Comparison of atorvastatin versus fenofibrate in reaching lipid targets and influencing biomarkers of endothelial damage in patients with familial combined hyperlipidemia

Statins and fibrates have different effects on lipid abnormalities of familial combined hyperlipidemia (FCHL); thus, the selection of the first-line drug is troublesome. We evaluated to what extent monotherapy with a potent statin is more effective than fibrate in reaching the recommended lipid targets in FCHL. Fifty-six patients were randomized to receive optimal dosage of atorvastatin (n = 27) or 200 mg/d micronized fenofibrate (n = 29) for 24 weeks. To reach the optimal dosage, atorvastatin was up-titrated at each follow-up visit if low-density lipoprotein (LDL) cholesterol >130 mg/dL (>100 mg/dL in patients with coronary or cerebrovascular disease). The effects of fenofibrate and atorvastatin on lipoprotein fractions as well as on plasma levels of endothelin-1 (ET-1) and adrenomedullin (AM) were also evaluated. At end of trial, a greater proportion of patients on atorvastatin (average dosage, 20.8 mg/d) reached lipid targets in comparison with those on fenofibrate (64% vs 32.1%, P = .02). Atorvastatin was significantly more effective in reducing total cholesterol, LDL cholesterol, apolipoprotein B, and non-high-density lipoprotein (HDL) cholesterol. Conversely, triglycerides decreased and HDL increased more during fenofibrate. Nevertheless, atorvastatin produced a marked reduction in very low-density lipoprotein and very low-density lipoprotein remnants. Atorvastatin lowered all LDL subtypes, although fenofibrate appeared to be more effective on denser LDL. Compared with 43 normolipemic controls, FCHL patients presented increased baseline plasma levels of ET-1 (P = .007) but not of AM. Fenofibrate, but not atorvastatin, significantly lowered ET-1 levels by 16.7% (P < .05). Neither drug significantly affected plasma concentrations of AM. In summary, although fenofibrate showed superiority in raising HDL and reducing ET-1, atorvastatin was more effective in reaching lipid targets in FCHL so that it can be proposed as the first-line option in the management of this atherogenic hyperlipidemia.     

Dendritic cells and natural killer cells in the pathogenesis of HIV infection

Dendritic cells (DC) and natural killer (NK) cells, the main cellular components of the innate immune system, participate in the most ancient first line of defense against infections. Both types of cells patrol peripheral tissues, whereas their rapid recruitment and activation at mucosal surfaces [the major entry point for the human immunodeficiency virus (HIV)] is a hallmark of acute inflammatory response. The ability of HIV to survive and replicate in the human host relies upon several molecular mechanisms eluding the immune surveillance of both adaptive immunity and of DC and NK cells beginning with the acute phase of primary HIV infection. DC and NK cells, unlike CD4⁺ T cells, are impaired more functionally rather than being depleted by HIV infection. In this article we will review some of the aspects of DC/NK cells interaction with HIV infection both in vitro and in vivo, and we will also speculate on the potential consequence for HIV pathogenesis and for the capacity of the virus to escape the surveillance of the innate immune system.     

Dynamic Graft-versus-Host Disease-Free,Relapse-Free Survival: Multistate Modeling of the Morbidity and Mortality of Allotransplantation

Graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) represents complete, ideal recovery after allogeneic hematopoietic cell transplantation (HCT). However, as originally proposed, this composite endpoint does not account for the possibility that HCT complications may improve after treatment. To more accurately estimate survival with response to GVHD and relapse after HCT, we developed a dynamic multistate GRFS (dGRFS) model with outcomes data from 949 patients undergoing their first allogeneic HCT for hematologic malignancy at the University of Minnesota. Because some patients were successfully treated for GVHD and relapse, dGRFS was higher than the originally defined time-to-event GRFS at 1 year (37.0 versus 27.6%) through 4 years (37.4% versus 22.2%). Mean survival without failure events was .52 years (95% confidence interval, .45 to .58 year) greater in dGRFS compared with the originally defined GRFS. Patient age (P< .001), disease risk (P < .001), conditioning intensity (P = .007), and donor type (P = .003) all significantly influenced dGRFS. The multistate model of dGRFS closely estimates the continuing and prevalent severe morbidity and mortality of allogeneic HCT. To serve the greater HCT community in more accurately modeling recovery from transplantation, we provide our R code for determination of dGRFS with annotations in Supplementary Materials.     

Delayed gastric emptying after pylorus-preserving pancreaticoduodenectomy: validation of International Study Group of Pancreatic Surgery classification and analysis of risk factors

Objectives

This study evaluates the incidence and clinical features and associated risk factors of delayed gastric emptying (DGE) after pancreaticoduodenectomy, employing the International Study Group of Pancreatic Surgery (ISGPS) consensus definition.

Methods

Demographic, pathological and surgical details for 260 consecutive patients who underwent pylorus-preserving pancreaticoduodenectomy at a single institution were analysed using univariate and multivariate models.

Results

Postoperative complications occurred in 108 (41.5%) and DGE was diagnosed in 36 (13.8%) of 260 patients. Among the 36 DGE patients, 16 had grade A, 18 grade B and two grade C DGE. Resumption of a solid diet (P < 0.001), time to passage of stool (P = 0.002) and hospital discharge (P < 0.001) occurred later in DGE patients. The need for total parenteral nutrition was significantly higher in DGE grade B/C patients (P < 0.001). In the univariate analysis, abdominal collections (P ≤ 0.001), pancreatic fistula (PF) grades B and C (P < 0.001), biliary fistula (P = 0.002), pulmonary complications (P < 0.001) and sepsis (P = 0.002) were associated with DGE. Only abdominal collections (P = 0.009), PF grade B/C (P < 0.001) and sepsis (P = 0.024) were associated with clinically relevant DGE. In the multivariate analysis, PF grade B/C (P = 0.004) and biliary fistula (P = 0.039) were independent risk factors for DGE.

Conclusions

The ISGPS classification and grading systems correlate well with the clinical course of DGE and are feasible for patient management. The principal risk factors for DGE seem to be pancreatic and biliary fistulas.     

Epidemiology of Spotted Fever Group and Typhus Group Rickettsial Infection in the Amazon Basin of Peru

A seroprevalence study for IgG antibodies against spotted fever group (SFGR) and typhus group (TGR) Rickettsia among humans and domestic pets was conducted in the city of Iquitos, located in the Amazon basin of Peru. Of 1,195 human sera analyzed, 521 (43.6%) and 123 (10.3%) were positive for SFGR and TGR antibodies, respectively. District of residence and participant age were associated with antibody positivity for both groups, whereas rodent sightings in the home were associated with TGR antibody positivity. Of the 71 canines tested, 42 (59.2%) were positive for SFGR antibodies, and two (2.8%) were positive for TGR antibodies; one active SFGR infection was detected by polymerase chain reaction. An uncharacterized SFGR species was detected in 95.9% (71/74) of Ctenocephalides felis pools collected from domestic pets. These data suggest that rickettsial transmission is widespread in Iquitos. Rickettsia species should be further explored as potential causes of acute febrile illnesses in the region.     

Hepatic cancer stem cells and drug resistance: Relevance in targeted therapies for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of most common malignancies in the world. Systemic treatments for HCC, particularly for advanced stages, are limited by the drug resistance phenomenon which ultimately leads to therapy failure. Recent studies have indicated an association between drug resistance and the existence of the cancer stem cells (CSCs) as tumor initiating cells. The CSCs are resistant to conventional chemotherapies and might be related to the mechanisms of the ATP Binding Cassette (ABC) transporters and alterations in the CSCs signaling pathways. Therefore, to contribute to the development of new HCC treatments, further information on the characterization of CSCs, the modulation of the ABC transporters expression and function and the signaling pathway involved in the self renewal, initiation and maintenance of the cancer are required. The combination of transporters modulators/inhibitors with molecular targeted therapies may be a potent strategy to block the tumoral progression. This review summarizes the association of CSCs, drug resistance, ABC transporters activities and changes in signaling pathways as a guide for future molecular therapy for HCC.     

ERCP in acute pancreatitis: What takes place in routine clinical practice?

AIM: To evaluate the data from a survey carried out in Italy regarding the endoscopic approach to acute pancreatitis in order to obtain a picture of what takes place after the release of an educational project on acute pancreatitis sponsored by the Italian Association for the Study of the Pancreas.METHODS: Of the 1 173 patients enrolled in our survey, the most frequent etiological category was biliary forms (69.3%) and most patients had mild pancreatitis (85.8%).RESULTS: 344/1 173 (29.3%) underwent endoscopic retrograde cholangiopancreatography (ERCP). The mean interval between the onset of symptoms and ERCP was 6.7 ± 5.0 d; only 89 examinations (25.9%) were performed within 72 h from the onset of symptoms. The main indications for ERCP were suspicion of common bile duct stones (90.3%), jaundice (44.5%), clinical worsening of acute pancreatitis (14.2%) and cholangitis (6.1%). Biliary and pancreatic ducts were visualized in 305 patients (88.7%) and in 93 patients (27.0%) respectively. The success rate in obtaining a cholangiogram was statistically higher (P = 0.003) in patients with mild acute pancreatitis (90.6%) than in patients with severe disease (72.2%). Biliary endoscopic sphincterotomy was performed in 295 of the 305 patients (96.7%) with no difference between mild and severe disease (P = 0.985). ERCP morbidity was 6.1% and mortality was 1.7%; the mortality was due to the complications of acute pancreatitis and not the endoscopic procedure.CONCLUSION: The results of this survey, as with those carried out in other countries, indicate a lack of compliance with the guidelines for the indications for interventional endoscopy.     

Interleukin-6 gene alleles affect the risk of Alzheimer's disease and levels of the cytokine in blood and brain

Two different polymorphic regions of the interleukin-6 (IL-6) gene were investigated in patients with Alzheimer's disease (AD) and non-demented controls. The -174 C allele in the promoter region of IL-6 gene was over-represented in AD patients compared to controls and significantly increased the risk of AD. Moreover, the -174 CC genotype was associated with a high risk of the disease in women. The D allele of a variable number of tandem repeat (VNTR) was in strong linkage disequilibrium with the -174 C allele and slightly increased AD risk. On the other hand, the frequency of the VNTR C allele was decreased in patients with AD and was negatively associated with the risk of developing AD. Both the -174 CC and VNTR DD genotypes were also associated with increased IL-6 levels in the blood and brain from AD. These findings suggest that IL-6 may play a multifaceted role in AD by affecting the turnover of the cytokine.