Survival of Melancholia: a Retrospective Study of Patients with Depressive Disorders.

BACKGROUND: The DSM-IV and the DSM-5 eliminated the importance of the syndromal identity of melancholic depression in favour of a dimensional model within the domain of major depressive disorders. Melancholic depression was excluded from DSM as a distinct disorder owing to the impact of ageing, genetics, and course of illness. We challenge these assertions using retrospective data collected from patients with depression. METHOD: Electronic medical records of 1073 patients with depressive-spectrum disorders in 12 centres across Germany spanning from January 2010 to June 2013 were retrospectively reviewed. The diagnosis of melancholia was made using the Hamilton Depression Rating Scale 21 items (HAMD-21). Patients were followed up every 2 weeks and yearly until discharge from inpatient units. The final dataset consisted of 1014 patients; each had received a minimum of two complete observations. RESULTS: At baseline, patients with melancholic depression had higher HAMD-21 score than did patients with non-melancholic depression (32.6 vs 23.13, p < 0.001). At the final visit, patients with melancholic depression responded to treatment more often than did patients with non-melancholic depression (81.3% vs 69.04%, p = 0.0156), whereas the two groups were comparable in terms of remission status (50.55 vs 48.68%, p = 0.1943). The relapse rate was higher in patients with melancholic depression than in patients with non-melancholic depression after 1 year (60% vs 45.01%, p = 0.0599), 2 years (77.78% vs 60.36%, p = 0.0233), and 4 years (80% vs 64.45%, p = 0.0452). CONCLUSION: Melancholic depression has an identifiable constellation of symptoms and it is not just a severe form of major depression. Melancholic depression is not the result of age-related or pathoplastic changes. We advocate including melancholia as its own illness entity in the next edition of the DSM.

Heart rate variability and Omega-3 Index in euthymic patients with bipolar disorders.

BACKGROUND: Affective disorders are associated with an increased risk of cardiovascular disease, which, at least partly, appears to be independent of psychopharmacological treatments used to manage these disorders. Reduced heart rate variability (SDNN) and a low Omega-3 Index have been shown to be associated with increased risk for death after myocardial infarction. Therefore, we set out to investigate heart rate variability and the Omega-3 Index in euthymic patients with bipolar disorders. METHODS: We assessed heart rate variability (SDNN) and the Omega-3 Index in 90 euthymic, mostly medicated patients with bipolar disorders (Bipolar-I, Bipolar-II) on stable psychotropic medication, free of significant medical comorbidity and in 62 healthy controls. Heart rate variability was measured from electrocardiography under a standardized 30 minutes resting state condition. Age, sex, BMI, smoking, alcohol consumption and caffeine consumption as potential confounders were also assessed. RESULTS: Heart rate variability (SDNN) was significantly lower in patients with bipolar disorders compared to healthy controls (35.4 msec versus 60.7 msec; P<0.0001), whereas the Omega-3 Index did not differ significantly between the groups (5.2% versus 5.3%). In a linear regression model, only group membership (patients with bipolar disorders versus healthy controls) and age significantly predicted heart rate variability (SDNN). CONCLUSION: Heart rate variability (SDNN) may provide a useful tool to study the impact of interventions aimed at reducing the increased risk of cardiovascular disease in euthymic patients with bipolar disorders. The difference in SDNN between cases and controls cannot be explained by a difference in the Omega-3 Index.

A plate reader-based method for cell water permeability measurement.

Cell volume and water permeability measurements in cultured mammalian cells are typically conducted under a light microscope. Many of the employed approaches are time consuming and not applicable to a study of confluent epithelial cell monolayers. We present here an adaptation of a calcein-quenching-based approach for a plate reader. A standard curve of fluorescence intensities at equilibrium has been recorded, following a shift from 285 mosmol/kgH(2)O to a series of altered extracellular osmolyte concentrations, ranging from final concentrations of 185 to 585 mosmol/kgH(2)O, by changing buffer d-mannitol concentrations. Similarly, according average cell volumes have been measured in suspension in a Coulter counter (particle-sizing device). Based on these measurements, we have derived an equation that facilitates the modeling of cell volume changes based on fluorescence intensity changes. We have utilized the method to study the role of a carboxyl-terminus aquaporin (AQP)-2 phosphorylation site, which is known to affect AQP2 membrane trafficking, in heterologous type I Madin-Darby canine kidney cells. We find that water permeability in cells expressing phosphorylation site mutants was in the following order: AQP2-S256D > AQP2 wild-type > AQP2-S256A. We propose that the method can be applied to study AQP function and more generally to study cell volume changes in adherent cell lines. Furthermore, it should be adaptable for AQP inhibitor screening in chemical compound libraries.

Expression of delta-like ligand 4 (Dll4) and markers of hypoxia in colon cancer.

BACKGROUND: Delta-like ligand 4 (Dll4) is a Notch ligand that is upregulated by hypoxia and vascular endothelial growth factor-A (VEGF-A) and is reported to have a role in tumor angiogenesis. Evidence from xenograft studies suggests that inhibiting Dll4-Notch signalling may overcome resistance to anti-VEGF therapy. The aim of this study was to characterise the expression of Dll4 in colon cancer and to assess whether it is associated with markers of hypoxia and prognosis. METHOD: In all, 177 colon cancers were represented in tissue microarrays. Immunohistochemistry was performed using validated antibodies against Dll4, VEGF, hypoxia-inducible factor (HIF)-1alpha, HIF-2alpha, prolyl hydroxylase (PHD)1, PHD2, PHD3 and carbonic anhydrase 9 (CA9). RESULTS: The expression of Dll4 was observed preferentially in the endothelium of 71% (125 out of 175) of colon cancers, but not in the endothelium adjacent to normal mucosa (none out of 107, P<0.0001). The expression of VEGF was significantly associated with HIF-2alpha (P<0.0001) and Dll4 (P=0.010). Only HIF-2alpha had a significant multivariate prognostic effect (hazard ratio 1.61, 95% confidence interval 1.01-2.57). Delta-like ligand 4 was also expressed by neoplastic cells, particularly neoplastic goblet cells. CONCLUSION: Endothelial expression of Dll4 is not a prognostic factor, but is significantly associated with VEGF. Assessing endothelial Dll4 expression may be critical in predicting response to anti-VEGF therapies.

Vasopressin-dependent short-term regulation of aquaporin 4 expressed in Xenopus oocytes.

Aquaporin 4 (AQP4) is abundantly expressed in the perivascular glial endfeet in the central nervous system (CNS), where it is involved in the exchange of fluids between blood and brain. At this location, AQP4 contributes to the formation and/or the absorption of the brain edema that may arise following pathologies such as brain injuries, brain tumours, and cerebral ischemia. As vasopressin and its G-protein-coupled receptor (V1(a)R) have been shown to affect the outcome of brain edema, we have investigated the regulatory interaction between AQP4 and V1(a)R by heterologous expression in Xenopus laevis oocytes. The water permeability of AQP4/V1(a)R-expressing oocytes was reduced in a vasopressin-dependent manner, as a result of V1(a)R-dependent internalization of AQP4. Vasopressin-dependent internalization was not observed in AQP9/V1(a)R-expressing oocytes. The regulatory interaction between AQP4 and V1(a)R involves protein kinase C (PKC) activation and is reduced upon mutation of Ser(180) on AQP4 to an alanine. Thus, the present study demonstrates at the molecular level a functional link between the vasopressin receptor V1(a)R and AQP4. This functional interaction between AQP4 and V1(a)R may prove to be a potential therapeutic target in the prevention and treatment of brain edema.

Multicenter assessment of reliability of cranial MRI.

Clinical utility of magnetic resonance imaging (MRI) for the diagnosis and assessment of neurodegenerative diseases may depend upon the reliability of MRI measurements, especially when applied within a multicenter context. In the present study, we assessed the reliability of MRI through a phantom test at a total of eleven clinics. Performance and entry criteria were defined liberally in order to support generalizability of the results. For manual hippocampal volumetry, automatic segmentation of brain compartments and voxel-based morphometry, multicenter variability was assessed on the basis of MRIs of a single subject scanned at ten of the eleven sites. In addition, cranial MRI scans obtained from 73 patients with Alzheimer's disease (AD) and 76 patients with mild cognitive impairment were collected at subset of six centers to assess differences in grey matter volume. Results show that nine out of eleven centers tested met the reliability criteria of the phantom test, where two centers showed aberrations in spatial resolution, slice thickness and slice position. The coefficient of variation was 3.55% for hippocampus volumetry, 5.02% for grey matter, 4.87% for white matter and 4.66% for cerebrospinal fluid (CSF). The coefficient of variation was 12.81% (S.D.=9.06) for the voxel intensities within grey matter and 8.19% (S.D.=6.9) within white matter. Power analysis for the detection of a difference in the volumes of grey matter between AD and MCI patients across centers (d=0.42) showed that the total sample size needed is N=180. In conclusion, despite minimal inclusion criteria, the reliability of MRI across centers was relatively good.

Association between cognitive performance and cortical glucose metabolism in patients with mild Alzheimer's disease.

BACKGROUND: Neuronal and synaptic function in Alzheimer's disease (AD) is measured in vivo by glucose metabolism using positron emission tomography (PET). OBJECTIVE: We hypothesized that neuronal activation as measured by PET is a more sensitive index of neuronal dysfunction than activity during rest. We investigated if the correlations between dementia severity as measured with the Mini Mental State Examination (MMSE) and glucose metabolism are an artifact of brain atrophy. METHOD: Glucose metabolism was measured using [18F]fluorodeoxyglucose PET during rest and activation due to audiovisual stimulation in 13 mild to moderate AD patients (MMSE score > or = 17). PET data were corrected for brain atrophy. RESULTS: In the rest condition, glucose metabolism was correlated with the MMSE score primarily within the posterior cingulate and parietal lobes. For the activation condition, additional correlations were within the primary and association audiovisual areas. Most local maxima remained significant after correcting for brain atrophy. CONCLUSION: PET activity measured during audiovisual stimulation was more sensitive to functional alterations in glucose metabolism in AD patients compared to the resting PET. The association between glucose metabolism and MMSE score was not dependent on brain atrophy.

Effect of 3T MRI on the function of shunt valves--evaluation of Paedi GAV, Dual Switch and proGAV.

The MR-compatibility of medical implants and devices becomes more and more important with the increasing number of high-field MR-scanners employed. Until the end of 2004, about twenty 3T MR in Germany will be in clinical practice. Patients with hydrocephalus need frequent follow-up MR-examinations to assure correct functioning of a shunt. We tested three types of gravitational valves: the Paedi GAV, the Dual Switch and as a new programmable valve the proGAV (Miethke Company, Berlin), that have not been evaluated at 3T, yet. In sum, there is strong evidence for maintenance of function of these valves after exposure to 3T. This also implies the programmable valve, as long as the brake mechanism is properly adjusted during MR-examination.

Cephalometric evaluation of children with Down syndrome after early intervention with the stimulating plate.

The aim of stimulating plate therapy in patients with trisomy 21 is to correct orofacial dysfunctions and prevent the establishment of subsequent morphological characteristics such as protrusion of the incisors and pseudoprognathia. This study investigated the effectiveness of this type of therapy in improving skeletal traits of patients with Down syndrome. The lateral cephalograms of 22 consecutive juveniles with Down syndrome, whose orofacial dysfunctions had been successfully treated with a stimulating plate according to Castillo Morales in infancy (17 months +/- 24 months), were examined 136 months on average (minimum of 78 months, maximum of 231 months) after initiation of treatment. In 16 of the 22 patients, the anomaly-typical bialveolar protrusion of the anterior teeth was diagnosed. The cephalometric results indicated larger values of cephalometric parameters concerning cranial base and maxilla, and markedly larger mandibular cephalometric values when compared to untreated children with Down syndrome. These results show that a stimulating plate may not always be indicated in patients with Down syndrome with a skeletal Class III pattern and minor orofacial findings.

CSF tau protein phosphorylated at threonine 231 correlates with cognitive decline in MCI subjects.

In this longitudinal study of 77 patients with mild cognitive impairment (MCI), the authors analyzed whether levels of tau protein phosphorylated at threonine 231 (p-tau(231)) in CSF correlate with progression of cognitive decline. High CSF p-tau(231) levels at baseline, but not total tau protein levels, correlated with cognitive decline and conversion from MCI to AD. Independently, old age and APOE-epsilon 4 carrier status were predictive as well. Our data indicate that an increased p-tau(231) level is a potential risk factor for cognitive decline in patients with MCI.

A non-randomised pilot study to compare complementary and conventional treatments of acute sinusitis.

BACKGROUND: It is still under discussion whether antibiotics are effective in the treatment of acute sinusitis. Moreover, they are known to have considerable side-effects. In contrast, complementary approaches are reported to have little side-effects and an equivalent efficiency. OBJECTIVES: To assess the success of conventional and complementary treatments of acute sinusitis and to estimate the patient numbers needed to confirm therapeutic equivalence. Treatment success was measured by three different scores, assessed by both patients and physicians. METHODS: Multicentre (2 complementary and 3 conventional ENT centres), non-randomised, controlled clinical trial with 63 patients (complementary group 30, conventional group 33 patients). To control for confounders treatment differences were estimated by propensity score techniques. TREATMENTS: The choice of medication was entirely left to the physician. We recommended to use antibiotics, secretolytics and symptomimetics in the conventional group and a combination of the herbal remedy Sinupret((R)) and the homeopathic remedy Cinnabaris 3X in the complementary group. RESULTS: Treatment differences varied substantially depending on the outcome measure, but they were always not clinically relevant. Conventional treatment was slightly better when the outcome was assessed by the physicians (1.8 score points) but slightly worse when it was assessed by patients (0.2 score points) or in terms of the HCG-5 quality of life score (0.8 score points). p values were always > 0.3. CONCLUSIONS: Both treatments appear to be equally effective (or ineffective). Results might be biased because both treatment groups differed substantially. Randomised trials including at least 400 patients are needed to produce valid results.

An example on the value of non-randomisation in clinical trials in complementary medicine.

BACKGROUND: Randomised clinical trials may in principle show a small external validity. Non-randomised clinical trials therefore are sometimes regarded as an appropriate alternative when complementary and conventional treatments are compared. OBJECTIVES: To assess the value of advanced statistical methods in the process of estimating differences between a complementary and a conventional treatment of acute sinusitis in a non-randomised clinical trial. METHODS: Multicentre, non-randomised, controlled clinical trial comparing 2 complementary and 3 conventional ENT centres. Patients were free to choose the physician (and hence the therapy). Treatment differences were estimated by controlling for confounders in analyses of covariance or by propensity score techniques. RESULTS: Most potential confounders (sex, age, life-style parameters) did not have significant effects on the choice of therapy. Disease severity and previous ENT surgery were the main confounding factors. At study onset they almost cause a defined separation of both treatment groups. As a result estimated treatment differences vary substantially depending on the chosen statistical model. CONCLUSIONS: When comparing complementary and conventional treatments, non-randomised clinical trials may be misleading. Results may be strongly biased even when advanced statistical methods are used. Trials of complex statistical designs are needed to give valid results.

A new rapid landmark-based regional MRI segmentation method of the brain.

BACKGROUND: Neurodegenerative and cerebrovascular diseases show a distinct distribution of regional atrophy and subcortical lesions. OBJECTIVE: To develop an easily applicable landmark-based method for segmentation of the brain into the four cerebral lobes from MRI images. METHOD: The segmentation method relies on a combination of anatomical landmarks and geometrical definitions. It is applied on the surface reconstruction of the MRI volume. The internal borders between the lobes are defined on the axial slices of the brain. The reliability of this method was determined from MRI scans of 10 subjects. To illustrate the use of the method, it was applied to MRI scans of an independent group of 10 healthy elderly subjects and 10 patients with vascular dementia to determine the regional distribution of white matter hyperintensities (WMH). RESULTS: The intra-rater relative error (and intra-class correlation coefficient) of the lobe segmentation ranged from 1.6% to 6.9% (from 0.91 to 0.99). The inter-rater relative error (and intra-class correlation coefficient) ranged from 1.4% to 5.2% (from 0.96 to 0.99). Density of WMH was significantly higher in all four lobes in VD patients compared to controls (p<0.05). Within each group, WMH density was significantly higher in frontal and parietal than in temporal and occipital lobes (p<0.05). CONCLUSION: This landmark based method can accommodate age and disease-related changes in brain morphology. It may be particularly useful for the study of neurodegenerative and cerebrovascular disease and for the validation of template-based automated techniques.

A polymorphism in the promoter of the serotonin transporter gene is not associated with suicidal behavior.

A 44 base pair deletion/insertion polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) was examined in 124 German suicide attempters, who were consecutively hospitalized, and 185 German normal control subjects without a history of any DSM-IV axis I or II mental disorder. Both patients and control subjects were recruited from the same geographic area. There was no significant difference in allele or genotype frequency between patients and control subjects. There were also no differences when the patients were divided into several subgroups (suicide attempters with a violent method, and suicide attempters with a lifetime history of mood disorders, unipolar depression, personality disorders). These results suggest that the 5-HTTLPR polymorphism is unlikely to play a major role in the genetic susceptibility to suicide attempts. Conflicting results among the present and previous studies regarding an association between the polymorphism and suicidal behavior, however, suggest the possibility that there may be unidentified specific subtypes of suicidal behavior that are significantly associated with the polymorphism or, alternatively, simply reflect false-positive association results.

Reduced levels of amyloid beta-peptide antibody in Alzheimer disease.

OBJECTIVE: To investigate whether it was possible to detect the presence and different levels of naturally occurring anti-beta-amyloid (Abeta) antibodies in the CSF of patients with AD and age-matched controls by employing a sensitive ELISA. BACKGROUND: Immunization with preaggregated amyloid beta-peptide (Abeta(1-42)) and administration of antibodies against Abeta into amyloid precursor protein APP(V717F)- transgenic mice (an animal model of AD) have recently been reported to dramatically reduce amyloid plaque deposition, neuritic dystrophy, and astrogliosis, most likely by enhancing Abeta clearance from brain. METHODS: A sensitive ELISA was performed to detect levels of naturally occurring anti-Abeta antibodies in the CSF of patients with AD and age-matched controls. Additionally, an immunoprecipitation assay was performed to confirm that naturally occurring anti-Abeta antibodies also exist in the human blood. RESULT: - Naturally occurring antibodies directed against Abeta were found in the CSF and plasma of patients with AD and healthy control subjects. Moreover, CSF anti-Abeta antibody titers are significantly lower in patients with AD compared with healthy control subjects. CONCLUSION: Naturally occurring antibodies directed against Abeta exist in human CSF and plasma. The CSF anti-Abeta antibody titers may be helpful in better understanding the effects of future immunologic therapies for AD.

Large-scale, multicenter study of cerebrospinal fluid tau protein phosphorylated at serine 199 for the antemortem diagnosis of Alzheimer's disease.

We surveyed a total of 570 cerebrospinal fluid (CSF) samples from a variety of diseases, including Alzheimer's disease (AD; n = 236), non-AD-demented and nondemented diseases (n = 239), and normal controls (n = 95) to quantitate levels of tau protein phosphorylated at serine 199 (CSF/phospho-tau199) by a recently established sandwich ELISA. The CSF/phospho-tau199 levels in the AD group were significantly elevated compared to those in all the other non-AD groups. Receiver operating characteristics curves showed that the diagnostic sensitivity and specificity for the AD group vs all the other non-AD groups using the CSF/phospho-tau199 were 85.2% and 85.0%, respectively. Furthermore, there was a significant positive correlation between CSF/phospho-tau199 and CSF/total-tau levels in the AD group. Elevated CSF/phospho-tau199 in the AD group was noted irrespective of age, gender, dementia severity, and number of apolipoprotein E4 alleles. Thus, we suggest that CSF/phospho-tau199 may be a novel and logical biomarker in supporting antemortem diagnosis of AD.

[Primary solitary malignant schwannoma of the trigeminal nerve, Report of a case and review of the literature]. / Primär solitäres malignes Schwannom des N. trigeminus. Fallbericht mit Literaturübersicht.

We present the case of a primary solitary malignant schwannoma of the trigeminal nerve. A total of 55 cases have been described in the literature; however, in these cases two tumors were affecting the supraorbital branch. This nerve-sheath tumor usually affects men in the fifth decade of life. The main clinical sign of malignant schwannomas of the head and neck is an indolent swelling. Hematogenic or lymphogenic metastasis has not been described. Because of the pleomorphism of the tumor cells immunohistochemical study is important. The treatment of choice is radical resection, possibly with adjuvant radio- or chemotherapy. The 5-year survival rate of malignant schwannoma of the trigeminal nerve is 41.7%.

Physical fitness influences water turnover and body water changes during trekking.

PURPOSE: This study was performed to assess water turnover and changes of body water during a trekking tour at moderate altitude. METHODS: Fifteen healthy normally trained adults participated in a 7-d backpack trek tour in the Swiss Alps (total walking distance: 120.5 km; cumulated altitude difference: 6990 m (uphill) and 7550 m downhill; lowest point: 1285 m; highest point: 3317 m). Total body water and water turnover were measured using deuterium dilution and elimination (oral load of 0.33 g 99.8% D2O per kg body weight, overnight equilibration period, pre- and postdose saliva samples immediately before and after sleep, analysis of D2O concentrations in saliva using Fourier-transform infrared spectroscopy, CV < 1%). Physical training state was assessed after the tour using the lactate-exercise intensity relationship obtained by performing 50-W increments every 3 min on a cycle ergometer. RESULTS: Body water decreased from the evening of day 0 to the evening of day 4 (from 45.3 +/- 7.3 L to 43.4 +/- 7.6 L, P < 0.05), and did not significantly decrease (43.5 +/- 7.9 L) until the evening of day 5 (maximum of trekking exercise intensity). Mean daily water turnover was 5.7 +/- 1.8 L x d(-1) corresponding to 78.7 +/- 17.5 mL x kg(-1) x d(-1). Body water changes and water turnover were significantly related to the exercise intensity obtained at the lactate threshold as well as at the level of 4 mM lactate. CONCLUSIONS: This correlation may be in part explained by differing glycogen content of muscle tissue.

[Homeopathic treatment of adenoid vegetations. Results of a prospective, randomized double-blind study]. / Die homöopathische Behandlung von adenoiden Vegetationen. Ergebnisse einer prospektiven, randomisierten Doppelblindstudie.

In a monocenter prospective randomized double-blind clinical trial the efficacy of homeopathic treatment was investigated on children with adenoid vegetations justifying an operation. Patients were treated with either homeopathic remedies such as Nux vomica D200, Okoubaka D3, Tuberculinum D200, Barium jodatum D4 and Barium jodatum D6 or with placebo. The duration of the study for each patient was 3 months. Examination of the ears using a microscope, rhinoscopy, stomatoscopy and pharyngoscopy, as well as tympanometry and audiometry were performed after 4, 8 and 12 weeks. Out of a total of 97 children studied between the ages of 4 to 10 years 82 could be analyzed. At the end of the study no operation was required in 70.7% of the placebo-treated children and in 78.1% of the children treated with homeopathic preparations. These results show no statistical significance.