[Healthcare behavior of migraine and headache patients when treatment is accompanied by the digital migraine app]. / Gesundheitsverhalten von Migräne- und Kopfschmerzpatienten bei digitaler Therapiebegleitung mit der Migräne-App.

BACKGROUND: Tension-type headache and migraine are the second and third most prevalent disorders of mankind worldwide, after dental caries. The widespread implementation of smartphones enables the use of specific software applications (apps) for digital treatment accompaniment. In this study, the use of the migraine app (Migräne-App) for iOS and Android was examined in the practical treatment of migraine and headache patients in an extensive population sample. METHODS: An online survey was developed for the analysis of experiences as part of the treatment accompaniment and app usage. It contains questions concerning sociodemographic variables, the course of headache disorders and the previous treatment as well as the usage of the migraine app. The survey establishes compliance to the recommended treatment, the treatment plan, and treatment rules devised by the treating physician. The data collected were compared to traditional pen and paper documentation, prior to using the migraine app. RESULTS: A total of 1464 users participated in the standardized survey. The average age was 47.19 ± 11.37 years (87.4% female, 12.5% male). On average, users suffered from headaches for 27.28 ± 13.6 years. The majority (76.5%) were cared for by a general practitioner. Of the users 70.9% reported that they presented the aggregated data from the app to their physician on consultation, 76.4% reported that the migraine app helped them to adhere to the treatment plan designed together with their physician and the rules about headache therapy. It showed both a highly significant reduction of headache days per months prior to usage (13.30 ± 7.45 days) in comparison to at the time of conducting the survey (10.03 ± 7.30 days) as well as a highly significant reduction of intake of acute medication (before 7.61 ± 5.58 vs. ongoing 6.78 ± 4.72 days). CONCLUSION: The data show that the digital treatment control for therapy decisions made by the physician is highly relevant and established. Therapy compliance is improved and possible complications such as headache due to medication overuse are reduced. At the same time, a significant improvement of headache parameters and a marked overall improvement of treatment quality, amongst other things due to more easily available information and self-help tools can be observed.

Brain stimulation in obesity.

Obesity is taking up epidemic proportions worldwide with significant impacts on the health of both the affected individual and on society as a whole. Treatment approaches consist of behavioural and pharmacological approaches, however, these are often found to be ineffective. In severe obesity, bariatric surgery is frequently performed. Unfortunately, 40% of patients show substantial weight gain over the long term or display the associated metabolic syndrome, making the development of novel therapies necessary. This review summarizes some of the current conceptual models, in particularly the 'food addiction' model, and then discusses specific therapeutic targets of brain stimulation, both non-invasive (transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS) and transcutaneous vagus nerve stimulation (VNS)) and invasive (deep brain stimulation and invasive VNS). As we will show, neuromodulatory approaches represent a promising tool for targeting specific brain structures implicated in the pathophysiology of obesity. Non-invasive techniques such as TMS, tDCS and transcutaneous VNS need further investigation before they may become ready for clinical usage. The currently available study data suggest that deep brain stimulation may become an effective and acceptable therapy for otherwise treatment-resistant obese patients. The results of the currently undergoing clinical trials are eagerly awaited.

[Peppermint oil in the acute treatment of tension-type headache]. / Oleum menthae piperitae (Pfefferminzöl) in der Akuttherapie des Kopfschmerzes vom Spannungstyp.

Tension-type headache is the most frequent form of headache. The local topical treatment with peppermint oil (oleum menthae piperitae) has proven to be significantly more effective than placebo in controlled studies. Peppermint oil targets headache pathophysiology in multiple ways. The efficacy is comparable to that of acetylsalicylic acid or paracetamol. Solutions of 10 % peppermint oil in ethanol are licensed for the treatment of tension-type headache in adults and children above 6 years. It is included in treatment recommendations and guidelines by the respective professional societies and is regarded as a standard treatment for the acute therapy of tension-type headaches.

[Classification and therapy of medication-overuse headache: impact of the third edition of the International Classification of Headache Disorders]. / Klassifikation und Therapie des Medikamenten-Übergebrauch-Kopfschmerzes (MÜK) : Auswirkungen der 3. Auflage der internationalen Kopfschmerzklassifikation auf die Praxis.

The diagnosis of medication-overuse headache (MOH) is of central importance because this secondary headache disorder can be treated very effectively and patients do not usually respond to headache prophylaxis as long as MOH persists. The article describes important changes in the diagnostic criteria of different MOH subtypes after publication of the International Classification of Headache Disorders (ICHD-3beta) in 2013. The new classification has a crucial and direct impact on prevention and treatment of MOH. In addition interactions exist with the new criteria of chronic migraine. With a controlled medication intake scheme according to the 10-20 rule and using a medication break, MOH usually remits in most patients. If patient education and advice does not lead to remission of MOH, a specialized managed medication break or withdrawal treatment becomes necessary. This can be done on an outpatient, day clinic or inpatient basis. In uncomplicated cases, the results of these three treatment settings do not differ. From a cost-effectiveness standpoint, the outpatient treatment should be given priority. In complicated cases, a fully inpatient withdrawal treatment using a multimodal treatment concept is significantly superior.

[Headache from increased cerebrospinal fluid pressure]. / Kopfschmerz durch Liquordrucksteigerung.

Increased cerebrospinal fluid (CSF) pressure is often accompanied by headache. The term idiopathic intracranial hypertension (pseudotumor cerebri) describes an increase in CSF pressure without a space-occupying intracranial lesion or hydrocephalus. After headaches, visual field defects are the second most common feature. Therapeutic measures include both drugs and surgical procedures. In high-pressure hydrocephalus, the volume of the CSF is increased, resulting either from increased production or reduced absorption. If an acquired or congenital obstruction of the ventricular system can be demonstrated, the term non-communicating hydrocephalus is used. In contrast, the CSF passage is blocked outside the ventricles in communicating hydrocephalus. Symptoms include diffuse headache worsening in the morning and with the Valsalva-like maneuver. Treatment is guided by etiology whenever possible; otherwise, drainage of CSF by ventriculostomy or shunt is necessary.

[Paroxysmal hemicrania and SUNCT]. / Paroxysmale Hemikranie und SUNCT.

Paroxysmal hemicrania is experienced as headache attacks with pain and accompanying symptoms similar to those of cluster headaches. Attacks are, however of shorter duration, occur more frequently, affect predominantly women and respond reliably to indomethacin. Paroxysmal hemicrania can also occur secondary to an identifiable cause. To exclude symptomatic, paroxysmal hemicrania, especially with an atypical clinical picture and poor response to indomethacin, a careful diagnostic approach is necessary. The SUNCT syndrome (short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing) is characterized by one-sided pain attacks of short duration, much shorter than other trigeminal autonomic cephalgias. Classically, the pain is accompanied by ipsilateral lacrimation and conjunctival injection. Some patients have been described with both cluster headache and trigeminal neuralgia. These patients should receive both diagnoses. It is important to differentiate these headache entities as specific therapy is needed for each to achieve optimal pain relief.

Disturbed glucocorticoid receptor autoregulation and corticotropin response to dexamethasone in depressives pretreated with metyrapone.

We studied glucocorticoid receptor autoregulation and corticotropin response to dexamethasone in depressed patients and controls, attempting to control for the confounding effect of endogenous glucocorticoids. After depletion of endogenous cortisol, depressed patients showed an attenuated suppressibility of corticotropin by dexamethasone in the face of unchanged dexamethasone plasma levels. Beta-endorphin levels were strongly correlated with adrenocorticotropic hormone (ACTH) concentrations. Although metyrapone administration resulted in a marked rise of glucocorticoid receptor sites per cell in controls, this effect was not present in depressives. These data support the hypothesis of a decreased glucocorticoid receptor plasticity and a partial steroid resistance in depression.

Autophosphorylation of cGMP-dependent protein kinase is stimulated only by occupancy of one of the two cGMP binding sites.

cGMP-Dependent protein kinase contains, per subunit, 2 binding sites for cGMP. The apparent KD values for site 1 and 2 were 12 and 55 nM. The analogues 8-benzyl-amino-cAMP and N2-monobutyryl-cGMP bind preferentially to site 1 and 2, respectively. Both analogues stimulate autophosphorylation of the enzyme at concentrations at which only half of the phosphotransferase activity of the enzyme is expressed. Complete expression of the phosphotransferase activity requires a high concentration of each analogue and is accompanied by inhibition of the autophosphorylation reactions. It is concluded that occupancy of site 1 or 2 stimulates autophosphorylation while occupancy of both sites prevents autophosphorylation.

A pathogen-inducible divinyl ether synthase (CYP74D) from elicitor-treated potato suspension cells.

In elicitor-treated potato cells, 9-lipoxygenase-derived oxylipins accumulate with the divinyl ether colneleic acid as the major metabolite. Here, the identification of a potato cDNA is described, whose predicted amino acid sequence corresponds to divinyl ether synthases, belonging to the recently identified new P450 subfamily CYP74D. The recombinant protein was expressed in Escherichia coli and shown to metabolize 9-hydroperoxy linoleic acid to colneleic acid at pH 6.5. This fatty acid derivative has been implicated in functioning as a plant antimicrobial compound. RNA blot analyses revealed accumulation of divinyl ether synthase transcripts both upon infiltration of potato leaves with Pseudomonas syringae and after infection with Phytophthora infestans.

Characterization of Glucocorticoid Binding Capacity in Human Mononuclear Lymphocytes: Increase by Metyrapone is Prevented by Dexamethasone Pretreatment.

Abstract Autoregulation of receptor systems by their own ligands is a well established biological phenomenon. While down-regulation of the glucocorticoid binding capacity by glucocorticoids has been shown in animals and humans, data on up-regulation processes in humans are lacking. To further explore glucocorticoid receptor plasticity in relation to endogenous ligands, glucocorticoid binding parameters were assessed in 15 healthy controls before and after oral administration of 1.5 g metyrapone with and without dexamethasone pretreatment. Administration of metyrapone resulted in blockade of the feedback of the hypothalamic-pituitary-adrenal system as shown by the rise in adrenocorticotropin levels, while pretreatment with 1 mg dexamethasone completely suppressed adrenocorticotropin concentrations. Glucocorticoid binding sites per lymphocyte exhibited an increase of 63% following metyrapone administration, which was prevented by dexamethasone pretreatment. Comparison of morning and afternoon glucocorticoid binding sites per cell in 11 healthy volunteers further revealed a diurnal rhythm of glucocorticoid receptor sites. These data suggest that human lymphocyte glucocorticoid receptors are under autoregulatory control.

Lymphocyte glucocorticoid receptor binding during depression and after clinical recovery.

Lymphocyte glucocorticoid receptor binding parameters were studied in 15 severely depressed patients during depression and after clinical recovery, and in 15 healthy controls. There was no difference in glucocorticoid receptor number or affinity between depressed patients and recovered or control subjects. Afternoon ACTH and cortisol concentrations did not differ significantly between the three groups. No relationship could be established between glucocorticoid receptor binding and antidepressant medication. These data support the view of an impaired ligand-induced plasticity of glucocorticoid receptor regulation rather than the hypothesis of decreased glucocorticoid receptor numbers during depression.

Platelet function and hemolysis in centrifugal pumps: in vitro investigations.

The effects of centrifugal pumps on blood components other than erythrocytes, namely platelets and their interaction with the coagulation system, are not very well known. In a comparative study with three centrifugal pumps (BioMedicus BP-80, St. Jude Isoflow, and Sarns Delphin) and the Stockert roller pump hemolysis, platelet counts, thromboplastin and partial thromboplastin times, as well as resonance thrombography (RTG) parameters for the assessment of platelet and coagulation function were evaluated in vitro. Normalized indices of hemolysis (NIH) with ACD anticoagulation after 360 minutes were 0.008+/-0.004 (Isoflow), 0.018+/-0.017 (BP-80), 0.085+/-0.051 (Delphin), and 0.049+/-0.010 g/1001 (roller pump). Plasmatic coagulation was activated in all circuits. Platelet function was severely inhibited by the BP-80, indicated by increase in RTG platelet time to 358%+/-150% of initial values compared to 42%+/-29% (Isoflow), 40%+/-20% (Delphin), and 12%+/-10% (roller pump). Fibrin polymerization was affected similarly. The large surface area of the BP-80 leads to an extensive activation of platelets and plasminogen.

[First experiences with a miniaturized heart-lung-machine]. / First experiences with a miniaturized heart-lung-machine.

Conventional heart-lung-machines (HLM) used for many cardiosurgical procedures lead to an impaired function of nearly all organs. This deleterious effect may be reduced by miniaturized HLMs. Therefore we report on our first experiences in 9 patients (4 women, 5 men) undergoing beating heart coronary artery bypass grafting from 10/01 to 04/02 in our department employing a miniaturized HLM with the Deltastream extracorporeal rotary blood pump. Eight patients had an uneventful postoperative course, one patient died on the first postoperative day. Using this miniaturized HLM beating heart coronary artery bypass grafting was successful in all patients. Further studies are necessary to support these results.

Functional expression cloning identifies COX-2 as a suppressor of antigen-specific cancer immunity.

The efficacy of immune surveillance and antigen-specific cancer immunotherapy equally depends on the activation of a sustained immune response targeting cancer antigens and the susceptibility of cancer cells to immune effector mechanisms. Using functional expression cloning and T-cell receptor (TCR) transgenic mice, we have identified cyclooxygenase 2/prostaglandin-endoperoxide synthase 2 (COX-2) as resistance factor against the cytotoxicity induced by activated, antigen-specific T cells. Expressing COX-2, but not a catalytically inactive COX-2 mutant, increased the clonogenic survival of E1A-transformed murine cancer cells when cocultured with lymphocytes from St42Rag2(-/-) mice harboring a transgenic TCR directed against an E1A epitope. COX-2 expressing tumors established in immune-deficient mice were less susceptible to adoptive immunotherapy with TCR transgenic lymphocytes in vivo. Also, immune surveillance of COX-2-positive tumor cells in TCR transgenic mice was less efficient. The growth of murine MC-GP tumors, which show high endogenous COX-2 expression, in immunocompetent mice was effectively suppressed by treatment with a selective COX-2 inhibitor, celecoxib. Mechanistically, COX-2 expression blunted the interferon-gamma release of antigen-specific T cells exposed to their respective cellular targets, and increased the expression of interleukin-4 and indoleamine 2,3-dioxygenase by tumor cells. Addition of interferon-gamma sensitized COX-2 expressing cancer cells to tumor suppression by antigen-specific T cells. In conclusion, COX-2, which is frequently induced in colorectal cancer, contributes to immune evasion and resistance to antigen-specific cancer immunotherapy by local suppression of T-cell effector functions.

Diagnosis of small bowel Crohn's disease: a prospective comparison of capsule endoscopy with magnetic resonance imaging and fluoroscopic enteroclysis.

BACKGROUND AND AIMS: The diagnostic yield of capsule endoscopy (CE) compared with magnetic resonance imaging (MRI) in small bowel Crohn's disease is not well established. We prospectively investigated CE, MRI, and double contrast fluoroscopy in patients with suspected small bowel Crohn's disease. METHODS: Fifty two consecutive patients (39 females, 13 males) were investigated by MRI, fluoroscopy and--if bowel obstruction could be excluded--by CE. In 25, Crohn's disease was newly suspected while the diagnosis of Crohn's disease (non-small bowel) had been previously established in 27. RESULTS: Small bowel Crohn's disease was diagnosed in 41 of 52 patients (79%). CE was not accomplished in 14 patients due to bowel strictures. Of the remaining 27 patients, CE, MRI, and fluoroscopy detected small bowel Crohn's disease in 25 (93%), 21 (78%), and 7 (of 21; 33%) cases, respectively. CE was the only diagnostic tool in four patients. CE was slightly more sensitive than MRI (12 v 10 of 13 in suspected Crohn's disease and 13 v 11 of 14 in established Crohn's disease). MRI detected inflammatory conglomerates and enteric fistulae in three and two cases, respectively. CONCLUSION: CE and MRI are complementary methods for diagnosing small bowel Crohn's disease. CE is capable of detecting limited mucosal lesions that may be missed by MRI, but awareness of bowel obstruction is mandatory. In contrast, MRI is helpful in identifying transmural Crohn's disease and extraluminal lesions, and may exclude strictures.

Calmodulin activates bovine-cardiac myosin light-chain kinase by increasing the affinity for myosin light-chain 2.

The basic mechanism by which calmodulin activates bovine-cardiac muscle myosin light-chain kinase was investigated using highly purified preparations of mixed bovine-cardiac myosin light chains or isolated myosin light chain 2. The apparent contamination of these substrate proteins by calmodulin, as detected by activation of calmodulin-sensitive phosphodiesterase, was less than 4 parts/million and was undetectable by antibodies against calmodulin. The apparent KA for calmodulin was 2 nM and 20 nM in the presence of isolated myosin light-chain 2 and mixed myosin light chains, respectively. Purified bovine cardiac troponin C activated myosin light-chain kinase by about 10% at a concentration of 2 microM. Mixed myosin light chains were phosphorylated in the absence and presence of calmodulin and in the presence of calcium with a V of 11.1 and 11.0 mumol phosphate transferred min-1 (mg enzyme)-1, respectively. The apparent Km values for mixed myosin light chains were 8.0 and 0.35 mg/ml in the absence and presence of calmodulin, respectively. Similarly calmodulin lowered the Km value for isolated myosin light-chain 2 over 20-fold and increased the V value only about 1.5-fold. Activity observed in the absence of calmodulin was dependent on the presence of calcium and was suppressed by chelating free calcium either before or during a phosphorylation reaction. The apparent KA for calcium was 1.2 microM and 0.4 microM in the absence and presence of calmodulin. Activity in the absence of calmodulin was inhibited at very high concentrations of the 'specific' calmodulin antagonists W-7, trifluoperazine and R24571 with apparent IC50 values of 0.3 mM, 0.2 mM and 0.02 mM. Antibiotics raised against calmodulin suppressed completely the kinase activity in the presence of calmodulin but had no effect on the activity measured in its absence. These results suggest that calmodulin stimulates the activity of bovine-cardiac myosin light-chain kinase by increasing over 20-fold the affinity for its substrate myosin light-chain 2.

Production of polyclonal and monoclonal antibodies against hyphae from arbuscular mycorrhizal fungi.

Polyclonal and monoclonal antibodies were produced against hyphae of the arbuscular mycorrhizal fungus Glomus monosporum. The polyclonal antibodies (pAbs) were raised in a rabbit by immunizing with hyphae. They were tested for their specificity by a dot-immunoblot assay (DIBA). After the third immunization, a distinct difference in the signal strength was observed between the antisera and the preimmune serum. The pAbs showed cross-reactions to a number of fungal species, both mycorrhizal and other. For the production of monoclonal antibodies (mAbs), mice were immunized intraperitoneally with hyphae. The resulting hybridoma cell culture supernatants were tested by an indirect immunolabeling procedure. For this purpose the hyphae were immobilized on silane-coated microscopic slides. The mAb 8A7 reacted with hyphae from all Glomus isolates tested so far. Cross-reactivities were not observed with hyphae from fungi of the family Acaulosporaceae, phytopathogenic fungi tested so far, or from spores from Glomus species.

Phosphorylation of cGMP-dependent protein kinase increases the affinity for cyclic AMP.

Cyclic-GMP-dependent protein kinase contains two binding sites for cGMP, which have different affinities for cGMP. Autophosphorylation of the enzyme affects mainly the binding of cGMP to the 'high'-affinity site (site 1). The enzyme binds cAMP and cAMP stimulates the phosphotransferase activity of the native enzyme half-maximally at 44 microM. Autophosphorylation of the enzyme decreases the apparent Ka value to 7 microM. Autophosphorylation does not affect the catalytic rate of the enzyme if measured at a saturating concentration of ATP. Tritiated cAMP apparently binds at 4 degrees C to one site with a Kd value of 3 microM. Binding to the second site is not measurable. Autophosphorylation of the enzyme increases the affinity of the high-affinity site for cAMP sixfold (Kd 0.46 microM) and allows the detection of a second site. In accordance with these data the dissociation rate of [3H]cAMP from the high-affinity site is decreased from 4.5 min-1 to 1.2 min-1 by autophosphorylation. Experiments in which unlabeled cAMP competes with [3H] cGMP for the two binding sites confirmed these results. Recalculation of the competition curves by a computer program for two binding sites indicated that autophosphorylation decreases the Kd value for binding of cAMP to the high-affinity site from 1.9 microM to 0.17 microM. Autophosphorylation does not affect significantly the affinity for the second site. Kd values for site 2 varied from 17 microM to 40 microM. These results suggest that autophosphorylation of cGMP-dependent protein kinase increases the affinity of the enzyme for cAMP by affecting mainly the properties of binding site 1.