Systolic Blood Pressure is Related to Catecholamine Sensitivity in Subcutaneous Abdominal Fat Cells

A relationship between abdominal obesity and hypertension is well established. In search for an early-onset defect in adipocyte function linking these two conditions, we compared catecholamine sensitivity in subcutaneous abdominal fat cells with 24-hour systolic, mean arterial and diastolic blood pressure in 16 healthy, normotensive subjects. Clear inter-individual variations in the adipocyte lipolytic adrenoceptor sensitivity (pD₂) for noradrenaline were observed in dose-response experiments (i.e., about 4 log units). An inverse and independent correlation was found between the 24-hour systolic blood pressure and pD₂ for noradrenaline (r = ?0.67, p < 0.01). The mean arterial blood pressure was also negatively correlated to peripheral noradrenaline sensitivity (r = ?0.58, p < 0.05). However, no significant relationship between the 24-hour diastolic blood pressure and pD₂ for noradrenaline was demonstrated. In conclusion we suggest that catecholamine resistance in subcutaneous fat cells may be associated with autonomic dysfunction and impaired blood pressure regulation. This finding is supported by the fact that both noradrenaline sensitivity and 24-hour systolic blood pressure also are correlated to the individual orthostatic heart rate responses, reflecting the sympathetic nervous system tone (r=0.61, p=0.01 and r= ?0.53, p=0.03, respectively). The relationship between noradrenaline sensitivity and systolic blood pressure may be of importance in the early development of hypertension in man.     

Induction of specific T cell immunity in patients with prostate cancer by vaccination with PSA146–154 peptide

T cell immunotherapy of prostate cancer (CaP) offers the potential for less toxic, more effective outcomes. A clinical trial was conducted in 28 patients with locally advanced or metastatic CaP to determine whether an HLA-A2 binding epitope of prostate-specific antigen, PSA146–154 (PSA-peptide), can induce specific T cell immunity. Patients were vaccinated either by intradermal injection of PSA-peptide and GM-CSF or by intravenous administration of autologous dendritic cells pulsed with PSA-peptide at weeks 1, 4 and 10. Delayed-type hypersensitivity (DTH) skin testing was performed at weeks 4, 14, 26 and 52. Fifty percent of the patients developed positive DTH responses to PSA-peptide. The size of the DTH induration progressively increased over time in the majority of responding patients. Skin biopsies from seven DTH-positive patients were available and T cells that developed in situ were also characterized. The phenotype of recovered T cells demonstrated variable proportions of CD4⁺CD8⁻, CD4⁻CD8⁺ and CD4⁺CD8⁺ T cell populations. Cytokine analysis of PSA-peptide stimulated T cells per bead array assay exhibited specific IFN-γ and TNF-α response in six of seven patients. Specific IL-4 response was observed in five patients, while IL-10 response was detected in one patient. Purified CD4⁻CD8⁺ T cells isolated from four patients demonstrated specific cytolytic activity per chromium release assay. In conclusion, immunization with PSA-peptide induced specific T cell immunity in one-half of the patients with locally advanced and hormone-sensitive, metastatic CaP. DTH-derived T cells exhibited PSA-peptide-specific cytolytic activity and predominantly expressed a type-1 cytokine profile.     

Assignment-free solution NMR method reveals CesT as an unswapped homodimer

The X-ray structure of the homodimeric chaperone CesT is the only structure among the type three secretion system (TTSS) chaperones that shows a domain swap. This swap has potential importance for the mechanism of effector translocation through a TTSS. Here we present two nuclear magnetic resonance strategies exploiting pre-existing structural models and residual dipolar couplings (RDCs), which reveal the unswapped 35.4-kDa dimer to be present in solution. Particularly efficient is the discrimination of a swapped and unswapped structural state performed simultaneously to automatic backbone assignment using only HN-RDCs and carbonyl backbone chemical shifts. This direct approach may prove to be generally useful to rapidly differentiate two structural models.     

Protein deiminases: new players in the developmentally regulated loss of neural regenerative ability

Spinal cord regenerative ability is lost with development, but the mechanisms underlying this loss are still poorly understood. In chick embryos, effective regeneration does not occur after E13, when spinal cord injury induces extensive apoptotic response and tissue damage. As initial experiments showed that treatment with a calcium chelator after spinal cord injury reduced apoptosis and cavitation, we hypothesized that developmentally regulated mediators of calcium-dependent processes in secondary injury response may contribute to loss of regenerative ability. To this purpose we screened for such changes in chick spinal cords at stages of development permissive (E11) and non-permissive (E15) for regeneration. Among the developmentally regulated calcium-dependent proteins identified was PAD3, a member of the peptidylarginine deiminase (PAD) enzyme family that converts protein arginine residues to citrulline, a process known as deimination or citrullination. This post-translational modification has not been previously associated with response to injury. Following injury, PAD3 up-regulation was greater in spinal cords injured at E15 than at E11. Consistent with these differences in gene expression, deimination was more extensive at the non-regenerating stage, E15, both in the gray and white matter. As deimination paralleled the extent of apoptosis, we investigated the effect of blocking PAD activity on cell death and deiminated-histone 3, one of the PAD targets we identified by mass-spectrometry analysis of spinal cord deiminated proteins. Treatment with the PAD inhibitor, Cl-amidine, reduced the abundance of deiminated-histone 3, consistent with inhibition of PAD activity, and significantly reduced apoptosis and tissue loss following injury at E15. Altogether, our findings identify PADs and deimination as developmentally regulated modulators of secondary injury response, and suggest that PADs might be valuable therapeutic targets for spinal cord injury.     

Shared and unique G alpha proteins in the zebrafish versus mammalian senses of taste and smell

Chemosensory systems in vertebrates employ G protein-coupled receptors as sensors. In mammals, several families of olfactory and gustatory receptors as well as specific G alpha proteins coupling to them have been identified, for example, gustducin for taste. Orthologous receptor families have been characterized in fish, but the corresponding G alpha genes have not been well investigated so far. We have performed a comprehensive search of several lower vertebrate genomes to establish the G alpha protein family in these taxa and to identify those genes that may be involved in chemosensory signal transduction in fish. We report that gustducin is absent from the genomes of all teleost and amphibian species analyzed, presumably due to independent gene losses in these lineages. However, 2 other G alpha genes, Gi1b and G14a, are expressed in zebrafish taste buds and 4 G proteins, Go1, Go2, Gi1b, and Golf2, were detected in the olfactory epithelium. Golf2, Gi1b, and G14a are expressed already shortly after hatching, consistent with the physiological and behavioral responses of larvae to odorants and tastants. Our results show general similarity to the mammalian situation but also clear-cut differences and as such are essential for using the zebrafish model system to study chemosensory perception.     

Segmental structure of the Brassica napus genome based on comparative analysis with Arabidopsis thaliana

Over 1000 genetically linked RFLP loci in Brassica napus were mapped to homologous positions in the Arabidopsis genome on the basis of sequence similarity. Blocks of genetically linked loci in B. napus frequently corresponded to physically linked markers in Arabidopsis. This comparative analysis allowed the identification of a minimum of 21 conserved genomic units within the Arabidopsis genome, which can be duplicated and rearranged to generate the present-day B. napus genome. The conserved regions extended over lengths as great as 50 cM in the B. napus genetic map, equivalent to approximately 9 Mb of contiguous sequence in the Arabidopsis genome. There was also evidence for conservation of chromosome landmarks, particularly centromeric regions, between the two species. The observed segmental structure of the Brassica genome strongly suggests that the extant Brassica diploid species evolved from a hexaploid ancestor. The comparative map assists in exploiting the Arabidopsis genomic sequence for marker and candidate gene identification within the larger, intractable genomes of the Brassica polyploids.     

Receiving Palliative Treatment Moderates the Effect of Age and Gender on Demoralization in Patients with Cancer

Background

Existential distress is an important factor affecting psychological well-being in cancer patients. We studied occurrence and predictors of demoralization, a syndrome of existential distress, in particular the interaction of age, gender, and curative vs. palliative treatment phase.

Methods

A cross-sectional sample of N = 750 patients with different tumor sites was recruited from in- and outpatient treatment facilities. Patients completed the following self-report questionnaires: Demoralization Scale, Patient Health Questionnaire-9, Illness-Specific Social Support Scale Short Version-8, and physical problems list of the NCCN Distress Thermometer. Moderated multiple regression analyses were conducted.

Results

We found high demoralization in 15% and moderate demoralization in 8% of the sample. Curative vs. palliative treatment phase moderated the impact of age and gender on demoralization (three-way interaction: b = 1.30, P = .02): the effect of age on demoralization was negative for women receiving palliative treatment (b = −.26, P = .02) and positive for men receiving palliative treatment (b = .25, P = .03). Effects of age and gender were not significant among patients receiving curative treatment. Female gender was associated with higher demoralization among younger patients receiving palliative treatment only. Analyses were controlled for significant effects of the number of physical problems (b = 6.10, P<.001) and social support (b = −3.17, P<.001).

Conclusions

Existential distress in terms of demoralization is a relevant problem within the spectrum of cancer-related distress. It is associated with a complex interaction of demographic and medical patient characteristics; existential challenges related to palliative treatment may exacerbate the impact of age- and gender-related vulnerability factors on demoralization. Psychosocial interventions should acknowledge this interaction in order to address the individual nature of existential distress in subgroups of cancer patients.