Severe cardiac disorders predispose to central sleep apnoea (CSA). We sought to examine the relationship between severe aortic stenosis, sleep disordered breathing (SDB), and CSA before and after ...transcatheter aortic valve implantation (TAVI).
Twenty-nine patients (81±6 yrs, 41% male, LVEF 48±14%) with severe aortic stenosis and high surgical risk underwent polygraphy before and three months after TAVI. Patients with an apnoea-hypopnoea index (AHI) >5/hr were considered to have SDB. SDB with ≥50% absence of both airflow and ventilatory effort was defined as CSA. Twenty-one of 29 patients (72%) had SDB (6/6/9 mild, moderate, and severe, respectively), 12 (41%) with CSA (0/4/8) and 9 (31%) with obstructive sleep apnoea (7/2/0). There was a strong correlation of CSA with LVEDP before TAVI (r=0.74, p=0.024), but not with LVEF, systolic pulmonary artery pressure or NT pro-BNP. After TAVI, AHI improved significantly, particularly in the CSA group (from 43.5±17.5 to 19.4±12.9/hr, p<0.001). Prevalence and severity of SDB were reduced from 72% to 59% (6/6/9 to 7/8/2 patients), triggered by the significant improvement of CSA.
Patients with severe aortic stenosis display a high prevalence of SDB, particularly of CSA. Definitive treatment with TAVI greatly resolved SDB in the CSA subgroup.
Increasing numbers of bacterial strains being resistant to conventional antibiotics emphasize the urgent need for new antimicrobial agents. One strategy is based on host defence peptides that can be ...found in every organism including humans. We have studied the antimicrobial peptide LF11, derived from the pepsin cleavage product of human lactoferrin, known for its antimicrobial and lipid A-binding activity, and peptide C12LF11, the N-lauryl-derivative of LF11, which has owing to the attached hydrocarbon chain an additional hydrophobic segment. The influence of this hydrocarbon chain on membrane selectivity was studied using model membranes composed of dipalmitoylphosphatidylglycerol (DPPG), mimicking bacterial plasma membranes, and of dipalmitoylphosphatidylcholine (DPPC), a model system for mammalian membranes. A variety of biophysical techniques was applied. Thereby, we found that LF11 did not affect DPPC bilayers and showed only moderate effects on DPPG membranes in accordance with its non-hemolytic and weak antimicrobial activity. In contrast, the introduction of the N-lauryl group caused significant changes in the phase behaviour and lipid chain packing in both model membrane systems. These findings correlate with the in vitro tests on methicillin resistant
S. aureus,
E. coli,
P. aeruginosa and human red blood cells, showing increased biological activity of C12LF11 towards these test organisms. This provides evidence that both electrostatic and hydrophobic interactions are crucial for biological activity of antimicrobial peptides, whereas a certain balance between the two components has to be kept, in order not to loose the specificity for bacterial membranes.
Huntington's disease (HD) is caused by an expanded CAG repeat leading to the synthesis of an aberrant protein and to the formation of polyglutamine (polyQ)-containing inclusions and aggregates. ...Limited information is available concerning the association of neuropathological markers with the development of behavioral markers in HD. Using a previously generated transgenic rat model of HD (tgHD rat), we performed association studies on the time-course of behavioral symptoms (motor function, learning, anxiety) and the appearance of striatal atrophy, 1C2 immunopositive aggregates and polyQ recruitment sites, a precursor to these aggregates. At the age of 1 month, tgHD rats exhibited reduced anxiety and improved motor performance, while at 6 months motor impairments and at 9 months cognitive decline occurred. In contrast, polyQ recruitment sites appeared at around 6–9 months of age, indicating that HD-like behavioral markers preceded the appearance of currently detectable neuropathological markers. Interestingly, numerous punctate sites containing polyQ aggregates were also seen in areas receiving afferents from the densely recruiting regions suggesting either transport of recruitment-competent aggregates to terminal projections where initially 1C2 positive aggregates were formed or different internal properties of neurons in different regions. Furthermore, striatal atrophy was observed at the age of 12 months. Taken together, our findings support the hypothesis of a dynamic process leading to region- and age-specific polyQ recruitment and aggregation. The dissociation of onset between behavioral and neuropathological markers is suggestive of as yet undetected processes, which contribute to the early phenotype of these HD transgenic rats.
Objectives The stabilization of the transcription factor and prognostic tumor marker hypoxia-inducible factor 1alpha (HIF1alpha) is considered to be crucial for cellular metabolic adaptations to ...hypoxia. However, HIF1alpha has also been shown to accumulate under normoxic conditions, although this phenomenon is poorly understood. Methods We investigated the conditions for normoxic HIF1alpha stabilization in different tumor cell lines (e.g., two mammary carcinoma cell lines and three oral squamous cell carcinoma cell lines) via Western blot analysis or immunohistochemical staining. The transcriptional activity of HIF1 was demonstrated by analyzing the messenger RNA (mRNA) expression of the HIF1 target carbonic anhydrase 9 (CA9) via PCR. Results Our data demonstrate that the combined incubation of tumor cells with glutamine and growth factors (e.g., EGF, insulin, and serum) mediates the normoxic accumulation of HIF1alpha in vitro. Consequently, the inhibition of glutaminolysis by a glutaminase inhibitor blocked the normoxic accumulation of HIF1alpha. Additionally, the normoxic HIF1alpha protein displayed nuclear translocation and transcriptional activity, which was confirmed by the induction of CA9 mRNA expression. Furthermore, the normoxic accumulation of HIF1alpha was associated with impaired proliferation of tumor cells. Finally, ammonia, the toxic waste product of glutaminolysis, induced a normoxic accumulation of HIF1alpha to the same extent as glutamine. Conclusion Our study suggests that HIF1alpha is involved in the regulation of glutamine metabolism and the cellular levels of the toxic metabolic waste product ammonia under normoxia. Hence, our results, together with data presented in the literature, support the hypothesis that HIF1alpha and its target genes play a crucial role in metabolic pathways, such as glutaminolysis and glycolysis, under both hypoxic and normoxic conditions. Clinical relevance Therefore, the inhibition of HIF1alpha (and/or HIF1alpha target genes) could emerge as a promising therapeutic approach that would result in the accumulation of toxic metabolic waste products in tumor cells as well as the reduction of their nutrition and energy supply.
Although recent data are contradictory, it is still claimed that Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC) would deliver an aerosol which distributes homogeneously throughout the ...entire abdominal cavity.
Tc-Pertechnetat was administered in four postmortem swine using either PIPAC or liquid intra-peritoneal chemotherapy (IPC). The animals were examined by planar scintigraphy and SPECT/CT. Planar distribution images were divided into four regions of interest (ROIs: right/left upper and lower abdominal quadrant). SPECT/CT slices were scanned for areas of intense nuclide accumulation ("hot spots"). The percentage of relative distribution for planar scintigraphy was calculated by dividing the summed individual counts of each ROI by total counts measured in the entire abdominal cavity. The relative distribution of the "hot spots" was analyzed by dividing the counts of the local volume of interest (VOI) by the summed volume counts measured in the entire abdominal cavity.
In all four animals, planar scintigraphy showed inhomogeneous nuclide distribution. After PIPAC only 8-10% of the delivered nuclide was detected in one ROI with a mean deviation of 40% and 74% from a uniform nuclide distribution pattern. In all animals, SPECT/CT revealed "hot spots" beneath the PIPAC Micropump, catheter tip, and in the cul-de-sac region which comprise about 25% of the total amount of delivered nuclide in 2.5% of the volume of the entire abdominal cavity.
Our present data indicate that the intra-abdominal aerosol distribution pattern of PIPAC therapy is non-homogeneous and that the currently applied technology has still not overcome the problem of inhomogeneous drug distribution of IPC.
•Reduction of APL antibodies by immunoadsorption may be a lifesaving therapy for the management of DAH with high titer of APL antibodies.•Autologous HSCT may be a valid treatment option in patients ...with primary APS and no response to standard immunosuppressive therapy.
Coordination of motoneuron activity is a fundamental prerequisite for the generation of functional locomotor patterns. We investigate the neural mechanisms that coordinate activity of motoneuron ...pools in the vertebrate spinal cord with differing phases of activity in the locomotor cycle in a simple motor system, the lamprey swimming network. In the region of dorsal fins the lamprey spinal cord contains two groups of motoneurons: the myotomal motoneurons that innervate the trunk muscles; and the fin motoneurons controlling muscle fibres of the dorsal fins. We investigated the activity of fin muscles during swimming in vivo and that of fin motoneurons during fictive swimming in vitro. During swimming in vivo with cycle periods of 4–8 Hz, fin muscle activity covered a broad portion of the cycle, with the peak of activity out‐of‐phase to the ipsilateral myotomal muscles. During fictive swimming evoked by N‐methyl‐d‐aspartate in the isolated spinal cord, fin motoneurons expressed similar out‐of‐phase activity. The phase relationship of the synaptic drive to fin motoneurons was examined by recording their activity intracellular during fictive swimming. Three different forms of membrane potential oscillation with different time courses in the locomotor cycle could be distinguished. Sagittal lesions of the spinal cord in the segment where fin motoneurons are recorded and up to one segment rostral and caudal from it did not influence the out‐of‐phase activity pattern of the motoneurons. Our results indicate that coordination of fin motoneuron activity with the locomotor activity of myotomal motoneurons does not depend on intrasegmental contralateral premotor elements.
During the past decade, Deep Learning (DL) algorithms, programming systems and hardware have converged with the High Performance Computing (HPC) counterparts. Nevertheless, the programming ...methodology of DL and HPC systems is stagnant, relying on highly-optimized, yet platform-specific and inflexible vendor-optimized libraries. Such libraries provide close-to-peak performance on specific platforms, kernels and shapes thereof that vendors have dedicated optimizations efforts, while they underperform in the remaining use-cases, yielding non-portable codes with performance glass-jaws. This work introduces a framework to develop efficient, portable DL and HPC kernels for modern CPU architectures. We decompose the kernel development in two steps: 1) Expressing the computational core using Tensor Processing Primitives (TPPs): a compact, versatile set of 2D-tensor operators, 2) Expressing the logical loops around TPPs in a high-level, declarative fashion whereas the exact instantiation (ordering, tiling, parallelization) is determined via simple knobs. We demonstrate the efficacy of our approach using standalone kernels and end-to-end workloads that outperform state-of-the-art implementations on diverse CPU platforms.
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