Abdelmoneim Eldali

Recombinant Activated Protein C Attenuates Endothelial Injury and Inhibits Procoagulant Microparticles Release in Baboon Heatstroke

Objectives—We tested the hypothesis that the antithrombotic and cytoprotective effects of recombinant human activated protein C (rhAPC) protect baboons against the lethal effects of heatstroke. Methods and Results—Fourteen anesthetized baboons assigned randomly to rhAPC (n=7) or control group (n=7) were heat-stressed in a prewarmed incubator at 44 to 47°C until systolic blood pressure fell below 90 mm Hg, which signaled severe heatstroke. rhAPC was administered intravenously (24 &mgr;g/kg/h) for 12 hours at onset of heatstroke. Heat stress induced coagulation and fibrinolysis activation as evidenced by a significant increase from baseline levels in plasma levels of thrombin-antithrombin (TAT) complexes, tissue plasminogen activator, and D-dimer. Heat stress elicited cell activation/injury as assessed by the release of interleukin (IL)-6, soluble thrombomodulin, and procoagulant microparticles (MPs). rhAPC did not significantly reduce heatstroke-induced thrombin generation, and D-dimer and had no effect on fibrinolytic activity. In contrast, rhAPC infusion attenuated significantly the plasma rise of IL-6 and inhibited the release of soluble thrombomodulin and MPs as compared with control group. No difference in survival was observed between rhAPC-treated and control group. Conclusions—rhAPC given to heatstroke baboons provided cytoprotection, but had no effect on heatstroke-induced coagulation activation and fibrin formation. Inhibition of MPs by rhAPC suggested a novel mechanism of action for this protein.

Association between HLA Variations and Chronic Hepatitis B Virus Infection in Saudi Arabian Patients

Hepatitis B virus (HBV) infection is a leading cause of liver diseases including cirrhosis and hepatocellular carcinoma. Human leukocyte antigens (HLAs) play an important role in the regulation of immune response against infectious organisms, including HBV. Recently, several genome-wide association (GWAS) studies have shown that genetic variations in HLA genes influence disease progression in HBV infection. The aim of this study was to investigate the role of HLA genetic polymorphisms and their possible role in HBV infection in Saudi Arabian patients. Variations in HLA genes were screened in 1672 subjects who were divided according to their clinical status into six categories as follows; clearance group, inactive carriers, active carriers, cirrhosis, hepatocellular carcinoma (HCC) patients and uninfected healthy controls. Three single nucleotide polymorphisms (SNPs) belonged to HLA-DQ region (rs2856718, rs7453920 and rs9275572) and two SNPs belonged to HLA-DP (rs3077 and rs9277535) were studied. The SNPs were genotyped by PCR-based DNA sequencing (rs2856718) and allele specific TaqMan genotyping assays (rs3077, rs7453920, rs9277535 and rs9275572). The results showed that rs2856718, rs3077, rs9277535 and rs9275572 were associated with HBV infection (p = 0.0003, OR = 1.351, CI = 1.147–1.591; p = 0.041, OR = 1.20, CI = 1.007–1.43; p = 0.045, OR = 1.198, CI = 1.004–1.43 and p = 0.0018, OR = 0.776, CI = 0.662–0.910, respectively). However, allele frequency of rs2856718, rs7453920 and rs9275572 were found more in chronically infected patients when compared to clearance group infection (p = 0.0001, OR = 1.462, CI = 1.204–1.776; p = 0.0178, OR = 1.267, CI = 1.042–1.540 and p = 0.010, OR = 0.776, CI = 0.639–0.942, respectively). No association was found when polymorphisms in HLA genes were compared in active carriers versus cirrhosis/HCC patients. In conclusion, these results suggest that variations in HLA genes could affect susceptibility to and clearance of HBV infection in Saudi Arabian patients.

Transplant tourism outcome: a single center experience.

Background. Transplant tourism is the term used for patients who travel abroad for transplantation. Transplant tourism has always been surrounded with controversy regarding how these organs were obtained, the donors care after transplantation, and the recipient outcome. Many authors have found that the outcome of the recipients in transplant tourism is inferior to those transplanted in their own countries. However, most these studies were small, with the latest one including only 33 patients. Here, we describe the outcome of 93 patients who were transplanted abroad compared with local transplantation. Material and Methods. All transplant patients who were followed up at our Nephrology Clinic from 1998 until 2008 were identified using our data base system. We selected patients transplanted from 2003 and forward because the computerized system for laboratory and electronic records began operation that year. Results. A total of 165 patients were identified (93 in the tourist group and 72 in the local one). Transplant tourists had a higher rate of acute rejection in the first year compared with local transplantation (27.9% vs. 9.9, P=0.005), higher mean creatinine at 6 months and 1 year (120 vs. 101 &mgr;mol/L, P=0.0007, 113 vs. 98 &mgr;mol/L, P=0.008). There was no statistical difference in graft or patient survival in 1 or 2 years after transplantation. However, transplant tourist had a higher rate of cytomegalovirus infection (15.1% vs. 5.6%, P=0.05) and hepatitis C seroconversion (7.5% vs. 0%, P=0.02). Conclusion. Transplant tourists had a more complex posttransplantation course with higher incidence of acute rejection and infectious complications.

Toll-like receptor 4 and high-mobility group box 1 are critical mediators of tissue injury and survival in a mouse model for heatstroke.

The molecular mechanisms that initiate the inflammatory response in heatstroke and their relation with tissue injury and lethality are not fully elucidated. We examined whether endogenous ligands released by damaged/stressed cells such as high-mobility group box 1 (HMGB1) signaling through Toll-like receptor 4 (TLR4) may play a pathogenic role in heatstroke. Mutant TLR4-defective (C3H/HeJ) and wild type (C3H/HeOuJ) mice were subjected to heat stress in an environmental chamber pre-warmed at 43.5°C until their core temperature reached 42.7°C, which was taken as the onset of heatstroke. The animals were then allowed to recover passively at ambient temperature. A sham-heated group served as a control. Mutant mice displayed more histological liver damage and higher mortality compared with wild type mice (73% vs. 27%, respectively, P<0.001). Compared to wild type mice, mutant mice exhibited earlier plasma release of markers of systemic inflammation such as HMGB1 (206±105 vs. 63±21 ng/ml; P = 0.0018 and 209±100 vs. 46±32 ng/ml; P<0.0001), IL-6 (144±40 vs. 46±20 pg/ml; P<0.001 and 184±21 vs. 84±54 pg/ml; P = 0.04), and IL-1β (27±4 vs. 1.7±2.3 pg/ml; P<0.0001 at 1 hour). Both strains of mice displayed early release of HMGB1 into the circulation upstream of IL-1β and IL-6 responses which remained elevated up to 24 h. Specific inhibition of HMGB1 activity with DNA-binding A Box (600 µg/mouse) protected the mutant mice against the lethal effect of heat stress (60% A Box vs. 18% GST protein, P = 0.04). These findings suggest a protective role for the TLR4 in the host response to severe heat stress. They also suggest that HMGB1 is an early mediator of inflammation, tissue injury and lethality in heatstroke in the presence of defective TLR4 signaling.

Glucocorticoids Do Not Protect Against The Lethal Effects Of Experimental Heatstroke In Baboons

The mortality and neurological morbidity in heatstroke have been attributed to the hosts inflammatory responses to heat stress, suggesting that anti-inflammatory therapy may improve outcome. We tested the hypothesis that a high dose of dexamethasone protects baboons against the lethal effects of heatstroke. Ten anesthetized baboons (Papio hamadryas) were assigned randomly to dexamethasone (n = 5) or control group (n = 5). Dexamethasone (2 mg/kg i.v.) was administered in four divided doses every 6 h starting immediately before heat stress and continuing during cooling. All animals were heat-stressed in a prewarmed neonatal incubator at 44°C to 47°C until systolic blood pressure fell less than 90 mmHg and then cooled passively at the ambient temperature. Mortality and neurological morbidity were noted, and biochemical markers of tissue injury/organ dysfunction were determined. Circulating interleukin (IL) 6 and complement components (C3 and C4) were measured sequentially. All heat-stressed animals had systemic inflammation indicated by increased plasma IL-6 and decreased C3 and C4 levels. Dexamethasone attenuated the complement system activation and maintained a higher plasma concentration of IL-6, with a significant augmentation of arterial blood pressure. Dexamethasone did not prevent the occurrence of severe heatstroke but unexpectedly aggravated significantly the tissue injury and multiorgan system dysfunction. Two animals (40%) in the control group and one in the steroid group survived (P > 0.05). Dexamethasone failed to protect the baboons from the lethal effects of heatstroke. These results do not support clinical testing of corticosteroids as beneficial in preventive or therapeutic strategies for the treatment of heatstroke in humans.

Tissue factor/factor VIIa pathway mediates coagulation activation in induced-heat stroke in the baboon.

Objective:Excessive activation of coagulation, which can culminate in overt disseminated intravascular coagulation, is a prominent feature of heat stroke. However, neither the mechanism that initiates the coagulation activation nor its pathogenic role is known. We examined whether the tissue factor/factor VIIa complex initiates the coagulation activation in heat stroke and, if so, whether upstream inhibition of coagulation activation through its neutralization may minimize cellular injury and organ dysfunction. We also examined whether coagulation inhibition influences heat stroke-induced fibrinolytic and inflammatory responses. Design:Randomized controlled study. Setting:Comparative Medicine Department, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. Subjects:Baboons (Papio Hamadryas). Interventions:Twelve anesthetized baboons assigned randomly to recombinant nematode anticoagulant protein c2, a powerful inhibitor of tissue factor/factor VIIa-dependent coagulation (n = 6), or a control group (n = 6) were heat-stressed in a prewarmed neonatal incubator at 44–47°C until systolic blood pressure fell <90 mm Hg, signaling the onset of severe heat stroke. Recombinant nematode anticoagulant protein c2 was administered as a single intravenous dose of 30 &mgr;g/kg body weight at onset of heat stroke. The control group received an equivalent volume of sterile saline intravenously. Measurements and Main Results:Heat stroke was associated with coagulation activation and fibrin formation as evidenced by the increased plasma thrombin–antithrombin complexes, endogenous thrombin potential, and D-dimer levels. Recombinant nematode anticoagulant protein c2 induced significant inhibition of thrombin generation and fibrin formation. Inhibition of coagulation in recombinant nematode anticoagulant protein c2-treated animals did not influence either fibrinolysis (assessed by tissue plasminogen activator, plasmin-&agr;2-antiplasmin complexes, and plasminogen activator inhibitor) or the release of pro- and anti-inflammatory cytokines. No difference in markers of cell injury and organ dysfunction was observed between recombinant nematode anticoagulant protein c2-treated and control groups. Conclusions:Tissue factor/factor VIIa-dependent pathway initiates coagulation activation in induced-heat stroke in the baboon without an effect on fibrinolysis and inflammation. The findings suggest also that coagulation activation is not a prerequisite of cell injury and organ dysfunction. (Crit Care Med 2012; 40:–1236)

The Relationship between 25 (OH) D Levels (Vitamin D) and Bone Mineral Density (BMD) in a Saudi Population in a Community-Based Setting

Background Vitamin D deficiency has been linked to an increased risk of osteoporosis. Vitamin D deficiency has reached high levels in the Saudi population, but there is conflicting evidence both in the Saudi population, and worldwide, regarding the existence of a correlation between these low vitamin D levels and reduced BMD (bone mineral density), or osteoporosis. Objective The objective of this study was primarily to determine whether there was a correlation between vitamin D deficiency and osteoporosis in the Saudi population. We aimed to investigate whether the high levels of vitamin D deficiency and insufficiency would translate to higher prevalence of osteoporosis, and whether there is a correlation between vitamin D levels and bone mineral density. Materials and methods This was a community based cross sectional study conducted in the Family Medicine Clinics at King Faisal Specialist Hospital and Research Centre in Riyadh, Saudi Arabia. Electronic records of 1723 patients were reviewed. Laboratory and radiology results were collected, including vitamin D levels, calcium levels, and bone mineral density scan results. Results Among the whole population, 61.5% had moderate to severe vitamin D deficiency with levels less than 50nmol/L. 9.1% of the population had osteoporosis, and 38.6% had osteopenia. Among the whole population, there was no significant correlation between spine or total femoral BMD and serum 25(OH) D. Conclusion Vitamin D deficiency is prevalent in the Saudi population. However, no correlation has been found between vitamin D deficiency and reduced bone mineral density in any age group, in males or females, Saudis or Non-Saudis, in our population in Riyadh, Saudi Arabia.

Prognostic role of KIR genes and HLA-C after hematopoietic stem cell transplantation in a patient cohort with acute myeloid leukemia from a consanguineous community

NK cell activity is tuned by a balance of activating and inhibitory signals transmitted via their respective receptors, including killer immunoglobulin-like receptors (KIRs). The impact of NK cells on graft-versus-leukemia following hematopoietic stem cell transplantation (HSCT) is well established. These effects sometimes lead to GvHD. The link between KIR/HLA interaction and GvHD remains unclear. Herein, we studied the impact of the KIR/HLA interaction on HSCT outcomes in a longitudinal follow-up study of a highly consanguineous HLA-matched related cohort. Peripheral blood DNA was collected from HSCT donor–recipient pairs (n = 87), including 41 AML pairs. KIR and HLA were genotyped and significant results were only measured when matching KIR (donor) with HLA (recipients). GvHD was observed in 47% of patients. KIR2DL1_C2 and 2DS2_C1 (P = 0.02 and 0.04, respectively) matching was associated with an increased incidence of acute GvHD in AML donor–recipient pairs. The rate of chronic GvHD also rose in AML patients who were matched for KIR2DS1_C2 (P = 0.004) and had either KIR2DL2 or KIR2DS2 (P = 0.03). In conclusion, matching of KIR2DL1, 2DS1, and 2DS2 in donors with their HLA-C ligands in recipients is associated with increased GvHD, and holds potential for selection of HSCT donors.

Extramedullary relapses after allogeneic stem cell transplantation for acute myeloid leukemia: clinical characteristics, incidence, risk factors and outcomes

Acute myeloid leukemia (AML) relapse after allogeneic hematopoietic cell transplant (allo-HCT) is challenging. Data on extramedullary relapse (EMR) after allo-HCT are limited. We analyzed 215 patients with AML who underwent allo-HCT in our institution between January 2005 and December 2015. We limited this retrospective review to patients who received a MA conditioning, were in complete remission (CR) at the time of transplant and who received a matched sibling transplant, all other patients were excluded to avoid heterogeneity. Seventy-seven (35.8%) patients experienced disease relapse, 45 had BMR, and 32 had EMR. The only variable that was statistically associated with EMR post allo-HCT was male sex (OR = 3.2 (1.2, 8.2), p-value = 0.01); there was a trend for association between transplant in >CR2 and EMR (OR = 0.38 (0.14, 1.06), p-value = 0.06). The median overall survival (OS) after relapse for all relapses was 10 months (95% CI 4.839–15.161). The median OS for BMR group was 8 months (95% CI 2.850–13.150) and 14 months for the EMR group (95% CI 5.776–22.224); however, this was not statistically significant, p-value = 0.4. Multivariate analysis revealed that gender, treatment modality, and time from allo-HCT to relapse (≥12 vs. <12 months) have significant association with the post-relapse death. Male gender was the only significant factor associated with EMR.