RESUMO
Background: A salient effect of addictive drugs is to hijack the dopamine reward system, an evolutionarily conserved driver of goal-directed behavior and learning. Reduced dopamine type 2 receptor availability in the striatum is an important pathophysiological mechanism for addiction that is both consequential and causal for other molecular, cellular, and neuronal network differences etiologic for this disorder. Here, we sought to identify gene expression changes attributable to innate low expression of the Drd2 gene in the striatum and specific to striatal indirect medium spiny neurons (iMSNs). Methods: Cre-conditional, translating ribosome affinity purification (TRAP) was used to purify and analyze the translatome (ribosome-bound messenger RNA) of iMSNs from mice with low/heterozygous or wild-type Drd2 expression in iMSNs. Complementary electrophysiological recordings and gene expression analysis of postmortem brain tissue from human cocaine users were performed. Results: Innate low expression of Drd2 in iMSNs led to differential expression of genes involved in GABA (gamma-aminobutyric acid) and cAMP (cyclic adenosine monophosphate) signaling, neural growth, lipid metabolism, neural excitability, and inflammation. Creb1 was identified as a likely upstream regulator, among others. In human brain, expression of FXYD2, a modulatory subunit of the Na/K pump, was negatively correlated with DRD2 messenger RNA expression. In iMSN-TRAP-Drd2HET mice, increased Cartpt and reduced S100a10 (p11) expression recapitulated previous observations in cocaine paradigms. Electrophysiology experiments supported a higher GABA tone in iMSN-Drd2HET mice. Conclusions: This study provides strong molecular evidence that, in addiction, inhibition by the indirect pathway is constitutively enhanced through neural growth and increased GABA signaling.
RESUMO
Simultaneous ventral hernia repair with panniculectomy (VHR-PAN) is associated with a high rate of wound complications. Closed incision negative pressure wound therapy (ciNPWT) has been shown to lower complications in high-risk wounds. There is a debate in the literature as to whether ciNPWT is effective at preventing complications in VHR-PAN. The aim of our study was to evaluate if ciNPWT improves outcomes of VHR-PAN. Methods: A retrospective review of patients who underwent VHR-PAN between 2009 and 2021 was conducted. Patients were divided into two groups: (1) those who received standard sterile dressings (SSD), or (2) ciNPWT. Primary outcomes were postoperative complications, including surgical site occurrences (SSO) and hernia recurrence. Results: A total of 114 patients were identified: 57 patients each in the SSD group and ciNPWT group. The groups were similar in demographics and comorbidities. There were more smokers in the SSD group (22.8% versus 5.3%, P = 0.013). Hernia defect size was significantly larger in patients who received ciNPWT (202.0 versus 143.4 cm2, P = 0.010). Overall SSO was similar between the two groups (23.2% versus 26.3%, P = 0.663). At a mean follow-up of 6.6 months, hernia recurrence rate was significantly higher in the SSD group compared with that in the ciNPWT group. (10.5% versus 0%, P = 0.027). Smoking, diabetes, component separation, mesh type, and location were not significantly associated with hernia recurrence. Conclusions: Application of incisional NPWT is beneficial in decreasing hernia recurrence in VHR-PAN, compared with standard dressings. Larger prospective studies are warranted to further elucidate the utility of ciNPWT in abdominal wall reconstruction.