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.

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.

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.

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.

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.

Covariation of plasma ghrelin and motilin in irritable bowel syndrome.

We have previously shown that ghrelin is mainly localized to the stomach but also occurs, together with the prokinetic hormone motilin, in endocrine cells in the proximal small intestine. This study explored ghrelin and motilin concentrations in plasma in relation to gastrointestinal motility and whether plasma ghrelin is changed in patients with irritable bowel syndrome (IBS). Nine patients with severe IBS and 10 healthy subjects underwent stationary antro-duodeni-jejunal manometry; blood was sampled during similar motility phases in the two groups. The motility phases were monitored and blood samples were collected during fasting and after food intake. Plasma was analyzed for two forms of ghrelin (octanylated and desoctanylated) as well as for motilin. In IBS patients circulating motilin levels covaried with total ghrelin levels (r=0.90; p<0.004), octanylated ghrelin (r=0.77; p<0.02) and desoctanylated ghrelin (r=0.69; p<0.04). No such correlations were seen in the control group. Octanylated ghrelin comprised 35.3+/-3.9% (mean+/-SEM) of the total circulating ghrelin in the IBS patients compared to 40.4+/-4.5% (mean+/-SEM) in the control group (NS). Ghrelin covaried with motilin in plasma in IBS but not in plasma from healthy subjects. This suggests the two peptides act together in IBS.

Non-suicidal self-injurious behavior, endogenous opioids and monoamine neurotransmitters.

BACKGROUND: Self-inflicted injury, including cutting or burning, is the most frequent reason for psychiatric visits to medical emergency departments. This behavior, particularly when there is no apparent suicidal intent, is poorly understood from both biological and clinical perspectives. OBJECTIVE: To examine the role of endogenous opioids and monoamine neurotransmitters in non-suicidal self-injury (NSSI). METHODS: We compared cerebrospinal fluid (CSF) levels of endogenous opioids, 5 hydroxyindolacetic acid (5-HIAA) and homovanillic acid (HVA) in individuals with a history of repetitive non-suicidal self-injury with a diagnostically-matched group of individuals who had never engaged in non-suicidal self-injury. History of suicidal behavior, demographic background and psychopathology was assessed. All patients were diagnosed with a Cluster B personality disorder (i.e. borderline, antisocial, narcissistic or histrionic) (N=29) and had a history of at least one suicide attempt. Fourteen participants had a history of repeated non-suicidal self-injurious behavior (NSSI) in adulthood and 15 did not (no NSSI). RESULTS: The NSSI group had significantly lower levels of CSF beta-endorphin and met-enkephalin when compared with the non-NSSI group. CSF dynorphin, HVA and 5-HIAA levels did not differ. Severity of depression, hopelessness and overall psychopathology was greater in the NSSI group. CONCLUSION: beta-endorphin and met-enkephalin, opioids acting upon receptors involved in mediating stress-induced and physical pain analgesia respectively, are implicated in NSSI. Serotonergic and dopaminergic dysfunctions do not appear to be related to NSSI. Based on our findings, we propose a model of non-suicidal self-injury. Our results suggest that drugs acting on the opioid system warrant exploration as pharmacological treatments for NSSI.

Monocyte chemotactic protein-1 (MCP-1) and growth factors called into question as markers of prolonged psychosocial stress.

BACKGROUND: Psychosocial stress is becoming a major contributor to increased mental ill-health and sick leave in many countries. Valid markers of chronic stress would be valuable for diagnostic and prognostic purposes. A recent study suggested monocyte chemotactic protein-1 (MCP-1), epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) as markers of chronic stress. We aimed to confirm these potential biomarkers of prolonged psychosocial stress in female patients. METHODOLOGY/PRINCIPAL FINDINGS: Circulating levels of MCP-1, EGF and VEGF, along with several other cytokines, were measured in plasma from 42 female patients suffering from exhaustion due to prolonged psychosocial stress and 42 control subjects, using a protein biochip immunoassay. There were no significant differences between patients and controls in any of the cytokines or growth factors analyzed. Furthermore, when using a different protein bioassay and reanalyzing MCP-1 and VEGF in the same samples, markedly different levels were obtained. To further explore if inflammation is present in patients with exhaustion, the classical inflammatory marker C-reactive protein (CRP) was measured in another group of patients (n=89) and controls (n=88) showing a small but significant increase of CRP levels in the patients. CONCLUSIONS/SIGNIFICANCE: MCP-1, EGF and VEGF may not be suitable markers of prolonged psychosocial stress as previously suggested. Furthermore, significant differences were obtained when using two different protein assays measuring the same samples, indicating that comparing studies where different analytic techniques have been used might be difficult. Increased levels of CRP indicate that low-grade inflammation might be present in patients with exhaustion due to prolonged stress exposure but this inflammation does not seem to be reflected by increase in circulating MCP-1 or other cytokines measured.

Motilin concentrations in relation to gastro intestinal dysmotility in diabetes mellitus.

AIM: Dysmotility in the upper gastro intestinal (GI) tract are common problems in diabetics. Many peptides are involved in the regulation of the motility. The aim of this study was to examine whether plasma levels of motilin were related to dysfunction in the oesophagus and stomach in a well-defined diabetic patient group. METHODS: Nineteen patients with symptoms from the GI tract who had been examined with oesophageal manometry, gastric emptying scintigraphy and deep-breathing test were included. They received a fat-rich meal, after which blood samples were collected and analysed for motilin concentrations. RESULTS: Symptoms of abdominal fullness and gastro oesophageal reflux significantly associated with delayed gastric emptying, whereas no symptom correlated to oesophageal dysmotility. Plasma levels of motilin were increased after the fat-rich meal (p=0.000), with no difference between the groups. Abnormal manometry was characterized by aperistalsis and/or simultaneous contractions. The percentage of simultaneous contractions correlated to basic and peak motilin values (r(s)=0.898, p=0.006 and r(s)=0.842, p=0.017, respectively). Gastric emptying did not influence motilin concentrations. CONCLUSION: Plasma motilin concentrations vary with abnormalities of oesophageal motility in diabetics, but not with abnormalities of gastric emptying.

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.

Novel biochemical markers of psychosocial stress in women.

BACKGROUND: Prolonged psychosocial stress is a condition assessed through self-reports. Here we aimed to identify biochemical markers for screening and early intervention in women. METHODS: Plasma concentrations of interleukin (IL) 1-alpha, IL1-beta, IL-2, IL-4, IL-6, IL-8, IL-10, interferon-gamma (INF-gamma), tumor necrosis factor-alpha (TNF-alpha), monocyte chemotactic protein-1 (MCP-1), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), thyroid stimulating hormone (TSH), total tri-iodothyronine (TT3), total thyroxine (TT4), prolactin, and testosterone were measured in: 195 women on long-term sick-leave for a stress-related affective disorder, 45 women at risk for professional burnout, and 84 healthy women. RESULTS: We found significantly increased levels of MCP-1, VEGF and EGF in women exposed to prolonged psychosocial stress. Statistical analysis indicates that they independently associate with a significant risk for being classified as ill. CONCLUSIONS: MCP-1, EGF, and VEGF are potential markers for screening and early intervention in women under prolonged psychosocial stress.

Sympathetic and sensory nerve activation during negative pressure therapy of sternotomy wounds.

Negative pressure wound therapy (NPWT) has been adopted as the first-line treatment for poststernotomy mediastinitis as a result of the excellent clinical outcome. The knowledge concerning the effects of NPWT on the cardiovascular system and homeostasis is still limited. The aim of the present study was to investigate whether the plasma levels of neurohormones change during NPWT. Six pigs underwent median sternotomy followed by NPWT at -125 mmHg. The plasma levels of noradrenaline, adrenaline, neuropeptide Y, substance P, vasoactive intestinal peptide (VIP), and calcitonin gene-related peptide (CGRP) were determined before (0 min) and 5, 20, 60 and 180 min after the application of NPWT. The results show a transient increase in the plasma levels of noradrenaline and adrenaline when NPWT was applied. The plasma level of the adrenergic co-transmitter neuropeptide Y was higher in NPWT--than in sham-treated pigs, after 180 min of negative pressure. After 180 min of NPWT there was an increase in the plasma levels of the sensory nerve transmitter substance P, while no such effect was observed for CGRP or VIP. In conclusion, the results suggest sympathetic nerve activation during NPWT. This may be the result of an increase in workload on the heart during the initial phase of NPWT.

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.

Analysis of proteins from a glioma cell line by using micro-scale solution isoelectric focusing in combination with liquid chromatography/tandem mass spectrometry.

In this study we have investigated whether micro-solution isoelectric focusing (microsol-IEF) can be used as a pre-fractionation step prior to liquid chromatography/tandem mass spectrometry (LC/MS/MS) and if extensive sample purification of the different fractions is required. We found that, in spite of the high concentrations of buffer and detergents, no clean up of the digested microsol-IEF fractions was necessary before analysis by LC/MS/MS. We also concluded that it is possible to identify at least twice as many proteins in a glioma cell lysate with the combination of microsol-IEF and LC/MS/MS than with LC/MS/MS alone. Furthermore, most of the proteins that were identified from one microsol-IEF fraction by using analytical narrow-range two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) and peptide mass fingerprinting with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS) were also identified by LC/MS/MS. Finally, we used the combination of microsol-IEF and LC/MS/MS to compare two sample preparation methods for glioma cells and found that several nuclear, mitochondria, and endoplasmic reticulum proteins were only present in the sample that had been subjected to lipid extraction by incubating the homogenized cells in chloroform/methanol/water.