MC4R dimerization in the paraventricular nucleus and GHSR/MC3R heterodimerization in the arcuate nucleus: is there relevance for body weight regulation?

The worldwide obesity epidemic is increasing, yet at this time, no long-acting and specific pharmaceutical therapies are available. Peripheral hormonal signals communicate metabolic status to the hypothalamus by activating their corresponding receptors in the arcuate nucleus (ARC). In this brain region, a variety of G protein-coupled receptors (GPCRs) are expressed that are potentially involved in weight regulation, but so far, the detailed function of most hypothalamic GPCRs is only partially understood. An important and underappreciated feature of GPCRs is the capacity for regulation via di- and heterodimerization. Increasing evidence implicates that heterodimerization of GPCRs results in profound functional consequences. Recently, we could demonstrate that interaction of the melanocortin 3 receptor (MC3R) and the growth hormone secretagogue receptor (GHSR)-1a results in a modulation of function in both receptors. Although the physiological role of GPCR-GPCR interaction in the hypothalamus is yet to be elucidated, this concept promises new avenues for investigation and understanding of hypothalamic functions dependent on GPCR signaling. Since GPCRs are important targets for drugs to combat many diseases, identification of heterodimers may be a prerequisite for highly specific drugs. Therefore, a detailed understanding of the mechanisms and their involvement in weight regulation is necessary. Fundamental to this understanding is the interplay of GPCR-GPCR in the hypothalamic nuclei in energy metabolism. In this review, we summarize the current knowledge on melanocortin receptors and GHSR-1a in hypothalamic weight regulation, especially as they pertain to possible drug targets. Furthermore, we include available evidence for the participation and significance of GPCR dimerization.     

Inflamación y apoptosis en la hipertensión arterial. Importancia de la extensión de la lesión de órgano diana

Introduction and objectives

To investigate the relationship between inflammatory and apoptotic parameters and the severity and extent of target organ damage in patients with essential hypertension.

Methods

We studied 159 consecutive patients with treated essential hypertension. An exhaustive evaluation of damage to heart, kidney, and blood vessels was performed and plasma levels of inflammatory (interleukin 6 and soluble receptor of tumor necrosis factor-alpha type 2) and apoptotic markers (soluble receptor of tumor necrosis factor-alpha type 1 and soluble Fas receptor) were determined. Patients were categorized into four groups: a) no organ damage (33 patients); b) 1 organ damaged (52 patients); c) 2 organs damaged (44 patients), and d) 3 organs damaged (30 patients).

Results

Serum levels of interleukin 6, soluble receptor of tumor necrosis factor-alpha type 1 and soluble receptor of tumor necrosis factor-alpha type 2 were higher in patients with target organ damage than in hypertensive patients without organ damage. Increasing levels of these molecules were progressively associated with an increase in the number of organs damaged, and the highest levels were observed in the group with damage to 3 organs (heart, kidney, and blood vessels). There were no differences in soluble Fas receptor levels between groups. Logistic regression analysis showed that age, smoking, diabetes mellitus, abdominal circumference, interleukin 6, and soluble receptor of tumor necrosis factor-alpha type 1 were independently related to the number of target organs damaged.

Conclusions

Extensive hypertensive disease with involvement of more target organs was associated with greater inflammatory and apoptotic activation in these hypertensive patients.Full English text available from:www.revespcardiol.org     

Semantic contributions to immediate serial recall: Evidence from two contrasting aphasic individuals

This paper examines the effect of semantic variables on serial recall in two contrasting aphasic cases and a group of controls. Experiment 1 manipulates word imageability and Experiment 2 manipulates semantic similarity. Controls not only showed better recall of imageable/semantically grouped lists, but under some conditions they also produced proportionately fewer phonological errors. These findings suggest that increasing the effectiveness of lexical/semantic support reduces reliance on phonological support. Consistent with this proposal, case TV, whose phonological impairment should increase his reliance on lexical/semantic support, produced abnormally low rates of phonological errors under some conditions. Conversely, case NP, who had a lexical/semantic impairment, produced abnormally high rates of phonological errors under some conditions. Analysis of serial recall curves in both aphasics and controls support the hypothesis that phonological processes are particularly critical for the recall of list-final items. However, there was no evidence that semantic support is especially crucial for list-initial recall. Controls did not exhibit stronger effects of semantic variables at list-initial position. Case NP (lexical/semantic impairment) performed disproportionately poorly on these items, but only under certain conditions.     

Improved performance of SPECT-CT In-111 capromab pendetide by correlation with diffusion-weighted magnetic resonance imaging for identifying metastatic pelvic lymphadenopathy in prostate cancer

Purpose

To preliminarily evaluate the potential for an improvement in diagnostic performance by a combined interpretation of In-111 capromab pendetide single photon emission computed tomography (SPECT) including computed tomography (CT) image fusion with magnetic resonance diffusion-weighted imaging (MR-DWI) for identifying prostate cancer in pelvic lymph nodes thru correlation with histopathology.

Materials and methods

This institutional approved, retrospective study identified patients with available histopathology of lymph nodes removed at the time of radical prostatectomy and who had undergone staging with In-111 capromab pendetide SPECT-CT and/or pelvic MRI (including DWI). The performance of In-111 capromab pendetide SPECT for identifying malignant lymph nodes was assessed. Subsequently, a combined reading of In-111 capromab pendetide SPECT and prostate MRI with DWI was performed and the performance assessed.

Results

18 patients underwent In-111 capromab pendetide SPECT-CT. Of these, 12 patients had also undergone imaging with MR-DWI. In-111 capromab pendetide SPECT-CT had a sensitivity of 40.0 % and specificity of 96.7 % for identification of malignant lymph nodes. However, In-111 capromab pendetide SPECT-CT combined with MRI with DWI had a sensitivity of 88.9 % and specificity of 98.5 %.

Conclusions

The addition of MR-DWI to the interpretation of In-111 capromab pendetide SPECT-CT may increase the sensitivity for detecting malignant lymph nodes in prostate cancer. Future prospective evaluation of combined In-111 capromab pendetide SPECT-CT and MR-DWI is indicated and may improve clinical evaluation of nodal disease in prostate cancer.     

Biomechanical and rheological characterization of mild intervertebral disc degeneration in a large animal model

Biomechanical properties of healthy and degenerated nucleus pulposus (NP) are thought to be important for future regenerative strategies for intervertebral disc (IVD) repair. However, which properties are pivotal as design criteria when developing NP replacement materials is ill understood. Therefore, we determined and compared segmental biomechanics and NP viscoelastic properties in normal and mildly degenerated discs. In eight goats, three lumbar IVDs were chemically degenerated using chondroitinase ABC (CABC), confirmed with radiography and MRI after euthanasia 12 weeks post‐operative. Neutral zone (NZ) stiffness and range of motion (ROM) were determined sagitally, laterally, and rotationally for each spinal motion segment (SMS) using a mechanical testing device. NPs were isolated for oscillatory shear experiments; elastic and viscous shear moduli followed from the ratio between shear stress and strain. Water content was quantified by weighing before and after freeze‐drying. Disc height on radiographs and signal intensity on MRI decreased (6% and 22%, respectively, p < 0.01) after CABC treatment, confirming that chemical degeneration provides a good model of disc degeneration. Furthermore, CABC‐injected IVDs had significantly lower NZ stiffness and larger ROM in lateral bending (LB) and axial rotation (AR) than controls. Rheometry consistently revealed significantly lower (10–12%) viscoelastic moduli after mild degeneration within goats, though the inter‐animal differences were relatively large (complex modulus ～12 to 41 kPa). Relative water content in the NP was unaffected by CABC, remaining at ～75%. These observations suggest that viscoelastic properties have a marginal influence on mechanical behavior of the whole SMS. Therefore, when developing replacement materials the focus should be on other design criteria, such as biochemical cues and swelling pressure. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 703–709, 2013