Differential Regulation of the PGC Family of Genes in a Mouse Model of Staphylococcus aureus Sepsis

The PGC family of transcriptional co-activators (PGC-1α [Ppargc1a], PGC-1β [Ppargc1b], and PRC [Pprc]) coordinates the upregulation of mitochondrial biogenesis, and Ppargc1a is known to be activated in response to mitochondrial damage in sepsis. Therefore, we postulated that the PGC family is regulated by the innate immune system. We investigated whether mitochondrial biogenesis and PGC gene expression are disrupted in an established model of Staphylococcus aureus sepsis both in mice with impaired innate immune function (TLR2−/− and TLR4−/−) and in wild-type controls. We found an early up-regulation of Ppargc1a and Ppargc1b post-infection (at 6 h) in WT mice, but the expression of both genes was concordantly dysregulated in TLR2−/− mice (no increase at 6 h) and in TLR4−/− mice (amplified at 6 h). However, the third family member, PRC, was regulated differently, and its expression increased significantly at 24 h in all three mouse strains (WT, TLR2−/−, and TLR4−/−). In silico analyses showed that Ppargc1a and Ppargc1b share binding sites for microRNA mmu-mir-202-3p. Thus, miRNA-mediated post-transcriptional mRNA degradation could account for the failure to increase the expression of both genes in TLR2−/− mice. The expression of mmu-mir-202-3p was measured by real-time PCR and found to be significantly increased in TLR2−/− but not in WT or TLR4−/− mice. In addition, it was found that mir-202-3p functionally decreases Ppargc1a mRNA in vitro. Thus, both innate immune signaling through the TLRs and mir-202-3p-mediated mRNA degradation are implicated in the co-regulation of Ppargc1a and Ppargc1b during inflammation. Moreover, the identification of mir-202-3p as a potential factor for Ppargc1a and Ppargc1b repression in acute inflammation may open new avenues for mitochondrial research and, potentially, therapy

Saudi SCD patients’ symptoms and quality of life relative to the number of ED visits

Background Individuals living with sickle cell disease (SCD) have significantly increased emergency department (ED) use compared to the general population. In Saudi Arabia, health care is free for all individuals and therefore has no bearing on increased ED visits. However, little is known about the relationship between quality of life (QoL) and frequency of acute care utilization in this patient population. Methods A cross-sectional study was conducted on 366 patients with SCD who attended the outpatient department at King Fahad Hospital, Hofuf, Saudi Arabia. Data were collected through self-administered surveys, which included: demographics, SCD-related ED visits, clinical issues, and QoL levels. We assessed the ED use by asking for the number of SCD-related ED visits within a 6-month period. Results The self-report survey of ED visits was completed by 308 SCD patients. The median number of SCD-related ED visits within a 6-month time period (IQR) was four (2-7 visits). According to the unadjusted negative binomial model, the rate of SCD-related ED visits increased by (46, 39.3, 40, and 53.5 %) for patients with fever, skin redness with itching, swelling, and blood transfusion, respectively. Poor QoL tends to increase the rate of SCD-related ED visits. Well education and poor general health positively influenced the rate of SCD-related ED visits. Well education tends to increase the rate of SCD-related ED visits by 50.2 %. The rate of SCD-related ED visits decreased by 1.4 % for every point increase in general health. Conclusion Saudi patients with sickle cell disease reported a wide range of SCD-related ED visits. It was estimated that six of 10 SCD patients had at least three ED visits within a 6-month period. Well education and poor general health resulted in an increase in the rate of SCD-related ED visits

The prevalence of abnormal leukocyte count, and its predisposing factors, in patients with sickle cell disease in Saudi Arabia

Anwar E Ahmed,1 Yosra Z Ali,2 Ahmad M Al-Suliman,3 Jafar M Albagshi,3 Majid Al Salamah,1 Mohieldin Elsayid,1 Wala R Alanazi,4 Rayan A Ahmed,5 Donna K McClish,6 Hamdan AL-Jahdali,1,2 1College of Public Health and Health Informatics, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia; 2King Abdulaziz Medical City, Riyadh, Saudi Arabia; 3King Fahad Hospital, Hofuf, Saudi Arabia; 4Al-Maarefa College for Science and Technology, Riyadh, Saudi Arabia; 5Dar Al Uloom University, Riyadh, Saudi Arabia; 6Department of Biostatistics, Virginia Commonwealth University, Richmond, VA, USA Introduction: High white blood cell (WBC) count is an indicator of sickle cell disease (SCD) severity, however, there are limited studies on WBC counts in Saudi Arabian patients with SCD. The aim of this study was to estimate the prevalence of abnormal leukocyte count (either low or high) and identify factors associated with high WBC counts in a sample of Saudi patients with SCD. Methods: A cross-sectional and retrospective chart review study was carried out on 290 SCD patients who were routinely treated at King Fahad Hospital in Hofuf, Saudi Arabia. An interview was conducted to assess clinical presentations, and we reviewed patient charts to collect data on blood test parameters for the previous 6 months. Results: Almost half (131 [45.2%]) of the sample had abnormal leukocyte counts: low WBC counts 15 (5.2%) and high 116 (40%). High WBC counts were associated with shortness of breath (P=0.022), tiredness (P=0.039), swelling in hands/feet (P=0.020), and back pain (P=0.007). The mean hemoglobin was higher in patients with normal WBC counts (P=0.024), while the mean hemoglobin S was high in patients with high WBC counts (P=0.003). After adjustment for potential confounders, predictors of high WBC counts were male gender (adjusted odds ratio [aOR]=3.63) and patients with cough (aOR=2.18), low hemoglobin (aOR=0.76), and low heart rate (aOR=0.97). Conclusion: Abnormal leukocyte count was common: approximately five in ten Saudi SCD patients assessed in this sample. Male gender, cough, low hemoglobin, and low heart rate were associated with high WBC count. Strategies targeting high WBC count could prevent disease complication and thus could be beneficial for SCD patients. Keywords: white blood cell, leukocyte, SCD, Saudi, hemoglobin, low heart rate, Saudi Arabi

Functional crosstalk of PGC-1 coactivators and inflammation in skeletal muscle pathophysiology

Skeletal muscle is an organ involved in whole body movement and energy metabolism with the ability to dynamically adapt to different states of (dis-)use. At a molecular level, the peroxisome proliferator-activated receptor γ coactivators 1 (PGC-1s) are important mediators of oxidative metabolism in skeletal muscle and in other organs. Musculoskeletal disorders as well as obesity and its sequelae are associated with PGC-1 dysregulation in muscle with a concomitant local or systemic inflammatory reaction. In this review, we outline the function of PGC-1 coactivators in physiological and pathological conditions as well as the complex interplay of metabolic dysregulation and inflammation in obesity with special focus on skeletal muscle. We further put forward the hypothesis that, in this tissue, oxidative metabolism and inflammatory processes mutually antagonize each other. The nuclear factor κB (NF-κB) pathway thereby plays a key role in linking metabolic and inflammatory programs in muscle cells. We conclude this review with a perspective about the consequences of such a negative crosstalk on the immune system and the possibilities this opens for clinical applications

Increased plasma sVCAM-1 is associated with severity in IgA nephropathy

<p>Abstract</p> <p>Background</p> <p>A considerable proportion of IgAN patients present with histological vasculitic/crescentic lesions in glomeruli, indicating activation of vascular inflammation. Using sVCAM-1, a well-proven marker for endothelial injury under inflammatory processes, we investigated vascular injury and its association with clinical and pathological manifestations in IgAN patients.</p> <p>Methods</p> <p>In this study, 327 biopsy-proven IgAN patients and 55 healthy controls were enrolled. The Oxford classification and two variables, Active Crescentic Lesion Percentage (ACLP) and Chronic Glomerular Lesion Percentage (CGLP), were used for evaluating pathological lesions. Human Umbilical Vein Endothelial Cells were treated with 25-400 ug/ml IgA1. sVCAM-1 in plasma and culture supernatant were measured by ELISA.</p> <p>Results</p> <p>Plasma sVCAM-1 in IgAN patients was significantly higher than healthy controls. In patients with IgAN, plasma sVCAM-1 was significantly correlated with eGFR, 24h urine protein excretion, tubular atrophy/interstitial fibrosis lesion and ACLP, but not CGLP. Meanwhile, compared to healthy volunteers, IgA1 from IgAN patients showed a tendency to increase the HUVECs supernatant sVCAM-1 expression. And IgA1 induced the sVCAM-1 increasing from HUVECs in time- and dose-dependent manner.</p> <p>Conclusions</p> <p>We found increased plasma sVCAM-1 in IgAN patients and its association with severe clinical and pathological manifestations, which might be partly resulted from effect of IgA1 to endothelial cells.</p

Days out of role due to mental and physical illness in the South African stress and health study

Background: Both mental and physical disorders can result in role limitation, such as ‘days out of role’, which have an important impact on national productivity losses. This paper analyses data from the South African Stress and Health Study (SASH) on the association of both mental and physical disorders with days out of role. Methods: Face-to-face interviews were conducted with a representative sample of 4,351 adult South Africans. The World Health Organization’s Composite International Diagnostic Interview (WHO-CIDI) was used to assess the presence of 21 mental and physical disorders that were grouped into 10 disorder categories for the analysis: major depressive disorder, any anxiety disorders, any substance abuse disorders, headaches or migraine, arthritis, chronic pain, cardiovascular, respiratory, diabetes and digestive disorders. Multiple regression techniques were used to explore associations between individual disorders, comorbid conditions, and annual days spent out of role. The estimated societal effects of the disorders [population attributable risk proportion (PARP)] were obtained. Results: The majority of respondents who reported a mental or physical disorder also reported another disorder (62.98 %). The average number of disorders reported by respondents who had at least one disorder was 2.3. Overall 12.4 % of respondents reported any days out of role due to mental or physical disorder. Anxiety disorders and depression were associated with highest days out of role (28.2 and 27.2, respectively) followed closely by arthritis and pain (24.7 and 21.7, respectively). Any mental disorder was associated with 23.6 days out of role, while any physical disorder was associated with 15.5 days out of role. Of the mental disorders, anxiety disorders had the highest PARP in relation to days out of role (9.0 %) followed by depression (4.8 %) and substance disorder (3.3. %). More than one-third (37.6 %) of days out of role are attributable to physical disorders and 16.1 % to mental disorders. Conclusions: Comorbidity is common in both mental and physical disorders, and both are associated with substantial days out of role in South Africa. These data indicate substantial social and economic loss associated with these conditions, and emphasize the need to integrate health services to include common mental disorders in all basic packages of care and to assess for and manage comorbid conditions.SM is supported by a postdoctoral fellowship awarded by the Faculty of Health Sciences (FHS), University of Cape Town. CL is supported by a grant from the Department for International Development (DFI