Novel Opipramol-Baclofen Combination Alleviates Depression and Craving and Facilitates Recovery From Substance Use Disorder—An Animal Model and a Human Study

Substance use disorders (SUDs) are associated with depression and anxiety, with the latter being one of the major factors in substance-seeking and relapse. Due to dose-dependent sedative side effects there is limited efficacy of baclofen treatment for SUDs. Here we suggest the use of a novel combination of opipramol and baclofen (O/B) which is known to attenuate anxiety and depression, for the facilitation of recovery from SUDs. Since both opipramol and baclofen have a common downstream signal transduction, their individual doses could be reduced while still maintaining the benefits of the combination. We tested the O/B combination in both animals and patients. Rats treated with O/B showed significant attenuation in craving behavior and in relapse rate during withdrawal from cocaine. In a double-blind, placebo-controlled pilot study, conducted in a residential detoxification center, 14 males and 3 females, aged 28–60 years were assigned to a study (n = 6) and a placebo (n = 11) group (placebo group: 40 ± 10.5 years; O/B group 40 ± 10.8 years). The participants completed scales measuring depression, anxiety and craving symptoms and provided saliva samples for stress hormone examination [cortisol and dehydroepiandrosterone-sulfate (DHEA-S)]. Participants with polysubstance use disorder (PsUD) treated with O/B showed a reduction in cravings and depression and an increase in DHEA-S and in the DHEA-S/cortisol ratio. Our findings indicate a beneficial effect of O/B treatment. This study suggests a novel candidate for pharmacological treatment of patients with SUD and comorbid mood/anxiety disorders that may facilitate their rehabilitation.

NLRP2 Is Overexpressed in Spinal Astrocytes at the Peak of Mechanical Pain Sensitivity during Complete Freund Adjuvant-Induced Persistent Pain

Our earlier findings revealed that interleukin-1 receptor type-1 (IL-1R1) was overexpressed in spinal neurons, and IL-1R1-deficient mice showed significant attenuation of thermal and mechanical allodynia during the course of the Complete Freund adjuvant (CFA)-induced persistent pain model. In the present study, we found that a ligand of IL-1R1, termed interleukin-1β (IL-1β), is also significantly overexpressed at the peak of mechanical pain sensitivity in the CFA-evoked pain model. Analysis of cellular distribution and modeling using IMARIS software showed that in the lumbar spinal dorsal horn, IL-1β is significantly elevated by astrocytic expression. Maturation of IL-1β to its active form is facilitated by the formation of the multiprotein complex called inflammasome; thus, we tested the expression of NOD-like receptor proteins (NLRPs) in astrocytes. At the peak of mechanical allodynia, we found expression of the NLRP2 inflammasome sensor and its significantly elevated co-localization with the GFAP astrocytic marker, while NLRP3 was moderately present and NLRP1 showed total segregation from the astrocytic profiles. Our results indicate that peripheral CFA injection induces NLRP2 inflammasome and IL-1β expression in spinal astrocytes. The release of mature IL-1β can contribute to the maintenance of persistent pain by acting on its neuronally expressed receptor, which can lead to altered neuronal excitability.

Optoelectrical Operation Stability of Broadband PureGaB Ge-on-Si Photodiodes with Anomalous Al-Mediated Sidewall Contacting

An anomalous aluminum-mediated material transport process was investigated in sets of Ge-on-Si photodiodes with broadband optoelectrical characteristics measured at wavelengths from 255 nm to 1550 nm. The diodes had “PureGaB” anode regions fabricated by depositing a Ga wetting layer capped with an 11-nm-thick B-layer on 0.5 µm-thick Ge islands grown on Si. The Al metallization was able to reach the Ge-Si interface through ~ 0.1-µm-wide holes inadvertently etched along the perimeter of the Ge-islands, and then traveled along the Ge-Si interface, displacing and recrystallizing Ge and Si. The rest of the Ge surface was protected from the Al contact metallization by the B-layer. For diodes that had received the standard 400°C Al alloying step, the responsivity was near-theoretical at 406 nm and 670 nm, but, at 1310 nm and 1550 nm, the proximity of Ge-Si interfacial defects caused significant attenuation. Extra annealing at 400°C or 500°C enhanced the formation of Si pits that were filled with modified Ge crystals alloyed with Si and p-doped with Al. All these diodes maintained low dark currents, below 50 µA/cm2 at 2 V reverse bias, but the responsivity was degraded, particularly for the long wavelengths. On the other hand, neither responsivity nor degradation of current–voltage (I–V) characteristics was observed for prolonged exposure to normal operating temperatures up to 100°C. Since the direct Al contacting of the Ge sidewalls does not degrade the dark current, for large diodes it could be a low-cost method of obtaining low contact resistance to an anode with p-type sidewall passivation and high fill-factor.

Specificity of the second sound standing waves behavior in a medium with nanoparticles

The experimental studies of the second sound waves propagation in a resonator with a deuterium-helium gel were carried out. The latest experimental results, combined with those obtained in earlier experiments, have shown that the propagation of the second sound waves in gels leads to their significant attenuation and a decrease in the propagation velocity. This behavior differs from the case of the propagation of the sound waves of a two-component system with a strongly slow normal component and may indicate changes in the properties of superfluidity under confined geometry conditions.

Geologic framework of Mount Diablo, California

ABSTRACT The basic stratigraphic and structural framework of Mount Diablo is described using a revised geologic map, gravity data, and aeromagnetic data. The mountain is made up of two distinct stratigraphic assemblages representing different depocenters that were juxtaposed by ~20 km of late Pliocene and Quaternary right-lateral offset on the Greenville-Diablo-Concord fault. Both assemblages are composed of Cretaceous and Cenozoic strata overlying a compound basement made up of the Franciscan and Great Valley complexes. The rocks are folded and faulted by late Neogene and Quaternary compressional structures related to both regional plate-boundary–normal compression and a restraining step in the strike-slip fault system. The core of the mountain is made up of uplifted basement rocks. Late Neogene and Quaternary deformation is overprinted on Paleogene extensional deformation that is evidenced at Mount Diablo by significant attenuation in the basement rocks and by an uptilted stepped graben structure on the northeast flank. Retrodeformation of the northeast flank suggests that late Early to early Late Cretaceous strata may have been deposited against and across a steeply west-dipping basement escarpment. The location of the mountain today was a depocenter through the Late Cretaceous and Paleogene and received shallow-marine deposits periodically into the late Miocene. Uplift of the mountain itself happened mostly in the Quaternary.

Trophic And Immunomodulatory Effects of Adipose Tissue-Derived Stem Cells In A Preclinical Murine Model of Endometriosis

Endometriosis, which exhibits enigmatic pathological features such as stromal fibrosis and proliferation of ectopic epithelial cells, is known as a refractory disease. Mesenchymal stem cells modulate the fibrosis in stromal tissues through their trophic and immunomodulatory properties. To investigate the potential of stem cells in treating endometriosis, we examined the secondary morphology and molecular alterations in endometriosis-like lesions after the administration of adipose tissue-derived stem cells (ASCs) to an experimental murine model of endometriosis. The infused ASCs were found integrated in the endometriosis-like lesions. Accompanied by the suppression of stromal fibrosis and proliferation of endometriotic epithelial cells, the infusion of ASCs with stemness potential suppressed the growth of endometriosis-like lesions and inhibited the expression of pro-inflammatory and pro-fibrotic cytokines, whereas no significant attenuation of endometriosis-like lesions occurred after the infusion of ASCs without stemness potential. Accordingly, it is plausible that the trophic and immunomodulatory properties of ASCs may regulate fibrosis in endometriosis-like lesions, suggesting that regenerative medicine has strong potential as an innovative treatment for patients with endometriosis.

Abstract MP57: Chronic Inhibition Of Brain Rhomboid-like Protein 2 (irhom2) Activity Decreases Arterial Blood Pressure In Salt-sensitive Hypertension In Mice

We previously reported that ADAM17 (aka tumor necrosis factor-α convertase) is critical for the development of hypertension in experimental models and patients. Recent studies highlighted that ADAM17’s formation of TNF-α relies on prior maturation of this sheddase, controlled by the rhomboid-like protein 2 (iRhom2) specifically in microglia. Genetic deletion of iRhom2 in mice shows significant attenuation of TNF-α and ADAM17 activity in a tissue specific manner. Here, we hypothesized that silencing iRhom2 activity specifically in the brain would decrease blood pressure (BP) in the DOCA-salt model of hypertension, in mice. Uninephrectomized mice were implanted subcutaneously (sc) with DOCA-pellets (50 mg) and provided with 1% saline in drinking water. In addition, mice were chronically implanted with an icv cannula connected to a sc osmotic minipump for delivery of: (1) iRhom2-siRNA (9.6 μg/kg/day), (2) scrambled siRNA (SCR 0.2 μg/kg/day), (3) ADAM17 antibody (ADAM17-Ab; 23.8 μg/kg/day) or (4) artificial cerebrospinal fluid (aCSF) for 2 weeks while BP was recorded by telemetry. DOCA-salt treatment led to a significant increase in BP in the control groups (SCR: 156 ±3 mmHg and aCSF: 161 ±1 mmHg; n=3/group; p<0.001) compared to baseline values (122 ±2 mmHg; n=12). ICV infusion of iRhom2-siRNA or ADAM17 neutralizing antibody for 2-weeks in DOCA-salt-treated mice resulted in a significant attenuation of BP (iRhom2-siRNA: 152 ±2 mmHg and ADAM17-Ab: 151 ±2 mmHg n=3/group, p<0.001). These data suggest that: 1) Selective silencing of iRhom2 from microglia is as potent as ADAM17 neutralization throughout the brain in lowering BP and 2) iRhom2 is a potential new therapeutic target for the treatment of salt-sensitive hypertension.

Shear Strength and Microstructure of Intact Loess Subjected to Freeze-Thaw Cycling

In the Loess Plateau, seasonal freeze and thaw cause great damage to the mechanical behavior and microstructure of soil, which leads to frequent geological disasters during winter and spring. To investigate the influence of freeze-thaw (FT) cycling (FTC) on the shear strength and microstructure of intact loess, triaxial shear, nuclear magnetic resonance, and scanning electron microscope tests were carried out on soil samples after target FT cycles. The results indicate that the FTC has limited changes to the soil stress-strain curve, but has a significant attenuation effect on the peak deviatoric stress. The peak deviatoric stress was attenuated by FTC but changed insignificantly after ten cycles. The cohesive force decays exponentially with the number of FT cycles, while the internal friction angle increases slightly. Moreover, under FTC, the T2 hydrogen spectra of soil samples showed a multimodal distribution, with the main peak appearing to have two obvious upward shifts that occurred at 6 and 10 FT cycles. Indeed, a depolarization phenomenon related to the directional frequency of soil particles was observed, and the mass fractal dimension of the pore network increased slightly. In an FT environment, the shear strength declines due to accumulated internal microstructural damage. These findings contribute to a better understanding of the response of loess to FTC and provide novel ideas for the prevention of frost damage in loess areas.

Activation of the Thiazide-Sensitive Sodium-Chloride Cotransporter by Beta3-Adrenoreceptor in the Distal Convoluted Tubule

We previously showed that the beta-3 adrenergic receptor (BAR3) is expressed in most segments of the nephron where its agonism promotes a potent antidiuretic effect. We localized BAR3 in distal convoluted tubule (DCT) cells expressing the thiazide-sensitive sodium-chloride cotransporter (NCC). Aim of this study is to investigate the possible functional role of BAR3 on NCC modulation in DCT cells. Here, we found that, in mice, the knockout of BAR3 was paralleled by a significant attenuation of NCC phosphorylation, paralleled by reduced expression and activation of STE-20/SPS1-related proline-alanine-rich kinase (SPAK) and WNKs the main kinases involved in NCC activation. Conversely, in BAR1/2 knockout mice, we found reduced NCC abundance with no changes in the phosphorylation state of NCC. Moreover, selective BAR3 agonism promotes both SPAK and NCC activation in wild-type mouse kidney slices. In conclusion, our findings suggest a novel role for BAR3 in the regulation of NCC in DCT.

Dexmedetomidine versus Lignocaine for extubation in patients undergoing craniotomies

Use of lignocaine and dexmedetomidine in terms of causing hemodymaic variation, sedation and pain management remains a question. Hence this was conducted to compare a bolus dose of dexmedetomidine 0.5mcg/kg/hr to a normal dose of 1.5mg/kg preservative free 2% lignocaine for extubation in patients undergoing craniotomies.This randomized controlled trial was conducted in the department of Anesthesiology at Sri Ramachandra Medical College and Research Institute, Chennai from January 2013 to June 2014. Patients aged between 18-60 years belongs to ASA class I and class II undergoing surgeries were included in the study. A total of fifty cases were included. Statistical analysis was done using SPSS version 17.Hemodynamic parameters showed significant attenuation of hemodynamic response during extubation when compared to lignocaine group and when the same were analyzed within the groups, the attenuation of extubation response was both clinically and statistically significant in both groups. Extubation and emergence time were similar in both the groups. Sedation and pain scores in dexmedetomidine group were low compared to lignocaine group. Single dose of dexmedetomidine given 10 minutes before extubation significantly attenuated the hemodynamic and airway response following extubation as compared to lignocaine given before reversal in patients undergoing craniotomy for intracranial space occupying lesions.