Effect of pharmacist care on medication adherence and cardiovascular outcomes among patients post-acute coronary syndrome: A systematic review

Background

The impact of collaborative and multidisciplinary health care on the outcomes of care in patients with acute coronary syndromes (ACS) is well-established in the literature. However, there is lack of high quality evidence on the role of pharmacist care in this setting.

False-positive results in transcranial motor evoked potentials for outcome prognostication during surgery for supratentorial lesions

During monitoring of motor evoked potentials (MEP) elicited by transcranial electrical stimulation (TES) for prognostication of postoperative motor deficit, significant MEP changes without postoperative deterioration of motor function represent false-positive results. We aimed to investigate this phenomenon in a large series of patients who underwent resection of supratentorial lesions. TES was applied in 264 patients during resection of motor-eloquent supratentorial lesions. MEP were recorded bilaterally from arm, leg, and/ or facial muscles. The threshold criterion was applied assessing percentage increase in threshold level, which was considered significant if being?>?20% higher on affected side than on the unaffected side. Subcortical stimulation was additionally applied to estimate the distance to corticospinal tract. Motor function was evaluated at 24 h after surgery and at 3-month follow-up. Patients with false-positive results were analyzed regarding tumor location, tumor volume, and characteristics of the monitoring. MEP were recorded from 399 muscles (264 arm muscles, 75 leg muscles, and 60 facial muscles). Motor function was unchanged postoperatively in 359 muscles in 228 patients. Among these cases, the threshold level did not change significantly in 354 muscles in 224 patients, while it increased significantly in the remaining 5 muscles in 4 patients (abductor pollicis brevis in all four patients and orbicularis oris in one patient), leading to a false-positive rate of 1.1%. Tumor volume, opening the ventricle, and negative subcortical stimulation did not significantly correlate with false-positive results, while the tumor location in the parietal lobe dorsal to the postcentral gyrus correlated significantly (p?=?0.012, odds ratio 11.2, 95% CI 1.8 to 69.8). False-negative results took place in 1.1% of cases in a large series of TES-MEP monitoring using the threshold criterion. Tumor location in the parietal lobe dorsal to the postcentral gyrus was the only predictor of false-positive results.

     

Neoadjuvant targeted molecular therapies in patients undergoing nephrectomy and inferior vena cava thrombectomy: is it useful?

Objective

To assess the effect of neoadjuvant targeted molecular therapies (TMTs) on size and level of inferior vena cava tumor thrombi and to evaluate their impact on surgical management.

Methods

We retrospectively analyzed the data of 14 patients treated for a clear cell renal cell carcinoma with inferior vena cava thrombi by neoadjuvant TMT before nephrectomy. Clinical, pathological and perioperative data were gathered retrospectively at each institution. The primitive tumor size and the thrombus size were defined by computed tomography before TMT. The tumor thrombus level was defined according to the Novick’s classification.

Results

Before TMT, thrombus level was staged I for 1 (7 %), II for 10 (72 %) and III (21 %) for 3 patients. First-line therapy was sunitinib in 11 cases and sorafenib in 3 cases. Median therapy duration was two cycles (1–5). Three patients experienced major adverse effects (grade III) during TMT. Following TMT, 6 (43 %) patients had a measurable decrease, 6 (43 %) had no change, and 2 (14 %) had an increase in the thrombus. One patient (7 %) had a downstage of thrombus level, 12 (85 %) had stable thrombi, and 1 (7 %) had an upstage. Regarding primary tumor, 7 (50 %), 5 (36 %) and 2 (14 %) patients had a decrease, stabilization and an increase in tumor size, respectively.

Conclusion

Neoadjuvant TMT appears to have limited effects on renal tumor thrombi. This retrospective study failed to demonstrate a significant impact of neoadjuvant TMT on surgical management of clear cell renal cell carcinoma with inferior vena cava tumor thrombi.     

Factors influencing outcome and incidence of long-term complications in children who underwent autologous stem cell transplantation for acute myeloid leukemia in first complete remission

To evaluate factors influencing outcome and incidence of long-term complications, we analyzed, in a retrospective, multicenter study, 387 children who underwent autologous hematopoietic stem cell transplantation (HSCT) for acute myeloid leukemia (AML) in first complete remission (CR). Median follow-up time from transplantation was 60 months. Transplantation of bone marrow cells was performed in 318 children, whereas in 60 patients peripheral blood progenitor cells (PBPCs) were used. In multivariate analysis, we investigated the variables influencing probability of hematopoietic recovery, transplantation-related mortality (TRM), relapse, and leukemia-free survival (LFS). We found that use of PBPCs as stem cell sources and use of BCNU (N,N-bis[2-chloroethyl]-N-nitrosourea), amsacrine, VP-16, and cytosine arabinoside (BAVC) as a preparative regimen were associated with faster neutrophil recovery. Infusion of PBPCs, young age of patients, use of BAVCs, and absence of marrow purging predicted an accelerated platelet reconstitution. The 5-year Kaplan-Meier estimates of TRM, relapse, and LFS were 3% +/- 1%, 39% +/- 3% and 60% +/- 3%, respectively. Relapse probability was increased in children given the BAVC regimen, and it was decreased after in vitro purging of hematopoietic progenitors and in children with a French-American-British classification of M3 and a time interval of 170 days or more between CR and HSCT. These 2 latter variables favorably influenced the probability of LFS, which was, by contrast, reduced with the BAVC regimen. Thirty-three percent of patients surviving more than 18 months experienced at least one late sequela; use of total body irradiation was the only predictive factor. The results obtained in this analysis can be of help in designing prospective studies of autologous HSCT in children with AML in first CR.     

Hematopoietic stem cell transplantation for de novo erythroleukemia: a study of the European Group for Blood and Marrow Transplantation (EBMT)

De novo erythroleukemia (EL) is a rare disease. Reported median survival are poor and vary from 4 to 14 months. The value of hematopoietic stem cell transplantation (HSCT) for EL is unknown. This EBMT registry study reports on the largest series of patients with EL treated with HSCT in first complete remission-103 autologous and 104 HLA identical sibling allogeneic HSCT. Outcome and identification of prognostic factors for each type of transplantation were evaluated. For autologous HSCT, outcome at 5 years showed a leukemia-free survival (LFS) of 26% +/- 5%, a relapse incidence (RI) of 70% +/- 6%, and a transplant-related mortality (TRM) of 13% +/- 4%. By multivariate analysis, the only prognostic factor was age. For allogeneic HSCT, outcome at 5 years showed an LFS of 57% +/- 5%, an RI of 21% +/- 5%, and a TRM of 27% +/- 5%. By multivariate analysis, prognostic factors were graft-versus-host disease and age. This study represents the largest series of de novo EL treated with HSCT and shows that allogeneic HSCT is by far the most effective treatment.     

Hepatic gene expression profiling reveals perturbed calcium signaling in a mouse model lacking both LDL receptor and Apobec1 genes

Atherosclerosis is a complex disease that gene and environment interaction influences the progression of atherosclerotic lesion development. Our laboratory used mice lacking both the low density lipoprotein (LDL) receptor and Apobec1 genes (LDLR-/-Apobec1-/-, designated LDb) to investigate gene-gene interaction and the influence of an environmental factor (high-fat diet) on gene networks. LDb mice (males and females) at 5 months of age were fed a chow or high fat diet for 3-month. The mice on a chow diet had elevated plasma cholesterol and triglyceride levels and developed atherosclerosis. Feeding a high-fat diet accelerated the development of lesions >1.5-fold. We performed microarray analysis of the expression of 12442 murine genes in the livers of these animals, which identified 54 genes in males and 77 genes in females were significantly perturbed by the high-fat diet. Moreover, most of these genes (>70%) were upregulated. The results suggested that glycolysis, fat transport, and steroid hormone biosynthesis pathways were upregulated, probably to compensate for the high fat intake. Furthermore, a batch of stress-responsive genes was upregulated. The study also shows a dynamic cellular communication network including T cells, neutrophils, and monocytes/macrophages, which related to inflammatory and immune/complement responses. Importantly, this study discovered that many genes involved in calcium signaling and bone formation were up regulated. Alizarin Red S staining was used to detect calcium deposits in the region of atherosclerotic lesions. Real-time quantitative RT-PCR and Western blot analyses provided verification of the gene expression levels. In conclusion, this study demonstrated the global differential gene expression profiles, which are influenced by feeding a high fat diet to LDb mice. The results of the study provide new insights into the significance of calcification in atherogenesis.     

Chemical properties of lipids strongly affect the kinetics of the membrane-induced aggregation of α-synuclein

Intracellular α-synuclein deposits, known as Lewy bodies, have been linked to a range of neurodegenerative disorders, including Parkinson’s disease. α-Synuclein binds to synthetic and biological lipids, and this interaction has been shown to play a crucial role for both α-synuclein’s native function, including synaptic plasticity, and the initiation of its aggregation. Here, we describe the interplay between the lipid properties and the lipid binding and aggregation propensity of α-synuclein. In particular, we have observed that the binding of α-synuclein to model membranes is much stronger when the latter is in the fluid rather than the gel phase, and that this binding induces a segregation of the lipids into protein-poor and protein-rich populations. In addition, α-synuclein was found to aggregate at detectable rates only when interacting with membranes composed of the most soluble lipids investigated here. Overall, our results show that the chemical properties of lipids determine whether or not the lipids can trigger the aggregation of α-synuclein, thus affecting the balance between functional and aberrant behavior of the protein.The protein α-synuclein is mainly found in the presynaptic termini of neurons (1). The protein has been shown to populate a highly unstructured form in its unbound state both in vitro and in vivo and to adopt an α-helical conformation when bound to membranes (2). The balance between these two states has been found to play a role both in the proposed biological function of the protein, including the regulation of synaptic plasticity, and in the kinetics of its pathogenic aggregation; the latter is the hallmark of a range of diseases, known as synucleinopathies, of which the most common is Parkinson’s disease (3, 4). α-Synuclein has been shown to have its highest affinity for membranes containing either anionic lipids or so-called ”packing defects” (5–7), where the latter are defined as low-density regions in bilayers with high exposure of the lipid hydrophobic chains attributable to a mismatch between lipid shape and bilayer curvature (6, 7).Biological membranes are highly heterogeneous and differ from one cell or organelle to another in terms of the physical and chemical properties of the membranes, including curvature, charge, fluidity, and packing of the hydrophobic chains (8–10). The variety of membrane structures in cells can be directly related to differences in lipid (and protein) composition, where properties such as length and saturation of the hydrocarbon chain as well as the charge and size of the polar head group are crucial in determining the properties of the membrane (8, 9). In particular, most chemical and thermotropic properties of a lipid molecule are known to vary almost linearly with the length of its hydrophobic chain. As some examples, the standard change in free energy of transfer of a lipid molecule from water into a bilayer (i.e., its solubility in water), the melting temperature, and the enthalpy of melting have all been found to be proportional to the number of aliphatic carbons in the hydrophobic chain, which ranges from 8 to 18 (11). In addition, the adsorption and partitioning of small molecules and proteins to membranes can also affect the structural and thermotropic properties of the latter, and the magnitude and characteristics of these changes depend on the nature of the molecular interactions (e.g., electrostatic, hydrophobic) (12, 13).The interactions between amphipathic proteins and membranes have been extensively studied over the last three decades (7, 14–22). In general, the amino acid sequences of these peripheral proteins are characterized by patterns of hydrophobic and polar residues such that the proteins fold into amphipathic α-helices upon binding to hydrophobic patches exposed at the membrane interface (16, 17). In particular, molecular dynamics simulations and neutron reflectometry studies of deposited bilayers have shown that the amphipathic helix in α-synuclein is primarily located in the vicinity of the lipid phosphate groups and the glycerol backbone (16, 23–25).Although the binding of α-synuclein to membranes has been well characterized for different lipid systems (26–28), the observed modulation of the kinetics of the conversion of monomeric α-synuclein into amyloid fibrils by different membranes is less well understood (29–32). Most studies of this phenomenon have been performed under conditions of mechanical agitation (32) and/or in the presence of catalyzing polymer surfaces (31), where α-synuclein aggregates also in the absence of lipids and where the mechanism of aggregation has not yet been elucidated. Here, we take a different approach using an experimental procedure with protein-repellant surfaces and under quiescent conditions (33) that enables the systematic study of the manner in which a change in lipid properties can affect the ability of a model membrane to initiate α-synuclein aggregation. Indeed, we have previously shown that the presence of model membranes composed of 1,2-dimyristoyl-sn-glycero-3-phospho-l-serine (DMPS) triggers the aggregation of α-synuclein by specifically enhancing the rate of primary nucleation (33). In addition, this study showed how the protein:lipid (P:L) ratio modulates the kinetics of α-synuclein aggregation in the presence of DMPS; at low P:L ratios, effectively all of the protein molecules are adsorbed onto the surface of the membrane in a thermodynamically stable α-helical state and no aggregation is observed. At high P:L ratios, however, the protein molecules populate both the free monomeric state and the membrane-bound state, leading to rapid amyloid formation (33).In the present study, we have applied this experimental procedure to probe how changes in the chemical (charge and solubility) and physical (thermotropic) properties of lipids affect the binding of α-synuclein and the magnitude by which model membranes can trigger α-synuclein aggregation. The results reveal that the efficiency of the binding of α-synuclein to model membranes is correlated with their fluidity and, conversely, that the self-assembly of the lipids is affected by their association with the protein. In addition, although α-synuclein has a high affinity for all of the fluid anionic model membranes investigated here, this interaction is not sufficient for the efficient induction of aggregation. Rather, the rate of amyloid fibril formation is shown to be inversely correlated with the free energy of transfer of the lipid molecule from water into the bilayer. These results indicate that the chemical properties of the lipids are likely to play an important role in perturbing the balance between functional and deleterious interactions of α-synuclein with membranes.