds to treatment.

Patient factors related to early attrition from an outpatient cocaine research clinic.

The dropout rates among cocaine abusers in outpatient treatment programs have averaged 55%. We sought to find patient predictor variables associated with early attrition. Dropouts were more likely to be African-American or Hispanic-American, younger, with an earlier onset of substance abuse. Among minorities, those with more education were less likely to drop out. Patients who were less educated and smoked or injected cocaine were particularly prone to discontinue treatment prematurely. The implications of these findings, and promising interventions for reducing the dropout problem, are discussed.