Interleukin-2 regulatory effect on P-selectin and interleukin-8 production in patients with chronic renal failure

Patients with chronic renal failure (CRF) show a clinical state of immunodysfunction that occurs in both humoral and cellular immunity as well as inflammatory response. In this study, we investigated the mononuclear-endothelial cells (MCs/ECs) interaction and the possible protective role of IL-2 as the main T lymphocyte activator in CRF patients. The levels of soluble P-selectin (sP-selectin) and interleukin-8 (IL-8) as the two main mediators of MCs/ECs interaction were measured in IL-2 supplemented and non-supplemented peripheral blood mononuclear cells (PBMCs) supernatant of CRF patients. The obtained results were correlated with those of sex and age matched controls. Significantly higher levels of sP-selectin and IL-8 were detected in both IL-2 supplemented and non-supplemented PBMCs culture supernatant of CRF patients than controls (P = 0.000). Those levels were significantly lower in IL-2 supplemented PBMCs culture supernatant than non-supplemented ones of both CRF (P = 0.000) (for both mediators) and normal control groups (P = 0.01, P= 0.04 for sP-selectin and IL-8 respectively). The higher sP-selectin in CRF indicates impairment of MCs/ECs interaction that may be resulted from blockade of P-selectin receptors on PBMCs by P-selectin molecules shedded from ECs to plasma and bind to PBMCs in vivo. The elevated IL-8 level in PBMCs of CRF reflect the imbalance of Thl/Th2 ratio and subsequent impairment of cellular immunity in those patients. The lower level of both sP-selectin and IL-8 in IL-2 supplemented PBMCs supernatant than in non-supplemented one seemed to be due to the IL-2 induced proliferation of Th1 lymphocytes yielding newly in vitro formed T cells which do not carry P-selectin as well as relative increase of Th1/Th2 ratio in both normal and CRF groups. Thus, IL-2 may improve the MCs/ECs interaction and correct the Th1/Th2 ratio in CRF providing a novel promising therapeutic approach to improve the immuno-pathological condition of those patients.     

A randomised trial of the effects of an additional communication strategy on recruitment into a large-scale, multi-centre trial

Timely participant recruitment remains a significant challenge for most clinical trials. We evaluated the effects on participant recruitment of communication between the central trial coordinators and the clinical sites in the setting of a large international multi-centre clinical trial. The effects of communication were determined in a single-blind randomised controlled trial involving 167 clinical sites in 19 countries. Clinical sites were randomised to either additional or usual communication strategies - the additional communication group received a communication package based on additional, individually-tailored feedback about recruitment, in addition to the usual correspondence from the central trial coordinators that was provided to the control group. The two study outcomes were the median time to half randomisation target and the median total number of participants randomised per clinical site. Eighty-five clinical centres were randomised to receive additional communication and 82 to receive usual communication. At the conclusion of recruitment, there was no significant difference in the median number of participants randomised per centre between the additional and usual groups (37.5 vs. 37.0, p=0.68). The median time to half randomisation target was lower in the additional communication group compared to the usual group, however this difference did not achieve conventional levels of statistical significance (4.4 months vs. 5.8 months, p=0.08). The findings suggest that the additional communication strategy may be of some incremental benefit in helping sites achieve recruitment targets sooner.     

Study of P53 in peripheral blood and synovial mononuclear cells of rheumatoid arthritis and osteoarthritis patients and its relation to the degree of disease activity

Over expression of P53 has been described in many inflammatory conditions including rheumatoid arthritis (RA) and osteoarthritis (OA) as a protective mechanism to induce apoptosis of synovial cells. Lack of P53 function through mutation in human synoviocytes increases the development of normal synovial fibroblasts into transformed aggressive synovial fibroblasts. P53 levels were determined in supernatant of cultured mononuclear cells (MCs) isolated from peripheral blood (PBMCs) of patients with RA (n = 10) and OA (n = 10) as well as 10 normal healthy controls (C). P53 levels were also determined in supernatants of MCs isolated from synovial fluid (SFMCs) of RA and OA patients. Results of this work revealed that P53 level was significantly higher in PBMCs supernatant of RA group than those of both (C) and (OA) groups (P = 0.022). P53 level was non-significantly higher in SFMCs supernatant of RA than OA group. Significantly higher levels of P53 was detected in SFMCs culture supernatant than that of PBMCs within each RA (P = 0.003) and OA (P = 0.001) group. Results also showed a significantly positive correlation between P53 levels (in both PBMCs and SFMCs) and the disease activity score (DAS) in RA group (P = 0.01, P = 0.02 respectively) while insignificantly positive correlations between P53 level (in both PBMCs and SFMCs) and radiological grading of OA group were obtained. These results indicate that mutations and consequent dysfunction of P53 gene may result in chronic inflammation and hyperplasia in RA patients. In conclusion, gene therapy targeting P53-dependent pathway could be a promising therapy for RA and OA diseases.     

Seroepidemiology of hepatitis A virus in Kuwait

AIM： To find the current seroepidemiology of hepatitis A virus （HAV） in Kuwait. METHODS： A total of 2851 Kuwaitis applying for new jobs were screened.RESULTS： HAV-positive cases were 28.8%; 59% were males and 41% were females. The highest prevalence was in the Ahmadi area. High prevalence was among the group of non-educated rather than educated parents. This is the first study in Kuwait demonstrating the shifting epidemiology of HAV. CONCLUSION： This study reflects the need of the Kuwaiti population for an HAV vaccine.     

Does the site of the orthotopic neobladder outlet matter? A prospective randomized comparative study

Background

To compare the results of urethral anastomosis to a button hole and to the lowest part of the anterior suture line during orthotopic neobladder substitution.

Protective effect of vitamin D supplementation in a rat modal of preeclampsia: a possible implication of chemerin

Background: Preeclampsia (PE) is a disorder of pregnancy associated with vitamin D (VD) deficiency. Chemerin is an adipokine significantly increased in preeclampsia and is regulated by VD.

Objectives: To determine whether VD supplementation would protect against development of PE through Chemerin reduction

Methods: PE was induced in albino rats by injection of 12.5 mg of deoxycorticosterone (DOCA). Rats were randomly divided into normal pregnant, PE group, VD supplemented PE group.

Results: VD supplementation decreased systolic blood pressure, proteinuria and decreased serum Chemerin level.

Conclusion: VD treatment reduced Chemerin level, and blood pressure in DOCA rat model of PE.     

Vitamin D status in diabetic Egyptian children and adolescents: a case–control study

Background

Recently, studies suggesting that vitamin D deficiency correlates with the severity and frequency of Type 1 (insulin-dependent) diabetes mellitus (T1DM) and that vitamin D supplementation reduces the risk of developing T1DM have been reported.

Objective

In this study, we aimed to assess vitamin D status in Egyptian children and adolescents with T1DM.

Methods

This was a case–control study including 80 T1DM diagnosed cases aged 6 to 16 years and 40 healthy children with comparable age and gender as the control group. For all subjects, serum 25 (OH) D levels were measured by ELISA, Serum parathyroid hormone (PTH) and serum insulin were measured by an electrochemiluminesce immunoassay. Serum glucose, Glycosylated hemoglobin (HbA1c) levels and homeostasis model assessment of insulin resistance (HOMA-IR) were also assessed.

Results

Compared to the control group, serum vitamin D levels were not significantly lower in diabetic subjects (24.7?±?5.6 vs 26.5?±?4.8 ng/ml; P?>?0.05). Among diabetic cases 44(55%) were vitamin D deficient; meanwhile 36(45%) cases had normal vitamin D level (P?<?0.01). In addition, 26(32.5%) diabetic cases had 2ry hyperparathyroidism and 54(67.5%) cases had normal parathyroid hormone level; meanwhile, none of the control group had 2ry hyperparathyroidism (P?<?0.01). Furthermore, we found a significant difference between vitamin D deficient diabetic cases and those with normal vitamin D level as regards HOMA-IR and diabetes duration (P?<?0.01).

Conclusion

Public health message on the importance of vitamin D status; especially in diabetic children and adolescents, should be disseminated to the public.

     

An Induction in Hepatic HDL Secretion Associated with Reduced ATPase Expression

Linoleic acid-phospholipids stimulate high-density lipoprotein (HDL) net secretion from liver cells by blocking the endocytic recycling of apoA-I. Experiments were undertaken to determine whether apoA-I accumulation in the cell media is associated with membrane ATPase expression. Treatment of HepG2 cells with dilinoeoylphosphatidylcholine (DLPC) increased apoA-I secretion fourfold. DLPC also significantly reduced cell surface F₁-ATPase expression and reduced cellular ATP binding cassette (ABC)A1 and ABCG1 protein levels by ∼50%. In addition, treatment of HepG2 cells with the ABC transporter inhibitor, glyburide, stimulated the apoA-I secretory effects of both DLPC and clofibrate. Pretreatment of HepG2 cells with compounds that increased ABC transport protein levels (TO901317, N-Acetyl-l-leucyl-l-leucyl-l-norleucinal, and resveratrol) blocked the DLPC-induced stimulation in apoA-I net secretion. Furthermore, whereas HepG2 cells normally secrete nascent preβ-HDL, DLPC treatment promoted secretion of α-migrating HDL particles. These data show that an linoleic acid-phospholipid induced stimulation in hepatic HDL secretion is related to the expression and function of membrane ATP metabolizing proteins.High-density lipoprotein (HDL) is predominantly produced in the liver in humans and is formed by the synthesis and secretion of apolipoprotein components, followed by the lipidation of these proteins with specific lipids.^1,2,3 HDL lipidation is believed to be regulated by the actions of the ATP-binding cassette (ABC) transporters, ABCA1 and ABCG1. ABCA1 and ABCG1 lipidate apolipoprotein (apo)A-I and convert nascent HDL particles to lipid-rich HDL.^4,5,6 Through this process, the ABC transport proteins have been thought to play a central role in both the production and maturation of HDL.⁶ ABC transporter expression is regulated by the liver X receptor (LXR), and LXR agonists such as the oxysterols have been shown to increase the expression and lipid secretory activity of ABCA1.⁷ Recent work has shown that despite the activation of ABCA1, LXR agonists such as TO901317 actually inhibit the synthesis and secretion of HDL and apoA-I by liver-derived cells.⁸ This suggests that ABC transporter expression may not be linked to the production of HDL.In addition to lipidating apoA-I, ABC transporters play other roles in HDL metabolism. ABCA1 has been shown to interact directly with apoA-I^9,10 and to impact the endocytic uptake and resecretion of apoA-I.^11,12,13,14 ABCA1-dependent endocytic uptake of apoA-I has been shown to promote the lysosomal degradation of apoA-I.^12,13 Therapeutic compounds that are inhibitors of ABC transporters have been shown to modestly increase plasma HDL levels.^15,16 Glyburide inhibits ABCA1 activity by blocking the ATPase activity of the protein.¹⁷ Glyburide has also been shown to block interactions between apoA-I and ABCA1^9,10 and to block apoA-I signaling through ABCA1.¹⁸ There is evidence to suggest that addition of an ABC transporter inhibitor, such as glyburide, to a fibrate therapy, may also increase the HDL raising potential of the fibrate.¹⁹A different membrane ATPase, F₁F₀-ATP synthase (F₁-ATPase), has also been shown to impact cellular HDL metabolism.^20,21,22,23 Studies have shown that apoA-I can stimulate a plasma membrane bound F₁-ATPase and promote the endocytic uptake of HDL through a specific plasma membrane G-protein coupled receptor, P2Y13.²² Inhibition of F₁-ATPase with antibodies or selective inhibitors (IF₁) blocks HDL endocytosis in hepatic cell culture and in vivo. Recent work suggests that niacin may act through this pathway and increase HDL secretion through reducing membrane F₁-ATPase levels.²⁴ Niacin reduces membrane F₁-ATPase levels and inhibits the reuptake and recycling of apoA-I.Linoleic acid (LA)-phospholipids are considerably more effective at stimulating hepatic apoA-I secretion and HDL production, than niacin and the fibrate drugs.²⁵ Much like niacin, these compounds act through protein kinase C and mitogen-activated protein kinase pathways to activate a peroxisome-proliferator activator receptor (PPAR)α-dependent secretion of apoA-I. However, in contrast to the fibrate drugs, LA-phospholipids do not increase cellular apoA-I mRNA levels and instead increase apoA-I secretion by blocking the endocytic recycling of apoA-I.²⁶ LA-phospholipids are therefore a novel class of HDL effectors that have a similar mechanism of action to niacin and are not metabolized by the cytochrome P450 enzymes.^25,26,27Experiments were undertaken to elucidate how an LA-phospholipid stimulation in apoA-I secretion may involve membrane ATPases. We show that increased apoA-I secretion is inversely related to cell membrane ATPase protein levels. Compounds that inhibit ATPase activity significantly stimulate apoA-I secretion and those that increase ABC transporter levels in HepG2 cells inhibit apoA-I secretion. The data suggests that hepatic apoA-I secretion is closely linked to the expression and function of membrane-bound ATP metabolizing proteins.