Anti-inflammatory and recycling properties of an apolipoprotein mimetic peptide,Ac-hE18A-NH2

Apolipoprotein E (apoE) exerts prominent anti-inflammatory effects and undergoes recycling by target cells. We previously reported that the peptide Ac-hE18A-NH₂, composed of the receptor binding domain (LRKLRKRLLR) of apoE covalently linked to the Class A amphipathic peptide 18A, dramatically lowers plasma cholesterol and lipid hydroperoxides and enhances paraoxonase activity in dyslipidemic animal models. The objective of this study was to determine whether this peptide, analogous to apoE, exerts anti-inflammatory effects and undergoes recycling under in vitro conditions. Pulse chase studies using [¹²⁵I]-Ac-hE18A-NH₂ in THP-1 derived macrophages and HepG2 cells showed greater amounts of intact peptide in the cells at later time points indicating recycling of the peptide. Ac-hE18A-NH₂ induced a 2.5-fold increase in preβ-HDL in the conditioned media of HepG2 cells. This effect persisted for 3 days after removal of the peptide from culture medium. Ac-hE18A-NH₂ also induced the secretion of cell surface apoE from THP-1 macrophages. In addition, the peptide increased cholesterol efflux from THP-1 cells by an ABCA1 independent mechanism. Moreover, Ac-hE18A-NH₂ inhibited LPS-induced vascular cell adhesion molecule-1 (VCAM-1) expression, and reduced monocyte adhesion in human umbilical vein endothelial cells (HUVECs). It also reduced the secretion of interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) from THP-1 macrophages even when administered post-LPS and abolished the 18-fold increase in LPS-induced mRNA levels for MCP-1 in THP-1 cells. Taken together, these results suggest that addition of the putative apoE receptor-domain to the Class A amphipathic peptide 18A results in a peptide that, similar to apoE, recycles, thus enabling the potentiation and prolongation of its anti-atherogenic and anti-inflammatory effects. Such a peptide has great potential as a therapeutic agent in the management of atherosclerosis and other inflammatory diseases.     

Comparison of serum enzyme activity in great sturgeon, Huso huso, cultured in brackish and freshwater earth ponds in Iran

Blood samples were collected from 60 great sturgeons, Huso huso, to establish the following serum enzyme activity: aspartate amino-transferase (AST), alanine amino-transferase (ALT), lactic acid dehydrogenase (LDH), creatine kinase (CK), and alkaline phosphatase (ALP) using an autoanalyzer, and acid phosphatase (ACP) by manual method. Thirty 5-year-old cultured fish were caught from each of two sites; a brackish-water earth pond in Bafgh and a freshwater pond in Gorgan in the centre and northeast of Iran, during May 2006. Results of the serum enzymes activity for H. huso samples from Bafgh and Gorgan were: AST, 502.9 ± 258.2 and 436.1 ± 186.8; ALT, 104.4 ± 35.1 and 53.1 ± 38.7; LDH, 3094.2 ± 1277.5 and 2486.3 ± 1393.3; CK, 3632.9 ± 2618.7 and 3967 ± 5054.9; ALP, 281.2 ± 112.7 and 762.2 ± 600.2; ACP, 13.3 ± 2.5 and 33 ± 6.8 IU/L. Mean values of ALT, ALP and ACP were significantly different in the fish from the two sites (p < 0.05). These results may be used to understand some biological (e.g., serum enzyme activity) and ecological characteristics of cultured H. huso.     

Transnasal, transfacial, anterior skull base resection of olfactory neuroblastoma

Purpose

Using a transnasal, transfacial, anterior skull base approach, we have removed olfactory neuroblastomas (OFN) obviating the need for a frontal craniotomy. The objectives were to present our surgical approach in achieving clear margins, to assess patient survival, and to recommend eligibility criteria.

Materials and methods

A retrospective chart review was done to identify patients diagnosed with OFN who underwent this surgical approach. Thirteen patients were identified who underwent our pictorially described approach. Postoperative assessment of pathologic margins, patient survival, and limitations of surgical approach was determined.

Results

Of the 13 patients, 12 (92%) had clear postsurgical margins. One patient had residual intracranial disease due to coagulopathy preventing further resection. Twelve patients remain alive with 10 patients remaining disease-free (follow-up ranging from 11 to 64 months). Three patients presented with recurrent disease initially, with 2 having had subsequent repeat local and regional recurrences, respectively; one of whom died recently of the rerecurrent disease. One patient had a postoperative cerebrospinal fluid leak repaired via the original surgical approach.

Conclusions

Although craniofacial resection remains an accepted approach for surgical treatment of OFN, we have adopted a transnasal, transfacial approach eliminating the need for a frontal craniotomy. This approach allows for adequate exposure of the cribriform plate, dura, and anterior skull base. Our technique minimizes dural defects and prevents many craniotomy-associated complications, including frontal lobe retraction. Long-term follow-up is needed to compare survival using this approach; however, our results to date are quite promising.     

Patterns of comorbidities in newly diagnosed COPD and asthma in primary care

STUDY OBJECTIVES: There is increasing interest in the frequency and nature of comorbidities in patients with obstructive lung disease: COPD and asthma. We aimed to quantify baseline rates of comorbidities in COPD and asthma patients and to compare the risks to the general population. DESIGN, SETTING, AND PARTICIPANTS: Within the UK General Practice Research Database, we compared incident patients with COPD (n = 2,699) and asthma (n = 7,931) physician diagnosed in 1998 with age, gender, time, and practice-matched cohorts. Rates were calculated and relative risks (RRs) were estimated for comorbidities in major organ systems and selected medical events of a priori interest. MEASUREMENTS AND RESULTS: In both COPD and asthma, the total sum of diagnoses related to major organ systems was higher than in their matched population controls. Among incident COPD patients, a frequency > 1% within the first year after diagnosis was observed for angina, cataracts, bone fractures, osteoporosis, pneumonia, and respiratory infections, the highest being angina with 4.0%. Compared to the non-COPD cohort, COPD patients were at increased risk for pneumonia (relative risk [RR] = 16.0), osteoporosis (RR = 3.1), respiratory infection (RR = 2.2), myocardial infarction (RR = 1.7), angina (RR = 1.7), fractures (RR = 1.6), and glaucoma (RR = 1.3) [all p < 0.05]. Of note, 2.0% of COPD patients had cataracts recorded, but this rate was no different than that of the non-COPD cohort (RR = 0.9). Among incident asthma patients, the occurrence of events was generally lower, likely due to the younger age distribution, except for 4.0% with respiratory infection (RR = 1.84) and 1.7% with fractures (RR = 1.5). Angina prevalence was 0.7% in the asthma cohort and 1.4 times more common than in patients without asthma. CONCLUSION: COPD and asthma are conditions associated with many comorbidities, albeit asthma to a lesser extent than COPD, which had not been systematically reviewed before. Baseline rates of cardiovascular-, bone-, and other smoking-related conditions are high.     

CSF phospho-tau is independent of age, cognitive status and gender of neurological patients

CSF phospho-tau (p-tau₁₈₁) levels have shown good diagnostic utility in differential diagnosis of Alzheimer disease (AD). Unlike total-tau (t-tau), age related changes of this promising biomarker are sparsely studied. The aim of the study was to determine whether p-tau₁₈₁ is dependent on age, cognitive status or gender in patients with different neurological diseases who underwent diagnostic lumbar puncture and who had no clinical evidence of neurodegenerative diseases. CSF levels of p-tau₁₈₁ and total-tau (t-tau) of 46 neurologic patients (age range 22–89 years; 22 male, 24 female) were analyzed. Clinical diagnoses were cerebral ischaemia (n = 6), multiple sclerosis (n = 13), epileptic seizures (n = 3), polyneuropathy (n = 9) and other neurological diagnoses (n = 15). Cognitive performance was assessed by the German version of the CERAD battery. The mean level of p-tau₁₈₁ was in accordance with previous findings in neurological patients (42.8 ± 15.3 pg/ml) and did not differ between neurological diseases. In contrast to t-tau (r = 0.38; P = 0.009), p-tau₁₈₁ did not correlate significantly to age (r = 0.15; P = 0.308). No influence of cognitive status or gender on p-tau₁₈₁ levels could be detected. The study corroborates the independence of p-tau₁₈₁ from age, cognitive status, gender and a wide spectrum of neurological diseases. The findings suggest that neither age related neurodegenerative processes nor ischaemic or inflammatory processes are accompanied by tau protein phosphorylation. In contrast, the data support the view that p-tau₁₈₁ seems to be a sign of the highly AD-specific pattern of tau phosphorylation during formation of neurofibrillary tangles.     

Trans polyunsaturated fatty acids have more adverse effects than saturated fatty acids on the concentration and composition of lipoproteins secreted by human hepatoma HepG2 cells

The objective of this study was to assess the relative long-term effects of linoleic (cis, cis 18:2), linolelaidic (trans, trans 18:2), and palmitic (16:0) acids on hepatic lipoprotein production in HepG2 cells. All fatty acids increased the mass of triglycerides (TG) in the medium and the incorporation of [(3)H]-glycerol into secreted TG; the increase was more pronounced with linoleic acid than with linolelaidic and palmitic acids. The net accumulation in the medium of apolipoprotein (apo) A-I was not affected by the fatty acids tested and moderate changes in that of apoB resulted in apoB/apoA-I mass ratios of 1.05, 1.27 and 0.86 with linoleic, linolelaidic and palmitic acids, respectively. The incorporation of [(14)C]-acetate into cellular plus secreted total sterols was 9.1%, 33.6% and 17.4% of total [(14)C]-labeled lipids with linoleic, linolelaidic and palmitic acids, respectively. Relative to linoleic acid, palmitic acid, and to a greater extent (P < 0.05) linolelaidic acid, increased the secretion and cellular accumulation of [(14)C]-labeled free cholesterol (FC) and cholesteryl esters and decreased those of TG and phospholipids (PL). Compared with linoleic acid, linolelaidic acid increased LDL-cholesterol (C) and HDL-C by 154% (P < 0.001) and 50% (P = 0.016), respectively, whereas palmitic acid increased LDL-C by 17% (P > 0.1) and did not affect HDL-C. The LDL-C to HDL-C ratios were 0.70, 1.18 and 0.96 with linoleic, linolelaidic and palmitic acids, respectively. These differences were not due to altered LDL receptor activity. The PL to C ratios of HDL particles were 1.61, 0.40 and 0.77 with linoleic acid, linolelaidic acid and palmitic acid, respectively. These results suggest that relative to cis polyunsaturated and saturated fatty acids, trans PUFA more adversely affect the concentration and composition of apoA-I- and apoB-containing lipoproteins secreted by HepG2 cells.