Ethical issues in funding orphan drug research and development

This essay outlines the moral dilemma of funding orphan drug research and development. To date, ethical aspects of priority setting for research funding have not been an issue of discussion in the bioethics debate. Conflicting moral obligations of beneficence and distributive justice appear to demand very different levels of funding for orphan drug research. The two types of orphan disease, rare diseases and tropical diseases, however, present very different ethical challenges to questions about allocation of research funds. The dilemma is analysed considering utilitarian and rights based theories of justice and moral obligations of non-abandonment and a professional obligation to advance medical science. The limitations of standard economic evaluation tools and other priority setting tools used to inform health policy decision makers on research funding decisions are outlined.     

Protein pattern of cerebrospinal fluid in various neurological diseases

CSF/serum albumin and immunoglobulin G ratios were determined in 520 patients suffering from various neurological diseases. Blood-brain barrier impairment was detectable in most cases of spinal tumour, meningitis, Guillain-Barré syndrome and in two-thirds of the patients with cerebral infarctions. A local IgG formation in the CNS has to be assumed for some cases of meningitis considering the course of the protein dysequilibrium. Autochthonous IgG production together with a barrier dysfunction was found in patients with encephalitis, meningoradiculitis and neurosyphilis. In cases of multiple sclerosis local IgG formation in the CNS was the predominant finding.     

Vergleichende elektromyographische und myelographische Untersuchungen bei lumbalen Bandscheibenoperationen

Zusammenfassung Bei 156 wegen eines lumbalen Bandscheibenschadens hemilaminektomierten Patienten wurden die Ergebnisse der präoperativen elektromyographischen und myelographischen Befunde mit denen der Operationsprotokolle mittels einer Kovarianzanalyse verglichen. Die Operations-und Myelographiebefunde wurden in vier Schweregrade, in mono- und bisegmentalen Befall und je nach der Lage des Bandscheibenschadens in laterale, extrem laterale und mediale Vorfälle unterteilt. Das Elektromyogramm (EMG) der Bein- und autochtonen lumbalen Rückenmuskulatur wurde nach Myotomen geordnet und in sechs Stadien eingeteilt. Die statistische Auswertung zeigt, daß das EMG in 69,2% exakt Höhe und Ausmaß einer lumbalen Discushernie feststellen kann und der Myelographie mit 31,2% an Treffsicherheit (bisegmentaler Befall bei monosegmentaler Diagnose oder umgekehrt) deutlich überlegen ist. Zusätzlich liegt eine Teilübereinstimmung mit dem Operationsbefund beim EMG in 19,5%, bei der Myelographie in 33,8% vor. Das EMG versagt bei akuten radikulären Syndromen innerhalb der ersten 14 Tage und bei Discushernien am thorakolumbalen Übergang. An Hand der Operations-und EMG-Befunde werden die Kennmuskeln für die Myotome L1–S1 festgelegt. Denervierungszeichen in drei Kennmuskeln eines Myotoms und Ableitung aus mehreren Myotomen erhöhen die Treffsicherheit elektromyographischer Diagnosen. Denervierungszeichen in der autochtonen lumbalen Paravertebralmuskulatur sind immer ein sicheres Zeichen für eine Nervenwurzelbeteiligung.Die Elektromyographie ist eine ambulante Untersuchungsmethode und ohne Risiko für den Patienten, während die Myelographie nur stationär durchgeführt werden kann und für den Patienten eine wesentlich größere Belastung darstellt. Die diagnostische Aussagekraft eines EMG ist bei unserer Fragestellung in den meisten Fällen der einer Myelographie überlegen. Nur wenn das EMG nicht exakt Höhe und Ausmaß eines radikulären Syndroms feststellen kann, ist eine präoperative Myelographie indiziert.

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Comperative analysis of electromyography and myelography in cases of lumbar radiculopathy

Summary Preoperative electromyographical and myelographical findings in 156 patients undergoing surgery because of lumbar radiculopathy were compared with the corresponding surgical reports by means of covariance analysis.The EMG's of leg and lumbar paravertebral muscles were rated according to severity of pathological signs using a rating scale of 6 stages. The EMG's were also divided into groups according to myotomes involved. The surgical and myelographical reports were divided into 4 groups according to severity of the process and further classified according to mono- or bisegmental lesions and to localization of the herniated disc, i. e. lateral, extremely lateral and medial.The statistical analysis proved that the EMG accurately revealed level and extent of the lumbar radiculopathy in 69.2% of the cases with a respective figure of 31.2% for the myelography. There was a partial agreement between findings during surgery and those of the EMG in 19.5% and those of myelography in 33.8%. The EMG was inconclusive during the first 2 weeks of acute radicular syndromes as it was in herniated discs of the thoracolumbar region and in symptoms arising from affections of the cauda equina.The crucial muscles for the myotomes L1 to S1 as determined by comparing the findings during surgery with the EMG recordings of the ventral leg muscles were as follows: L1 and L2: M. adductores; L3: M. quadriceps femoris; L4: M. quadriceps femoris and M. tibialis anterior; L5: M. extensor hallucis longus, M. tibialis posterior and Mm. peronei, and S1: M. triceps surae and M. extensor digitorum brevis. Signs of denervation in three crucial of one myotome and in the lumbar paravertebral muscles were enhancing the diagnostic accuracy of the EMG.While the EMG may be performed on an outpatient basis without risk there is some stress inherent in myelography requiring the patient to stay in the hospital. Apart from the aforementioned exceptions recording the EMG from leg and paravertebral muscles should be preferred over myelography in cases of lumbar radiculopathy because of its greater diagnostic conclusiveness.

     

Effect of the isolation method and staining procedure on the morphology of the virion ribonucleoprotein of Sendai virus

Electron microscopic examinations of morphology of Sendai virus ribonucleoprotein (RNP) isolated from purified virions by two methods and simultaneous staining of the preparations with uranyl acetate and phosphotungstate acid (PTA) were carried out. The staining method was shown not to influence the kind of nucleoproteins which had been isolated from disrupted virions by sucrose density gradient centrifugation. With both strains RNP appeared as strongly helixed filaments. The staining method, however, strongly influenced morphology of RNP isolated from disrupted virions by equilibrium centrifugation in cesium chloride density gradient. After uranyl acetate staining RNP had an appearance of hard filaments whereas in the same preparation stained with PTA partially and completely unwound spirals of nucleocapsid were found alongside with strongly spiralized structures.     

Surgical therapy of cerebrovascular insufficiency with reference to advanced age

After brief discussion of epidemiology, aetiology, localization, diagnosis and surgical management of vascular stenoses leading to cerebral insufficiency, the results of 433 carotid artery TEAs are reported. Short- and long-term results were investigated to determine to what extent age of the patients affects outcome. The analysis of our patients sample showed with respect to perioperative mortality, morbidity and long-term outcome no significant difference between the under- and over-70-year age groups. In stage I (asymptomatic bruits) the perioperative mortality of the younger group (N = 119) was 1% and in the older group no perioperative death occurred. The long-term survival rate and the proportion of patients without neurological dysfunction after 4 years was 65% and 85% respectively for the younger group and 88% and 80% for the over 70-year age group. In stage II patients (with transient ischaemic attacks) the perioperative mortality was the same for both groups (2%). The long-term survival rate for the younger group (N = 106) was 77% and 76% in the older group (N = 91) proportion of patients without neurological dysfunction was 87% for the younger group and 93% for the older patient sample. There were no patients with stage III occlusion (acute stroke) in our patient sample. In stage IV (completed stroke) the younger patients had a perioperative mortality of 5.7%. In the older group (N = 18) no patient died perioperatively. The 2-year survival rates were 61% for the older age group and 57% für the younger. The corresponding proportions of patients without neurological dysfunction after 4 years were 83% and 71% for the older and younger patient groups respectively.     

Inhibitors of cation-chloride-cotransporters affect hypoxic/hypoglycemic injury in hippocampal slices

Electroneutral cation-chloride cotransporters are abundantly expressed in the brain and are involved in the regulation of the intracellular Cl(-) concentration and thus gamma-aminobutyric acid-dependent inhibition of neuronal excitability. As yet there is little evidence whether or not Na(+)-K(+)-2Cl(-) or K(+)-Cl(-) cotransporters are involved in neuronal hyperexcitability and death in cerebral ischemia. In this study, by measuring propidium iodide staining in organotypic hippocampal slice cultures from young rats and population spike recovery in acutely isolated hippocampal slices from adult rats after a hypoxic/hypoglycemic insult, we were able to assess if cation-chloride cotransport inhibitors reduce neuronal injury. The Na(+)-K(+)-2Cl(-) cotransport inhibitor bumetanide in the range of 1-10 microM reduced neuronal damage in the slice cultures by 25%, but did not affect population spike recovery in acutely isolated slices. In contrast the K(+)-Cl(-) cotransport inhibitor [(dihydroindenyl)oxy] alkanoic acid (DIOA, 100 microM) significantly diminished the restitution of the population spikes from 33% before to 8% after hypoxia/hypoglycemia and increased the damage in the slice cultures by 60%. Consequently, our data suggest that the Na(+)-K(+)-2Cl(-) cotransporter may contribute to neuronal injury and that the activity of the K(+)-Cl(-) cotransporters is an intrinsic protective mechanism of neurons against ischemic damage.     

Time is brain — Competence is brain

Zusammenfassung Das angelsächsische Stroke-Unit-Konzept entwickelte sich zunächst als eine rehabilitative Einrichtung mit akutmedizinischer Versorgung, während in Deutschland beim Aufbau der Stroke Units das multimodale Monitoring des Schlaganfallpatienten als neurovaskulärer Notfall und die zunehmende Anwendung der Lysetherapie konzeptionell bestimmend waren. In den angelsächsischen Stroke Units wurde die eindrucksvolle Prognoseverbesserung der Schlaganfallpatienten durch die Stroke-Unit-Behandlung evidenzbasiert bewiesen. Dem therapeutischen Erfolg liegen zwei wesentliche Prinzipien zugrunde, (1) die ausschließliche Behandlung von Schlaganfallpatienten in dieser Einheit und (2) der Team-Approach, d. h. die multiprofessionelle Expertengruppe als Therapeuten. Beide Prinzipien wurden in den deutschen Stroke Units konsequent umgesetzt. Zwei Entwicklungen in Richtung einer Komplettierung und Vereinheitlichung der Stroke-Unit-Behandlung zeichnen sich inzwischen in Europa ab: In England und Skandinavien wird in den Stroke Units zunehmend akzeptiert, dass das multimodale apparative Monitoring notwendig ist und die Prognose zusätzlich verbessert. In den deutschen Stroke Units wird die Schnittstelle zwischen der 3- bis 4-tägigen Stroke-Unit-Behandlung und der nachbehandelnden Allgemeinstation durch Einbeziehung der bereits vorhandenen Ressourcen in eine erweiterte Stroke Unit überwunden. Diese erweiterte Stroke Unit kommt dem britischen Konzept der Comprehensive Stroke Unit, d. h. der Akutbehandlung mit früh einsetzenden Rehabilitationstherapie aus einer Hand, sehr nahe. Die übrigen Mitglieder der Stroke Unit Kommission sind:Peter Berlit, Essen; Christoph Diener, Essen; Karl-Heinz Grotemeyer, Saarbrücken; Roman L. Haberl, München; Werner Hacke, Heidelberg; Lutz Harms, Berlin; Manfred Kaps, Gießen; Christoph Kessler, Greifswald und Klaus Lowitzsch, Heidelberg     

Quantification of tension in Thera-Band and Cando tubing at different strains and starting lengths

AIM: Elastic resistance exercise is frequently used in rehabilitation programs. Precise quantification using color coded bands is not possible. A method to predict forces for any length of mostly used elastic tubings and thereby a general equation for the comparison of elastic material is presented. METHODS: In an in vitro-series the tubing tension in relation to elongation of 6 colors of Thera-Band and Cando tubings was directly measured. The relation between tension and elongation was determined depending on different resting lengths. In clinical practice tension and elongation are prescribed. Two mathematical methods to calculate the resting length as regulatory variable are presented. One is based on the construction of iso-tension curves, the 2nd on the general mathematical relation delta % tension=K* % length change+n. RESULTS: 1. The tension/elongation relation is linear beyond a threshold in the early part of elongation. 2. The iso-tension method works graphically and facilitates the precise determination of resting length. 3. The double % relation between tension and elongation method describes the general properties of all tubings, where K=0.75 is a general constant. To calculate absolute values for the resting length, corresponding to a given tension and elongation, special 'color constants' are presented. CONCLUSIONS: The prediction of maximum tension values for any given elongation is possible by simple variation of resting length. These findings may improve the usefulness of elastic tubings in rehabilitation programs. The mathematical method further may be used for the comparison of elastic materials with linear characteristics.