Dehydroepiandrosterone modulates T-cell response after major abdominal surgery

Background

The immune balance controlled by T-helper (Th)1 and Th2 cells is critical in protecting the host from pathogenic invasion, and its imbalance may increase susceptibility to infection in patients undergoing major surgery. The differentiation of naive T cells to Th1 and Th2 cells is largely driven by cytokines. In addition, steroid hormones have been shown to affect Th1/Th2 balance, particularly in autoimmune diseases. The regulation of Th1/Th2 balance in patients undergoing surgery and its potential clinical relevance remain unclear.

Materials and methods

Blood samples were obtained from patients both before and 2 h after major abdominal surgery. Peripheral blood mononuclear cells were isolated and cultured in wells coated with either anti-CD3 (direct T-cell stimulation) or phytohemagglutinin (PHA) (indirect T-cell stimulation), with or without 10⁻⁵ M dehydroepiandrosterone (DHEA). The release of interleukin (IL)-2, interferon gamma, and IL-10 was measured by an enzyme-linked immunosorbent assay, and the expression of CD4, CD8, and CD69 was determined by flow cytometry.

Results

DHEA decreased the release of IL-2 and IL-10 in directly (anti-CD3) and indirectly (PHA)-stimulated T cells from postoperative samples, whereas the release of interferon gamma in PHA-stimulated T cells was not affected. The distribution of CD4/CD8 was not significantly different after surgery or DHEA. DHEA was associated with a decrease in the expression of the activation marker CD69 on CD4⁺ T cells, whereas the activation of CD8⁺ T cells remained unchanged.

Conclusions

These results demonstrate that DHEA plays a critical role in controlling Th1/Th2 balance in the immediate postoperative period. Attenuation of both the Th1 and Th2 responses has been suggested to have immunoprotective effects. The role of DHEA in the regulation of Th1/Th2 balance in patients undergoing major abdominal surgery may, therefore, also be of significant clinical relevance and warrants further investigation.     

Polygenic inheritance of Tourette syndrome,stuttering, attention deficit hyperactivity,conduct, and oppositional defiant disorder: The additive and subtractive effect of the three dopaminergic genes—DRD2, DβH,and DAT1

Polymorphisms of three different dopaminergic genes, dopamine D₂ receptor (DRD2), dopamine β-hydroxylase (DβH), and dopamine transporter (DAT1), were examined in Tourette syndrome (TS) probands, their relatives, and controls. Each gene individually showed a significant correlation with various behavioral variables in these subjects. The additive and subtractive effects of the three genes were examined by genotyping all three genes in the same set of subjects. For 9 of 20 TS associated comorbid behaviors there was a significant linear association between the degree of loading for markers of three genes and the mean behavior scores. The behavior variables showing the significant associations were, in order, attention deficit hyperactivity disorder (ADHD), stuttering, oppositional defiant, tics, conduct, obsessive-compulsive, mania, alcohol abuse, and general anxiety-behaviors that constitute the most overt clinical aspects of TS. For 16 of the 20 behavior scores there was a linear progressive decrease in the mean score with progressively lesser loading for the three gene markers. These results suggest that TS, ADHD, stuttering, oppositional defiant and conduct disorder, and other behaviors associated with TS, are polygenic, due in part to these three dopaminergic genes, and that the genetics of other polygenic psychiatric disorders may be deciphered using this technique. © 1996 Wiley-Liss, Inc.     

Proteasome inhibitors and Smac mimetics cooperate to induce cell death in diffuse large B-cell lymphoma by stabilizing NOXA and triggering mitochondrial apoptosis

Copy number gains and increased expression levels of cellular Inhibitor of Apoptosis protein (cIAP)1 and cIAP2 have been identified in primary diffuse large B-cell lymphoma (DLBCL) tissues. Second mitochondria-derived activator of caspases (Smac) mimetics were designed to antagonize IAP proteins. However, since their effect as single agents is limited, combination treatment represents a strategy for their clinical development. Therefore, we investigated the Smac mimetic BV6 in combination with proteasome inhibitors and analyzed the molecular mechanisms of action. We discovered that BV6 treatment sensitizes DLBCL cells to proteasome inhibition. We show a synergistic decrease in cell viability and induction of apoptosis by BV6/Carfilzomib (CFZ) treatment, which was confirmed by calculation of combination index (CI) and Bliss score. BV6 and CFZ acted together to trigger activation of BAX and BAK, which facilitated cell death, as knockdown of BAX and BAK significantly reduced BV6/CFZ-mediated cell death. Activation of BAX and BAK was accompanied by loss of mitochondrial membrane potential (MMP) and activation of caspases. Pretreatment with the caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD.fmk) rescued BV6/CFZ-induced cell death, confirming caspase dependency. Treatment with CFZ alone or in combination with BV6 caused accumulation of NOXA, which was required for cell death, as gene silencing by siRNA or Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9-mediated NOXA inactivation inhibited BV6/CFZ-induced cell death. Together, these experiments indicate that BV6 and CFZ cooperatively induce apoptotic cell death via the mitochondrial pathway. These findings emphasize the role of Smac mimetics for sensitizing DLBCL cells to proteasome inhibition with important implications for further (pre)clinical studies.     

Longitudinal micromorphological 15-year results of posterior composite restorations using three-dimensional scanning electron microscopy

Objectives

Hybrid composite restorations in posterior teeth were evaluated over 15 years using the semiquantitative Clinical, Photographic and Micromorphologic (CPM) index. It was a further aim to quantitate the surface morphology by three-dimensional scanning electron microscopy (3D-SEM).

Methods

Thirty seven hybrid composite restorations (Ketac-Bond/Visio-Molar X, ESPE, Seefeld/Germany) were longitudinally followed up.Parallel to clinical assessment replicas were taken at baseline, after 1, 5, 10 and 15 years and evaluated by SEM, and profilometrical analyses of 3D-SEM data were computed. The profilometrical results were statistically analysed by ANOVA. The level of significance was set to p < 0.05.

Results

The semiquantitative micromorphological evaluation exhibited the most considerable deterioration within the first year and up to 5 years of function. Less change was detected during the next 10 years. The profilometrical quantification showed raising depth of the negative marginal ledges with a mean of 27.2 μm (range 0.6–94.5 μm) after 10 years, with no statistically significant changes from 5 to 10 and 10 to 15 years. The 3D-SEM revealed marginal grooves beneath the level of the ledges (mean 34.5 μm after 5 years) within the bonding zone, exposing enamel margins. Leakages, marginal fractures and surface roughness did not seriously deteriorate the quality of restorations.

Conclusions

Hybrid composite restorations of Class I and II cavities surviving the first five years performed well over 15 years of function. Quantitative 3D-SEM profilometrical measurements revealed the dynamics of marginal behaviour over time.

Clinical significance

Long-term parallel clinical and micromorphological evaluation of posterior composite restorations of Class I and Class II cavities documented the clinical safety and acceptable longevity. The longitudinal 3D micromorphologic assessment of the surface changes and of the marginal behaviour revealed deteriorating as well as improving factors hidden in clinical performance.     

Risk factors for surgical site infection after major breast operation

BACKGROUND: Understanding surgical site infection (SSI) risk factors after breast operation is essential to develop infection-prevention strategies and improve surgical outcomes. METHODS: We performed a retrospective case-control study with subjects selected from a cohort of mastectomy, breast reconstruction, and reduction surgical patients between January 1998 and June 2002 at a university-affiliated hospital. SSI cases within 1 year after operation were identified using ICD-9-CM diagnosis codes for wound infection and complication or positive wound cultures, or both. Medical records of 57 patients with breast SSI and 268 randomly selected uninfected control patients were reviewed. Multivariate logistic regression was used to identify independent risk factors for SSI. RESULTS: Significant independent risk factors for breast incisional SSI included insertion of a breast implant or tissue expander (odds ratio [OR] = 5.3; 95% CI, 2.5 to 11.1), suboptimal prophylactic antibiotic dosing (OR = 5.1; 95% CI, 2.5 to 10.2), transfusion (OR = 3.4; 95% CI, 1.3 to 9.0), mastectomy (OR = 3.3; 95% CI, 1.4 to 7.7), previous chest irradiation (OR = 2.8; 95% CI, 1.2 to 6.5), and current or recent smoking (OR = 2.1; 95% CI, 0.9 to 4.9). Local infiltration of an anesthetic agent was associated with substantially reduced odds of SSI (OR = 0.4; 95% CI, 0.1 to 0.9). CONCLUSIONS: Suboptimal prophylactic antibiotic dosing is a potentially modifiable risk factor for SSI after breast operation. SSI risk was increased in patients undergoing mastectomy and in patients who had an implant or tissue expander placed during operation. This information can be used to develop a specific risk stratification index to predict SSI and infection-preventive strategies tailored for breast surgery patients.