Plasma Brain-Derived Neurotrophic Factor and Psychopathology in Attempted Suicide.

BACKGROUND/AIMS: Increasing evidence suggests a link between brain-derived neurotrophic factor (BDNF) and suicidal behaviour (SB). Furthermore, decreased peripheral BDNF levels have been associated with clinical symptoms in various psychiatric disorders as well as with personality dimensions in healthy individuals. However, the relationship between BDNF and psychopathology is poorly investigated regarding SB. METHODS: Plasma BDNF concentrations were analysed in 61 recent suicide attempters. Clinical symptoms were evaluated using the Comprehensive Psychopathological Rating Scale. Personality dimensions were assessed using the Marke-Nyman Temperament Scale. RESULTS: Plasma BDNF correlated positively and significantly with the personality dimension Solidity but not with the other personality dimensions or with clinical symptoms. CONCLUSION: BDNF plays an important role in the regulation of neuroplasticity and neurogenesis in humans. Our results indicate that lower BDNF concentrations are associated with higher levels of impulsiveness and changeability (low scores on the Solidity scale). Furthermore, low plasma BDNF levels may be proposed as a trait marker rather than a state marker for attempted suicide.

Unimpaired postprandial pancreatic polypeptide secretion in Parkinson's disease and REM sleep behavior disorder.

BACKGROUND: Pancreatic polypeptide is released immediately after food ingestion. The release is operated by vagal-abdominal projections and has therefore been suggested as a test for vagal nerve integrity. Pathoanatomical and clinical studies indicate vagal dysfunction in early Parkinson's disease (PD). METHODS: We assessed the postprandial secretion of pancreatic polypeptide and motilin in healthy controls (n = 18) and patients with idiopathic rapid-eye-movement sleep behavior disorder (iRBD, n = 10), a potential premotor stage of PD, as well as in drug-naive (n = 19) and treated (n = 19) PD patients. RESULTS: The postprandial pancreatic polypeptide secretion showed a physiological pattern in all groups and even an enhanced response in drug-naive PD and iRBD. Motilin concentrations correlated with pancreatic polypeptide concentrations. CONCLUSIONS: Postprandial pancreatic polypeptide secretion is not a suitable test for vagal nerve integrity in PD. The unimpaired pancreatic polypeptide response in iRBD and PD might be explained by partially intact vagal-abdominal projections or compensatory mechanisms substituting a defective neuronal brain-gut axis.

Subjective health perception in healthy young men changes in response to experimentally restricted sleep and subsequent recovery sleep.

Sleep and subjective health are both prospectively related to objective indices of health and health care use. Here, we tested whether five days with restricted sleep and subsequent recovery days affect subjective health and is related to increased levels of circulating IL-6 and TNF-α and fatigue. Nine healthy men (23-28 ears) went through a 6-week sleep protocol with subjects as their own controls in a repeated measures design with a total of 11 nights in a sleep laboratory. The experimental part of the protocol included three baseline days (sleep 23-07 h), five days with sleep restriction (03-07 h) and three recovery days (23-07 h) in the sleep laboratory. Subjective health and fatigue was recorded daily. Eight blood samples were drawn each day (every third hour) on 8 days of the protocol and analyzed with respect to IL-6 and TNF-α. Subjective health deteriorated gradually during restricted sleep (p=.002) and returned to baseline levels after three days of recovery. IL-6 and TNF-α did not change significantly. Fatigue increased gradually during sleep restriction (p=.001), which significantly contributed to the association between restricted sleep and subjective health. The study is the first to show that subjective health is directly responsive to changes in sleep length and related to increased fatigue. Thus, subjective health is differently appraised after manipulation of one of its presumed determinants. Larger experimental studies would be beneficial to further distinguish causation from association regarding the underpinnings of subjective health.

The acute response of plasma brain-derived neurotrophic factor as a result of exercise in major depressive disorder.

Brain-derived neurotrophic factor (BDNF) and other neurotrophins are believed to play an important role in affective disorders. In this study we investigated plasma-BDNF response during an incremental exercise test in 18 patients suffering from moderate major depressive disorder (MDD) and 18 controls. The patients were not treated with antidepressants or neuroleptics. Possible associations between plasma plasma-BDNF levels, dexamethasone suppression test cortisol levels and Montgomery-Asberg Depression Rating Scale (MADRS) scores were also tested. No difference in basal BDNF levels between patients and controls was found. BDNF increased significantly during exercise in both male and female patients as well as in male controls, with no significant differences between the groups. BDNF levels declined after exercise, but after 60 min of rest BDNF levels showed tendencies to increase again in male patients. No correlation between BDNF and cortisol or MADRS scores was found. We conclude that unmedicated patients with moderate depression and normal activity of the hypothalamic-pituitary-adrenal axis do not have a disturbed peripheral BDNF release during exercise. The BDNF increase 60 min after interruption of exercise in male patients might indicate up-regulated BDNF synthesis, but this needs to be further investigated in future studies.

Total gastrectomy causes a sustained, long-term elevation of somatostatin in plasma, independent of the mode of reconstruction in pigs.

AIM: The long-term effects of gastrectomy and various reconstructions of the gastrointestinal tract on fasting plasma levels of gastrointestinal hormones known to contribute to the control of gastrointestinal motor function were evaluated in pigs. MATERIALS AND METHODS: Domestic pigs were randomly selected to sham surgery or total gastrectomy (TG) followed by reconstruction with oesophago-jejunostomy on a Roux-en-Y loop (OJRY), jejunal interposition between the oesophagus and the duodenum (OJD), or an oesophagojejunostomy with a proximal jejunal pouch reservoir (J-pouch) on a Roux-en-Y loop. Blood was collected just before surgery and ten weeks later and peptide levels were analysed by radioimmunoassay. RESULTS: Somatostatin levels were sustained at a high level after TG, regardless of the mode of reconstruction, but were significantly lower in sham-operated animals. Levels of vasoactive intestinal peptide (VIP), neurotensin and motilin were unchanged. CONCLUSION: TG by itself leads to high levels of somatostatin long term, however, somatostatin, motilin, neurotensin and VIP are unaffected by the mode of reconstruction.

Jejunal pouch reconstruction but not preservation of duodenal passage after total gastrectomy reduces plasma cholecystokinin and pancreatic polypeptide long term in pigs.

AIM: The long-term effects of reconstructions of the gastrointestinal tract after gastrectomy on plasma levels of gastrointestinal hormones that contribute to food intake controls were evaluated. MATERIALS AND METHODS: Domestic pigs were randomly assigned to sham-surgery or total gastrectomy followed by reconstruction with oesophagojejunostomy on a Roux-en-Y loop (OJRY), jejunal interposition between the oesophagus and the duodenum (OJD), or an oesophagojejunostomy with a jejunal pouch reservoir (J-pouch) on a Roux-en-Y loop. Plasma levels of peptides were analysed by radioimmunoassay (RIA). RESULTS: Ten weeks after surgery, levels of cholecystokinin (CCK) and pancreatic polypeptide (PP) were significantly lowered (79.6% and 67.0%, respectively) in animals with a J-pouch, but not in sham-operated animals or animals with OJRY or OJD, as compared to preoperative levels. The levels of neuropeptide Y (NPY) and peptide YY (PYY) remained unchanged, irrespective of the mode of reconstruction. CONCLUSION: J-pouch, but not preservation of duodenal passage after total gastrectomy, lowers levels of CCK and PP, peptides that reduce food intake.

The outcome of tactile touch on oxytocin in intensive care patients: a randomised controlled trial.

AIM: To explore the effects of five-day tactile touch intervention on oxytocin in intensive care patients. The hypotheses were that tactile touch increases the levels of oxytocin after intervention and over a six-day period. BACKGROUND: Research on both humans and animals shows a correlation between touch and increased levels of oxytocin which inspired us to measure the levels of oxytocin in arterial blood to obtain information about the physiological effect of tactile touch. DESIGN: Randomised controlled trial. METHOD: Forty-four patients from two general intensive care units, were randomly assigned to either tactile touch (n = 21) or standard treatment--an hour of rest (n = 23). Arterial blood was drawn for measurement of oxytocin, before and after both treatments. RESULTS: No significant mean changes in oxytocin levels were found from day 1 to day 6 in the intervention group (mean -3.0 pM, SD 16.8). In the control group, there was a significant (p = 0.01) decrease in oxytocin levels from day 1 to day 6, mean 26.4 pM (SD 74.1). There were no significant differences in changes between day 1 and day 6 when comparing the intervention group and control group, mean 23.4 pM (95% CI -20.2-67.0). CONCLUSION: Our hypothesis that tactile touch increases the levels of oxytocin in patients at intensive care units was not confirmed. An interesting observation was the decrease levels of oxytocin over the six-day period in the control group, which was not observed in the intervention group. RELEVANCE TO CLINICAL PRACTICE: Tactile touch seemed to reduce the activity of the sympathetic nervous system. Further and larger studies are needed in intensive care units to confirm/evaluate tactile touch as a complementary caring act for critically ill patients.

Acetylcholine synthesis, muscarinic receptor subtypes, neuropeptides and secretion of ferret salivary glands with special reference to the zygomatic gland.

Studies on salivary secretion are usually focused on parotid and submandibular glands. However, the film of mucin, that protects the oral structures and is responsible for the feeling of oral comfort, is produced by the submucosal glands. The submucosal zygomatic and molar glands are particularly large in carnivores such as the ferret. Comparisons between the mucous sublingual, zygomatic and molar glands, serous parotid and sero-mucous submandibular glands showed the acetylcholine synthesis, in terms of concentration, to be three to four times higher in the mucous glands than in the parotid and submandibular glands. Bromoacetylcholine inhibited 95-99% of the synthesis of acetylcholine in the incubates of the five types of glands, showing the acetylcholine synthesis to depend on the activity of choline acetyltransferase. The high acetylcholine synthesis in the zygomatic gland was of nervous origin, since cutting the buccal nerve, aiming at parasympathetic denervation, and allowing time for nerve degeneration, reduced the acetylcholine synthesising capacity of the gland by 95%. A similar reduction (96%) in the parotid gland followed upon the avulsion of the parasympathetic auriculo-temporal nerve. Zygomatic saliva was very viscous. The salivary flow rate in response to electrical stimulation (20 Hz) of the buccal nerve (zygomatic gland), expressed per gland weight, was one-third of that to stimulation of the auriculo-temporal nerve (parotid gland) or the chorda-lingual nerve (submandibular gland). As previously shown for the parotid and submandibular gland, a certain fraction (25%) of the parasympathetic secretory response of the zygomatic gland depended on non-adrenergic, non-cholinergic transmission mechanisms, probably involving substance P and vasoactive intestinal peptide and possibly calcitonin gene-related peptide. Particularly, high concentrations of vasoactive intestinal peptide were found in the sublingual and molar glands, and of substance P in the submandibular, zygomatic and molar glands; notably, the concentration of calcitonin gene-related peptide of the sublingual gland was not detectable. All five muscarinic receptor subtypes were detected in the five glands. The receptor protein profile, as judged by immunoblotting and semi-quantitative estimations, was about the same in the glands: high level of M3, low level of M2 and levels roughly in the same range of M1, M4 and M5. Compared to the parotid and submandibular glands, the M5 receptor level was particularly low in the mucin-secreting glands. The present study points out both similarities and dissimilarities between the five types of glands investigated. The zygomatic gland, in particular, appears to be a suitable model for future studies aiming at causing relief of dry mouth by local pharmacological treatment.

Proteomics and peptidomics in neuroscience. Experience of capabilities and limitations in a neurochemical laboratory.

The increasing use of proteomics has created a basis for new strategies to develop methodologies for rapid identification of protein patterns in living organisms. It has also become evident that proteomics has other potential applications than protein and peptide identification, e.g. protein characterization, with the aim of revealing their structure, function(s) and interactions of proteins. In comparative proteomics studies, the protein expression of a certain biological system is compared with another system or the same system under perturbed conditions. Global identification of proteins in neuroscience is extremely complex, owing to the limited availability of biological material and very low concentrations of the molecules. Moreover, in addition to proteins, there are number of peptides that must also be considered in global studies on the central nervous system. In this overview, we focus on and discuss problems related to the different sources of biological material and sample handling, which are part of all preparatory and analytical steps. Straightforward protocols are desirable to avoid excessive purification steps, since loss of material at each step is inevitable. We would like to merge the two worlds of proteomics/peptidomics and neuroscience, and finally we consider different practical and technical aspects, illustrated with examples from our laboratory.

Dynamic training and circulating neuropeptides in rheumatoid arthritis: a two-year follow-up study.

Previous research has suggested that a short-term (6 week) high-intensity and a subsequent long-term (1 year) low-intensity dynamic training programme in 8 patients with rheumatoid arthritis (RA) increased circulating levels of beta-endorphin (beta-EP) during the high-intensity training and of corticotropin-releasing factor (CRF) and beta-lipotropin (beta-LPH) levels during the low-intensity training, without an increase of pain experience. The present follow-up study of the patients, using the data obtained after an additional 1-year period of no standardized training as reference values, indicated that CRF levels decreased significantly (P less than 0.01) in relation to those obtained 1 year earlier. For beta-LPH and beta-EP, no corresponding decreases were noted. No significant difference concerning experience of pain over time was found. High-performance liquid chromatography demonstrated a complex elution pattern with low basal concentration of beta-LPH, which increased after 60 min of training.

Dynamic training and circulating levels of corticotropin-releasing factor, beta-lipotropin and beta-endorphin in rheumatoid arthritis.

The study aimed at evaluating the effects of a dynamic training program on circulating levels of corticotropin-releasing factor (CRF), beta-lipotropin (beta-LPH), and beta-endorphin (beta-EP) in 8 patients (5 females and 3 males, aged 39-65 years) with classical/definite rheumatoid arthritis (RA). Blood samples were collected immediately before, in the middle of, and after a 6-week high-intensity training period as well as after a subsequent 1-year period of low-intensity training. In addition, baseline data were obtained 3 weeks before the start of the training program. Use of multivariate analyses of variance, and of analyses of variance of contrast variables, indicated a short-term effect of the high-intensity training program for beta-EP with increased levels (P less than 0.05) between the 3rd and the 6th weeks, no significant differences being obtained for CRF or beta-LPH here. Corresponding analyses with regard to the combined high and low-intensity training program revealed CRF (P less than 0.01), and beta-LPH (P less than 0.01) levels to increase over time, no long-term effect being found for beta-EP. Despite the intensity of the dynamic training program, no change was found in pain experience as measured on a visual analogue scale.

Decreased cerebrospinal fluid neuropeptide Y (NPY) in patients with treatment refractory unipolar major depression: preliminary evidence for association with preproNPY gene polymorphism.

Extensive animal studies suggest neuropeptide Y (NPY) to be involved in coping with a wide range of stressors, and that impaired central NPY signalling could be involved in the pathophysiology of anxiety and depression. Human studies of central NPY levels in depression have, however, been inconclusive. Here, we examined levels of NPY-like immunoreactivity (NPY-LI) in the cerebrospinal fluid (CSF) of medication-free subjects with treatment refractory unipolar depression. Patients were admitted to a research inpatient unit, examined under standardized conditions, and compared with a sample of volunteers in whom psychiatric morbidity was excluded. A robust suppression of NPY levels in patient CSF was found, while other putative CSF markers (monoamine metabolites, somatostatin) did not differ between the groups. We then explored whether this finding might be related to a recently described T1128C coding polymorphism which results in a Leu7-> Pro7 substitution of the signal peptide, and a previously not described T -399C polymorphism in the promoter region of the preproNPY gene. Preliminary evidence was found for an association of both markers with a diagnosis of depression, indicating the possibility of an underlying haplotype influencing the vulnerability for developing depressive illness. Our present findings are in line with an extensive animal literature, and further support the notion that impaired NPY function could contribute to depressive illness.

Cerebrospinal neuropeptide Y and substance P in suicide attempters during long-term antidepressant treatment.

This study describes cerebrospinal fluid (CSF), neuropeptide Y (NPY) and substance P (SP) in patients with a recent suicide attempt and during antidepressant treatment. Seven out of 13 patients received antidepressants. The patients were examined on three separate occasions, i.e. at pre-treatment, followed by every 3 or 4 months. Antidepressant treatment seemed to affect the levels of CSF NPY, which decreased significantly between the second and last lumbar puncture despite no significant changes of clinical scores. When the whole group was taken into consideration, both CSF NPY and SP decreased significantly. At pre-treatment, Brief Scale of Anxiety scores were significantly and negatively correlated to CSF SP and tended to be negatively correlated to CSF NPY. There were also significant positive correlations between CSF NPY and SP during the entire study in the whole group, possibly reflecting an inter-relationship between these neuropeptides.

Suicide-attempters having immunoglobulin G with affinity for dopamine in cerebrospinal fluid.

Altered immunological functions and changes in the monoaminergic neurotransmitter systems are two important observations made previously in the study of possible etiological and pathophysiological factors for psychiatric disorders. In search of tentative autoimmune mechanisms involved in these disorders we studied the presence of immunoglobulin G (DA-IgG) with affinity for the monoamine dopamine (DA) in cerebrospinal fluid (CSF) using ELISA. In CSF from 49 suicide attempters the titer of DA-IgG was significantly higher (P<0.001) than in CSF obtained from control subjects undergoing neurological investigation. The results in the present study indicate that an autoimmune mechanism may be involved in the dopaminergic neurotransmitter system and may be of pathophysiological importance in psychiatric disorders connected to an attempt of suicide.

Effects of sustained sleep restriction on mitogen-stimulated cytokines, chemokines and T helper 1/ T helper 2 balance in humans.

BACKGROUND: Recent studies suggest that acute sleep deprivation disrupts cellular immune responses by shifting T helper (Th) cell activity towards a Th2 cytokine profile. Since little is known about more long-term effects, we investigated how five days of sleep restriction would affect pro-inflammatory, chemotactic, Th1- and Th2 cytokine secretion. METHODS: Nine healthy males participated in an experimental sleep protocol with two baseline sleep-wake cycles (sleep 23.00-07.00 h) followed by 5 days with restricted sleep (03.00-07.00 h). On the second baseline day and on the fifth day with restricted sleep, samples were drawn every third hour for determination of cytokines/chemokines (tumor necrosis factor alpha (TNF-α), interleukin (IL) -1ß, IL-2, IL-4 and monocyte chemoattractant protein-1 (MCP-1)) after in vitro stimulation of whole blood samples with the mitogen phytohemagglutinin (PHA). Also leukocyte numbers, mononuclear cells and cortisol were analysed. RESULTS: 5-days of sleep restriction affected PHA-induced immune responses in several ways. There was a general decrease of IL-2 production (p<.05). A shift in Th1/Th2 cytokine balance was also evident, as determined by a decrease in IL2/IL4 ratio. No other main effects of restricted sleep were shown. Two significant interactions showed that restricted sleep resulted in increased TNF-α and MCP-1 in the late evening and early night hours (p's<.05). In addition, all variables varied across the 24 h day. CONCLUSIONS: 5-days of sleep restriction is characterized by a shift towards Th2 activity (i.e. lower 1L-2/IL-4 ratio) which is similar to the effects of acute sleep deprivation and psychological stress. This may have implications for people suffering from conditions characterized by excessive Th2 activity like in allergic disease, such as asthma, for whom restricted sleep could have negative consequences.

Plasma ANP and BNP during exercise in patients with major depressive disorder and in healthy controls.

BACKGROUND: Increased levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) have been shown to reduce the hormones in the HPA axis. In this study we addressed the question whether patients with unmedicated major depressive disorder (MDD) might have altered baseline levels of these natriuretic peptides and an altered response to acute exercise. METHODS: An incremental exercise test was performed in 18 patients with MDD and in 18 healthy controls. Plasma concentrations of ANP and BNP were determined at rest, during the exercise test and 30 min post exercise using immunoradiometric assays. RESULTS: During the exercise test the concentrations of ANP and BNP increased significantly in both groups. The MDD group showed significantly lower levels of ANP than the controls at rest, at maximal work rate and post exercise and of BNP at rest and at maximal work rate. The dynamic changes of both ANP and BNP, respectively, from baseline to maximal work rate were significantly lower in the MDD group. A slightly lower (non-significant) maximal work rate was observed in the MDD group compared with the controls. LIMITATIONS: Group sizes are relatively limited. CONCLUSION: Lower concentrations of ANP and BNP during rest and exercise were observed in the MDD patients together with a decreased dynamic response to maximal exercise. Hypothetically, the reduced ANP and BNP concentration contributes to the high hormone levels in the HPA system seen in depressive disorders. Of interest for future research is whether physical training might increase the levels of ANP and BNP and thereby diminish depressive symptoms.