VitalStim therapy seems to help those with mild to moderate dysphagia. However, the patients with the most severe dysphagia in our study did not gain independence from their feeding tubes. The authors conclude that VitalStim therapy clearly has a place in the management of dysphagia, but that the most severely afflicted are unlikely to gain dramatic improvement.

We have previously described novel histone acetyltransferase (HAT) inhibitors that block neuroblastoma cell growth in vitro. Here we show that two selected pyridoisothiazolone HAT inhibitors, PU139 and PU141, induce cellular histone hypoacetylation and inhibit growth of several neoplastic cell lines originating from different tissues. Broader in vitro selectivity profiling shows that PU139 blocks the HATs Gcn5, p300/CBP-associated factor (PCAF), CREB (cAMP response element-binding) protein (CBP) and p300, whereas PU141 is selective toward CBP and p300. The pan-inhibitor PU139 triggers caspase-independent cell death in cell culture. Both inhibitors block growth of SK-N-SH neuroblastoma xenografts in mice and the PU139 was shown to synergize with doxorubicin in vivo. The latter also reduces histone lysine acetylation in vivo at concentrations that block neoplastic xenograft growth. This is one of the very few reports on hypoacetylating agents with in vivo anticancer activity.

No abstract

The objective of the present study was to determine the potency of dexmedetomidine in relation to medetomidine in sheep undergoing orthopaedic surgery by comparing the anaesthetic requirements and cardiovascular changes at a dose relationship that represented equipotency in vitro. Twenty-four non-pregnant, female sheep were used. The study was carried out as a blind, randomized, experimental trial. Group 1 received 5 micrograms/kg bodyweight (BW) dexmedetomidine and group 2 received 10 micrograms/kg BW medetomidine intravenously 5 min prior to induction of anaesthesia. Anaesthesia was induced with ketamine (2.0 mg/kg BW intravenously) and maintained with isoflurane in 100% oxygen. End expired anaesthetic concentration (FEIso), end expired carbon dioxide concentration (FECO2), respiratory frequency (fR), direct arterial blood pressures, heart rates (HR) and arterial blood gases were monitored. Data were averaged over time and tested for differences between groups by independent t-tests, and analysis of variance for repeated measures. Average FEIso concentrations required to maintain a surgical plane of anaesthesia were not different between groups (1: 1.02 +/- 0.04%; 2: 0.99 +/- 0.07%). There was no difference in HR, arterial blood pressures, fR, FECO2 and arterial blood gases between groups. Average mean PaO2 were 279.54 +/- 113.37 mmHg and 220.21 +/- 102.15 mmHg with individual minimum values of 27.2 mmHg and 58.5 mmHg in groups 1 and 2, respectively. In conclusion, intravenous dexmedetomidine at 5 micrograms/kg BW and medetomidine at 10 micrograms/kg BW have the same effects on isoflurane requirements and cardiopulmonary parameters in sheep, indicating an equipotent dose relationship. Both preparations induced moderate to severe hypoxaemia in individual sheep.

Heritable changes in gene expression that are not based upon alterations in the DNA sequence are defined as epigenetics. The most common mechanisms of epigenetic regulation are the methylation of CpG islands within the DNA and the modification of amino acids in the N-terminal histone tails. In the last years, it became evident that the onset of cancer and its progression may not occur only due to genetic mutations but also because of changes in the patterns of epigenetic modifications. In contrast to genetic mutations, which are almost impossible to reverse, epigenetic changes are potentially reversible. This implies that they are amenable to pharmacological interventions. Therefore, a lot of work in recent years has focussed on the development of small molecule enzyme inhibitors like DNA-methyltransferase inhibitors or inhibitors of histonemodifying enzymes. These may reverse misregulated epigenetic states and be implemented in the treatment of cancer or other diseases, e.g., neurological disorders. Today, several epigenetic drugs are already approved by the FDA and the EMEA for cancer treatment and around ten histone deacetylase (HDAC) inhibitors are in clinical development. This review will give an update on recent clinical trials of the HDAC inhibitors used systemically that were reported in 2009 and 2010 and will present an overview of different biomarkers to monitor the biological effects.