[Gaucher's disease and imiglucerase in 2009/2010: what leads to a suddenly enforced prioritisation?]. / M. Gaucher und Imiglucerase 2009/2010: Was leitet eine plötzlich erzwungene Priorisierung?

Gaucher's disease is, when left untreated, a progressive and in some subsets even life-threatening lysosomal storage disease. It is caused by a genetically linked deficit of acid beta-glucocerebrosidase. The enzyme can be replaced by Cerezyme(®)/imiglucerase produced by Genzyme Corp. The therapy has the potential to induce remis-sion and normalise the patient's life. In June 2009 Genzyme had to announce a viral contamination of its bioreactors which led to a sudden stop of the entire production of imiglucerase. Subsequently only 50-20% of the former supply could be provided worldwide. The situation was not normalised until the beginning of the year 2011. Due to this unexpected shortage the relevant actors had to clarify quickly and unprepared which patient groups to prioritise and whom to supply with what quantities of imiglucerase. The shortly enforced prioritisation and rationing provide an opportunity to describe and analyse the spontaneously choosen prioritisation criteria and reveal value preferences shared by clinicians, patients, patient representatives, and company representatives. To reconstruct the chain of events and reactions and the revealed criteria and value preferences partly standardised interviews with representatives of the relevant stakeholder groups were conducted. Very clearly, the actors spontaneously chose to follow a medical need and a social solidarity principle.

Non-enzymatic regeneration of nicotinamide and flavin cofactors for monooxygenase catalysis.

Biocatalytic oxygenation chemistry is a rapidly evolving field in which monooxygenases are the tools of choice. Monooxygenases catalyze many industrially important synthetic transformations; however, their use in preparative applications is hampered by their intrinsic requirement for reducing equivalents. As a result, non-enzymatic strategies--where the reducing equivalents are introduced directly into the catalytic cycle--are being developed to supersede the well-established enzymatic NAD(P)H regeneration systems currently in use. In this review we summarize and evaluate recent achievements in this area.

Positive allosteric modulation of native and recombinant gamma-aminobutyric acid(B) receptors by 2,6-Di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) and its aldehyde analog CGP13501.

The compounds CGP7930 [2,6-Di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol] and its close analog CGP13501 were identified as positive modulators of gamma-aminobutyric acid(B) (GABA(B)) receptor function. They potentiate GABA-stimulated guanosine 5'-O-(3-[(35)S]thiotriphosphate) (GTP gamma[(35)S]) binding to membranes from a GABA(B(1b/2)) expressing Chinese hamster ovary (CHO) cell line at low micromolar concentrations and are ineffective in the absence of GABA. The structurally related compounds propofol and malonoben are inactive. Similar effects of CGP7930 are seen in a GTP gamma[(35)S] binding assay using a native GABA(B) receptor preparation (rat brain membranes). Receptor selectivity is demonstrated because no modulation of glutamate-induced GTP gamma[(35)S] binding is seen in a CHO cell line expressing the metabotropic glutamate receptor subtype 2. Dose-response curves with GABA in the presence of different fixed concentrations of CGP7930 reveal an increase of both the potency and maximal efficacy of GABA at the GABA(B(1b/2)) heteromer. Radioligand binding studies show that CGP7930 increases the affinity of agonists but acts at a site different from the agonist binding site. Agonist affinity is not modulated by CGP7930 at homomeric GABA(B(1b)) receptors. In addition to GTP gamma[(35)S] binding, we show that CGP7930 also has modulatory effects in cellular assays such as GABA(B) receptor-mediated activation of inwardly rectifying potassium channels in Xenopus laevis oocytes and Ca(2+) signaling in human embryonic kidney 293 cells. Furthermore, we show that CGP7930 enhances the inhibitory effect of L-baclofen on the oscillatory activity of cultured cortical neurons. This first demonstration of positive allosteric modulation at GABA(B) receptors may represent a novel means of therapeutic interference with the GABA-ergic system.

The auditory cortex of the mouse: connections of the ultrasonic field.

The cortical and subcortical connections of the ultrasonic field (UF) of the auditory cortex of the house mouse (Mus musculus) were studied by using retrograde and anterograde transport of horseradish peroxidase (HRP). Small amounts of HRP were locally injected into the electrophysiologically defined UF. Superficial (layer I-IV) and deep (layer IV-VI) injections were prepared. Superficial injections led to labelling of both cells (retrograde) and terminals (anterograde) in areas of the ipsilateral primary and secondary auditory cortex and in its dorsoposterior field, in an ipsilateral dorsal association area (patches of label), probably in ipsilateral secondary somatosensory cortex, in the contralateral homotopic UF, and in the ipsilateral medial geniculate body (MGBv, MGBd, and MGBm) and caudal posterior nucleus complex. Deep injections showed the same connectivities as superficial ones and, in addition, terminals in the very caudal caudatoputamen, in the nucleus limitans and the nucleus reticularis of the thalamus, in the rostral pole, the dorsomedial, and lateral nucleus of the inferior colliculus, in the stratum griseum intermediale of the superior colliculus, and in a pontine nucleus ventromedial of the lateral lemniscus. All these projections occurred only ipsilaterally. The majority of connections, except those with the nucleus limitans, superior colliculus and pontine nucleus, suggest that UF is part of the primary anditory cortex (AI) and/or of the anterior anditory field (AAF) of the auditory cortex. Since UF has no regular tonotopy, this has important implications for the functional role that AI/AAF can have in communication-sound analysis.

Color induction via non-opponent lateral interactions in the human retina.

Retinal connections causing colors in Benham's top (pattern induced flicker colors, PIFCs) are investigated by psychophysical experiments. PIFCs are still seen when stimuli to different cones are demodulated selectively, indicating the involvement of non-opponent channels. PIFCs also occur on retinal areas next to those affected by modulated stimuli; further, both monochromat and dark-adapted trichromats perceive PIFCs which are achromatic. These additional findings point to horizontal cells as neuronal mediators of modulated excitation leading to PIFCs. The unspecifity of the postulated connection with respect to cone types agrees with anatomic findings of Boycott, B. B., Hopkins, J. M. and Sperling, H. G. (1987, Proceedings of the Royal Society of London, B, 229, 345-379) on horizontal cells.

Cerebral perfusion deficit masked by Paget's disease of skull.

Prominent extracerebral perfusion on an emission angiogram of the head in a patient with Paget's disease of the skull masked an underlying intracerebral perfusion deficiency, due to occlusion of the left middle cerebral artery.

Detection of bronchopleural-subarachnoid fistula by radionuclide myelography: case report.

Radionuclide myeloscintigraphy has previously been used to demonstrate subarachnoid fistulae. In the present case a patient with bronchogenic carcinoma developed spontaneous pneumocephalus postoperatively. Chest radiographs showed an air-fluid level in the postoperative area. Various diagnostic tests were used, but only a radionuclide myeloscintigram showed the presence of a bronchopleural-subarachnoid fistula.