Hot and cold cognitive disturbances in antidepressant-free patients with major depressive disorder: a NeuroPharm study.

BACKGROUND: Cognitive disturbances are common and disabling features of major depressive disorder (MDD). Previous studies provide limited insight into the co-occurrence of hot (emotion-dependent) and cold (emotion-independent) cognitive disturbances in MDD. Therefore, we here map both hot and cold cognition in depressed patients compared to healthy individuals. METHODS: We collected neuropsychological data from 92 antidepressant-free MDD patients and 103 healthy controls. All participants completed a comprehensive neuropsychological test battery assessing hot cognition including emotion processing, affective verbal memory and social cognition as well as cold cognition including verbal and working memory and reaction time. RESULTS: The depressed patients showed small to moderate negative affective biases on emotion processing outcomes, moderate increases in ratings of guilt and shame and moderate deficits in verbal and working memory as well as moderately slowed reaction time compared to healthy controls. We observed no correlations between individual cognitive tasks and depression severity in the depressed patients. Lastly, an exploratory cluster analysis suggested the presence of three cognitive profiles in MDD: one characterised predominantly by disturbed hot cognitive functions, one characterised predominantly by disturbed cold cognitive functions and one characterised by global impairment across all cognitive domains. Notably, the three cognitive profiles differed in depression severity. CONCLUSION: We identified a pattern of small to moderate disturbances in both hot and cold cognition in MDD. While none of the individual cognitive outcomes mapped onto depression severity, cognitive profile clusters did. Overall cognition-based stratification tools may be useful in precision medicine approaches to MDD.

Oral contraceptives and the serotonin 4 receptor: a molecular brain imaging study in healthy women.

OBJECTIVE: Sex steroid hormones potently shape brain functions, including those critical to maintain mental health such as serotonin signaling. Use of oral contraceptives (OCs) profoundly changes endogenous sex steroid hormone levels and dynamics. Recent register-based studies show that starting an OC is associated with increased risk of developing depression. Here, we investigate whether use of OCs in healthy women is associated with a marker of the serotonin system in terms of serotonin 4 receptor (5-HT4R) brain imaging. METHODS: [11C]SB207145-PET imaging data on 53 healthy women, of whom 16 used OCs, were available from the Cimbi database. We evaluated global effects of OC use on 5-HT4R binding in a latent variable model based on 5-HT4R binding across cortical and subcortical regions. RESULTS: We demonstrate that OC users have 9-12% lower global brain 5-HT4R binding potential compared to non-users. Univariate region-based analyses (pallidostriatum, caudate, hippocampus, amygdala, anterior cingulate cortex, and neocortex) supported the global effect of OC use with the largest difference present in the hippocampus (-12.8% (95% CI [-21.0; -3.9], Pcorrected = 0.03). CONCLUSION: We show that women who use OCs have markedly lower brain 5-HT4R binding relative to non-users, which constitutes a plausible molecular link between OC use and increased risk of depressive episodes. We propose that this reflects a reduced 5-HT4R gene expression, possibly related to a blunted ovarian hormone state among OC users.

Outcome of AL amyloidosis after high-dose melphalan and autologous stem cell transplantation in Sweden, long-term results from all patients treated in 1994-2009.

High-dose melphalan and autologous stem cell transplantation (HDM/ASCT) is widely used in immunoglobulin light chain (AL) amyloidosis, but the benefit is debated mainly because of the high treatment-related mortality (24% in a randomised study comparing HDM/ASCT with oral melphalan/dexamethasone). We report here on the long-term outcome of all patients treated with HDM/ASCT for AL amyloidosis in Sweden between 1994 and 2009. Seventy-two patients were treated at eight Swedish centres. Median follow-up was 67.5 months. At least partial response (organ or haematological) was seen in 64% of the patients. Median overall survival was 98 months or 8.2 years, with 5-year survival 63.9% and 10-year survival 43.4%. In patients with cardiac involvement or multiple organ involvement, survival was significantly shorter, median overall survival 49 and 56 months, respectively. All mortality within 100 days from ASCT was 12.5% for all patients and 17.2% in the patients with cardiac involvement. For patients treated in the earlier time period (1994-2001), 100-day mortality was 23.8% compared with 7.8% in the later period (2002-2009). In conclusion, long survival times can be achieved in patients with AL amyloidosis treated with HDM/ASCT, also in smaller centres. Early mortality is high, but with a decreasing trend over time.

Rho mediates calcium-dependent activation of p38alpha and subsequent excitotoxic cell death.

Excitotoxic neuronal death contributes to many neurological disorders, and involves calcium influx and stress-activated protein kinases (SAPKs) such as p38alpha. There is indirect evidence that the small Rho-family GTPases Rac and cdc42 are involved in neuronal death subsequent to the withdrawal of nerve growth factor (NGF), whereas Rho is involved in the inhibition of neurite regeneration and the release of the amyloidogenic Abeta(42) peptide. Here we show that Rho is activated in rat neurons by conditions that elevate intracellular calcium and in the mouse cerebral cortex during ischemia. Rho is required for the rapid glutamate-induced activation of p38alpha and ensuing neuronal death. The ability of RhoA to activate p38alpha was not expected, and it was specific to primary neuronal cultures. The expression of active RhoA alone not only activated p38alpha but also induced neuronal death that was sensitive to the anti-apoptotic protein Bcl-2, showing that RhoA was sufficient to induce the excitotoxic pathway. Therefore, Rho is an essential component of the excitotoxic cell death pathway.

Viscoelastic and histologic properties in scarred rabbit vocal folds after mesenchymal stem cell injection.

OBJECTIVE/HYPOTHESIS: The aim of this study was to analyze the short-term viscoelastic and histologic properties of scarred rabbit vocal folds after injection of human mesenchymal stem cells (MSC) as well as the degree of MSC survival. Because MSCs are antiinflammatory and regenerate mesenchymal tissues, can MSC injection reduce vocal fold scarring after injury? STUDY DESIGN: Twelve vocal folds from 10 New Zealand rabbits were scarred by a localized resection and injected with human MSC or saline. Eight vocal folds were left as controls. MATERIAL AND METHODS: After 4 weeks, 10 larynges were stained for histology and evaluation of the lamina propria thickness. Collagen type I content was analyzed from six rabbits. MSC survival was analyzed by fluorescent in situ hybridization staining from three rabbits. Viscoelasticity for 10 vocal folds was analyzed in a parallel-plate rheometer. RESULTS: The rheometry on fresh-frozen samples showed decreased dynamic viscosity and lower elastic modulus (P<.01) in the scarred samples injected with MSC as compared with the untreated scarred group. Normal controls had lower dynamic viscosity and elastic modulus as compared with the scarred untreated and treated vocal folds (P<.01). Histologic analysis showed a higher content of collagen type 1 in the scarred samples as compared with the normal vocal folds and with the scarred folds treated with MSC. MSCs remained in all samples analyzed. CONCLUSIONS: The treated scarred vocal folds showed persistent MSC. Injection of scarred rabbit vocal folds with MSC rendered improved viscoelastic parameters and less signs of scarring expressed as collagen content in comparison to the untreated scarred vocal folds.

Effect of allergen provocation on inflammatory cell profile and endothelin-like immunoreactivity in guinea-pig airways.

The effect of allergen challenge on the number of leucocytes and the concentration of endothelin 1-like immunoreactivity (ET-LI) in bronchoalveolar lavage fluid (BALF) was investigated in guinea-pigs sensitized to Ascaris suum. The animals were twice exposed to allergen aerosol. All animals responded to the second challenge with bronchoconstriction. Twelve hours later, a significant increase in the number of eosinophilic granulocytes in BALF, compared to unsensitized and unprovoked control animals, was noted. Twenty-four hours after provocation, there was also an elevation of ET-LI concentration and content of neutrophils. During the first day post-challenge, the ET-LI values were moderately correlated to the eosinophil levels. One week after challenge, the ET-LI level and the neutrophil count did not differ from corresponding values in control animals whereas the number of eosinophils remained elevated. Pretreatment with dexamethasone before the second allergen challenge did not consistently affect the parameters studied during the first 24 h. Bronchoconstriction induced by carbachol aerosol affected significantly neither the ET-LI concentration nor the number of inflammatory cells in BALF. It is concluded that the allergen-induced inflammation in the guinea-pig airways causes an elevation in the ET-LI concentration in BALF and that this is moderately correlated to the influx of eosinophils during the first 24 h.

Quantification of nasal involvement in a guinea pig plethysmograph.

We have developed a technique for measuring lung function in conscious guinea pigs using a whole body plethysmograph. Because guinea pigs breathe through the nose, a technique was also developed to measure nasal and lower respiratory system conductance simultaneously in anesthetized animals. The upper and the lower airways could be challenged separately and studied in a manner similar to the conditions in the plethysmograph. Aerosols of histamine, carbachol, or ovalbumin delivered to the nose in sensitized animals had no effect on nasal conductance, even in doses 100 times higher than that required to reduce lower respiratory system conductance. However, intravenous histamine increased nasal conductance. Thus, although nasal resistance constitutes the majority of the total respiratory system resistance measured in the plethysmograph, nasal resistance is unaffected by the aerosol drugs studied. We therefore consider changes in resistance measured in the plethysmograph to originate at or below the larynx. The plethysmographic technique described here is a reliable, reproducible, and rapid technique that enables repeated measurement in animals and minimizes animal trauma.

Phenotypic characterization of stem cell factor-dependent human foetal liver-derived mast cells.

Human foetal liver cells are an enriched source of mast cell progenitors that complete their differentiation and mature in response to stem cell factor, the ligand for Kit, in liquid culture. These mast cells are Kit+, metachromatic with toluidine blue+, tryptase+, histamine+ and show ultrastructure features of mast cells. Using a panel of monoclonal antibodies (mAb) against different cell-surface antigens (33 mAb were used), the cell-surface phenotype of human stem cell factor-dependent foetal liver-derived mast cells was examined by flow cytometry. Consistent with previous reports on tissue-derived mast cells, those derived from foetal liver in vitro expressed HLA class I, CD9, CD29, CD33, CD43, CD45 and Kit. Unlike mast cells dispersed from tissue, a high expression of CD13 was found. Also, these in vitro-derived mast cells express little, if any, high-affinity IgE receptor. However, small amounts of mRNA for the alpha-chain in foetal liver-derived mast cells compared to KU812 cells (a human basophil-like cell line) could be detected by Northern blotting. Full expression of Fc epsilon RI may require additional growth factor(s).

Respiratory and cardiovascular effects of inhaled and intravenous bradykinin, PGE2, and PGF2 alpha in dogs.

Prostaglandins (PGs) and bradykinin act as potent respiratory irritants in both normal and asthmatic subjects, but their sites of action are unknown. We compared the cardiorespiratory effects of bradykinin, PGE2, and PGF2 alpha nebulized into the isolated "in situ" larynx, inhaled into the tracheobronchial tree, and injected intravenously in anesthetized spontaneously breathing dogs. Laryngeal administration only resulted in a brief burst of rapid shallow breaths produced by bradykinin (1,000 micrograms/ml) in one of five dogs. Tracheobronchial administration of bradykinin (1,000 micrograms/ml) increased breathing rate and tidal volume (VT) in four of seven dogs without changing cardiovascular parameters, whereas PGE2 (500 micrograms/ml) caused similar effects in two of six dogs. Lower concentrations of both agents were essentially without effect. PGF2 alpha (50-500 micrograms/ml) inhaled into the lower airway increased breathing rate, reduced VT, and caused a concentration-dependent bronchoconstriction that was significantly reduced by atropine. Inhaled PGF2 alpha only slightly increased arterial blood pressure (5.8 +/- 2.8%) and heart rate (12.0 +/- 6.4%). Intravenous PGF2 alpha (5 micrograms/kg) increased upper and lower airway resistances, which were accompanied by a decrease in breathing rate and VT, hypertension, and bradycardia. Bradykinin (1 micrograms/kg) and PGE2 (1 and 3 micrograms/kg) produced apnea followed by rapid shallow breathing, bradycardia, and hypotension. These results indicate that the tracheobronchial tree is considerably more responsive to aerosolized bradykinin, PGE2, and PGF2 alpha than the laryngeal region. Moreover, the stronger effects produced by intravascular administration suggest a greater accessibility of rapidly adapting stretch receptors and C-fiber endings from the vascular bed than from the airway lumen.

Expression of functional PDGF beta receptors in a human large-cell lung-carcinoma cell line.

In this study we have investigated a panel of lung-cancer cell lines, both of small-cell carcinoma and non-small-cell type, for the expression of receptors for platelet-derived growth factor. Although we found mRNA expression for the beta-type receptor on one small-cell and one non-small-cell line and alpha-type receptor mRNA expression on one small-cell-cancer cell line, only the beta receptors of the non-small-cell line (H-157) proved to be functional. Thus, the cell line H-157 displayed specific binding of 125I-PDGF-BB in addition to mRNA expression of the 6-kb transcript for the PDGF beta type receptor. Further evidence for the presence of functional PDGF beta receptors in H-157 cells was obtained from an in vitro kinase assay, which demonstrated a ligand-induced receptor autophosphorylation as well as the phosphorylation of a number of potential substrates associated with the activated receptor.

Constitutive and inducible expression of PDGF in the human basophilic cell line, KU 812.

The human basophilic cell line KU 812, that also has some mast cell characteristics, was found to express the PDGF-A gene and secrete PDGF-A like activity. After treatment with IL-6+ TNF-alpha, the PDGF-A mRNA expression increased as did cytoplasmic immunostaining with anti-PDGF antibodies. Secretion of PDGF-A was visualized by immunoprecipitation. An augmentation of non-secreted PDGF-like activity after IL-6+ TNF-alpha treatment was not accompanied by induction of the long splice variant of the PDGF-A-chain mRNA. Treatment with TPA caused an increase in PDGF-A expression and in addition, an induction of PDGF-B transcripts were seen. Staining of cytospin preparations with anti-PDGF antibodies visualized a substantial increase in immunostaining of the TPA treated cells and both intracellular and secreted PDGF-AA-like activity was substantially increased as compared to untreated control cultures. There was a concomitant induction of exon 6 specific mRNA, corresponding to a cellular retention signal after TPA treatment. Our results show that PDGF can be produced by a cell line of the basophilic/mast cell lineage, i.e. cells involved in allergic disorders and inflammation.

Platelet-derived growth factor (PDGF) in oncogenesis: development of a vascular connective tissue stroma in xenotransplanted human melanoma producing PDGF-BB.

Human WM9 melanoma cells, previously shown to be devoid of PDGF expression, were stably transfected with a PDGF-B cDNA under the transcriptional control of a cytomegalovirus promoter. Northern blot analysis revealed high expression of an mRNA of the expected size in the PDGF-B-transfected cells. Synthesis and secretion of PDGF-BB was confirmed by immunoprecipitation. Furthermore, conditioned medium from PDGF-B-transfected cells contained a mitogenic activity for fibroblasts. For analysis of tumor growth in vivo, cells of each type were injected subcutaneously into BALB/c nu/nu mice. Tumors from mice injected with WM9 cells transfected with the vector only contained large necrotic areas; only scant blood vessels with narrow lumina were observed. No connective tissue was present. In the tumors from PDGF-B-transfected WM9 cells, nests of tumor were divided by connective tissue septa. An abundance of blood vessels was observed in the connective tissue septa and within the tumor cell nests. There was a complete absence of necrosis in these tumors. The present results suggest that tumor-derived PDGF-BB is a potent mediator of connective tissue stroma formation. The connective tissue framework that is generated in response to PDGF-BB may form a solid support for newly formed blood vessels and, thereby, facilitate the formation of a functional vascular system in the tumor.

Relationship of airway responsiveness to agents causing bronchoconstriction and cough in sensitized guinea-pigs.

The relationship between airway responsiveness to bronchoconstrictor- and cough-inducing stimuli has been examined in Ascaris suum-sensitized conscious guinea-pigs. Guinea-pigs were sensitized to Ascaris suum [4000 PNU and 100 mg Al(OH)3 i.p. on days 1 and 7] and then challenged with aerosolized antigen on days 21, 28 and 35. At day 35, antigen-exposure produced an early bronchoconstrictor response (EBR) and in about 50% of the animals also a late bronchoconstrictor response (LBR) commencing 4-8 h later. The bronchial responsiveness to inhaled histamine was increased in sensitized guinea-pigs and increased further 20-24 h after acute antigen challenge. Guinea-pigs developing only EBR were equally sensitive to histamine as those having both EBR and LBR. In contrast, the cough and reflex bronchoconstriction produced by inhaled citric acid (0.40 M, acting on capsaicin-sensitive sensory neurons) and cigarette smoke (3 min exposure; exciting both capsaicin-sensitive neurons and rapidly adapting stretch receptors) were not altered by sensitization. Furthermore, acute antigen challenge did not alter the effect of citric acid as measured 24 h later. The antigen-induced airway hyperresponsiveness to histamine was not accompanied by an altered sensitivity of airway sensory nerves mediating cough (and reflex bronchoconstriction), demonstrating that bronchial- (airway obstruction) and sensory- (cough) hyperresponsiveness involve separate and independent mechanisms.

Effects of pressure and gaseous anesthetics on the aggregation of human blood platelets and marine sponge cells: similarities in responses.

1. Aggregation of blood platelets and marine sponge cells was inhibited by nitrous oxide (N2O) and helium (He) at elevated pressure but potentiated by xenon (Xe) despite the fact that Xe and N2O are equipotent gaseous anesthetics. 2. The above aggregations are dependent on an extracellular source of calcium. 3. Platelet aggregation induced by phorbol myristate is independent of extracellular calcium and was inhibited by both N2O and Xe and by high pressures of He. 4. The results argue against a common mechanism for Xe and N2O and suggest that pressure may affect calcium interactions with binding site.

Coxarthrosis on the island of Gotland. Increased prevalence in a rural population.

On the island of Gotland and in the city of Malmö, the prevalence of coxarthrosis was calculated using the hip projections in colon roentgen examinations. The prevalence of coxarthrosis among the Gotland islanders was about twice that of the Malmö urbanites, and the condition became obvious earlier in life. The population of the local Gotland city of Visby did not contribute to this difference; the difference was entirely due to an increased incidence in the rural population of the island. Heavy labor in conjunction with farming is believed to be the cause of the deviation.

Effects of growth factors on a human glioma cell line during invasion into rat brain aggregates in culture.

Cultures of fetal rat brain cell aggregates and tumor spheroids from the human glioma cell line GaMG were treated with epidermal growth factor (EGF), fibroblast growth factor (FGF) or isoforms of platelet-derived growth factor (PDGF AA or BB). Radioreceptor binding studies displayed a high binding capacity for EGF and FGF, but not binding of PDGF isoforms in the glioma cells. In serum-free culture, 10 ng/ml of both EGF and FGF caused increased growth and cell shedding in the tumor spheroids, whereas PDGF produced no such effect. Similarly, EGF and FGF stimulated tumor cell migration. EGF increased the proliferation and outgrowth of glial fibrillary acidic protein (GFAP)-positive cells in brain cell aggregates, while PDGF AA and BB both stimulated the outgrowth of oligodendrocyte-like cells which were negative for GFAP and neuron-specific enolase. FGF stimulated GFAP+ as well as GFAP- cell types. In co-culture experiments using brain aggregates and tumor spheroids, both EGF and FGF treatment caused increased tumor cell invasion. PDGF had no effect on the tumor cells, but instead stimulated the proliferation of oligodendrocyte-like cells in the brain aggregates. The present results indicate that growth factors may facilitate glioma growth as well as invasiveness, and cause reactive changes in the surrounding normal tissue.

Selective inhibition of cough and bronchoconstriction in conscious guinea pigs.

In guinea-pigs citric acid-induced cough and bronchoconstriction were inhibited by beta 2-agonist and xanthine drugs. Lidocaine inhibited only cough. Cromoglycate and ipratropium bromide inhibited only bronchoconstriction. We conclude that cough and bronchoconstriction in guinea-pigs are distinct reflexes and that the inhibitory pharmacology of these airway reflexes may agree in many respects, with that observed in asthmatic subjects.

Cigarette smoke-induced changes in guinea-pig airway responsiveness to histamine and citric acid.

The effect of 50 min cigarette smoke exposure on airway responsiveness to the bronchoconstrictor and tussive effects of histamine and citric acid has been examined in guinea-pigs. Intravenous histamine increased intratracheal pressure (ITP) in anaesthetized guinea-pigs and the dose-response curve was significantly (P less than 0.05) steeper in cigarette smoke- than in air-exposed animals. ED50 values were 11.4 nmol kg-1 (7.4-16.8, 95% confidence interval) and 42.5 nmol kg-1 (28.8-61.4, 95% confidence interval), respectively (P less than 0.05) in smoke- and air-exposed guinea-pigs indicating an enhanced reactivity. However, the sensitivity to intravenous histamine was not changed by the cigarette smoke exposure, and the maximum increase in intratracheal pressure was the same as in control animals (air: 247 +/- 21%, n = 4; smoke: 223 +/- 18%, n = 7). The cigarette smoke-induced hyperresponsiveness to intravenous histamine was not altered by pretreatment with nebulized lidocaine (0.20 M), ipratropium bromide (0.30 mM) or cromoglycate (0.06 M), suggesting that a neural reflex is unlikely to be involved in the development of hyperresponsiveness. Conscious, smoke-exposed guinea-pigs had a significantly (P less than 0.001) reduced responsiveness to citric acid (0.40 M) and cigarette smoke. Both cough and bronchoconstriction were suppressed for about 1 h, but unchanged 24 h after exposure. The hyporesponsiveness to citric acid was inhibited by atropine (1.4 mumol kg-1 i.p.) and may therefore, at least in part, be due to increased airway secretions. The present data demonstrate that inhalation of cigarette smoke may alter guinea-pig airway responsiveness to tussive and bronchoconstrictor stimuli.(ABSTRACT TRUNCATED AT 250 WORDS)

Assessment of hypothalamic-pituitary function in patients with familial amyloidotic polyneuropathy.

This study was performed to evaluate hypothalamic-pituitary hormone regulation in patients with familial amyloidotic polyneuropathy. Twenty-two patients without clinically overt endocrinological dysfunction were studied. A thyrotropin-releasing hormone test revealed abnormal growth hormone regulation in 9 of 17 (53%) patients, and abnormal prolactin regulation in 9 of 18 (50%) patients. Abnormalities in either growth hormone or prolactin regulation were found in 12 of 17 (71%) patients. Serum somatomedin C levels were normal in all 22 patients. In 3 of 18 (17%) patients the plasma arginine vasopressin levels were low relative to the serum osmolality levels. Thus abnormalities in hypothalamic-pituitary hormone regulation may be common in familial amyloidotic polyneuropathy.

Growth inhibition of mitogen-stimulated fibroblasts induced by double-stranded RNA depends on cell density.

Polyinosinic-polycytidylic acid [poly(I:C)], a synthetic double-stranded RNA, is an inhibitor of mitogen-induced proliferation of normal fibroblasts. We show that this inhibition depends strongly on cell density. While cultures with densities at or above confluence are completely inhibited by poly(I:C) in their proliferative response to epidermal growth factor (EGF), the proliferation of sparse (subconfluent) cultures is only delayed. Conditioned medium from dense fibroblasts exposed to poly(I:C) inhibits EGF stimulation of sparse cells, indicating that the inhibition is, at least in part, mediated by a factor released from the cells. Preincubation of quiescent cultures with poly(I:C) renders the cells refractory to the inhibitory effects of poly(I:C). This desensitization correlates with a decreased production of the inhibitor. Since the inhibition of mitogenic stimulation by poly(I:C) is completely overcome by antisera recognizing interferon-beta (IFN-beta) and interleukin-6 (IL-6), we tested the effect of IL-6 and IFN-beta on EGF mitogenicity. None of the available IL-6 preparations had any effect on cell cycle entry. IFN-beta caused a dose-dependent delay of cell division but did not affect the density-dependent proportion of cells entering the cell cycle in response to EGF. Thus, IFN-beta cannot be the sole mediator of the poly(I:C)-induced inhibition. In the presence of dexamethasone, poly(I:C) did not inhibit EGF mitogenis. Indeed, the combined presence of poly(I:C) and dexamethasone did more than just restore the density-dependent control levels of EGF stimulation; most cells entered the cell cycle even at extremely high cell densities. Thus, poly(I:C) in combination with dexamethasone could deactivate the cell density-dependent negative control of proliferation.