The MCP-4/MCP-1 ratio in plasma is a candidate circadian biomarker for chronic post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is psychiatric disease, which can occur following exposure to traumatic events. PTSD may be acute or chronic, and can have a waxing and waning course of symptoms. It has been hypothesized that proinflammatory cytokines and chemokines in the cerebrospinal fluid (CSF) or plasma might be mediators of the psychophysiological mechanisms relating a history of trauma exposure to changes in behavior and mental health disorders, and medical morbidity. Here we test the cytokine/chemokine hypothesis for PTSD by examining levels of 17 classical cytokines and chemokines in CSF, sampled at 0900 hours, and in plasma sampled hourly for 24 h. The PTSD and healthy control patients are from the NIMH Chronic PTSD and healthy control cohort, initially described by Bonne et al. (2011), in which the PTSD patients have relatively low comorbidity for major depressive disorder (MDD), drug or alcohol use. We find that in plasma, but not CSF, the bivariate MCP4 (CCL13)/ MCP1(CCL2) ratio is ca. twofold elevated in PTSD patients compared with healthy controls. The MCP-4/MCP-1 ratio is invariant over circadian time, and is independent of gender, body mass index or the age at which the trauma was suffered. By contrast, MIP-1ß is a candidate biomarker for PTSD only in females, whereas TARC is a candidate biomarker for PTSD only in males. It remains to be discovered whether these disease-specific differences in circadian expression for these specific immune signaling molecules are biomarkers, surrogates, or drivers for PTSD, or whether any of these analytes could contribute to therapy.

Serotonin versus catecholamine deficiency: behavioral and neural effects of experimental depletion in remitted depression.

Despite immense efforts into development of new antidepressant drugs, the increases of serotoninergic and catecholaminergic neurotransmission have remained the two major pharmacodynamic principles of current drug treatments for depression. Consequently, psychopathological or biological markers that predict response to drugs that selectively increase serotonin and/or catecholamine neurotransmission hold the potential to optimize the prescriber's selection among currently available treatment options. The aim of this study was to elucidate the differential symptomatology and neurophysiology in response to reductions in serotonergic versus catecholaminergic neurotransmission in subjects at high risk of depression recurrence. Using identical neuroimaging procedures with [(18)F] fluorodeoxyglucose positron emission tomography after tryptophan depletion (TD) and catecholamine depletion (CD), subjects with remitted depression were compared with healthy controls in a double-blind, randomized, crossover design. Although TD induced significantly more depressed mood, sadness and hopelessness than CD, CD induced more inactivity, concentration difficulties, lassitude and somatic anxiety than TD. CD specifically increased glucose metabolism in the bilateral ventral striatum and decreased glucose metabolism in the bilateral orbitofrontal cortex, whereas TD specifically increased metabolism in the right prefrontal cortex and the posterior cingulate cortex. Although we found direct associations between changes in brain metabolism and induced depressive symptoms following CD, the relationship between neural activity and symptoms was less clear after TD. In conclusion, this study showed that serotonin and catecholamines have common and differential roles in the pathophysiology of depression.

[ENT surgery in anticoagulate patients]. / HNO-Chirurgie bei Patienten unter oraler Antikoagulation und Plättchenhemmer-Therapie.

BACKGROUND: In elective ENT surgery, one frequently sees -patients on oral anticoagulants and platelet inhibitors. While continuation of these therapies increases the risk of bleeding complications, indiscriminate discontinuation can have severe thromboembolic consequences. Furthermore, the number of -anticoagulants and platelet inhibitors in use has increased. The ENT-specialist is regulary confronted with the question of continuation, discontinuation, or bridging of this therapy. METHODS: Review of the available literature on bleeding complications associated with ENT interventions performed with and without anticoagulants. Overview of the indications for anticoagulants and the different mechansims of action and properties of the different agents. Development of protocols for risk stratification and for perioperative management. CONCLUSIONS: Patients on oral anticoagulants and platelet inhibitors have significant morbidity and mortality not only due to the underlying diseases, but also due to the perioperative management of these therapies. Perioperative management should be based on well-established treatment guidelines or, in high-risk patients, on multidisciplinary consultation. Even though the recommendations here are evidence-based and cover a multitude of clinical contingencies, they cannot replace clinical decision making, which must consider the specific characteristics and circumstances of the patient, the planned intervention, and the surgical environment.

Serotonin transporter polymorphisms predict response inhibition in healthy volunteers.

Serotoninergic transmission is reliably implicated in inhibitory control processes. The aim of this study was to test the hypothesis if serotonin transporter polymorphisms mediate inhibitory control in healthy people. 141 healthy subjects, carefully screened for previous and current psychopathology, were genotyped for the 5-HTTLPR and rs25531 polymorphisms. Inhibitory control was ascertained with the Stop Signal Task (SST) from the Cambridge Neuropsychological Test Automated Battery (CANTAB). The triallelic gene model, reclassified and presented in a biallelic functional model, revealed a dose-dependent gene effect on SST performance with Individuals carrying the low expressive allele had inferior inhibitory control compared to high expressive carriers. This directly implicates serotonin transporter polymorphisms (5-HTTLPR plus rs25531) in response inhibition in healthy subjects.

Biodegradable polymeric coatings on cochlear implant surfaces and their influence on spiral ganglion cell survival.

To improve the electrode-nerve interface of cochlear implants (CI), the role of poly(L-lactide) (PLLA) and poly(4-hydroxybutyrate) (P(4HB)) as potential coating matrices for CI was assessed both in vitro and in vivo in terms of degradation behavior and effects on spiral ganglion neurons, the main target of the electrical stimulation with a CI. Growth rates of fibroblasts on the polymers were investigated and a direct-contact test with freshly isolated spiral ganglion cells (SGC) was performed. In addition, the effects of the polymer degradation inside the inner ear were evaluated in vivo. The polymer degradation was assessed by use of scanning electron microscopy in combination with an energy-dispersive X-ray analysis. In vitro, no influence of the polymers was detected on fibroblasts' viability and on SGC survival rate. In vivo, SGC density was decreased only 6 months after implantation in the basal and middle turns of the cochlea in comparison to normal-hearing animals but not between implanted groups (coated or uncoated). The analysis of the electrode models showed that in vivo P(4HB) is characterized by a gradual degradation completed after 6 months; whereas, the PLLA coatings burst along their longitudinal axis but showed only little degradation within the same time frame. In conclusion, both polymers seem to justify further evaluation as possible coating for CI electrodes. Of the two options, due to its excellent coating adhesion/stability and optimal degradation behavior, P(4HB) may prove to be the more promising biodegradable polymer for designing a drug delivery system from the surface of CI electrodes.

Elevated brain cannabinoid CB1 receptor availability in post-traumatic stress disorder: a positron emission tomography study.

Endocannabinoids and their attending cannabinoid type 1 (CB1) receptor have been implicated in animal models of post-traumatic stress disorder (PTSD). However, their specific role has not been studied in people with PTSD. Herein, we present an in vivo imaging study using positron emission tomography (PET) and the CB1-selective radioligand [(11)C]OMAR in individuals with PTSD, and healthy controls with lifetime histories of trauma (trauma-exposed controls (TC)) and those without such histories (healthy controls (HC)). Untreated individuals with PTSD (N=25) with non-combat trauma histories, and TC (N=12) and HC (N=23) participated in a magnetic resonance imaging scan and a resting PET scan with the CB1 receptor antagonist radiotracer [(11)C]OMAR, which measures the volume of distribution (VT) linearly related to CB1 receptor availability. Peripheral levels of anandamide, 2-arachidonoylglycerol, oleoylethanolamide, palmitoylethanolamide and cortisol were also assessed. In the PTSD group, relative to the HC and TC groups, we found elevated brain-wide [(11)C]OMAR VT values (F(2,53)=7.96, P=0.001; 19.5% and 14.5% higher, respectively), which were most pronounced in women (F(1,53)=5.52, P=0.023). Anandamide concentrations were reduced in the PTSD relative to the TC (53.1% lower) and HC (58.2% lower) groups. Cortisol levels were lower in the PTSD and TC groups relative to the HC group. Three biomarkers examined collectively--OMAR VT, anandamide and cortisol--correctly classified nearly 85% of PTSD cases. These results suggest that abnormal CB1 receptor-mediated anandamide signaling is implicated in the etiology of PTSD, and provide a promising neurobiological model to develop novel, evidence-based pharmacotherapies for this disorder.

Stenting of stenotic mesenteric arteries for symptomatic chronic mesenteric ischemia.

BACKGROUND: We report the results of our single center series of patients with chronic mesenteric ischemia (CMI) to determine the role of stenting in the management of patients. PATIENTS AND METHODS: We retrospectively reviewed all patients with CMI treated endovascularly with stent revascularisation from January 2008 to January 2011.CMI diagnosis was made according to clinical symptoms, including postprandial abdominal pain, food fear, and weight loss. Additionally, the diagnosis was confirmed by duplex ultrasonography and/or computed tomography angiography and/or contrast-enhanced magnetic resonance angiography. RESULTS: All 45 patients presented with typical CMI symptoms: 45/45 (100 %) had postprandial pain, 31/45 (68.8 %) had a weight loss of more than 10 kilograms, and 11/45 (24.4 %) suffered from ischemic colitis combined with lower gastrointestinal bleeding. In three patients occlusion could not be crossed, therefore considered as technical failure. A total of 55 arteries were stented in the remaining 42 patients. Nineteen patients underwent SMA stenting alone, eight underwent celiac stenting, alone and three patients underwent stenting of inferior mesenteric artery (IMA) alone. We performed combined stenting of the celiac artery and superior mesenteric artery in ten patients, and one patient underwent a combined stenting of the celiac artery and the IMA. All three mesenteric arteries were stented in only one patient. Primary technical success was achieved in 42/45 (94.8 %) patients. Clinical symptom relief was achieved in 39/45 (86.6 %) patients with abdominal pain. Increased body weight was observed in 28/31 (90.3 %) patients with an average weight gain of 8.8 kilograms (5 - 12 kilograms), and 10/11 (90.9 %) patients recovered from ischaemic colitis/lower gastrointestinal bleeding. CONCLUSIONS: Stent revascularisation can be considered as the first-line therapy for patients with chronic mesenteric ischemia.

Effects of duloxetine in treatment-refractory men with posttraumatic stress disorder.

INTRODUCTION: Although there is evidence that selective serotonin reuptake inhibitors provide some benefit in the treatment of post-traumatic stress disorder (PTSD), most meta-analytical reviews have concluded that effect sizes are small and, moreover, that there may be relatively little benefit for some populations (e. g., combat veterans with co-morbid major depression, MDD). This study aimed to evaluate the effectiveness and tolerability of the dual reuptake inhibitor duloxetine in the treatment of PTSD and co-morbid MDD. METHODS: Twenty-one treatment refractory, male, combat-related patients with PTSD and co-morbid MDD were enrolled in a naturalistic study and twenty completed the trial. Duloxetine was given between 60 and 120 mg daily over 8 weeks. RESULTS: Duloxetine led to a significant improvement of PTSD-characteristic symptoms as well as co-morbid MDD. Duloxetine effectively reduced nightmares, which is important because decreasing nightmares has been associated with improved sleep in PTSD. DISCUSSION: The results of this naturalistic study suggest that duloxetine is an effective and well-tolerated treatment for patients with PTSD and co-morbid MDD. These initial results need to be extended to the study of women with PTSD.

[Interventional revascularization for severe mesenteric ischemia in contribution with venal artery angioplasty]. / Interventionelle Revaskularisation bei schwerer mesenterialer Ischämie kombiniert mit einer Angioplastie einer Nierenarterie.

A 82 year old lady presented with haemorraghic erosive gastritis, progressing lost of weight, hypertension, diabetes mellitus and renal dysfunction. Colour flow duplex scanning and MRA revealed subtotal stenosis of the celiac artery and the right renal artery, proximal occlusion of the superior mesenteric artery and complete occlusion of the inferior mesenteric artery. There were also stenoses in the left renal artery. The patient was accessed via the left brachial artery, because of the relatively unfavourable angle of the mesenteric arteries. The procedures were done using F8-sheath-, F7-guiding catheter and vertebral shaped F5-diagonstic catheter. The celiac trunk und the right renal artery were initially treated with 7 x 12 and 5 x 17 mm balloon-expanding Stents. 7 x 40 mm self-expanding stent (Carotid wallstent) was inserted in the superior mesenteric artery following balloon dilatation with 5-mm-PTA-ballon. Dilatation of the superior mesenteric artery was done also after placement of the stent with 7-mm-PTA-ballon. One stage successful endovascular treatment was performed in the three vascular territories. A follow-up of 3 months period with colour duplex sonography revealed the stent to be patent with normal flow, better control of the hypertension and improvement of the renal function.

Anxiety disorders: noradrenergic neurotransmission.

The past decade has seen a rapid progression in our knowledge of the neurobiological basis of fear and anxiety. Specific neurochemical and neuropeptide systems have been demonstrated to play important roles in the behaviors associated with fear and anxiety-producing stimuli. Long-term dysregulation of these systems appears to contribute to the development of anxiety disorders, including panic disorder, posttraumatic stress disorder (PTSD), and social anxiety disorder. These neurochemical and neuropeptide systems have been shown to have effects on distinct cortical and subcortical brain areas that are relevant to the mediation of the symptoms associated with anxiety disorders. Moreover, advances in molecular genetics portend the identification of the genes that underlie the neurobiological disturbances that increase the vulnerability to anxiety disorders. This chapter reviews clinical research pertinent to the neurobiological basis of anxiety disorders. The implications of this synthesis for the discovery of anxiety disorder vulnerability genes and novel psychopharmacological approaches will also be discussed.

A polymorphism (5-HTTLPR) in the serotonin transporter promoter gene is associated with DSM-IV depression subtypes in seasonal affective disorder.

Serotonergic mechanisms are thought to play an important role in the pathogenesis of seasonal affective disorder (SAD). The expression of the serotonin transporter (5-HTT) is regulated in part by an insertion/deletion polymorphism in the serotonin transporter gene promoter region (5-HTTLPR). The 5-HTTLPR short allele (s) has been associated with anxiety-related personality traits and depression, and one study observed an association between the 5-HTTLPR s-allele and SAD and the trait of seasonality. We genotyped 138 SAD patients and 146 healthy volunteers with low seasonality for 5-HTTLPR. No difference between patients and controls was found for genotype distribution and s-allele frequency. However, genotype distribution and allele frequencies were strongly associated with DSM-IV depression subtypes. Melancholic depression was associated with the 5-HTTLPR long (l) allele and atypical depression with the 5-HTTLPR s-allele (two-sided Fisher's exact test: genotype distribution: P=0.0038; allele frequencies: P=0.007). Our data are compatible with the hypothesis of a disease process that is not causally related to 5-HTTLPR, but involves 5-HT neurotransmission and 5-HTTLPR somewhere on its way to phenotypic disease expression.

The serotonin transporter promoter repeat length polymorphism, seasonal affective disorder and seasonality.

BACKGROUND: Conflicting results have been reported in previous association studies of the serotonin transporter promoter repeat length polymorphism (5-HTTLPR), seasonal affective disorder (SAD) and seasonality (seasonal variations in mood and behaviour). The aim of this study was to test for association in new case-control and population-based materials, and to perform a combined analysis of all published studies of 5-HTTLPR and SAD. METHOD: One hundred and forty-seven new SAD cases and 115 controls were genotyped for 5-HTTLPR and in total 464 patients and 414 controls were included in the pooled analysis. In addition, 226 individuals selected for unusually high or low seasonality scores from a population based material and 46 patients with non-seasonal depression were analysed. Different genetic models were tested and seasonality was analysed both as a qualitative (high v. low) and as a quantitative trait in the different sample sets. RESULTS: No association between 5-HTTLPR and SAD was found in the new case-control material, in the combined analysis of all samples, or when only including 316 patients with controls (N = 298) selected for low seasonality. A difference was detected between the population based high and low seasonality groups, when assuming a recessive effect of the short allele (20% and 10% short allele homozygotes, respectively, OR (95% CI): 2.24 (1.03-4.91)). Quantitative analysis of seasonality revealed no association with 5-HTTLPR in any sample set. CONCLUSIONS: These results do not suggest a major role of the short variant of 5-HTTLPR in susceptibility to SAD, but provide modest evidence for an effect on seasonality.

[Seasonal affective depression in 2 German speaking university centers: Bonn, Vienna. Clinical and demographic characteristics]. / Saisonal abhängige Depression in zwei deutschsprachigen Universitätszentren: Bonn, Wien. Klinische und demographische Charakteristika.

Six hundred ten patients with seasonal affective disorder (SAD) were diagnosed and treated at the university hospitals for psychiatry in Bonn, Germany (1989-1992) and Vienna, Austria (1993-2001). The aim of this study was to compare our sample with other SAD populations in the literature and to investigate differences between the two study locations. We found female:male sex ratios of 5.0:1.0 in unipolar depressives and 1.5:1.0 in patients with bipolar affective disorder. Of our patients, 21.7% suffered from bipolar II disorder, and 1.3% were diagnosed as having bipolar I. Our patients obtained a mean global seasonality score (GSS) of 15.4. Women had a higher GSS than men (t = 2.127, P = 0.035), and Viennese patients had higher scores than patients in Bonn (t = 3.104, P = 0.002). Totals of 66.3% of all patients suffered from atypical depression and 17.8% from melancholic depression. Patients with atypical depression were more frequent in Vienna, whereas patients with melancholic depression predominated in Bonn (chi 2 = 54.952, df = 2, P < 0.001). The demographic and clinical characteristics of the patients described in this article confirm the findings of other epidemiological investigations obtained in non-German-speaking samples.

Changes of clinical pattern in seasonal affective disorder (SAD) over time in a German-speaking sample.

OBJECTIVE: The goals of this study are to provide estimates of clinical and demographic variables of patients with seasonal affective disorder (SAD) in Germany and Austria, to compare our results with those of previously published SAD studies, and to find out whether the clinical pattern of SAD remained stable over several years. METHOD: We investigated 610 SAD patients from the outpatient clinics in Bonn (n = 190) and Vienna (n = 420). Patients in Bonn were recruited in the fall-winter season of the years 1989-1992, those in Vienna in the years 1993-2001. RESULTS: We observed a change in the clinical pattern in our patients: patients from Bonn, who were diagnosed and treated about 5 years earlier, were more likely to suffer from melancholic depression, whereas Viennese patients rather suffered from atypical depression (chi(2) = 54.952, df = 2, p < 0.001). The symptoms of hypersomnia, daytime fatigue, increased eating and carbohydrate-craving were more frequent in the Viennese sample, anxiety and deterioration of patients' capacity to perform at work predominated in Bonn. In addition, patients from Vienna obtained a higher GSS (global seasonality score, measured by the SPAQ - Seasonal Pattern Assessment Questionnaire) than those from Bonn (15.7 +/- 3.3 and 14.6 +/- 4.1 respectively; t = 3.104, p = 0.002). Taken together, our results were in good accordance to other published SAD materials, but we were able to demonstrate that our patients reported "feeling worst" (measured by item 13H of the SPAQ) in November and December, whereas SAD patients in the USA clearly had their worst months in January and February. CONCLUSIONS: We suggest that an increase in awareness of fall-winter depression in the last decade by both doctors, who referred patients, as well as patients or the entire population must have caused patients to sign up for light therapy at the Viennese SAD clinic because of having heard about the atypical symptom profile. This increased awareness of SAD can also be measured by a statistically significant reduction in the diagnostic latency (from the age of onset to the diagnosis of SAD) when comparing the two study locations.

[Pharmacotherapy of seasonal depression]. / Die Pharmakotherapie der saisonal abhängigen Depression.

Seasonal affective disorder (SAD), first described in 1984, is a condition characterized by recurring depressive episodes in fall and winter alternating with nondepressive episodes in spring and summer. Various neurotransmitters have been implicated in the etiology of SAD, with the strongest evidence for an involvement of serotonin. Moreover, researchers have focused on the development of treatment modalities for SAD. Despite the proven efficacy of light therapy in SAD, some patients do not experience sufficient relief of depressive symptoms with light, and a number of them feel unable to comply because of logistical difficulties in administering bright light therapy. Comparatively few studies have examined the role of pharmacotherapy in the treatment of SAD. So far, selective serotonin reuptake inhibitors and possibly compounds with a distinct noradrenergic mechanism of action seem to be the treatment of choice for seasonal depression. There is, however, a clear need for further placebo-controlled studies to evaluate pharmacological treatment options for SAD.

Intravenous mirtazapine in the treatment of depressed inpatients.

Mirtazapine is a novel antidepressant with a noradrenergic and specific serotonergic mode of action. So far, mirtazapine has been administered orally. This naturalistic study evaluates the antidepressant efficacy, safety, and tolerability of mirtazapine 15 mg/day administered intravenously to 27 inpatients with moderate to severe major depression. Compared with baseline, we found a significant decrease of the Hamilton Depressive Rating Scale (HDRS) total score (P<0.001). Side effects were mild and transient. Altogether, the results of this preliminary study show that intravenous mirtazapine is an effective, safe and well tolerated treatment for depressed inpatients.

Evidence for an altered tryptophan metabolism in fibromyalgia.

Fibromyalgia (FM) is a prevalent syndrome with chronic pain and a hypothesized underlying disturbance of the tryptophan (TRP) metabolism. We performed a tryptophan depletion (TD) test in 17 FM patients and 17 controls. TRP, 5-hydroxyindoleacetic acid (5-HIAA), kynurenine (KYN), and interleukin-6 (IL-6) were measured. Additionally pain perception was monitored in the FM patients. FM patients and controls exhibited a decrease of TRP and KYN during TD. 5-HIAA levels also decreased in all controls and in 11 FM patients, but showed a marked increase in 6 FM patients. IL-6 significantly increased during TD in the patients, but not in the controls. Pain perception was not affected in the FM patients. These data demonstrate an altered TRP metabolism in a subgroup of FM patients, where the TD seems to activate 5-HT metabolism. Our findings may have diagnostic as well as therapeutic implications in the field of fibromyalgia.

The effects of light therapy on mini-mental state examination scores in demented patients.

BACKGROUND: Preliminary evidence suggests that demented patients may experience beneficial effects of light therapy. The authors tested whether bright light therapy (BLT) is capable of improving cognitive functions in patients with Alzheimer-type dementia (AD) or vascular dementia (VD). METHODS: Twenty-three patients with AD or VD were randomly assigned to either evening BLT or dim light therapy (DLT). Effects of light therapy on cognitive functions were assessed before and after light therapy using Mini-Mental State Examination (MMSE) scores. Body temperature rhythm (BTR) was additionally recorded pre- and posttreatment. RESULTS: Irrespective of their diagnosis, patients treated with BLT (p =.0012) but not with DLT (p =.73) showed a statistically significant increase in MMSE total scores after light therapy. Evening BLT simultaneously induced a significant phase delay of 56 min on BTR (p =.025). CONCLUSION: Our preliminary results suggest that short-term evening BLT may exert beneficial effects on cognitive functioning in patients with dementia.

Dopamine transporter availability in symptomatic depressed patients with seasonal affective disorder and healthy controls.

BACKGROUND: During recent years hypotheses about the pathophysiology of seasonal affective disorder/winter type (SAD) have focused monoaminergic mechanisms. There is substantial evidence that serotonergic systems play an important role. The potential role of catecholaminergic pathways has not been fully explored. METHODS: Eleven drug-free, symptomatic depressed patients with SAD and 11 healthy age- and gender-matched healthy controls were invited to participate in a 123Ibeta-CIT single photon emission computed tomography (SPECT) study to assess striatal density of dopamine transporters (DATs). The cerebellum was used as reference region. Ratios were calculated between mean counts in left and right striatum and cerebellum. These ratios minus I represent specific/non-displaceable binding and are assumed to be directly related to DAT availability at the time of binding equilibrium. RESULTS: Displaceable 153Ibeta-CIT binding in the area corresponding to the left striatum was significantly reduced in SAD patients compared to healthy controls (10.49+/-0.91 v. 1195+/-1.54, respectively; 2-tailed P = 0.017, Mann-Whitney U test). CONCLUSIONS: These data suggest reductions in the availability of striatal DAT binding sites in untreated symptomatic depressed SAD patients. It remains unclear whether these reductions represent a primary defect or an attempt to overcome a state of possible lowered dopamine availability in the synaptic cleft during a depressive episode of SAD. However, these findings provide evidence that brain dopaminergic systems may be involved in the pathophysiology of SAD.