Studies on Propafenone-type Modulators of Multidrug-Resistance IV: Synthesis and Pharmacological Activity of 5-Hydroxy and 5-Benzyloxy Derivatives

A series of 5-hydroxy and 5-benzyloxy analogs of the antiarrhythmic and multidrug resistance (MDR) modulating drug propafenone was synthesized and the MDR-modulating activity of the compounds was evaluated using a daunomycin efflux assay system. The key step of the synthesis is the selective reduction of the double bond in 1 without cleavage of the benzyl group thus leading to the phenol 3 . Alkylation with epichlorohydrine followed by nucleophilic epoxide ring opening gave the benzylated target compounds 5a–d . Subsequent cleavage of the benzyl group gave the 5-hydroxy analogs 6a–d . Structure activity relationship studies showed, that the 5-hydroxy derivates 6a–d fit the log P/log potency correlation line previously established for a series of propafenone analogs. In contrast, all four 5-benzyloxy analogs 5a–d showed almost identical EC₅₀ values, independent of their log P value.     

Familial hemiplegic migraine and autosomal dominant arteriopathy with leukoencephalopathy (CADASIL)

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a recently described familial cerebrovascular disorder shown to map to chromosome 19q12. Familial hemiplegic migraine has also been shown in some families to map close to the CADASIL locus. The fully developed CADASIL phenotype consists of recurrent strokes developing in the fourth decade, progressing to a pseudobulbar palsy, spastic quadriparesis, and subcortical dementia. In an Irish family 15 members were fully investigated by magnetic resonance scanning; 10 had typical magnetic resonance features of CADASIL. Five members of this family had familial hemiplegic migraine and 4 of these had magnetic resonance evidence of CADASIL. Two other members had migraine with and without aura as a presenting clinical symptom of CADASIL. This disorder has been shown by linkage analysis to map to the CADASIL locus at chromosome 19. The phenotype at presentation of CADASIL in this family was variable and age related and included familial hemiplegic migraine, migraine with and without aura, transient ischemic attacks, strokes, and spinal cord infarction. This family study increases our understanding of the spectrum of clinical manifestations of this underrecognized familial cerebrovascular disorder.     

Effect of positioning on oxygenation in single-lung transplant recipients.

BACKGROUND: Many benefits and adverse effects of positioning are related to changes in ventilation and perfusion. A number of unique factors related to the allograft make the effects of positioning difficult to determine in single-lung transplant recipients. OBJECTIVES: To determine the effect of 3 body positions (supine, lateral with allograft lung down, and lateral with native lung down) on oxygenation and blood flow in single-lung transplant recipients in the 24 hours immediately after surgery. METHODS: A quasi-experimental repeated-measures design with stratified assignment to 1 of 3 different sequencing patterns for turning group was used to study 15 transplant recipients, 9 with emphysema and 6 with fibrosis. Oxygenation, ventilation, and blood flow measures (heart rate, blood pressure) were assessed after each turn. The effect of ischemic reperfusion injury was also explored. RESULTS: The oxygenation, ventilation, and bloodflow variables did not differ significantly across group, diagnosis, or time. Oxygenation variables measured when the allograft lung was dependent did not differ significantly from such measurements obtained when the native lung was dependent. CONCLUSIONS: No single position maximizes oxygenation in the immediate postoperative period in single-lung transplant recipients. Although a single standard protocol for positioning cannot be supported, the study does support the idea that transplant recipients can be safely turned in the immediate postoperative period without compromising oxygenation or hemodynamic status.     

Messung der psychischen Belastung nach akutem Myokardinfarkt mit Hilfe der SCL-90-R

Zusammenfassung. Ziel: Die psychische Belastung bei Patienten mit akutem Herzinfarkt innerhalb der ersten 48 h auf der Intensivstation des Städtischen Krankenhauses Kiel wird mit Hilfe der Symptom-Checkliste (SCL-90-R) gemessen. Patienten und Methodik: 134 hauptsächlich wegen eines akuten Herzinfarkts aufgenommene Patienten wurden zwischen August 1996 und Juli 1999 randomisiert ausgewählt. Sie füllten einen der Intensivstation angepassten Fragebogen aus, der u. a. neben Fragen zu sozioökonomischen Daten die standardisierten SCL-90-R enthält. Ergebnisse: Erhöhte Mittelwerte zeigten sich vor allem für die Skalen Somatisierung, Ängstlichkeit, Depressivität und GSI (Global Severity Index) bei solchen Patienten, die wenig soziale Unterstützung bekamen und über ein niedriges Einkommen verfügten. Schlussfolgerung: Da für Patienten mit schlechtem sozialen Netzwerk, niedrigem sozialen Status, erhöhter Angst und Depressivität eine schlechtere Prognose hinsichtlich der Mortalität und Wiedereingliederung in den Beruf beschrieben wurde, ist es im prospektiven Verlauf dieser Studie notwendig, gerade diese Patienten hinsichtlich der Entwicklung ihrer Angst zu erfassen und zu behandeln. Abstract. Objective: 134 patients with acute myocardial infarction, who were treated in an intensive care unit (ICU) of a German hospital in Kiel between 1996 and 1999 were selected for the study to examine their psychologic symptoms. Patients and Methods: The patients were asked to fill in the self-report inventory, the Symptom Checklist-90-Revised (SCL-90-R) within the first 48 h after their arrival in the ICU. Results: Patients with a low social status were found to have elevated mean values of the following scales: somatization (0.93), depression (0.66), and anxiety (0.59). The Global Severity Index (GSI) as a global measure of psychologic distress was elevated as well (0.46). Conclusion: Since patients with a limited social network and low social status, increased anxiety and depressive scores have a poor prognosis as to their mortality and their professional reintegration, it it considered necessary for the prospective setting of this study to register particularly those patients in order to treat their anxiety.     

Changing patterns of intellectual strengths and weaknesses in males with fragile X syndrome

Examined the changing profiles of intelligence in males with fragile X syndrome as these individuals increased in chronological age. Using a psychometric instrument designed to measure styles of information processing, 21 males aged 4 to 27 years were examined cross-sectionally in sequential processing, simultaneous processing, and achievement. The age of the subject was associated with age-equivalent levels of both simultaneous processing and achievement, but fragile X males did not show higher levels of sequential processing with increasing chronological age. Compared to younger fragile X males, the older subjects were more delayed in sequential processing skills relative to their abilities in other areas. A smaller longitudinal study confirmed the presence of a plateau in sequential processing among those subjects tested two times after the age of 10 years. Implications are discussed for diagnosis, intervention, and the matching of subject groups in mental retardation research.This research was supported in part by the John Merck Fund, the Joseph P. Kennedy, Jr. Foundation, NIH grants RR00125 and HD03008, and NIMH grants MH18268 and MH30929. We thank Wendy Marans and Joel Bregman for their comments on an earlier draft of this paper.     

Evaluation of Functional Capacity after Stroke as a Basis for Active Intervention

ABSTRACT This paper describes further testing of an Activity Index introduced by Hamrin & Wohlin, which was designed especially to evaluate the functional capacity of patients after stroke. The results of reliability tests and validation procedures are presented, in particular in comparison with the internationally well known Katz Index of Independence in Activities of Daily Living. The standardised item alpha reliability coefficient for the Activity Index was 0.97 for the total score (n= 231) and the corresponding value for the Katz Index of ADL was 0.94. Using factor analysis with four factors, 88.3% of the variances of the 16 variables of the Activity Index could be explained, and the different variables were found to have a logical distribution between the factors. In a two-factor analysis of the Katz Index of ADL, 89.6% of the variance of the six variables could be explained, and the hierarchical structure of the test was recognised. Compared with the Katz Index of ADL, the Activity Index had a higher predictive capacity and it also better measured changes in the patient's functional ability between different test occasions.     

Behavioural Problems in Children with Infantile Hydrocephalus

The occurrence of behavioural problems in a population-based series of children with infantile hydrocephalus (non-spina bifida) was analysed, using parent questionnaires. Children with both infantile hydrocephalus and mental retardation had significantly more behavioural problems compared with those with no mental retardation and controls. Inattentiveness and hyperactivity were particularly typical. No differences were found between children with infantile hydrocephalus and no mental retardation and the control group.