Zur Konkurrentenklage auf Zulassung als Vertragsarzt im entsperrten Planungsbereich

Ohne Zusammenfassung     

Bedarfunabhängige Zulassung/ermächtigung nichtärztlicher Psychotherapeuten nach § 95 Abs. 10, 11 SGB V

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Central drive and ventilatory failure in late-onset Pompe disease: At the gates of a new phenotype

Subjects with late-onset Pompe disease (LOPD) typically present as slowly progressive proximal muscle weakness. Respiratory muscle weakness and diaphragmatic paralysis are common features, and may be the initial manifestation of the disease. There is often a poor correlation between the severity of limb and respiratory muscle weakness. Early clinical observations about disproportionate hypercapnia to the respiratory muscular weakness in late-onset Pompe disease were recognized and will be discussed with special reference to blunted respiratory drive, and the connections between early clinical observations, respiratory functional studies and anatomical findings. According to new evidence about blunted respiratory drive in Pompe disease, it is necessary to rethink what is meant by “asymptomatic Pompe disease” and propose a new phenotype with its therapeutic implications. The conceptual model of the mechanisms leading to respiratory failure in this disease could be considered according to these new findings. It may broaden the diagnostic spectrum of the adult forms and warrants a closer interaction between neurologists and pulmonologists. The recognition of this new phenotype of predominant central alveolar hypoventilation in Pompe disease will improve the understanding of the underlying mechanisms of ventilatory failure and could lead to improved future therapeutic strategies.     

Spinal administration of the monoacylglycerol lipase inhibitor JZL184 produces robust inhibitory effects on nociceptive processing and the development of central sensitization in the rat

Background and Purpose

The cannabinoid receptor-mediated analgesic effects of 2-arachidonoylglycerol (2-AG) are limited by monoacylglycerol lipase (MAGL). 4-nitrophenyl 4-[bis (1,3-benzodioxol-5-yl) (hydroxy) methyl] piperidine-1-carboxylate (JZL184) is a potent inhibitor of MAGL in the mouse, though potency is reportedly reduced in the rat. Here we have assessed the effects of spinal inhibition of MAGL with JZL184 on nociceptive processing in rats.

Experimental Approach

In vivo spinal electrophysiological assays in anaesthetized rats were used to determine the effects of spinal administration of JZL184 on spinal nociceptive processing in the presence and absence of hindpaw inflammation. Contributions of CB₁ receptors to these effects was assessed with AM251. Inhibition of 2-oleoylglycerol hydrolytic activity and alterations of 2-AG in the spinal cord after JZL 184 were also assessed.

Key Results

Spinal JZL184 dose-dependently inhibited mechanically evoked responses of wide dynamic range (WDR) neurones in naïve anaesthetized rats, in part via the CB₁ receptor. A single spinal administration of JZL184 abolished inflammation-induced expansion of the receptive fields of spinal WDR neurones. However, neither spinal nor systemic JZL184 altered levels of 2-AG, or 2-oleoylglycerol hydrolytic activity in the spinal cord, although JZL184 displayed robust inhibition of MAGL when incubated with spinal cord tissue in vitro.

Conclusions and Implications

JZL184 exerted robust anti-nociceptive effects at the level of the spinal cord in vivo and inhibited rat spinal cord MAGL activity in vitro. The discordance between in vivo and in vitro assays suggests that localized sites of action of JZL184 produce these profound functional inhibitory effects.

Linked Articles

This article is part of a themed section on Cannabinoids. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.167.issue-8     

Favorably skewed X‐inactivation accounts for neurological sparing in female carriers of Menkes disease

Desai V, Donsante A, Swoboda KJ, Martensen M, Thompson J, Kaler SG. Favorably skewed X‐inactivation accounts for neurological sparing in female carriers of Menkes disease. Classical Menkes disease is an X‐linked recessive neurodegenerative disorder caused by mutations in ATP7A, which is located at Xq13.1‐q21. ATP7A encodes a copper‐transporting P‐type ATPase and plays a critical role in development of the central nervous system. With rare exceptions involving sex chromosome aneuploidy or X‐autosome translocations, female carriers of ATP7A mutations are asymptomatic except for subtle hair and skin abnormalities, although the mechanism for this neurological sparing has not been reported. We studied a three‐generation family in which a severe ATP7A mutation, a 5.5‐kb genomic deletion spanning exons 13 and 14, segregated. The deletion junction fragment was amplified from the proband by long‐range polymerase chain reaction and sequenced to characterize the breakpoints. We screened at‐risk females in the family for this junction fragment and analyzed their X‐inactivation patterns using the human androgen‐receptor (HUMARA) gene methylation assay. We detected the junction fragment in the proband, two obligate heterozygotes, and four of six at‐risk females. Skewed inactivation of the X chromosome harboring the deletion was noted in all female carriers of the deletion (n = 6), whereas random X‐inactivation was observed in all non‐carriers (n = 2). Our results formally document one mechanism for neurological sparing in female carriers of ATP7A mutations. Based on review of X‐inactivation patterns in female carriers of other X‐linked recessive diseases, our findings imply that substantial expression of a mutant ATP7A at the expense of the normal allele could be associated with neurologic symptoms in female carriers of Menkes disease and its allelic variants, occipital horn syndrome, and ATP7A‐related distal motor neuropathy.     

Hunger and associated harms among injection drug users in an urban Canadian setting

Background  

Food insufficiency is often associated with health risks and adverse outcomes among marginalized populations. However, little is known about correlates of food insufficiency among injection drug users (IDU).     

Methamphetamine use and malnutrition among street-involved youth

We sought to explore the effect of crystal methamphetamine use on the risk of experiencing malnutrition among street-involved youth in Vancouver, Canada. Risk of malnutrition was defined as being hungry but not having enough money to buy food. Socio-demographic and drug use factors associated with risk of malnutrition were investigated using univariate and multivariate analysis among a prospective cohort of street-involved youth known as the At-Risk Youth Study (ARYS). Between September 2005 and December 2006, 509 street-involved youth were enrolled in ARYS, among whom 21% reported being at risk of malnutrition as defined above in the previous six months. In multivariate analysis, only non-injection crystal methamphetamine was significantly associated with being at risk of malnutrition among this cohort (Adjusted Odds Ratio [AOR] = 1.60, 95% Confidence Interval [CI]: 1.03 - 2.48, p = 0.036). Interventions seeking to address food insecurity among street youth may benefit from considering drug use patterns since methamphetamine use predicted higher risk in this setting.