Psychometric properties of an Arabic translation of the chronic pain acceptance questionnaire (CPAQ) in a sample of patients with chronic pain.

PURPOSE: Chronic pain (CP) acceptance is a major factor in determining the well-being of patients with chronic pain. The chronic pain acceptance questionnaire (CPAQ) was translated and validated into Arabic (CPAQ-Ar). METHODS: 244 patients with CP completed the CPAQ-Ar, the Beck Depression Inventory-II (BDI-II), the short form health survey (SF-36), the Pain Catastrophizing Scale (PCS), the Pittsburgh Sleep Quality Index (PSQI), the Modified Fatigue Impact Scale (MFIS), and the Depression Anxiety Stress Scale 21 (DASS-21). 110 patients completed the CPAQ-Ar twice separated by two weeks to investigate test-retest reliability. RESULTS: Cronbach's α was 0.902 while the intraclass correlation coefficient (ICC) was 0.917. The standard error measurement (SEM) was seven points while the minimal detectable change with 95% confidence interval (MDC95) was seventeen points. The CPAQ-Ar showed moderate to high correlations with the PCS, the BDI-II, the SF-36, the MFIS, the PSQI, and the DASS-21 indicating a good concurrent validity. Exploratory factor analysis confirmed that the CPAQ-Ar consists of two subscales. Better pain acceptance associated with male gender, older people, employed participants, low pain intensity, and single pain site. CONCLUSIONS: The CPAQ-Ar is a valid and reliable tool for the measurement of pain acceptance in Arabic speaking patients with CP.

Electronic health records perception among three healthcare providers specialties in Saudi Arabia: A cross-sectional study.

Worldwide, more health care facilities are adapting the use of electronic health record (EHR). Healthcare providers (HCP) have different perceptions toward the use of EHR. To investigate the perception of three classes of HCP in Saudi Arabia toward using EHR, a questionnaire (targeting satisfaction, easiness, and benefits of use as major perception indicators) was prepared. The questionnaire was assessed by an expert panel for content validity. The questionnaire internal consistency was examined using Cronbach's alpha. 108 physicians, physical therapists (PT) and respiratory care therapists (RT) from different hospitals in Saudi Arabia answered the questionnaire. Most of respondents perceived EHR systems as beneficial and made work easier. Most HCP were satisfied with the use of EHR, however, with the use of EHR more time was needed to finish the work. Age, experience, job, and job rank of HCP are of different importance in determining responses, perception, and obstacles of using EHR. Moreover, the perception of using EHR seems to be field specific. There is a positive perception among Saudi Arabia HCP about EHR use.

Cold exposure induces vaso-occlusion and pain in sickle mice that depend on complement activation.

Vaso-occlusive pain episodes (VOE) cause severe pain in patients with sickle cell disease (SCD). Vaso-occlusive events promote ischemia/reperfusion pathobiology that activates complement. We hypothesized that complement activation is linked to VOE. We used cold to induce VOE in the Townes sickle homozygous for hemoglobin S (HbSS) mouse model and complement inhibitors to determine whether anaphylatoxin C5a mediates VOE. We used a dorsal skinfold chamber to measure microvascular stasis (vaso-occlusion) and von Frey filaments applied to the plantar surface of the hind paw to assess mechanical hyperalgesia in HbSS and control Townes mice homozygous for hemoglobin A (HbAA) mice after cold exposure at 10°C/50°F for 1 hour. Cold exposure induced more vaso-occlusion in nonhyperalgesic HbSS mice (33%) than in HbAA mice (11%) or HbSS mice left at room temperature (1%). Cold exposure also produced mechanical hyperalgesia as measured by paw withdrawal threshold in HbSS mice compared with that in HbAA mice or HbSS mice left at room temperature. Vaso-occlusion and hyperalgesia were associated with an increase in complement activation fragments Bb and C5a in plasma of HbSS mice after cold exposure. This was accompanied by an increase in proinflammatory NF-κB activation and VCAM-1 and ICAM-1 expression in the liver. Pretreatment of nonhyperalgesic HbSS mice before cold exposure with anti-C5 or anti-C5aR monoclonal antibodies (mAbs) decreased vaso-occlusion, mechanical hyperalgesia, complement activation, and liver inflammatory markers compared with pretreatment with control mAb. Anti-C5 or -C5aR mAb infusion also abrogated mechanical hyperalgesia in HbSS mice with ongoing hyperalgesia at baseline. These findings suggest that C5a promotes vaso-occlusion, pain, and inflammation during VOE and may play a role in chronic pain.

The BACH1 inhibitor ASP8731 inhibits inflammation and vaso-occlusion and induces fetal hemoglobin in sickle cell disease.

In sickle cell disease (SCD), heme released during intravascular hemolysis promotes oxidative stress, inflammation, and vaso-occlusion. Conversely, free heme can also activate expression of antioxidant and globin genes. Heme binds to the transcription factor BACH1, which represses NRF2-mediated gene transcription. ASP8731, is a selective small molecule inhibitor of BACH1. We investigated the ability of ASP8731 to modulate pathways involved in SCD pathophysiology. In HepG2 liver cells, ASP8731 increased HMOX1 and FTH1 mRNA. In pulmonary endothelial cells, ASP8731 decreased VCAM1 mRNA in response to TNF-α and blocked a decrease in glutathione in response to hemin. Townes-SS mice were gavaged once per day for 4 weeks with ASP8731, hydroxyurea (HU) or vehicle. Both ASP8731 and HU inhibited heme-mediated microvascular stasis and in combination, ASP8731 significantly reduced microvascular stasis compared to HU alone. In Townes-SS mice, ASP8731 and HU markedly increased heme oxygenase-1 and decreased hepatic ICAM-1, NF-kB phospho-p65 protein expression in the liver, and white blood cell counts. In addition, ASP8731 increased gamma-globin expression and HbF+ cells (F-cells) as compared to vehicle-treated mice. In human erythroid differentiated CD34+ cells, ASP8731 increased HGB mRNA and increased the percentage of F-cells 2-fold in manner similar to HU. ASP8731 and HU when given together induced more HbF+ cells compared to either drug alone. In CD34+ cells from one donor that was non-responsive to HU, ASP8731 induced HbF+ cells ~2-fold. ASP8731 and HU also increased HBG and HBA, but not HBB mRNA in erythroid differentiated CD34+ cells derived from SCD patients. These data indicate that BACH1 may offer a new therapeutic target to treat SCD.

Sickle red blood cell-derived extracellular vesicles activate endothelial cells and enhance sickle red cell adhesion mediated by von Willebrand factor.

Endothelial activation and sickle red blood cell (RBC) adhesion are central to the pathogenesis of sickle cell disease (SCD). Quantitatively, RBC-derived extracellular vesicles (REVs) are more abundant from SS RBCs compared with healthy RBCs (AA RBCs). Sickle RBC-derived REVs (SS REVs) are known to promote endothelial cell (EC) activation through cell signalling and transcriptional regulation at longer terms. However, the SS REV-mediated short-term non-transcriptional response of EC is unclear. Here, we examined the impact of SS REVs on acute microvascular EC activation and RBC adhesion at 2 h. Compared with AA REVs, SS REVs promoted human pulmonary microvascular ECs (HPMEC) activation indicated by increased von Willebrand factor (VWF) expression. Under microfluidic conditions, we found abnormal SS RBC adhesion to HPMECs exposed to SS REVs. This enhanced SS RBC adhesion was reduced by haeme binding protein haemopexin or VWF cleaving protease ADAMTS13 to a level similar to HPMECs treated with AA REVs. Consistent with these observations, haemin- or SS REV-induced microvascular stasis in SS mice with implanted dorsal skin-fold chambers that was inhibited by ADAMTS13. The adhesion induced by SS REVs was variable and was higher with SS RBCs from patients with increased markers of haemolysis (lactate dehydrogenase and reticulocyte count) or a concomitant clinical diagnosis of deep vein thrombosis. Our results emphasise the critical contribution made by REVs to the pathophysiology of SCD by triggering acute microvascular EC activation and abnormal RBC adhesion. These findings may help to better understand acute pathophysiological mechanism of SCD and thereby the development of new treatment strategies using VWF as a potential target.

MASP-2 and MASP-3 inhibitors block complement activation, inflammation, and microvascular stasis in a murine model of vaso-occlusion in sickle cell disease.

Patients with sickle cell disease (SCD) have ongoing hemolysis that promotes endothelial injury, complement activation, inflammation, vaso-occlusion, ischemia-reperfusion pathophysiology, and pain. Complement activation markers are increased in SCD in steady-state and further increased during vaso-occlusive crisis (VOC). However, the mechanisms driving complement activation in SCD have not been completely elucidated. Ischemia-reperfusion and heme released from hemoglobin during hemolysis, events that characterize SCD pathophysiology, can activate the lectin pathway (LP) and alternative pathway (AP), respectively. Here we evaluated the role of LP and AP in Townes sickle (SS) mice using inhibitory monoclonal antibodies (mAb) to mannose binding lectin (MBL)-associated serine protease (MASP)-2 or MASP-3, respectively. Townes SS mice were pretreated with MASP-2 mAb, MASP-3 mAb, isotype control mAb, or PBS before they were challenged with hypoxia-reoxygenation or hemoglobin. Pretreatment of SS mice with MASP-2 or MASP-3 mAb, markedly reduced Bb fragments, C4d and C5a in plasma and complement deposition in the liver, kidneys, and lungs collected 4 hours after challenge compared to control mAb-treated mice. Consistent with complement inhibition, hepatic inflammation markers NF-ĸB phospho-p65, VCAM-1, ICAM-1, and E-selectin were significantly reduced in SS mice pretreated with MASP-2 or MASP-3 mAb. Importantly, MASP-2 or MASP-3 mAb pretreatment significantly inhibited microvascular stasis (vaso-occlusion) induced by hypoxia-reoxygenation or hemoglobin. These studies suggest that the LP and the AP are both playing a role in promoting inflammation and vaso-occlusion in SCD. Inhibiting complement activation via the LP or the AP might inhibit inflammation and prevent VOC in SCD patients.

Varied Composition and Underlying Mechanisms of Gut Microbiome in Neuroinflammation.

The human gut microbiome has been implicated in a host of bodily functions and their regulation, including brain development and cognition. Neuroinflammation is a relatively newer piece of the puzzle and is implicated in the pathogenesis of many neurological disorders. The microbiome of the gut may alter the inflammatory signaling inside the brain through the secretion of short-chain fatty acids, controlling the availability of amino acid tryptophan and altering vagal activation. Studies in Korea and elsewhere highlight a strong link between microbiome dynamics and neurocognitive states, including personality. For these reasons, re-establishing microbial flora of the gut looks critical for keeping neuroinflammation from putting the whole system aflame through probiotics and allotransplantation of the fecal microbiome. However, the numerosity of the microbiome remains a challenge. For this purpose, it is suggested that wherever possible, a fecal microbial auto-transplant may prove more effective. This review summarizes the current knowledge about the role of the microbiome in neuroinflammation and the various mechanism involved in this process. As an example, we have also discussed the autism spectrum disorder and the implication of neuroinflammation and microbiome in its pathogenesis.

Plasma-Derived Hemopexin as a Candidate Therapeutic Agent for Acute Vaso-Occlusion in Sickle Cell Disease: Preclinical Evidence.

People living with sickle cell disease (SCD) face intermittent acute pain episodes due to vaso-occlusion primarily treated palliatively with opioids. Hemolysis of sickle erythrocytes promotes release of heme, which activates inflammatory cell adhesion proteins on endothelial cells and circulating cells, promoting vaso-occlusion. In this study, plasma-derived hemopexin inhibited heme-mediated cellular externalization of P-selectin and von Willebrand factor, and expression of IL-8, VCAM-1, and heme oxygenase-1 in cultured endothelial cells in a dose-responsive manner. In the Townes SCD mouse model, intravenous injection of free hemoglobin induced vascular stasis (vaso-occlusion) in nearly 40% of subcutaneous blood vessels visualized in a dorsal skin-fold chamber. Hemopexin administered intravenously prevented or relieved stasis in a dose-dependent manner. Hemopexin showed parallel activity in relieving vascular stasis induced by hypoxia-reoxygenation. Repeated IV administration of hemopexin was well tolerated in rats and non-human primates with no adverse findings that could be attributed to human hemopexin. Hemopexin had a half-life in wild-type mice, rats, and non-human primates of 80-102 h, whereas a reduced half-life of hemopexin in Townes SCD mice was observed due to ongoing hemolysis. These data have led to a Phase 1 clinical trial of hemopexin in adults with SCD, which is currently ongoing.

Factors that influence quality of life in patients with multiple sclerosis in Saudi Arabia.

PURPOSE: To study the factors which may contribute to quality of life (QOL) in patients with multiple sclerosis (pwMS) in Saudi Arabia. METHODS: 175 pwMS and 71 age-, gender-, and BMI-matched healthy subjects participated in this cross-sectional study. QOL was studied by the multiple sclerosis quality of life-54 (MSQOL-54) while depression, disability, and fatigue were measured by the beck depression inventory-II (BDI-II), the expanded disability status scale (EDSS), and the modified fatigue impact scale (MFIS), respectively. The effects of demographic and clinical characteristics on MSQOL-54 were studied. RESULTS: QOL was worse in pwMS. A better QOL in pwMS was linked to being male, having relapsing-remitting MS, having lower BMI, being employed, having a low disability, having no or minimal depression, and not fatigued. Age, disease duration, marital status, living status, and level of education did not affect the QOL. QOL showed a moderate to strong correlation with depression and fatigue and a weak correlation with EDSS. Depression and fatigue were the strongest predictors of QOL. Other predictors included gender and BMI but not EDSS. CONCLUSIONS: Many of the factors which seem to influence QOL in pwMS are modifiable. Evaluation and management of such factors may improve QOL in pwMS.Implications for rehabilitationAssessment of QOL (using a proper tool) should be part of every pwMS evaluation.Depression and fatigue are the main predictors of QOL in pwMs, therefore, attention should be paid for their evaluation and management.Sexual dysfunction and pain should be assessed and managed early in the course of the disease.

Sciatic nerve excursion during neural mobilization with ankle movement using dynamic ultrasound imaging: a cross-sectional study.

PURPOSE: Ankle movement is used as a sensitizing maneuver for sciatica during neurodynamic techniques. In vivo studies on the sciatic nerve biomechanics associated with ankle movement during different positions of neighboring joints are scarce. The aim of this study was to investigate sciatic nerve excursion during ankle dorsiflexion in different positions in a healthy population. METHODS: This is a cross-sectional study. High-resolution dynamic ultrasound imaging was used to measure longitudinal excursion of the sciatic nerve in the posterior thigh of 27 healthy participants during ankle dorsiflexion in six positions of the neck, hip, and knee. Both the long and short distance of the nerve excursion were measured. Wilcoxon signed-rank tests were used for data analysis, and Eta squared (r) was used to quantify the effect size. RESULTS: Ankle dorsiflexion resulted in distal sciatic nerve excursion that was significantly higher in positions in which the knee was extended (median 0.7-1.6 mm) than in positions in which the knee was flexed (median 0.5-1.4 mm) (P ≤ 0.049, r ≥ 0.379). There were no significant differences in nerve excursion between positions where the neck was neutral compared with positions where the neck was flexed (P ≥ 0.710, r ≤ 0.072) or between positions where the hip was neutral compared with positions where the hip was flexed (P ≥ 0.456, r ≤ 0.143). CONCLUSION: The positions of adjacent joints, particularly the knee, had an impact on the excursion of the sciatic nerve in the thigh during ankle movement.

Soluble MD-2 and Heme in Sickle Cell Disease Plasma Promote Pro-Inflammatory Signaling in Endothelial Cells.

Recent evidence indicates that hemolysis in sickle cell disease (SCD) promotes inflammation via innate immune signaling through toll-like receptor 4 (TLR4). Free heme released by hemolyzed red blood cells can bind to myeloid differentiation factor-2 (MD-2) and activate TLR4 pro-inflammatory signaling on endothelium to promote vaso-occlusion and acute chest syndrome in murine models of SCD. MD-2 is co-expressed with TLR4 on cell membranes, but in inflammatory conditions, soluble MD-2 (sMD-2) is elevated in plasma. sMD-2 levels were significantly increased in human and murine sickle (SS) plasma as compared to normal (AA) plasma. Human umbilical vein endothelial cells (HUVEC) and human lung microvascular endothelial cells incubated with human SS plasma had significant increases in pro-inflammatory IL-8, IL-6, and soluble VCAM-1 secretion compared to endothelial cells incubated with AA plasma. The increase in HUVEC IL-8 secretion was blocked by depletion of sMD-2 from SS plasma and enhanced by the addition of sMD-2 to AA plasma. The TLR4 signaling inhibitor, TAK-242, inhibited HUVEC IL-8 secretion in response to SS plasma by 85%. Heme-agarose pull-down assays and UV/Vis spectroscopy demonstrated that heme binds to sMD-2. Hemopexin, a high affinity heme-binding protein, inhibited HUVEC IL-8 secretion induced by SS plasma or SS and AA plasma supplemented with sMD-2. These data suggest that sMD-2 bound to heme might play an important role in pro-inflammatory signaling by endothelium in SCD.

Psychometric properties of an Arabic translation of the modified fatigue impact scale in patients with multiple sclerosis.

PURPOSE: To translate and validate the modified fatigue impact scale into Arabic (MFIS-A) in patients with multiple sclerosis (MS). METHODS: A total of 116 patients with relapsing remitting MS and 59 healthy participants were recruited. Fifty patients filled the MFIS-A twice with one week difference. Reliability was assessed by measuring Cronbach's α and intraclass correlation coefficient (ICC). The MFIS-A was correlated with the fatigue severity scale (FSS), the vitality domain of the Short Form 36 (SF-36V), the fatigue visual analogue scale (VAS-F), and the Beck Depression Inventory II (BDI-II) to assess validity. Dimensionality of the MFIS-A was investigated. A receiver operating characteristic (ROC) curve analysis was done and specificity and sensitivity were calculated. RESULTS: Factor analysis (based on 116 patients) revealed that the MFIS-A consists of two subscales: the physical/social and the cognitive subscales. The MFIS-A showed excellent test-retest reliability (ICC = 0.920) and internal consistency (Cronbach's α = 0.968). The minimal detectable change with 95% confidence interval was 14.68 (32.0%). The MFIS-A showed strong positive correlation with FSS and BDI-II, moderate positive correlation with VAS-F, negative moderate correlation with SF-36V, and weak correlation with EDSS. The MFIS-A differentiated healthy participants from patients with 79.3% sensitivity and 89.8% specificity. CONCLUSIONS: The MFIS-A showed good validity and reliability indicating its usefulness as an assessment measure for patients with MS.IMPLICATIONS FOR REHABILITATIONMFIS-A is a valid and reliable tool for fatigue evaluation for patients with relapsing remitting MS.The optimal cutoff scores of the total MFIS-A, the physical/social, and cognitive subscales which indicate fatigue are 35.5, 18.5, and 15.5, respectively.Changes of 14.68 or more points may indicate a clinically important change (a true change) in fatigue in patients with MS.

A novel, highly potent and selective phosphodiesterase-9 inhibitor for the treatment of sickle cell disease.

The most common treatment for patients with sickle cell disease (SCD) is the chemotherapeutic hydroxyurea, a therapy with pleiotropic effects, including increasing fetal hemoglobin (HbF) in red blood cells and reducing adhesion of white blood cells to the vascular endothelium. Hydroxyurea has been proposed to mediate these effects through a mechanism of increasing cellular cGMP levels. An alternative path to increasing cGMP levels in these cells is through the use of phosphodiesterase-9 inhibitors that selectively inhibit cGMP hydrolysis and increase cellular cGMP levels. We have developed a novel, potent and selective phosphodiesterase-9 inhibitor (IMR-687) specifically for the treatment of SCD. IMR-687 increased cGMP and HbF in erythroid K562 and UT-7 cells and increased the percentage of HbF positive erythroid cells generated in vitro using a two-phase liquid culture of CD34+ progenitors from sickle cell blood or bone marrow. Oral daily dosing of IMR-687 in the Townes transgenic mouse SCD model, increased HbF and reduced red blood cell sickling, immune cell activation and microvascular stasis. The IMR-687 reduction in red blood cell sickling and immune cell activation was greater than that seen with physiological doses of hydroxyurea. In contrast to other described phosphodiesterase-9 inhibitors, IMR-687 did not accumulate in the central nervous system, where it would inhibit phosphodiesterase-9 in neurons, or alter rodent behavior. IMR-687 was not genotoxic or myelotoxic and did not impact fertility or fetal development in rodents. These data suggest that IMR-687 may offer a safe and effective oral alternative for hydroxyurea in the treatment of SCD.

Effects of pulsed low-frequency magnetic field therapy on pain intensity in patients with musculoskeletal chronic low back pain: study protocol for a randomised double-blind placebo-controlled trial.

INTRODUCTION: The aim of the present study is to investigate the effectiveness of pulsed low-frequency magnetic field (PLFMF) on the management of chronic low back pain (CLBP). METHODS AND ANALYSIS: A randomised double-blinded controlled clinical trial will be conducted, involving 200 patients with CLBP. Participants will be randomised in a 1:1 ratio to receive either active PLFMF (experimental arm) or sham treatment (control arm) using a permuted-block design which will be stratified according to three subtypes of musculoskeletal CLBP (nociceptive, peripheral neuropathic or central sanitisation). The intervention consists of three sessions/week for 6 weeks. The primary outcome is the percentage change in Numerical Rating Scale (NRS) pain at week 24 after treatment completion with respect to the baseline. Secondary outcomes include percentage NRS pain during treatment and early after treatment completion, short form 36 quality of life, Roland and Morris Disability Questionnaire; Depression Anxiety Stress Scale 21, Patient Specific Functional Scale, Global perceived effect of condition change, Pittsburgh Sleep Quality Index and Modified Fatigue Impact Scale. Measures will be taken at baseline, 3 and 6 weeks during the intervention and 6, 12 and 24 weeks after completing the intervention. Adverse events between arms will be evaluated. Data will be analysed on an intention-to-treat basis. ETHICS AND DISSEMINATION: The study is funded by Imam Abdulrahman Bin Faisal University (IAU). It has been approved by the institutional review board of IAU (IRB- 2017-03-129). The study will be conducted at King Fahd Hospital of the University and will be monitored by the Hospital monitoring office for research and research ethics. The trial is scheduled to begin in September 2018. Results obtained will be presented in international conferences and will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ACTRN12618000921280, prospectively.

Psychometric properties of an Arabic version of the fatigue severity scale in patients with stroke.

Background: Post-stroke fatigue is a common symptom which needs to be assessed by a psychometrically sound tool. Objectives: To investigate the psychometric properties of an Arabic version of the fatigue severity scale (FSS-A) in patients with stroke. Methods: An observational, cross-sectional design was applied to 147 survivors of first-time stroke and 70 healthy participants. Internal consistency was measured by Cronbach's α, while test-retest reliability was measured by intraclass correlation coefficients (ICCs). To assess validity, the FSS-A was correlated with the Fatigue Visual Analogue Scale (VAS-F), the Short Form 36 (SF-36) and its vitality domain (SF-36V), the stroke specific quality of life (SSQOL-A) and its energy domain (SSQOL-A-E), and the Beck Depression Inventory II (BDI-II). Results: The FSS-A showed excellent internal consistency (Cronbach's α = 0.934) and test-retest reliability (ICC = 0.920, 95% confidence interval (CI): 0.85-0.96). Exploratory factor analysis confirmed that the FSS-A is unidimensional. The FSS-A had high positive correlation with VAS-F, moderate positive correlation with BDI-II, high negative correlation with SSQOL-A-E and moderate negative correlations with SF-36, SF-36V, and SSQOL-A. It differentiated patients from healthy participants with a sensitivity of 78.4% and a specificity of 77.1%. The minimal detectable change with 95% CI was 1.02 (22.4%). Conclusions: The FSS-A showed good psychometric properties suggesting its usefulness as a fatigue evaluation tool in patients diagnosed with stroke.

Translation and validation of the stroke specific quality of life scale into Arabic.

BACKGROUND: There is a need to validate one of the specific stroke quality of life (QOL) scales into Arabic. OBJECTIVE: To translate and validate the stroke specific quality of life (SSQOL) into Arabic. METHODS: The SSQOL was translated into Arabic (SSQOL-A) according to a forward/backward translation protocol. 147 first time stroke survivors and 60 healthy subjects were recruited. Cronbach's α was used to measure internal consistency, test-retest reliability was measured by intraclass correlation coefficient (ICC). Acceptability was established by studying floor and ceiling effects. A linear correlation between SSQOL-A and the Short Form 36, the Beck Depression Inventory II, the Barthel Index and the National Institutes of Health Stroke Scale was done to assess construct validity. Discriminant and convergent validity were evaluated by correlating item to scale of each of the domains using Pearson correlation (rp). RESULTS: The SSQOL-A has shown good internal consistency (Cronbach's α  = 0.78-0.94) and test-retest reliability (ICC = 0.77-0.94). It has also shown acceptable construct validity (r2 = 0.06-0.55). Item to scale correlation showed acceptable convergent (0.76-0.98) and discriminant (0.12-0.53) validity. Mann-Whitney U test showed the ability of the SSQOL-A to differentiate between stroke survivors and healthy participants QOL. CONCLUSIONS: SSQOL-A has good validity and reliability for patients with mild to moderate stroke.

Critical role of C5a in sickle cell disease.

Innate immune complement activation may contribute to sickle cell disease (SCD) pathogenesis. Ischemia-reperfusion physiology is a key component of the inflammatory and vaso-occlusive milieu in SCD and is associated with complement activation. C5a is an anaphylatoxin, a potent pro-inflammatory mediator that can activate leukocytes, platelets, and endothelial cells, all of which play a role in vaso-occlusion. We hypothesize that hypoxia-reoxygenation (H/R) in SCD mice activates complement, promoting inflammation and vaso-occlusion. At baseline and after H/R, sickle Townes-SS mice had increased C3 activation fragments and C5b-9 deposition in kidneys, livers and lungs and alternative pathway Bb fragments in plasma compared to control AA-mice. Activated complement promoted vaso-occlusion (microvascular stasis) in SS-mice; infusion of zymosan-activated, but not heat-inactivated serum, induced substantial vaso-occlusion in the skin venules of SS-mice. Infusion of recombinant C5a induced stasis in SS, but not AA-mice that was blocked by anti-C5a receptor (C5aR) IgG. C5a-mediated stasis was accompanied by inflammatory responses in SS-mice including NF-κB activation and increased expression of TLR4 and adhesion molecules VCAM-1, ICAM-1, and E-selectin in the liver. Anti-C5aR IgG blocked these inflammatory responses. Also, C5a rapidly up-regulated Weibel-Palade body P-selectin and von Willebrand factor on the surface of human umbilical vein endothelial cells in vitro and on vascular endothelium in vivo. In SS-mice, a blocking antibody to P-selectin inhibited C5a-induced stasis. Similarly, an antibody to C5 that blocks murine C5 cleavage or an antibody that blocks C5aR inhibited H/R-induced stasis in SS-mice. These results suggest that inhibition of C5a may be beneficial in SCD.

Oral carbon monoxide therapy in murine sickle cell disease: Beneficial effects on vaso-occlusion, inflammation and anemia.

Carbon monoxide (CO) at low, non-toxic concentrations has been previously demonstrated to exert anti-inflammatory protection in murine models of sickle cell disease (SCD). However CO delivery by inhalation, CO-hemoglobin infusion or CO-releasing molecules presents problems for daily CO administration. Oral administration of a CO-saturated liquid avoids many of these issues and potentially provides a platform for self-administration to SCD patients. To test if orally-delivered CO could modulate SCD vaso-occlusion and inflammation, a liquid CO formulation (HBI-002) was administered by gavage (10 ml/kg) once-daily to NY1DD and Townes-SS transgenic mouse models of SCD. Baseline CO-hemoglobin (CO-Hb) levels were 1.6% and 1.8% in NY1DD and Townes-SS sickle mice and 0.6% in Townes-AS control mice. CO-Hb levels reached 5.4%, 4.7% and 3.0% within 5 minutes in NY1DD, SS and AS mice respectively after gavage with HBI-002. After ten treatments, each once-daily, hemoglobin levels rose from 5.3g/dL in vehicle-treated Townes-SS mice to 6.3g/dL in HBI-002-treated. Similarly, red blood cell (RBC) counts rose from 2.36 x 106/µL in vehicle-treated SS mice to 2.89 x 106/µL in HBI-002-treated mice. In concordance with these findings, hematocrits rose from 26.3% in vehicle-treated mice to 30.0% in HBI-002-treated mice. Reticulocyte counts were not significantly different between vehicle and HBI-002-treated SS mice implying less hemolysis and not an increase in RBC production. White blood cell counts decreased from 29.1 x 103/µL in vehicle-treated versus 20.3 x 103/µL in HBI-002-treated SS mice. Townes-SS mice treated with HBI-002 had markedly increased Nrf2 and HO-1 expression and decreased NF-κB activation compared to vehicle-treated mice. These anti-inflammatory effects were examined for the ability of HBI-002 (administered orally once-daily for up to 5 days) to inhibit vaso-occlusion induced by hypoxia-reoxygenation. In NY1DD and Townes-SS sickle mice, HBI-002 decreased microvascular stasis in a duration-dependent manner. Collectively, these findings support HBI-002 as a useful anti-inflammatory agent to treat SCD and warrants further development as a therapeutic.

Haptoglobin and hemopexin inhibit vaso-occlusion and inflammation in murine sickle cell disease: Role of heme oxygenase-1 induction.

During hemolysis, hemoglobin and heme released from red blood cells promote oxidative stress, inflammation and thrombosis. Plasma haptoglobin and hemopexin scavenge free hemoglobin and heme, respectively, but can be depleted in hemolytic states. Haptoglobin and hemopexin supplementation protect tissues, including the vasculature, liver and kidneys. It is widely assumed that these protective effects are due primarily to hemoglobin and heme clearance from the vasculature. However, this simple assumption does not account for the consequent cytoprotective adaptation seen in cells and organs. To further address the mechanism, we used a hyperhemolytic murine model (Townes-SS) of sickle cell disease to examine cellular responses to haptoglobin and hemopexin supplementation. A single infusion of haptoglobin or hemopexin (± equimolar hemoglobin) in SS-mice increased heme oxygenase-1 (HO-1) in the liver, kidney and skin several fold within 1 hour and decreased nuclear NF-ĸB phospho-p65, and vaso-occlusion for 48 hours after infusion. Plasma hemoglobin and heme levels were not significantly changed 1 hour after infusion of haptoglobin or hemopexin. Haptoglobin and hemopexin also inhibited hypoxia/reoxygenation and lipopolysaccharide-induced vaso-occlusion in SS-mice. Inhibition of HO-1 activity with tin protoporphyrin blocked the protections afforded by haptoglobin and hemopexin in SS-mice. The HO-1 reaction product carbon monoxide, fully restored the protection, in part by inhibiting Weibel-Palade body mobilization of P-selectin and von Willebrand factor to endothelial cell surfaces. Thus, the mechanism by which haptoglobin and hemopexin supplementation in hyperhemolytic SS-mice induces cytoprotective cellular responses is linked to increased HO-1 activity.

Neonatal indirect hyperbilirubinemia and glucose-6-phosphate dehydrogenase deficiency.

PURPOSE: This study aimed to determine the prevalence of glucose-6-phosphate dehydrogenase (G6PD) deficiency among infants with neonatal indirect hyperbilirubinemia (NIH); compare G6PD-deficient and G6PD-normal patients regarding hyperbilirubinemia and need for exchange transfusions (ET); and assess risk factors for ET and kernicterus. METHODS: This is a case-control retrospective study. Medical records of NIH patients admitted to the Pediatric Department, Salmaniya Medical Complex, Bahrain, between January 2007 and June 2010 were reviewed. Data on sex, age at presentation, hospitalization duration, need for ET, hemoglobin (Hb) level, reticulocyte count, direct Coombs test, serum total and indirect bilirubin levels, thyroid function, blood and urine cultures, G6PD status, and blood groups were collected and compared between the G6PD-deficent and G6PD-normal patients. RESULTS: Of 1,159 NIH patients admitted, 1,129 were included, of whom 646 (57%) were male. Among 1,046 patients tested, 442 (42%) were G6PD deficient, 49 (4%) needed ET, and 11 (1%) had suspected Kernicterus. The G6PD-deficient patients were mainly male (P<0.0001), and had lower Hb levels (P<0.0001) and higher maximum bilirubin levels (P=0.001). More G6PD-deficient patients needed ET (P<0.0001). G6PD deficiency (P=0.006), lower Hb level (P=0.002), lower hematocrit count (P=0.02), higher bilirubin level (P<0.0001), higher maximal bilirubin level (P<0.0001), and positive blood culture result (P<0.0001) were significant risk factors for ET. Maximal bilirubin level was a significant risk factor for kernicterus (P=0.021) and independently related to ET (P=0.03). CONCLUSION: G6PD deficiency is an important risk factor for severe NIH. In G6PD-deficent neonates, management of NIH should be hastened to avoid irreversible neurological complications.