Chronic alcoholism (CA) decreases bone mass and increases the risk of hip fracture. Alcohol and its main metabolite, acetaldehyde impairs osteoblastogenesis by increasing oxidative stress. Aldehyde dehydrogenase (ALDH) is the rate-limiting enzyme in clearing acetaldehyde from the body. The clinical relevance of ALDH in skeletal function has been established by the discovery of single nucleotide polymorphism, SNP (rs671) in the ALDH2 gene giving rise to an inactive form of the enzyme (ALDH2*2) that causes increased serum acetaldehyde and osteoporosis in the affected individuals. Subsequent mouse genetics studies have replicated human phenotype in mice and confirmed the non-redundant role of ALDH2 in bone homeostasis. The activity of ALDH2 is amenable to pharmacological modulation. ALDH2 inhibition by disulfiram (DSF) and activation by alda-1 cause reduction and induction of bone formation, respectively. DSF also inhibits peak bone mass accrual in growing rats. On the other hand, DSF showed an anti-osteoclastogenic effect and protected mice from alcohol-induced osteopenia by inhibiting ALDH1a1 in bone marrow monocytes. Besides DSF, there are several classes of ALDH inhibitors with disparate skeletal effects. Alda-1, the ALDH2 activator induced osteoblast differentiation by increasing bone morphogenic protein 2 (BMP2) expression via ALDH2 activation. Alda-1 also restored ovariectomy-induced bone loss. The scope of structure-activity based studies with ALDH2 and the alda-1-like molecule could lead to the discovery of novel osteoanabolic molecules. This review will critically discuss the molecular mechanism of the ethanol and its principal metabolite, acetaldehyde in the context of ALDH2 in bone cells, and skeletal homeostasis.Anticonvulsant drugs are used to treat a wide range of non-epileptic conditions, including chronic, neuropathic pain. We obtained a phenoxyalkylaminoalkanol derivative, KM-416 which had previously demonstrated a significant anticonvulsant activity and had also been shown to bind to 5-HT1A, α2-receptors and SERT and not to exhibit mutagenic properties. As KM-416 is a promising compound in our search for drug candidates, in the present study we further assessed its pharmacological profile (analgesic, local anesthetic, and antidepressant-like activities) accompanied with patch-clamp studies. Considering the importance of drug safety, its influence on the cardiovascular system was also evaluated. Moreover, KM-416 was subjected to forced degradation and pharmacokinetic studies to examine its stability and pharmacokinetic parameters. KM-416 revealed a significant antinociceptive activity in the tonic – the formalin test, neurogenic – the capsaicin test, and neuropathic pain model – streptozotocin-induced peripheral neuropathy. Moreover, it exerted a local anesthetic effect. In addition, KM-416 exhibited anti-depressant like activity. The results from the patch-clamp studies indicated that KM-416 can inhibit currents elicited by activation of NMDA receptors, while it also exhibited a voltage-dependent inhibition of Na+ currents. KM-416 did not influence ventricular depolarization and repolarization. Following oral administration, pharmacokinetics of KM-416 was characterized by a rapid absorption in the rat. The brain-to-plasma AUC ratio was 6.7, indicating that KM-416 was well distributed to brain. The forced degradation studies showed that KM-416 was very stable under stress conditions. All these features made KM-416 a promising drug candidate for further development against neuropathic pain and epilepsy.Endothelins regulate catecholaminergic activity in the olfactory bulb (OB) in normotensive and hypertensive animals. Administration of an endothelin ETA receptor antagonist decreases blood pressure in deoxycorticosterone acetate-salt (DOCA-salt) rats along with a reduction in tyrosine hydroxylase (TH) activity and expression. In the present work, we sought to establish the role of brain endothelin ETB receptor on blood pressure regulation and its relationship with the catecholaminergic system within the OB of DOCA-Salt rats. Sprague-Dawley male rats were divided into control and DOCA-Salt groups. Blood pressure, heart rate and TH activity as well as neuronal nitric oxide synthase (nNOS) expression were assessed following IRL-1620 (selective endothelin ETB receptor agonist) applied to be brain. IRL-1620 significantly reduced systolic, diastolic, and mean arterial pressure in DOCA-Salt hypertensive rats. It also decreased TH activity, TH total and phosphorylated forms expression as well as its mRNA in the OB of hypertensive animals. The expression of phospho-Ser1417-nNOS, which reflects nNOS activation, was significantly decreased in the of OB of DOCA-salt rats, but it was enhanced by IRL-1620. These findings suggest that DOCA-Salt hypertension depends on endogenous central endothelin ETA receptor activity, rather than on ETB, and that low endothelin ETB stimulation is essential for blood pressure elevation in this animal model. The effect of endothelin ETA receptor antagonism may also result from endothelin ETB receptor overstimulation. The present study shows that endothelin receptors are involved in the regulation of TH in the OB and that such changes are likely implicated in the hemodynamic control and sympathetic outflow.The cardiac plexus, which contains parasympathetic ganglia, plays an important role in regulating cardiac function. Histamine is known to excite intracardiac ganglion neurons, but the underlying mechanism is obscure. In the present study, therefore, the effect of histamine on rat intracardiac ganglion neurons was investigated using perforated patch-clamp recordings. Histamine depolarized acutely isolated neurons with a half-maximal effective concentration of 4.5 μM. This depolarization was markedly inhibited by the H1 receptor antagonist triprolidine and mimicked by the H1 receptor agonist 2-pyridylethylamine, thus implicating histamine H1 receptors. Consistently, reverse transcription-PCR (RT-PCR) and Western blot analyses confirmed H1 receptor expression in the intracardiac ganglia. Under voltage-clamp conditions, histamine evoked an inward current that was potentiated by extracellular Ca2+ removal and attenuated by extracellular Na+ replacement with N-methyl-D-glucamine. This implicated the involvement of non-selective cation channels, which given the link between H1 receptors and Gq/11-protein-phospholipase C signalling, were suspected to be transient receptor potential canonical (TRPC) channels. This was confirmed by the marked inhibition of the inward current through the pharmacological disruption of either Gq/11 signalling or intracellular Ca2+ release and by the application of the TRPC blockers Pyr3, Gd3+ and ML204. Consistently, RT-PCR analysis revealed the expression of several TRPC subtypes in the intracardiac ganglia. Whilst histamine was also separately found to inhibit the M-current, the histamine-induced depolarization was only significantly inhibited by the TRPC blockers Gd3+ and ML204, and not by the M-current blocker XE991. These results suggest that TRPC channels serve as the predominant mediator of neuronal excitation by histamine.The opioid crisis has underscored the urgent need to identify safe and effective therapeutic strategies to overcome opioid-induced liabilities. We recently reported that LY2828360, a slowly signaling G protein-biased cannabinoid CB2 receptor agonist, suppresses neuropathic nociception and attenuates the development of tolerance to the opioid analgesic morphine in paclitaxel-treated mice. Whether beneficial effects of LY2828360 are dependent upon the presence of a pathological pain state are unknown and its impact on unwanted opioid-induced side-effects have never been investigated. Here, we asked whether LY2828360 would produce synergistic anti-allodynic effects with morphine in a paclitaxel model of chemotherapy-induced neuropathic pain and characterized its impact on opioid-induced reward and other unwanted side-effects associated with chronic opioid administration. Isobolographic analysis revealed that combinations of LY2828360 and morphine produced synergistic anti-allodynic effects in suppressing paclitaxel-induced mechanical allodynia. In wildtype (WT) mice, LY2828360 blocked morphine-induced reward in a conditioned place preference assay without producing reward or aversion when administered alone. The LY2828360-induced attenuation of morphine-induced reward was absent in CB2 knockout (CB2KO) mice. In the absence of a neuropathic pain state, LY2828360 partially attenuated naloxone-precipitated opioid withdrawal in morphine-dependent WT mice, and this withdrawal was itself markedly exacerbated in CB2KO mice. Moreover, LY2828360 did not reliably alter morphine-induced slowing of colonic transit or attenuate tolerance to morphine antinociceptive efficacy in the hot plate test of acute nociception. Our results suggest that cannabinoid CB2 receptor activation enhances the therapeutic properties of opioids while attenuating unwanted side-effects such as reward and dependence that occur with sustained opioid treatment.

The 2 surgical strategies for neonates with ductal-dependent pulmonary atresia and ventricular septal defect are primary biventricular repair (BVR) or initial palliation with a modified Blalock-Taussig shunt (BTS) followed by second stage repair. In this study, we report the combined outcomes from 2 hospitals using different strategies.

Between 2004 and 2017, 66 neonates underwent surgery with palliative shunts (BTS group n= 30, 45.5%) or primary biventricular repair (pBVR group n= 36, 54.5%). The 2 groups were similar in age, body weight, and Nakata index scores. The overall mean follow-up duration was 7.51 ± 4.35 years, and early and late results were compared between the groups.

The 10-year overall survival was 84.8% (94.4% for pBVR vs 75.7% for BTS, P= .032). The BTS group had 2 early and 6 interstage mortalities, and the pBVR group had no early and 2 late mortalities. In the BTS group, the Nakata index score significantly increased during the interstage period (P < .001). In univariable analysisrtality are significant. Genetic and extracardiac anomalies are significant risk factors for mortality.

Bundled payments for coronary artery bypass grafting (CABG) provide a single reimbursement for care provided from admission through 90 days post-discharge. We aim to explore the impact of complications on total institutional costs, as well as the drivers of high costs for index hospitalization.

We linked clinical and internal cost data for patients undergoing CABG from 2014 to 2017 at a single institution. We compared unadjusted average variable direct costs, reporting excess cost from an uncomplicated baseline. We stratified by The Society of Thoracic Surgeons preoperative risk and quality outcome measures as well as value-based outcomes (readmission, post-acute care utilization). We performed multivariable linear regression to evaluate drivers of high costs, adjusting for preoperative and intraoperative characteristics and postoperative complications.

We reviewed 1789 patients undergoing CABG with an average of 2.7 vessels (SD 0.89). A significant proportion of patients were diabetic (51.2%) and obese (mean body mass index 30.