A phase I trial of the pharmacokinetics, toxicity, and activity of KNI-272, an inhibitor of HIV-1 protease, in patients with AIDS or symptomatic HIV infection.

The pharmacokinetics, toxicity, and activity of KNI-272, a transition state inhibitor of HIV-1 protease, was assessed in a phase I trial. After an initial phase in which the pharmacokinetics were assessed, 37 patients with AIDS or symptomatic HIV infection and 100-400 CD4 cells/mm3 were entered in an escalating dose study. KNI-272 was administered four times daily for up to 12 weeks. Oral bioavailability ranged from 22 to 55% and was not appreciably different in the fasting and post-prandial state. The dose limiting toxicity was hepatic transaminase elevation; this could be reduced by escalating the dose over 4 weeks. When administered this way, the maximum tolerated oral dose was 40 mg/kg per day. At the highest two tolerated doses (26.4 and 40 mg/kg per day), there was some evidence of an anti-HIV effect with median decreases of 0.2-0.3 log10 copies/ml plasma HIV RNA; these decreases persisted through 7-8 weeks of treatment. There was an upward trend in the CD4 count at the 40 mg/kg per day dose but not at other doses. Additional studies focused on approaches to improve the therapeutic index of KNI-272 may be warranted.     

Co-cultivation of Niemann-Pick disease type C fibroblasts belonging to complementation groupsα andβ stimulates LDL-derived cholesterol esterification

Summary Niemann-Pick disease type C (NPC) is a neurovisceral storage disorder with an unknown primary deficiency. Somatic cell hybridization experiments using human cultured fibroblasts have shown that two complementation groups (NPC- and NPC-) are associated with the biochemical and clinical phenotypes comprising NPC. We identified the rarer complementation group NPC- originally using the technique of filipin staining as a marker for complementation. In this study we show that the esterification of cholesterol derived from the LDL pathway can be used as an isotopic assay. However, multinuclear hybrids exhibit a delayed induction in this pathway. Furthermore, we discovered that, in the presence of an LDL source, co-cultivation of fibroblasts belonging to NPC- and NPC- stimulated cholesterol esterification.     

Translating clinical practice into health policy: an example from China

Understanding a health problem and even having the technological capability to solve it are often not enough to lead to changes in health policy. To help accomplish such policy changes, we propose a five-step approach that involves (1) specifying the disciplines; (2) developing multidisciplinary hypotheses; (3) investigating the hypotheses; (4) developing a policy 'story'; and (5) advocating these solutions to policy makers. We use the example of neonatal hypothermia in Eastern China to illustrate this approach. We found that the approach both better informed policy and better motivated policy change. Using the approach extended our involvement from the hospital to a wider population; in addition our initial solutions expanded from clinical interventions to broader public health approaches that proved to be quite different from our original recommendations.     

EEG mapping investigations of psychomotor and music perception brain dysfunction in untreated schizophrenic patients

Twenty-six untreated schizophrenic inpatients and 34 control persons were investigated using 16-channel EEG mapping during resting, manumotor and music perception tasks. Power values of activation tasks were each referenced to a separate, immediately preceding resting condition, using conventional delta, theta, alpha and 2 beta frequency bands. Results in delta and alpha bands, which maximally separated the two groups, are reported only for space reasons. Results indicated a “nonreactivity” (in all frequency bands) on the two activation paradigms in schizophrenic patients as a group. Major gender effects were obtained in normal persons, but not signs of nonreactivity comparable to patients. Subdividing patients exclusively by means of their EEG changes on activation produced meaningful clinical subgroups of “positive/negative” schizophrenics. This latter finding could contribute towards clinical utility of EEG mapping in psychiatry.

Résumé

Vingt-six malades schizophrènes non traités par des médicaments étaient étudiés par l'EEG topographique à 16 voies pendant des tâches psychomotrices et de la perception musicale. Ils étaient comparés à 34 personnes contrôles. Les valeurs de la puissance étaient calculées dans les états de repos et d'activation dans les bandes de fréquences (conventionnelles) delta, theta, alpha et bêta 1 et 2. Seules les bandes delta et alpha, qui séparaient au maximum les deux groupes, sont montrées dans l'article en raison de l'espace. Tandis que les sujets normaux montraient des changements majeurs de l'EEG pendant les deux types de tâches — modifié par le sexe, les malades schizophrènes montraient au contraire des signes de « non-réactivité . L'essai de grouper les malades exclusivement par leurs changements de l'EEG pendant l'activation cérébrale qu'effectuait un groupe était cliniquement significative, en séparant les malades portant des symptomes « positivesde ceux avec des symptomes « négatives . Le résultat final pourrait indiquer une valeur clinique de l'EEG quantifié pour la psychiatrie.     

Electrical stimulation of osteonecrosis of the femoral head

Osteonecrosis of the femoral head in the adult is a progressive condition that, if untreated, usually results in femoral head collapse and secondary osteoarthritis. The experimental application of electrical and electromagnetic fields has been shown to favorably affect a number of biological processes pertinent to osteonecrosis of the femoral head and has led to several clinical trials. The condition has been treated by the application of electrical fields invasively by the surgical implantation of electrodes within the femoral head and noninvasively by capacitative or inductive coupling. This review describes results in osteonecrosis of the femoral head with these therapeutic techniques. Stimulation by means of inductive coupling with pulsed magnetic fields seems to be the most promising technique studied so far, but the optimal signal characteristics and device design are not yet known.