Antibodies for targeted cancer therapy -- technical aspects and clinical perspectives.

The efficacy of traditional anti-cancer agents comes with the price of toxicity to normal cells, which limits the success of therapy. In the past 2 decades, greater understanding of the molecular differences between malignant and normal cells has led to the development of therapies that more specifically target human tumors. These include new anti-cancer agents directed against intracellular targets associated with malignant alterations, such as increased proliferation, impaired apoptosis or angiogenesis. In addition, antibodies have been developed that are directed towards tumor-associated antigens and provide tailor-made effector functions by inhibiting cell growth, inducing apoptosis or constituting cytotoxic drug delivery systems. Since the targeted approach of anti-cancer therapies increases the exposure of malignant cells and at the same time reduces the exposure of normal tissues, it offers the promise of enhanced efficacy and lower side effects. Antibodies, immunoconjugates and liposomal drug delivery systems derived thereof are now mainstream cancer therapeutics, and by the end of 2003 17 marketed antibody-based products generated several billion in combined annual sales. This study highlights the most recent breakthroughs in antibody technology and summarizes major achievements in antibody-based cancer therapy in oncology trials.     

Fatigue in neuroimmunological diseases

Journal of Neurology - Fatigue is a widespread symptom in numerous neuroimmunological diseases like multiple sclerosis (MS), myasthenia gravis, morbus Behcet, neurosarcoidosis, neuroborreliosis or...     

Heart Transplantation in a 68-Year-Old Patient with Senile Systemic Amyloidosis

Senile systemic amyloidosis (SSA) results from deposition, predominantly in the heart, of amyloid fibrils derived from wild-type transthyretin (T TR) molecules. Cardiac autopsies indicate that SSA progressively increases in subjects 80 years of age and older. However, only a few cases of patients with SSA and cardiac failure have been recognized by cardiac biopsies during life. Here, we report a case of heart transplantation in a 68-year-old male patient with SSA. After cardiopulmonary resuscitation in October 1998, he underwent complete evaluation. Myocardial biopsies revealed the presence of amyloid deposition. Immunohistochemical staining of the amyloid indicated T TR. Genomic DNA analysis of the T TR exons did not result in any identification of a mutation. In 2001, heart transplantation was performed because progressive heart failure occurred. At the 1-year follow-up, no amyloid deposits were found in the donor heart. At the 2-year follow-up, the patient's physical and mental health was excellent. We conclude that heart transplantation can be an effective treatment in progressive heart failure due to SSA.     

Nonlinear excitation profiles for three-dimensional inflow MR angiography

An RF excitation pulse for three-dimensional (3D) time-of-flight (TOP) MR angiography (MRA) with a nonlinear excitation profile was numerically calculated under the condition of uniform vessel signal across the excitation volume (slab), and the superiority of the optform pulse as compared with conventional RF pulses and TONE pulses was demonstrated. For this purpose we acquired MRA of the lower leg and of the carotid and vertebral arteries in a 30-year-old healthy volunteer. Although the flow velocity ranges in these two anatomic locations are different by about a factor of 10, in both cases the corresponding optform pulse provided the best signal homogeneity at the highest level.     

Poverty and health in West Germany

Summary The relationship between poverty and several health-related characteristics in West Germany was investigated. Data were derived from the National and Regional Health Surveys conducted in West Germany from 1984 to 1992. 25544 males and 25719 females with German nationality aged 25–69 years were examined. Poverty was defined as a household income of 50% less than the mean for West Germany. Multiple logistic regression analysis was used to analyze the relationship between poverty and four health variables: individual health behavior, subjective assessment of health status, cardiovascular disease risk factors, and self-reported prevalence of lifetime chronic diseases. 10.2% of males and 12.8% of females were classified as being below the poverty line. For most but not all health parameters, less favourable results were found for the segment of the population with a household income below the poverty line. The most striking poverty-related differences were observed for lack of regular sport activities, subjective health satisfaction, obesity and myocardial infarction/stroke. Significantly lower prevalence rates for study subjects below the poverty line were observed for hypercholesterolemia in females only. Allergic disorders were the only chronic diseases reported significantly less often in males and females below the poverty line. Poverty has strong effects on individual health status and the prevalence of chronic diseases. Due to the rising unemployment rates in Germany in the last years it is very likely that the strong negative consequences of poverty for health are increasing.

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Zusammenfassung Es wird untersucht, welche Zusammenhänge zwischen Armut und verschiedenen gesundheitsbezogenen Merkmalen bestehen. Datenbasis sind die nationalen und regionalen Gesundheitssurveys, die in den Jahren 1984 bis 1992 in Westdeutschland durchgeführt wurden. 25544 Männer und 25719 Frauen mit deutscher Nationalität im Alter von 25 bis 69 Jahren wurden einbezogen. Armut wurde definiert als ein Haushaltseinkommen, das um 50% niedriger ist als das mittlere Einkommen in Westdeutschland. Die statistische Auswertung erfolgte mittels multipler logischer Regressionsanalyse, 10,2% der Männer und 12,8% der Frauen hatten ein Haushaltseinkommen unterhalb der Armutsgrenze. Die ausgeprägtesten armutsbezogenen Unterschiede wurden beobachtet für den Mangel an körperlicher Bewegung, die subjektive Gesundheitszufriedenheit, das starke. Übergewicht und die kardiovaskulären Krankheiten. Signifikant niedrigere Prävalenzen für Personen mit Einkommen unterhalb der Armutsgrenze ergaben sich bei den Frauen für den Risikofaktor Hypercholesterinämie. Allergien waren die einzige chronische Krankheit, die bei beiden Geschlechtern signifikant seltener in der von Armut betroffenen Bevölkerungsgruppe berichtet wurde. Vor dem Hintergrund der in den letzten Jahren stark angestiegenen Arbeitslosigkeit in Deutschland ist zu befürchten, dass die negativen Konsequenzen der Armut für die gesundheitliche Lage deutlich zugenommen haben.

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Résumé Les rapports entre pauvreté et differents indices sanitaires ont été examinés. Les donnees proviennent des surveys de santé nationales et régionales, réalisées en Allemagne de l'Ouest durant les années 1984 à 1992. 25719 femmes et 25544 hommes de nationalité allemande entre 25 et 69 ans ont paticipé. Le seuil de pauvreté a été fixé à un revenu égal a 50% du revenu moyen en Allemagne de l'Ouest. On a analysé les indices sanitaires suivants: le comportement sanitaire individuell, l'auto-estimation de sa santé, les facteurs de risque cardio-vasculaires et la prévalence des maladies chroniques. L'analyse statistique a été réalisée par regression logique multiple. 12,8% des femmes et 10,2% des hommes avaient un revenu inferieur au seuil de pauvreté. Pour la majorité des indices sanitaires on a trouvé des résultats défavorables pour la groupe ayant un revenu au dessous du seuil de pauvreté. Le manque de mouvement, l'auto-estimation de sa santé, l'excés de poids et les maladies cardio-vasculaires sont les indices quid diffèrent, relatif à la pauvreté, le plus. Les femmes ayant un revenu au-dessous du seuil de pauvreté ont des pourcentages de prévalence inférieurs significatifs pour le facteur de risque hypercholestérolémie. Les allergies sont les seules maladies qui existent significativement moins souvent chez les deux sexes de la groupe des pauvres. En résumé, la pauvreté présente un désavantage pour la santé individuelle et la prévalence des maladies chroniques. Sachant que le taux de chômage s'est aggravé pendant les dernières années, il est à craindre que les effets négatifs de la pauvreté sur la situation sanitaire ont nettement augmenté.

     

Azulene als Dienophile in der [4+2]-Cycloaddition mit inversem Elektronenbedarf,eine Ergänzung

Azulenes as Dienophiles in the [4+2]-Cycloaddition with Inverse Electron Demand, a Supplement [4+2] Cycloadditions of azulene ( 2 ) und 1-Nitroazulene ( 14 ) with the extremely electron-deficient, s-cis-fixed diazadiene system of 3,6-bis(trifluoromethyl)-1,2,4,5-tetrazine ( 1 ) are described. In addition to earlier findings 1 reacts with 2 probably in a two step [4+2] cycloaddition via 8 and 10 to yield the benzo[f]phthalazine 5a , via 8 and 9 to furnish the azuleno[d]pyridazine 3 and the azine 4 . The reaction of 1 with 1-Nitroazulene ( 14 ) leads to the azuleno[d]pyridazines 3 and 19 in low yield.     

Amplification of the c-erbB oncogene is associated with malignancy in primary tumours of neuroepithelial tissue

Summary In various primary brain tumours of neuroepithelial tissue recombinant DNA techniques were used to demonstrate changes of the epidermal growth factor receptor gene, which is homologous to the c-erbB oncogene. Twenty-one of 40 grade III/IV tumours, but only 1 of 16 grade I/II tumours were found to contain amplified and/or rearranged c-erbB sequences. This highly significant difference suggest that c-erbB amplification, rearrangement, or both, are important steps in malignant transformation in a subset of patients with neuroepithelial tumours.     

Responses of Neurons of the Nucleus of the Optic Tract and the Dorsal Terminal Nucleus of the Accessory Optic Tract in the Awake Monkey

The nucleus of the optic tract (NOT) and the dorsal terminal nucleus of the accessory optic tract (DTN) are essential nuclei for the generation of slow-phase eye movements during horizontal optokinetic nystagmus. We recorded from 101 neurons (all directionally selective) in four NOT/DTN of three trained and behaving rhesus monkeys. Neuronal activity increased when stimuli moved ipsiversively with respect to the recording site and decreased below spontaneous activity when stimuli moved contraversively. While the monkey fixated a small spot, some NOT/DTN neurons did not respond at all to the retinal image slip of a whole-field random dot pattern; others showed a monotonic increase of activity to increasing velocities of that stimulus. The velocity range tested was up to 100°/s. During the execution of optokinetic nystagmus, 39 of 73 cells tested showed a velocity-tuned response with an average optimum at 21°/s retinal image slip. Following saccades during optokinetic nystagmus (quick phases), the NOT/DTN neuronal activity briefly attained the level of spontaneous activity, as predicted from the velocity selectivity during optokinetic nystagmus. Immediately upon cessation of optokinetic stimulation in the preferred direction, NOT/DTN activity returned to the spontaneous level and did not reflect the ongoing optokinetic afternystagmus in darkness. Most NOT/DTN neurons displayed direction selectivity also during smooth pursuit. Twenty-one of 50 cells tested (42%) always responded to the retinal slip of the target (target velocity cells), 16 cells (32%) responded to the retinal slip of the background (background velocity cells), and 13 cells (26%) did not respond at all during smooth pursuit. We conclude from our results that the NOT/DTN is an essential structure for the processing of the direction and speed of retinal image slip. This information is then used for the generation and maintenance of slow eye movements, preferentially during horizontal optokinetic nystagmus but also during pursuit eye movements.