IL-17/Notch1/STAT3 Pathway Contributes to 5-Fluorouracil-Induced Intestinal Mucositis in Rats: Amelioration by Thymol Treatment.

5-Fluorouracil (5-FU) is an anticancer drug with intestinal mucositis (IM) as a deleterious side effect. Thymol is a monoterpene phenol which has been reported to possess an antioxidant and anti-inflammatory activity versus 5-FU-induced IM. The Notch pathway affects multiple cellular activities, such as cellular proliferation, in addition to inflammatory responses modulation. Accordingly, this work was carried out in order to elucidate the role of the Notch pathway in 5-FU-induced IM and to further elucidate the immunomodulatory protective mechanisms of thymol. Experimental rats were divided randomly into four groups: Control, 5-FU, 5-FU+thymol (60 mg/kg/day), and 5-FU+thymol (120 mg/kg/day). 5-FU was injected intraperitoneally at a dose of 150 mg/kg on days 6 and 7, while thymol was orally administered daily for 11 days. By the end of the study, intestinal tissues were collected for the determination of IL-17, CD4, CD8, Notch1, Hes-1, pSTAT3, and STAT-3 protein expressions. The effect of thymol on 5-FU cytotoxicity was also examined using WST1 assay. 5-FU induced a marked increase in IL-17 levels, along with a marked downregulation of CD4 and the upregulation of CD8, Notch1, Hes-1 protein expressions, and activation of STAT3 in the intestinal tissue when compared with the control group. Thymol ameliorated the changes that occurred in these parameters. Additionally, cytotoxicity testing revealed that thymol augmented the antiproliferative action of 5-FU against breast and colorectal human cancer cell lines. This study was the first to show that the IL-17/Notch1/STAT3 pathway is involved in the molecular mechanism of 5-FU-induced IM, as well as the immunomodulatory activity of thymol.

Perceived Clinical Barriers to Employment for Males with Spinal Cord Injury in Saudi Arabia.

Return to work is a challenging aspect of community integration for individuals with disabilities. The reintegration of individuals with spinal cord injury (SCI) is multifactorial; hence, regional challenges need to be investigated in the context of their clinical attributes and perceptions. A total of 121 male participants above 18 years of age with diagnosis of SCI and living at home were included in this cross-sectional survey. The study was conducted at a tertiary care rehabilitation facility in Saudi Arabia. The most common reported clinical barriers to employment were mobility, bladder incontinence, spasticity, musculoskeletal pain, and neuropathic pain. Bladder incontinence and musculoskeletal pain were the most common perceived clinical barriers for individuals with paraplegia and tetraplegia, respectively. A significant difference was observed for bowel incontinence as a reported barrier (p = 0.024) among adults less than thirty years of age in comparison with those older than thirty years. Spasticity as a barrier was reported more among patients who were older than thirty years (54.0%) compared to those younger than thirty years of age (37.9%) (p = 0.077). Twenty-two (23.7%) participants with paraplegia reported transfers as a perceived barrier to employment, which was significant (p = 0.014), and it was also reported as a significant barrier (p = 0.001) in individuals with tetraplegia (56%). This study shows that clinical conditions associated with SCI are considered potential barriers to employment by individuals with SCI. In terms of priority, the perceived barriers between individuals with tetraplegia and paraplegia were mostly different. This shows the need to consider relevant secondary health care conditions in goal setting while planning for employment in individuals with SCI.

Liraglutide Effect on Weight, Glycated Hemoglobin, and Blood Pressure: A Single-Center Experience in the Eastern Province of Saudi Arabia.

Background Liraglutide has pleiotropic effects beneficial to patients with cardiovascular and renal risks. These effects have been linked to weight and blood pressure reduction in type 2 diabetes (T2D) patients. However, whether this reduction is similar in all patients regardless of their ethnicity, baseline demographic, or clinical characteristics is unknown. This study aimed to identify the efficacy of liraglutide on weight, glycated hemoglobin (HbA1c), and blood pressure in Saudi patients with T2D who attended King Fahad Hospital of the University and received liraglutide as add-on therapy to other antihyperglycemic agents. The study also aimed to describe the pattern of change in these clinical parameters before and after the treatment and assess whether sex differences affect liraglutide's efficacy. Methods We conducted a retrospective longitudinal study reviewing medical records of 220 Saudi patients with T2D treated at King Fahad Hospital of the University (KFHU), in Al-Khobar city in the Eastern Province of Saudi Arabia, from December 2016 to November 2021. Patient cases were included if the patient was Saudi, aged 18 or older, and received liraglutide in a dose of at least 0.6 mg/day for at least three months in combination with other antihyperglycemic agents/diabetes medications. We recorded the effect on patient HbA1c, systolic blood pressure (SBP) and diastolic blood pressure (DBP), body mass index (BMI), and body weight at baseline, during, and after treatment. We used the paired t-test and repeated measure analysis of variance to compare the mean study parameters before and after treatment. Furthermore, an independent t-test was used to compare the mean study parameters among men and women. Results Treatment with liraglutide from 0.6 mg/day to 3 mg/day for three to 18 months had optimal results across the outcomes measured in our cohort study. There was a significant reduction in weight from baseline to 18 months from a mean weight of 97.9±20 kg to 96.51±18.45 kg with (p<0.001). Mean HbA1c at baseline was 9.34%±1.95%, dropped to 7.67%±1.11% (p<0.001) at 18 months. Moreover, mean SBP also significantly decreased from 126.61±10.4 mmHg to 122.48±7.29 mmHg by the last follow-up (p<0.001). Mean DBP was 76.54±8.37 mmHg at baseline and decreased to 74.29±6.22 mmHg at last follow-up (p<0.001). Men treated with liraglutide had greater reductions in weight than women throughout the study (p<0.05), and while men had greater reductions in SBP and DBP than women early in treatment (p<0.05), by the end of treatment, there were no significant differences in blood pressure between men and women. Likewise, we saw no significant difference between HbA1c reductions in men and women treated with liraglutide. Conclusion Liraglutide effectively reduces HbA1c, weight, BMI, SBP, and DBP in T2D patients. These study results reflect real-world liraglutide clinical practices from KFHU and can be beneficial for physicians when considering using liraglutide as add-on therapy in this population.

Retraction: Liraglutide Effect on Weight, Glycated Hemoglobin, and Blood Pressure: A Single-Center Experience in the Eastern Province of Saudi Arabia.

[This retracts the article DOI: 10.7759/cureus.23554.].

Upfront Alternative Donor Transplant versus Immunosuppressive Therapy in Patients with Severe Aplastic Anemia Who Lack a Fully HLA-Matched Related Donor: Systematic Review and Meta-Analysis of Retrospective Studies, on Behalf of the Severe Aplastic Anemia Working Party of the European Group for Blood and Marrow Transplantation.

Idiopathic aplastic anemia is a rare and life-threatening disorder, and hematopoietic stem cell transplantation (HSCT) from a matched sibling donor (MSD) is the standard treatment strategy for young patients. Alternative donor transplantation (ADT) from a matched unrelated donor or an HLA haploidentical donor is not commonly used in the frontline setting. This systematic review/meta-analysis was conducted to compare ADT as an upfront, rather than delayed, treatment strategy in the absence of an MSD to immunosuppressive therapy (IST) in severe aplastic anemia (SAA). We searched PubMed/MEDLINE and Embase (1998 to 2019) for studies that compared the outcomes of ADT with IST as upfront therapy in patients with SAA. We included studies with 5 patients or more in each arm. Studies that included patients with inherited forms of bone marrow failure syndromes were excluded. The primary outcome was the 5-year overall survival (OS) rate. Five studies met the inclusion criteria and were included in this meta-analysis. The pooled 5-year odds ratio (OR) for OS was statistically significant at 0.44 (95% confidence interval [CI], 0.23 to 0.85) in favor of upfront ADT. In addition, survival was compared between upfront ADT versus salvage ADT in 6 studies. The pooled 5-year OR for OS was statistically significant at 0.31 (95% CI, 0.15 to 0.64) in favor of upfront ADT. Although this analysis has some limitations, including the retrospective nature of the included studies, the lack of ethnic diversity, the predominantly pediatric population, and the relatively suboptimal IST regimen used in some of the studies, it indicates that upfront ADT is a potential alternative treatment option in young and pediatric SAA patients who lack an HLA identical sibling donor, particularly when optimal IST is not available. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Case Report: Klippel-Trenaunay Syndrome - Recurrent Venous Thromboembolism and Vascular Malformation.

Klippel-Trenaunay Syndrome (KTS) is a rare genetic vascular disorder characterized by a limb affected by varicose veins, port wine stains, and hypertrophy of bone and soft tissue. It can also present with vascular malformations in the gastrointestinal tract, liver, spleen, genitourinary tract, and heart. We present a 27-year-old case of KTS diagnosed in adulthood associated with recurrent venous thromboembolism and gastrointestinal bleeding.

Carvacrol and Thymol Modulate the Cross-Talk between TNF-α and IGF-1 Signaling in Radiotherapy-Induced Ovarian Failure.

Premature ovarian failure (POF) is a common cause of infertility in premenopausal women who are unavoidably exposed to cytotoxic therapy. Radiotherapy is one of the most effective cytotoxic treatments. However, the radiosensitivity of ovarian tissues limits its therapeutic outcome and results in the depletion of the primordial follicle and loss of fertility. Therefore, the need for an effective radioprotective therapy is evident especially when none of the current clinically used modalities for radioprotection succeeds efficiently. The present study investigated the potential radioprotective effect of carvacrol (CAR) (80 mg) or thymol (80 mg) on gamma- (γ-) irradiation-induced ovarian damage as well as their role in the cross-talk between IGF-1 and TNF-α signaling and antioxidative activity. In immature female Wister rats, a single dose of whole-body irradiation (3.2 Gy, LD20) produced considerable ovarian damage, which was evident by histopathological findings and hormonal changes. Interestingly, pretreatment with CAR or thymol significantly enhanced the follicular development and restored the anti-Mullerian hormone (AMH), E2, and FSH levels. Both essential oils improved the irradiation-mediated oxidative stress and reduction in proliferating cell nuclear antigen (PCNA) expression. Moreover, irradiated rats exhibited an inverse relationship between IGF-1 and TNF-α levels two days post irradiation, which was further inverted by the pretreatment with CAR and thymol and ought to contribute in their radioprotective mechanisms. In conclusion, CAR and thymol showed a radioprotective effect and rescued the ovarian reserve mainly through counteracting oxidative stress and the dysregulated cross-talk between IGF-1 and TNF-α.