Interplay between RAS and opioids: Opening the Pandora of complexities

Angiotensin and endogenous opioids are important bioactive neuropeptides, which are widely distributed in the brain and peripheral regions to produce diverse biological and neurobiological activities. An endogenous opioid system includes proopiomelanocortin-derived enkephalin, dynorphin and endorphin that act on their specific receptors such as delta (δ), kappa (κ) and mu (μ) receptors. Research evidence demonstrates significant positive as well as negative interactions between renin angiotensin system (RAS) and endogenous opioids in the brain and periphery. The diverse actions of Ang II are possibly mediated indirectly through endogenous opioids, while opioids are also shown to activate RAS components suggesting the up-regulation of each system in concern with each other. On the contrary, there are reports suggesting a negative correlation between RAS and opioid system. Research evidence also supports the notion that Ang II acts as anti-opioid peptide to decrease the actions of opioids. Moreover, opioids-induced decline in angiotensin release and functioning has also been reported. Co-administration of ACE inhibitors with opioids exhibits significant interactions possibly due to decreased metabolism of opioids leading to potentiation of their actions. The present review describes the complexities of positive and negative interactions between RAS and opioids along with possible mechanisms responsible for these interactions.     

Complete mucostatic impression: a new attempt

Hypermobile ridges or flabby edentulous ridges are a common occurrence in edentulous patients. The literature reveals that the mucostatic impression technique is one of the treatment options in this scenario. Conventional mucostatic methods like employing a window tray technique, multiple relief holes, or double spacers can be employed when the flabby tissue is localized. But in cases of generalized flabbiness of the residual ridge, even the manual placement and manipulation of a custom tray may distort the tissues, violating the principle of mucostatics. This presentation is a clinical report of a patient with a generalized flabby maxillary edentulous ridge opposing a partially edentulous mandibular arch. A split two-part special tray using the principle of magnetic attraction for self retention was fabricated. This self retention ruled out finger pressure during impression making, helping to achieve mucostatics.     

CCR1 blockade reduces tumor burden and osteolysis in vivo in a mouse model of myeloma bone disease

The chemokine CCL3/MIP-1α is a risk factor in the outcome of multiple myeloma (MM), particularly in the development of osteolytic bone disease. This chemokine, highly overexpressed by MM cells, can signal mainly through 2 receptors, CCR1 and CCR5, only 1 of which (CCR1) is responsive to CCL3 in human and mouse osteoclast precursors. CCR1 activation leads to the formation of osteolytic lesions and facilitates tumor growth. Here we show that formation of mature osteoclasts is blocked by the highly potent and selective CCR1 antagonist CCX721, an analog of the clinical compound CCX354. We also show that doses of CCX721 selected to completely inhibit CCR1 produce a profound decrease in tumor burden and osteolytic damage in the murine 5TGM1 model of MM bone disease. Similar effects were observed when the antagonist was used prophylactically or therapeutically, with comparable efficacy to that of zoledronic acid. 5TGM1 cells were shown to express minimal levels of CCR1 while secreting high levels of CCL3, suggesting that the therapeutic effects of CCX721 result from CCR1 inhibition on non-MM cells, most likely osteoclasts and osteoclast precursors. These results provide a strong rationale for further development of CCR1 antagonists for the treatment of MM and associated osteolytic bone disease.     

Lung-enriched Organisms and Aberrant Bacterial and Fungal Respiratory Microbiota after Lung Transplant

Rationale: Long-term survival after lung transplantation is limited by infectious complications and by bronchiolitis obliterans syndrome (BOS), a form of chronic rejection linked in part to microbial triggers. Objectives: To define microbial populations in the respiratory tract of transplant patients comprehensively using unbiased high-density sequencing. Methods: Lung was sampled by bronchoalveolar lavage (BAL) and upper respiratory tract by oropharyngeal wash (OW). Bacterial 16S rDNA and fungal internal transcribed spacer sequencing was used to profile organisms present. Outlier analysis plots defining taxa enriched in lung relative to OW were used to identify bacteria enriched in lung against a background of oropharyngeal carryover. Measurements and Main Results: Lung transplant recipients had higher bacterial burden in BAL than control subjects, frequent appearance of dominant organisms, greater distance between communities in BAL and OW indicating more distinct populations, and decreased respiratory tract microbial richness and diversity. Fungal populations were typically dominated by Candida in both sites or by Aspergillus in BAL but not OW. 16S outlier analysis identified lung-enriched taxa indicating bacteria replicating in the lower respiratory tract. In some cases this confirmed respiratory cultures but in others revealed enrichment by anaerobic organisms or mixed outgrowth of upper respiratory flora and provided quantitative data on relative abundances of bacteria found by culture. Conclusions: Respiratory tract microbial communities in lung transplant recipients differ in structure and composition from healthy subjects. Outlier analysis can identify specific bacteria replicating in lung. These findings provide novel approaches to address the relationship between microbial communities and transplant outcome and aid in assessing lung infections.     

Large magnetodielectric effect and negative magnetoresistance in NiO nanoparticles at room temperature

Nickel oxide nanoparticles having a mean particle size of 19.5 nm were synthesized by a simple chemical method. Those nanoparticles exhibited a spin glass like behaviour at a temperature around 9 K. The samples showed electronic conduction arising out of small polaron hopping between the Ni²⁺ and Ni³⁺ species present in the material. A large magnetodielectric parameter with a maximum value of 52.2% was observed in the sample at room temperature which resulted from the Maxwell–Wagner polarization effect. This was explained as arising due to a large negative magnetoresistance caused by spin polarized electron hopping between Ni²⁺ and Ni³⁺ sites with the consequential formation of space charge polarization at the interfaces of the NiO nanoparticles. This was substantiated by direct measurement of magnetoresistance of the samples which gave identical results. It is believed that negative magnetoresistance after direct measurement occurred due to the interaction between ferromagnetic and antiferromagnetic phases and the value was 37%, the highest reported in the literature so far. As a result of the presence of Ni³⁺ ions, antiferromagnetic phase and ferromagnetic like behaviour of NiO nanoparticles gave higher magnetization than other reported nanoparticles. Such large values of magnetoresistance of the samples will make the material useful as an ideal magnetic sensor.

This work presents NiO nanoparticles synthesized by simple chemical route showing large magnetodielectric effect at room temperature resulted from Maxwell–Wagner polarization effect which was arising due to large negative magnetoresistance.     

Association of rs11643718 SLC12A3 and rs741301 ELMO1 Variants with Diabetic Nephropathy in South Indian Population

This study reports on the association of genetic variants selected from previous genome‐wide association studies for type 2 diabetic nephropathy in south Indians. Eight variants were genotyped in 601 type 2 diabetic subjects without nephropathy (DM) and 583 type 2 diabetic subjects with nephropathy (DN) by MassARRAY. The minor allele frequencies of rs11643718 SLC12A3 variant and rs741301 ELMO1 variant were significantly different between DM and DN groups (P = 0.029 and 0.016, respectively). A combined analysis showed that the subjects carrying the risk genotypes of both these variants (GG of rs11643718 + AG/AA of rs741301) had a significant association with DN with an odds ratio [adjusted for age, sex, Body Mass Index (BMI), HbA1c, and systolic Blood Pressure (BP)] of 1.73 (1.30–2.30, P = 1.72 × 10^–4) as compared to subjects carrying all other genotype combinations. This is the first study to report a significant association of the SLC12A3 rs11643718 and ELMO1 rs741301 (Single nucleotide Polymorphism) SNPs with diabetic nephropathy in south Indians.