[New aspects of immunotherapy in multiple sclerosis]. / Neues aus der Immuntherapie bei Multipler Sklerose.

The spectrum of therapeutic options for immunotherapy of multiple sclerosis is continuously broadening. After the approval of cladribine and ocrelizumab in Europe, two new drugs are now available with ocrelizumab being the first approved option for treatment of primary progressive multiple sclerosis; however, the increased use of highly effective therapies is accompanied by a rise in severe side effects. During recent months, special attention was paid to the new progressive multifocal leukoencephalopathy (PML) risk assessment in natalizumab-treated patients, cardiac side effects of fingolimod, cases of idiopathic thrombocytopenic purpura and listeria meningitis associated with alemtuzumab and cases of daclizumab-treated patients with liver failure or encephalitis. These case reports highlight the importance of careful monitoring of all patients treated with immunomodulatory therapies.

[Actual medical care situation and therapeutic needs in multiple sclerosis: Impact of the Pharmaceutical Market Restructuring Act (AMNOG)]. / Versorgungsrealität und therapeutischer Bedarf bei Multipler Sklerose : Auswirkungen des AMNOG.

BACKGROUND: The treatment of patients with multiple sclerosis (MS) is associated with constantly rising costs for the healthcare system and pharmaceuticals constitute 60 % of the direct medical costs. The Pharmaceutical Market Restructuring Act (Arzneimittelmarkt-Neuordnungsgesetz, AMNOG) came into force on 1 January 2011 with the aim of limiting the costs of pharmaceuticals by obligating newly approved products to be subjected to an early evaluation of the additional benefits by the Federal Joint Committee (FJC, Gemeinsamer Bundesausschuss, G­BA). The majority of products evaluated up to October 2015 in neurology (5 out of 8) were approved for treatment of MS. OBJECTIVE: Has the AMNOG been able to fulfill the original aims? MATERIAL AND METHODS: Analysis of available information on MS therapies evaluated by the FJC between December 2010 and October 2015. RESULTS: For various reasons an additional benefit could be shown in only 2 out of 5 assessment procedures for MS drugs. It is obvious that some methodological shortcomings of the process have to be improved. Additionally requirements for pivotal clinical trials have to be harmonized with AMNOG requirements taking the best available evidence and real-life data into consideration (e.g. non-interventional studies) and a closer collaboration between the FJC, healthcare providers and the neurological societies is necessary. CONCLUSION: The AMNOG procedure currently only partially fulfills the original aims, which could be the reason why guidelines play a more important role for therapy decision-making than FJC decisions. As the early evaluation procedure is an adaptive process methodological shortcomings might be overcome in the future; however, this requires a much closer collaboration between the FJC and neurological societies.

PT symmetry and spontaneous symmetry breaking in a microwave billiard.

We demonstrate the presence of parity-time (PT) symmetry for the non-Hermitian two-state Hamiltonian of a dissipative microwave billiard in the vicinity of an exceptional point (EP). The shape of the billiard depends on two parameters. The Hamiltonian is determined from the measured resonance spectrum on a fine grid in the parameter plane. After applying a purely imaginary diagonal shift to the Hamiltonian, its eigenvalues are either real or complex conjugate on a curve, which passes through the EP. An appropriate basis choice reveals its PT symmetry. Spontaneous symmetry breaking occurs at the EP.

[Pregabalin and gabapentin in multiple sclerosis: clinical experiences and therapeutic implications]. / Ionenkanalmodulatoren bei Multipler Sklerose : Bestandsaufnahme der Anwendung in der Praxis.

BACKGROUND: Due to a plethora of additional symptoms patients with multiple sclerosis (MS) receive symptomatic treatment besides disease-modifying therapies. Among the substances which are commonly used are ion channel modulators (e. g. pregabalin, gabapentin, carbamazepine). The aim of this study was to investigate the use of these drugs in clinical practice in a larger patient cohort. PATIENTS: Data from 533 MS patients [439 without and 94 patients with add-on therapy (treatment group)] were evaluated retrospectively. All patients received a detailed neurological examination including evaluation of EDSS scores. RESULTS: Pregabalin and gabapentin are used most commonly. Abnormal sensations are the most frequent reason for therapy initiation. Patients with higher EDSS values and/or under mitoxantrone treatment most frequently receive additional therapy. CONCLUSION: So far, it is not known whether the investigated agents exert a beneficial influence on the disease course of MS itself beyond a mere symptomatic treatment. Further research efforts and clinical studies are necessary to address this question.

The five bromotryptophans.

The five regioisomeric bromotryptophans (BrTrps) play an important role in the life of sponges and lower marine invertebrates. These bromo-amino acids, which are formed by post-translational modifications, are not found in nature in their free state, but rather are involved in more complex structures. Any of the BrTrps can be part of a peptide, a cyclic peptide, an indole alkaloid, an ergot alkaloid, a macrocycle and others. The present review covers the synthesis, physical and spectroscopic properties of the five BrTrps. It also describes the many exiting pharmacological and biological activities played by the BrTrps and by various secondary metabolites containing brominated tryptophan moieties. Of special interest are cyclic peptides containing the 2-BrTrp unit, which were isolated from marine sponges e.g. konbamide, orbiculamide A, the various keramamides, jaspamide eusynstyelamide and more. Important families of non-cyclic peptides containing the 6-BrTrp, include the styelins, the conotoxins, the cathelicidins and several constrained macrocyclic peptides. Many marine secondary BrTrp-containing, non-peptidic metabolites also display a remarkable spectrum of bioactivities, which can be harnessed for therapeutic and other purposes. Examples are: barettin, bromotryptanthrin, tetraacetyl clionamide, cyclocinamide A, clavicipitic acid, various brominated beta-carbolines. In this review we have presented the various synthetic routes leading to the preparation of the five BrTrps and many of its derivatives. Also, we have introduced the reader to many synthetic routes leading to BrTrp-containing non-peptidic natural products. Although the functional role of the various compounds in the human body is only poorly understood, its effects were extensively studied. Almost all of these compounds exhibit important therapeutic properties e.g. antifungal, antimicrobial, antihelmintic, insecticidal ichthyotoxic and anticancer activity. In the present review attempts have been made to provide synopsis, synthesis and symbiosis of chemical and biological actions, which may provide future guidance and facilitate further research in this area.

Insights from mathematical modelling for T cell migration into the central nervous system.

The migration of immune cells from peripheral immune organs into the central nervous system (CNS) through the blood-brain barrier (BBB) is a tightly regulated process. The complex interplay between cells of the BBB and immune cells coordinates cell migration as a part of normal immune surveillance while its dysregulation is critically involved in the pathogenesis of various CNS diseases. To develop tools for a deeper understanding of distribution and migratory pattern of immune cells regulated by the BBB, we made use of a mathematical modelling approach derived from Markov chain theory. We present a data-driven model using a derivation of kinetic differential equations from a particle game. According to the theory of gases, these equations allow one to predict the mean behaviour of a large class of cells by modelling cell-cell interactions. We used this model to assess the distribution of naive, central memory and effector memory T lymphocytes in the peripheral blood and cerebrospinal fluid. Our model allows us to evaluate the impact of activation status, migratory capacity and cell death for cell distribution in the peripheral blood and the CNS.

Experiencia de aplicación de modelos de seguimiento de cumplimiento del perfil de egreso en el plan de estudios en las carreras de la Facultad de Medicina de la Universidad Finis Terrae / Experience of applying models for monitoring compliance with the graduation profile in the study plan in the careers of the Faculty of Medicine of the Finis Terrae University

El Perfil de egreso constituye un modelo teórico y la imagen del profesional que la institución de educación superior aspira formar. Es un conjunto de atributos que son certificados y le permiten a una persona ser reconocida y aceptada por la sociedad como profesional. La emergencia de estándares de calidad, utilizados por las agencias de acreditación de carreras universitarias, hoy exigen la necesidad de evaluar y rendir cuentas acerca del logro de las competencias establecidas y declaradas en el perfil de egreso, sin embargo, hay escasa evidencia concreta que demuestre modelos operativos de cómo abordar ese proceso de evaluación en distintos programas. Dada la relevancia del Perfil de Egreso de una carrera de pregrado y considerando que constituye el eje fundamental para el desarrollo curricular de los programas educativos, para realizar el proceso de autoevaluación y la posterior acreditación de las carreras, diseñamos e implementamos un modelo de seguimiento del cumplimiento del perfil de egreso en el plan de estudios de las carreras de la Facultad de Medicina de la Universidad Finis Terrae.

The Graduate Profile constitutes the theoretical model and the professional image that higher education aspires to form. It is a set of certified attributes and allows a person to be recognized and accepted by society as a professional. The emergence of quality standards, used by university careers' accreditation agencies, demands the need to evaluate and be accountable for achieving the competencies established and declared in the Graduate Profile. However, the is limited concrete evidence to demonstrate operational models of how to approach this evaluation process in different programs. Given the relevance of the Graduate Profile of an undergraduate career and considering that it constitutes the fundamental axis for the curricular development of educational programs, to carry out the self-evaluation process and the subsequent accreditation of the degrees, we design and implement a model for monitoring the compliance with the graduation profile in the study plan of the Faculty of Medicine of Universidad Finis Terrae.

Electrical pharyngeal stimulation increases substance P level in saliva.

BACKGROUND: Substance P (SP) is a neuropeptide known to enhance the swallow response. It likely acts as a neurotransmitter in the pharyngeal mucosa in response to local stimuli. It has been proposed that dysphagia after stroke may be related to reduced levels of SP, which therefore constitutes a therapeutic target. In the present pilot study, we evaluated whether electrical pharyngeal stimulation (EPS), a neuromodulation device to enhance cortical reorganization for the restoration of swallowing function after brain injury, is able to increase SP in saliva or serum. METHODS: In a randomized crossover study design, 20 healthy volunteers were treated with 10 min of real (0.2-ms pulses, 5 Hz, 280 V, stimulation intensity (mA) individually adjusted to tolerance level) or sham EPS on two separate sessions. Stimulation was delivered via a pair of bipolar ring electrodes mounted on an intraluminal catheter positioned in the pharynx. Blood and saliva samples were taken prior to, during, and up to 1 h after EPS and analyzed for their SP concentration by ELISA. KEY RESULTS: Following real EPS but not sham stimulation, SP levels in saliva increased immediately and significantly about 28% (p < 0.01) compared to baseline. Serum levels remained unchanged. CONCLUSIONS & INFERENCES: Electrical pharyngeal stimulation is able to induce pharyngeal SP release in healthy subjects.

Taurine analogues; a new class of therapeutics: retrospect and prospects.

Taurine was discovered more than two hundred years ago from animal sources. It is distributed in both mammals and non-mammals and its content is high in several tissues. For more than a century-and-a-half, taurine was regarded just as an end product of sulfur metabolism. Recently, taurine has been rediscovered and its beneficial effects in processes like epilepsy, hypertension, congestive heart failure and diabetes have been well-documented. It was patented and found some clinical utility, but being an amino acid, therapeutic use confronts limitations like restricted permeability and more. This necessitates the development of pro-drugs (analogues) mainly derivatives of taurine. A large number of taurine derivatives have been reported in the literature with partial to marked activity. Taurine derivatives like taltrimide, acamprosate and tauromustine, are already in the market as anti-convulsant, anti-alcoholic and anti-cancer agents. Many other analogues are effective in experimental models. The in depth analysis of these analogues and their biological actions can provide certain clues for further consideration. In the present review, attempts have been made to provide synopsis, synthesis and symbiosis of chemical and biological actions, which may provide future guidance and facilitate further research in this area. The successful journey of these analogues to clinical utility is a healthy and happy sign and an index of bright future, and we hope that this review will provide enough input to ignite the minds.

The role of soluble growth factors in inducing transient growth and clonal extinction of stroma cell dependent erythroblastic leukemia cells.

A coculture system of a murine erythroblastic leukemia cell line (ELM-D) with its supportive stromal cell line (MS-5) was established. Long-term growth of ELM-D cells is strictly stroma cell dependent. Interaction between stem cell factor (SCF) and its receptor, c-kit, was demonstrated to be important for stroma cell-dependent growth by anti c-kit neutralizing monoclonal antibody (mAb) inhibition experiments. Significantly, soluble growth factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3) or SCF of MS-5 stromal cells (MS-5 CM) could replace the requirement of stroma cells for a considerable period. However, ELM-D cells maintained in these growth factors underwent clonal extinction after 3-6 weeks unless contact with stroma was re-established. Furthermore, IL-3 or GM-CSF acted in a dominant manner in inducing cell death in the presence of stroma cells. Cells showing clonal extinction undergo programmed cell death and do not differentiate. These altered growth properties of ELM-D cells exposed to soluble growth factors or to stroma cells appear to be analogous to those described for T or B cells primed by antigen presenting cells and then grown in growth factors.

Glucocorticoid-induced lymphoma cell growth inhibition: the role of leukotriene B4.

Glucocorticoid-sensitive murine S49.1 lymphoma cells respond in a biphasic way to the steroid challenge. The first effect of corticosteroids is to induce a reversible growth inhibition, which is probably permissive for the following cytolysis. Distinct mechanisms for the two effects are likely. Since dilution of S49.1 lymphoma cultures resulted in a drastic reduction of the proliferation rate, which could be overcome by the addition of conditioned medium, the proliferation appears to depend on the presence of autocrine growth factors. Therefore, the cytostatic effect of corticosteroids could possibly be attributable to an interference with the production of endogenous growth factors. Analysis of the growth-promoting activity in culture supernatant showed that the critical growth factor in diluted cultures is an arachidonic acid metabolite, the leukotriene B4. The role of leukotriene B4 in S49.1 cell proliferation received further support from the finding that while nordihydroguaiaretic acid, an inhibitor of the lipoxygenase pathway which is necessary for leukotriene formation blocked lymphoma multiplication, indomethacin, an inhibitor of cyclooxygenase activity, did not affect proliferation. Quantitation of the leukotriene B4 content of dexamethasone-treated vs. untreated cultures revealed an almost complete inhibition of leukotriene production, pointing to the significance of this mechanism for the glucocorticoid-induced lymphoma growth inhibition. Moreover, these findings offer a new approach to increase the therapeutic effectiveness of glucocorticoid therapy of steroid-sensitive leukemias and lymphomas.

Effects of SC-56525, a potent, orally active renin inhibitor, in salt-depleted and renal hypertensive dogs.

SC-56525 is a nanomolar inhibitor of plasma renin activity in human, cynomolgus monkey, dog, guinea pig, Yucatan micropig, and rabbit but is less active in rat. The oral bioavailability of SC-56525 in conscious dogs at doses of 5 mg/kg IV and 30 mg/kg PO was 66.1 +/- 16.4%. Oral dosing with SC-56525 at 3, 10, and 30 mg/kg in salt-depleted dogs induced a dose-dependent reduction in mean arterial pressure and inhibition of plasma renin activity with no significant effect on heart rate. In two-kidney, one clip renal hypertensive dogs, SC-56525 given orally at 10, 30, and 60 mg/kg daily for 4 days lowered blood pressure significantly. In conscious dogs monitored in their home cages via radiotelemetry, no significant changes in heart rate occurred in response to large drops in blood pressure in both renal hypertensive and salt-depleted dogs with the renin inhibitor SC-56525. SC-56525 is a nanomolar, orally active inhibitor of renin and effectively lowers blood pressure in both salt-depleted and renal hypertensive dogs.

Long-term disease-free survival of patients with advanced mantle-cell lymphoma following high-dose chemotherapy.

In advanced stage mantle cell lymphoma, conventional chemotherapy yields a complete remission rate below 40%, and the median survival rate is only about 3 years. Between 1991 and 1996 we treated nine such patients (six male; three female) with high-dose chemotherapy (six of these also with 12 Gy fractionated total body irradiation (TBI)) and peripheral stem cell support (n = 8) or allogeneic bone marrow transplantation (n = 1). The median age was 47 years (range, 28-61). At the time of high-dose chemotherapy, five patients were in first complete remission (CR), two in first partial remission (PR) and two in second remission (CR = 1; PR = 1). High-dose chemotherapy included TBI (12 Gy), etoposide and cyclophosphamide (patients 1-5), TBI and cyclophosphamide (patient 7), busulfan, etoposide and cyclophosphamide (patients 6 and 9), cyclophosphamide and busulfan (patient 8). The patterns of toxicity according to the Bearman score were usually mild (mucositis grade 2, n = 7; renal grade I, n = 2) with no therapy-related fatality. Only one patient developed hepatic toxicity grade III (veno-occlusive disease) but recovered completely. The median time to neutrophil engraftment was 10 days (range, 8-15). After high-dose chemotherapy all patients achieved complete remission. After a median follow-up of 22 months (range, 9.4-64) all patients remain in continuous complete remission. These encouraging results suggest that high-dose chemotherapy can be applied safely and leads to long-term disease-free survival in otherwise incurable disease.

Effects of a high-dose treatment of methamphetamine on caudate dopamine and anorexia in rats.

Dose-effect curves of d-methamphetamine (MA) on intake of sweetened condensed milk by rats were obtained before and after twice a day treatment for four days with either saline (control) or a high (50 mg/kg) dose of MA previously shown to decrease the dopamine levels of the caudate. The animals that were more sensitive to MA's anorexic effect during the before-treatment determination were found to be more sensitive to the lethal effects of the high-dose treatment. This treatment produced a six month decrease in brain dopamine but no change in the anorexic effect on milk intake or in the stereotypic behavior elicited by the drug. Subsequently, the daily administration of 2.5 mg/kg of MA, 15 min before presentation of the milk, to both control and treatment groups produced tolerance to the drug's anorexic effect. After 4 to 5 weeks of repeated administration of this dose there was a significant difference between the control group's intake of milk and treatment group's intake as well as body weight. These differences indicate an effect on the treatment upon the formation of tolerance to the anorexic effects of MA.

An alternative to managed care: a "guild" model for the independent practice of psychotherapy.

As health care is reconfigured by HMOs and managed care organizations, family therapists often have to decide whether or not to cooperate with the new power structures and their ways of doing things. The chief concern of many therapists is the ethical bind created when the managed care organization demands breaches of confidentiality or makes decisions about the course of treatment that may not, in the therapist's opinion, be in the best interest of the family. Associations of independent, nonmanaged care psychotherapists are springing up in response to these dilemmas. This paper describes the philosophical evolution and organizational development of one such association.

XIAP-targeting drugs re-sensitize PIK3CA-mutated colorectal cancer cells for death receptor-induced apoptosis.

Mutations in the oncogenic PIK3CA gene are found in 10-20% of colorectal cancers (CRCs) and are associated with poor prognosis. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and agonistic TRAIL death receptor antibodies emerged as promising anti-neoplastic therapeutics, but to date failed to prove their capability in the clinical setting as especially primary tumors exhibit high rates of TRAIL resistance. In our study, we investigated the molecular mechanisms underlying TRAIL resistance in CRC cells with a mutant PIK3CA (PIK3CA-mut) gene. We show that inhibition of the constitutively active phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway only partially overcame TRAIL resistance in PIK3CA-mut-protected HCT116 cells, although synergistic effects of TRAIL plus PI3K, Akt or cyclin-dependent kinase (CDK) inhibitors could be noted. In sharp contrast, TRAIL triggered full-blown cell death induction in HCT116 PIK3CA-mut cells treated with proteasome inhibitors such as bortezomib and MG132. At the molecular level, resistance of HCT116 PIK3CA-mut cells against TRAIL was reflected by impaired caspase-3 activation and we provide evidence for a crucial involvement of the E3-ligase X-linked inhibitor of apoptosis protein (XIAP) therein. Drugs interfering with the activity and/or the expression of XIAP, such as the second mitochondria-derived activator of caspase mimetic BV6 and mithramycin-A, completely restored TRAIL sensitivity in PIK3CA-mut-protected HCT116 cells independent of a functional mitochondrial cell death pathway. Importantly, proteasome inhibitors and XIAP-targeting agents also sensitized other CRC cell lines with mutated PIK3CA for TRAIL-induced cell death. Together, our data suggest that proteasome- or XIAP-targeting drugs offer a novel therapeutic approach to overcome TRAIL resistance in PIK3CA-mutated CRC.

Dielectric square resonator investigated with microwave experiments.

We present a detailed experimental study of the symmetry properties and the momentum space representation of the field distributions of a dielectric square resonator as well as the comparison with a semiclassical model. The experiments have been performed with a flat ceramic microwave resonator. Both the resonance spectra and the field distributions were measured. The momentum space representations of the latter evidenced that the resonant states are each related to a specific classical torus, leading to the regular structure of the spectrum. Furthermore, they allow for a precise determination of the refractive index. Measurements with different arrangements of the emitting and the receiving antennas were performed and their influence on the symmetry properties of the field distributions was investigated in detail, showing that resonances with specific symmetries can be selected purposefully. In addition, the length spectrum deduced from the measured resonance spectra and the trace formula for the dielectric square resonator are discussed in the framework of the semiclassical model.

Long-term effects of dalfampridine in patients with multiple sclerosis.

BACKGROUND/OBJECTIVE: Dalfampridine is the extended-release formulation of 4-aminopyridine and is approved for the symptomatic treatment of impaired mobility in patients with multiple sclerosis. Our aim was to examine the short- and long-term effects of treatment with dalfampridine on motoric and cognitive assessment parameters of multiple sclerosis (MS) patients over 9-12 months. METHODS: Fifty-two patients with MS with an EDSS between 4.0 and 7.0 and impaired mobility were evaluated for parameters of walking ability, MSFC, cognitive and motor fatigue and evoked potentials at treatment initiation with dalfampridine as well as 2 weeks and after 9-12 months later. RESULTS: Thirty out of fifty-two patients (~60%) were still on treatment after 9-12 months. Two weeks after treatment initiation, significant ameliorations could be found for T25FW, maximum walking distance as well as motoric and cognitive fatigue which still persisted after 9-12 months. In contrast significant effects for velocity were observed only after 2 weeks, for improvement in PASAT only after 9-12 months. A tendency for improvement of somatosensory evoked potentials was found in a subset of patients. CONCLUSION: Dalfampridine shows positive short- and long-term effects on motoric and cognitive assessment parameters in an open-label observational study in a cohort of patients with MS.

Localized lasing modes of triangular organic microlasers.

We investigated experimentally the ray-wave correspondence in organic microlasers of various triangular shapes. Triangular billiards are of interest since they are the simplest cases of polygonal billiards and the existence and properties of periodic orbits in triangles are not yet fully understood. The microlasers with symmetric shapes that were investigated exhibited states localized on simple periodic orbits, and their lasing characteristics like spectra and far-field distributions could be well explained by the properties of the periodic orbits. Furthermore, asymmetric triangles that do not feature simple periodic orbits were studied. Their lasing properties were found to be more complicated and could not be explained by periodic orbits.