Apolipoprotein CIII reduces proinflammatory cytokine-induced apoptosis in rat pancreatic islets via the Akt prosurvival pathway

Apolipoprotein CIII (ApoCIII) is mainly synthesized in the liver and is important for triglyceride metabolism. The plasma concentration of ApoCIII is elevated in patients with type 1 diabetes (T1D), and in vitro ApoCIII causes apoptosis in pancreatic β-cells in the absence of inflammatory stress. Here, we investigated the effects of ApoCIII on function, signaling, and viability in intact rat pancreatic islets exposed to proinflammatory cytokines to model the intraislet inflammatory milieu in T1D. In contrast to earlier observations in mouse β-cells, exposure of rat islets to ApoCIII alone (50 μg/ml) did not cause apoptosis. In the presence of the islet-cytotoxic cytokines IL-1β + interferon-γ, ApoCIII reduced cytokine-mediated islet cell death and impairment of β-cell function. ApoCIII had no effects on mitogen-activated protein kinases (c-Jun N-terminal kinase, p38, and ERK) and had no impact on IL-1β-induced c-Jun N-terminal kinase activation. However, ApoCIII augmented cytokine-mediated nitric oxide (NO) production and inducible NO synthase expression. Further, ApoCIII caused degradation of the nuclear factor κB-inhibitor inhibitor of κB and stimulated Ser473-phosphorylation of the survival serine-threonine kinase Akt. Inhibition of the Akt signaling pathway by the phosphatidylinositol 3 kinase inhibitor LY294002 counteracted the antiapoptotic effect of ApoCIII on cytokine-induced apoptosis. We conclude that ApoCIII in the presence of T1D-relevant proinflammatory cytokines reduces rat pancreatic islet cell apoptosis via Akt.     

The vasodilatory beta-blockers

Although well established in treating hypertension and cardiovascular (CV) disease, clinical trial data suggest that beta-blockers (eg, atenolol) may be less effective than other antihypertensive classes in reducing stroke and CV mortality despite similar blood pressure (BP) reductions. One possible explanation is that atenolol is less effective in reducing central aortic pressure. Newer vasodilating beta-blockers may prove more effective in reducing central pressure and cardiovascular events. Carvedilol and labetalol appear to cause vasodilation through alpha(1)-receptor blockade; nebivolol induces endothelium-dependent vasodilation by stimulating nitric oxide bioactivity. Their favorable hemodynamic profile includes reduction of peripheral vascular resistance (PVR) while maintaining or improving cardiac output (CO), stroke volume, and left ventricular function, whereas nonvasodilating beta-blockers tend to raise PVR and reduce CO and left ventricular function. Compared with conventional beta-blockers, vasodilating beta-blockers have beneficial hemodynamic effects including decreased pressure wave reflection from the periphery, leading to decreases in central aortic blood pressure. Larger trials are needed to determine whether reduced central pressure will translate into improved CV outcomes compared with nonvasodilating beta-blockers.     

Preoperative BMD does not influence femoral stem subsidence of uncemented THA when the femoral T-score is > –2.5

Background and purpose — It is believed that in uncemented primary total hip arthroplasty (THA) the anchorage of the stem is dependent on the level of bone mineral density (BMD) of the femoral bone. This is one of the reasons for the widely accepted agreement that a cemented solution should be selected for people with osteoporosis or age > 75 years. We evaluated whether preoperative BMD of the femur bone is related to femoral stem migration in uncemented THA.Patients and methods — We enrolled 62 patients (mean age 64 years (range 49–74), 34 males) scheduled for an uncemented THA. Before surgery we undertook DEXA scans of the proximal femur including calculation of the T- and Z-scores for the femoral neck. Evaluation of stem migration by radiostereometric analysis (RSA) was performed with 24 months of follow-up. In 56 patients both preoperative DEXA data and RSA data were available with 24 months of follow-up.Results — None of the patients had a T-score below –2.5. We found no statistically significant relationship between preoperative BMD and femoral stem subsidence after 3 or 24 months. When comparing the average femoral stem subsidence between 2 groups with T-score > –1 and T-score ≤ –1, respectively, we found no statistically significant difference after either 3 or 24 months when measured with RSA.Interpretation — In a cohort of people ≤ 75 years of age and with local femur T-score > –2.5 we found no relationship between preoperative BMD and postoperative femoral stem subsidence of a cementless THA.

Early migration of total hip arthroplasty (THA) femoral stems is expected to some extent (Alfaro-Adrian et al. 2001). Cemented stems migrate less than uncemented do, because the initial stabilization is secured with bone cement, but both migrate in a similar pattern (Nysted et al. 2014, Van Der Voort et al. 2015, Teeter et al. 2018). The fixation of the stem and the risk of fracture are believed to rely on the density of the surrounding bone, which is why it is considered rational to fixate THAs in elderly and/or people with osteoporosis (or other disorders affecting the bone) by using bone cement (Piarulli et al. 2013, Troelsen et al. 2013, Gulati and Manktelow 2017).The BMD of the hip is the most reliable estimate to predict hip fracture risk and is interpreted by using the World Health Organization’s definition of T- and Z-score (Johnell et al. 2005, Blake and Fogelman 2007).Radiostereometric analysis (RSA) is used to measure the rotations and translations. The migration of interest is primarily translation along the Y-axis (Y-translation), where a negative value is distal migration, i.e., subsidence (Li et al. 2014, Weber et al. 2014, Matejcic et al. 2015).There are few studies comparing the local BMD with the migration of an uncemented THA stem, but some show that lower femoral BMD leads to increased subsidence (Mears et al. 2009), while other studies cannot demonstrate such a relationship (Moritz et al. 2011). Women with low systemic BMD have been reported to have a tendency to higher migration (Aro et al. 2012, Nazari-Farsani et al. 2020).Our study is partly based on secondary endpoint data from a randomized controlled trial (RCT) (Dyreborg et al. 2020). The main aim of the present study was to evaluate whether preoperative BMD of 3 regions in the femoral bone is related to femoral stem subsidence in uncemented THA. Furthermore, we determined whether a standard hip dual-energy X-ray absorptiometry (DEXA) scan, normally used for diagnosis of osteoporosis, could be used for the above purpose.We hypothesized that low preoperative femoral BMD is related to higher stem subsidence.     

Nestin expression in cutaneous melanomas and melanocytic nevi

BACKGROUND: Nestin is one of the intermediate filaments that are expressed in proliferating neural progenitor cells during development of the central nervous system (CNS) and peripheral nervous system. Postnatal re-expression of the protein occurs mainly under pathological conditions, including injury and neoplasia. In this study, nestin expression was detected in both benign and malignant melanocytic skin lesions and its diagnostic relevance was then evaluated. METHODS: Altogether 139 bioptic tissue samples consisting of 42 nodular melanomas, 32 superficial spreading melanomas, 12 metastatic melanomas, 10 dysplastic nevi and 43 common melanocytic intradermal and dermoepidermal nevi were analysed using indirect immunohistochemical staining. RESULTS: We demonstrated that nestin immunostaining was significantly increased in melanomas where it correlated with more advanced stages of the disease. CONCLUSION: We conclude that expression of the intermediate filament protein nestin might be an indicator of tumor dedifferentiation and more aggressive behaviour. Furthermore, we suggest that nestin might be a relevant marker of tumorous and non-tumorous angiogenesis.     

Disparate activation of the coronary sinus and inferior left atrium during atrial tachycardia after persistent atrial fibrillation ablation: prevalence, pitfalls, and impact on mapping

Partial Coronary Sinus Disconnection During Atrial Tachycardia . Introduction: Persistent atrial fibrillation (AF) ablation may lead to partial disconnection of the coronary sinus (CS). As a result, disparate activation sequences of the local CS versus contiguous left atrium (LA) may be observed during atrial tachycardia (AT). We aimed to evaluate the prevalence of this phenomenon and its impact on activation mapping. Methods: AT occurring after persistent AF ablation were investigated in 74 consecutive patients. Partial CS disconnection during AT was suspected when double potentials with disparate activation sequences were observed on the CS catheter. Endocardial mapping facing CS bipoles was performed to differentiate LA far‐field from local CS potentials. Results: A total of 149 ATs were observed. Disparate LA–CS activations were apparent in 20 ATs after magnifying the recording scale (13%). The most common pattern (90%) was distal to proximal endocardial LA activation against proximal to distal CS activation, the latter involving the whole CS or its distal part. Perimitral macroreentry was more common when disparate LA–CS activations were observed (67% vs 29%; P = 0.002). Partial CS disconnection also resulted in “pseudo” mitral isthmus (MI) block during LA appendage pacing in 20% of patients as local CS activation was proximal to distal despite distal to proximal activation of the contiguous LA. Conclusion: Careful analysis of CS recordings during AT following persistent AF ablation often reveals disparate patterns of activation. Recognizing when endocardial LA activation occurs in the opposite direction to the more obvious local CS signals is critical to avoid misleading interpretations during mapping of AT and evaluation of MI block. (J Cardiovasc Electrophysiol, Vol. 23, pp. 697‐707, July 2012)