Association Between Lipid Profile and Diabetic Foot Ulcer

Diabetic foot ulcer is a serious disabling consequence of Diabetes Mellitus. They are characterized by the breakdown of skin and underlying tissues in the feet, and are a major cause of lower limb amputations. Various risk factors have been identified for the development of diabetic foot ulcers, including poor glycemic control, peripheral neuropathy, peripheral arterial disease, and impaired wound healing. it is considered that the lipid profile is one of many factors that contribute to the formation and progression of diabetic foot ulcers. To stratify the incidence of diabetic foot ulcers (DFUs), biomarkers are required. The aim of this review is to assess the relationship between the risk of DFU and lipid profile in diabetic patients

Gubernaculum Sparing Laparoscopic Orchiopexy in Cryptorchidism with Ipsilateral Congenital Absence of the Vas Deferens: Unique Outcome

Congenital absence of the vas deferens (CAVD) is an uncommon anomaly that occurs in up to 1% of the male population. It can be associated with various other anomalies, including cryptorchidism and renal anomalies, such as renal agenesis. We here present a case of cryptorchidism with ipsilateral congenital absence of the vas deferens and renal agenesis and used the Stephen-Fowler technique for Orchiopexy depending on gubernacular vessels. A 7-month-old boy was referred to our center with left grade 2 hydronephrosis, right renal agenesis, and right impalpable, undescended testis. Examination under anesthesia and laparoscopic exploration with staged Stephen-Fowler orchiopexy were performed. The patient was followed up at 3, 6, and 12 months and had an excellent outcome. Cryptorchidism with congenital ipsilateral absence of the vas deferens and renal agenesis is a rare diagnostic entity. Our case supports the suggested theory that the gubernacular vessels can increase the blood supply to the testis, although further studies are needed to confirm this hypothesis

Total endoscopic and anal irrigation management approach to noncompliant neuropathic bladder and bowel in children: A long-term follow-up

Purpose: To evaluate the long-term efficacy and durability of combined intradetrusor botulinum-A toxin (BTX-A), endoscopic treatment of vesicouerteral reflux and anal irrigation for stool incontinence (SI) via a total endoscopic and anal irrigation management (TEAM®) approach in patients with myelomeningocele and neuropathic bladder and bowel who did not respond to conservative measures. Materials and Methods: Fourteen myelomeningocele patients with at least 3 years follow-up were included in the study. All patients have urinary and SI not responded to conservative management. All patients received a cystoscopic intradetrusor injection of 12 U/kg (maximum 300 U) BTX-A. There was vesicoureteral reflux in 22 ureters, and a Deflux® injection was completed during the same procedure. SI was managed using trans-anal irrigation, either with a fleet enema or Peristeen® system regularly. Results: After at least 3 years of follow-up, mean maximum bladder capacity increased significantly from 78 ± 36 ml to 200 ± 76 ml (P < 0.0001) and the maximum detrusor pressure decreased from 56 ± 12 cm H2O to 29 ± 7 cm H2O (P < 0.001). Twenty-one refluxing ureters (95%) showed complete resolution and one persisted. Ten patients (72%) achieved complete dryness between catheterizations. Four patients (28%) went for augmentation cystoplasty, due to progressive hydronephrosis and/or persistent urinary incontinence. Thirteen patients achieved complete stool continence. Conclusions: Over long-term follow-up, major reconstruction surgery can be avoidable or delayable; the TEAM® approach is a minimally invasive, safe, simple, and effective way to achieve upper urinary tract protection and provide urinary and stool continence

Neurofibroma of the external genitalia, extreme enlargement of the clitoris

Neurofibromatosis of the genitourinary tract is rare, with a prevalence of 0.65%, and it is exceedingly rare to involve the external genitalia. Involvement of the clitoris, labia majora, and prepuce was reported with clitoromegaly being the most frequently occurring. Herein, we are reporting the case of a 6-year-old girl who was diagnosed with a neurofibroma of the clitoris; measuring 9.4 cm in its largest dimension. To the best of our knowledge, this is the largest clitoral neurofibroma reported in the literature. Due to the rarity of such cases and reports limitations in the literature, the diagnosis of neurofibroma of the external genitalia requires a high index of suspicion by health-care providers. Surgical excision and postoperative follow-up for possible recurrence remain the gold standard of management

Inhibition of ITK Signaling Causes Amelioration in Sepsis-Associated Neuroinflammation and Depression-like State in Mice

Sepsis affects millions of people worldwide and is associated with multiorgan dysfunction that is a major cause of increased morbidity and mortality. Sepsis is associated with several morbidities, such as lung, liver, and central nervous system (CNS) dysfunction. Sepsis-associated CNS dysfunction usually leads to several mental problems including depression. IL-17A is one of the crucial cytokines that is expressed and secreted by Th17 cells. Th17 cells are reported to be involved in the pathogenesis of depression and anxiety in humans and animals. One of the protein tyrosine kinases that plays a key role in controlling the development/differentiation of Th17 cells is ITK. However, the role of ITK in sepsis-associated neuroinflammation and depression-like symptoms in mice has not been investigated earlier. Therefore, this study investigated the efficacy of the ITK inhibitor, BMS 509744, in sepsis-linked neuroinflammation (ITK, IL-17A, NFkB, iNOS, MPO, lipid peroxides, IL-6, MCP-1, IL-17A) and a battery of depression-like behavioral tests, such as sucrose preference, tail suspension, and the marble burying test. Further, the effect of the ITK inhibitor on anti-inflammatory signaling (Foxp3, IL-10, Nrf2, HO-1, SOD-2) was assessed in the CNS. Our data show that sepsis causes increased ITK protein expression, IL-17A signaling, and neuroinflammatory mediators in the CNS that are associated with a depression-like state in mice. ITK inhibitor-treated mice with sepsis show attenuated IL-17A signaling, which is associated with the upregulation of IL-10/Nrf2 signaling and the amelioration of depression-like symptoms in mice. Our data show, for the first time, that the ITK inhibition strategy may counteract sepsis-mediated depression through a reduction in IL-17A signaling in the CNS

Blockade of Tyrosine Kinase, LCK Leads to Reduction in Airway Inflammation through Regulation of Pulmonary Th2/Treg Balance and Oxidative Stress in Cockroach Extract-Induced Mouse Model of Allergic Asthma

Asthma is one of the most common inflammatory diseases affecting the airways. Approximately 300 million individuals suffer from asthma around the world. Allergic immune responses in the asthmatic airways are predominantly driven by Th2 cells and eosinophils. Lymphocyte-specific protein tyrosine kinase (LCK) is a non-receptor tyrosine kinase which regulates several key intracellular events through phosphorylation of its substrates. Some of the intracellular signaling pathways activated by LCK phosphorylation help in differentiation of Th2 cells which secrete allergic cytokines that amplify airway inflammation. Therefore, this investigative study was designed to determine the role of LCK in a cockroach extract (CE)-induced airway inflammation murine model of allergic asthma. Further, the effect of a pharmacological LCK inhibitor, A-770041, on allergic airway inflammation and key intracellular pathways in CD4+ T cells was assessed. Our data exhibit that there is an activation of LCK during allergic airway inflammation as depicted by increased p-LCK levels in CD4+ T cells. Activated LCK is involved in the activation of ITK, PLC-γ, GATA3, NFkB, and NFATc1. Activated LCK is also involved in the upregulation of Th2 related cytokines, such as IL-4/IL-5/IL-13 and oxidative stress, and the downregulation of Treg cells. Furthermore, utilization of LCK inhibitor causes the reduction in p-LCK, PLC-γ, GATA3, and NFATc1 as well as Th2 cytokines and oxidative stress. LCK inhibitor causes upregulation of Treg cells in allergic mice. LCK inhibitor also caused a reduction in CE-induced airway inflammation and mucus secretion. Therefore, the inhibition of LCK signaling could be a fruitful approach to adjust allergic airway inflammation through the attuning of Th2/Treg immune responses. This study could lead to the design of newer treatment options for better management of allergic inflammation in asthma

Pharmacological Inhibition of STAT3 by Stattic Ameliorates Clinical Symptoms and Reduces Autoinflammation in Myeloid, Lymphoid, and Neuronal Tissue Compartments in Relapsing–Remitting Model of Experimental Autoimmune Encephalomyelitis in SJL/J Mice

Multiple sclerosis (MS) is an immune-mediated inflammatory disease that leads to demyelination and neuronal loss in the central nervous system. Immune cells of lymphoid and myeloid origin play a significant role in the initiation and amplification of neuronal inflammation in MS. STAT3 signaling plays a pivotal role in both myeloid and lymphoid immune cells, such as neutrophils and CD4+ T cells, through regulation of their inflammatory potential. Dysregulation in STAT3 signaling in myeloid and lymphoid cell compartments has been reported in MS. In this report, we attempted to investigate the effect of a small molecular inhibitor of STAT3, i.e., Stattic, in a relapsing–remitting (RR) model of experimental autoimmune encephalomyelitis (EAE). The effect of Stattic was investigated for clinical features, oxidative stress parameters, and Th17-related signaling in both the periphery and brain of SJL/J mice. Our data report that p-STAT3 expression is elevated in granulocytes, CD4+ T cells, and brain tissue in myelin proteolipid protein (PLP)-immunized SJL/J mice, which is associated with the presence of clinical symptoms and upregulation of inflammatory markers in these cells/tissues. Treatment with Stattic leads to the amelioration of disease symptoms and attenuation of inflammatory markers in neutrophils (iNOS/nitrotyrosine/IL-1β), CD4+ T cells (IL-17A/IL-23R), and brain tissue (IL-17A/iNOS/IL-1β/MPO activity/lipid peroxides) in mice with EAE. These data suggest that the blockade of STAT3 signaling in cells of lymphoid and myeloid origin may cause the attenuation of systemic and neuronal inflammation, which could be responsible for the amelioration of disease symptoms in an RR model of EAE. Therefore, pharmacological inhibition of STAT3 in RRMS could be a potential therapeutic strategy

Thioredoxin 1 and Thioredoxin Reductase 1 Redox System Is Dysregulated in Neutrophils of Subjects with Autism: In Vitro Effects of Environmental Toxicant, Methylmercury

Autism spectrum disorder (ASD) is a complex developmental disorder in children that results in abnormal communicative and verbal behaviors. Exposure to heavy metals plays a significant role in the pathogenesis or progression of ASD. Mercury compounds pose significant risk for the development of ASD as children are more exposed to environmental toxicants. Increased concentration of mercury compounds has been detected in different body fluids/tissues in ASD children, which suggests an association between mercury exposure and ASD. Thioredoxin1 (Trx1) and thioredoxin reductase1 (TrxR1) redox system plays a crucial role in detoxification of oxidants generated in different immune cells. However, the effect of methylmercury and the Nrf2 activator sulforaphane on the Trx1/TrxR1 antioxidant system in neutrophils of ASD subjects has not been studied previously. Therefore, this study examined the effect of methylmercury on Trx1/TrxR1 expression, TrxR activity, nitrotyrosine, and ROS in neutrophils of ASD and TDC subjects. Our study shows that Trx1/TrxR1 protein expression is dysregulated in ASD subjects as compared to the TDC group. Further, methylmercury treatment significantly inhibits the activity of TrxR in both ASD and TDC groups. Inhibition of TrxR by mercury is associated with upregulation of the Trx1 protein in TDC neutrophils but not in ASD neutrophils. Furthermore, ASD neutrophils have exaggerated ROS production after exposure to methylmercury, which is much greater in magnitude than TDC neutrophils. Sulforaphane reversed methylmercury-induced effects on neutrophils through Nrf2-mediated induction of the Trx1/TrxR1 system. These observations suggest that exposure to the environmental toxicant methylmercury may elevate systemic oxidative inflammation due to a dysregulated Trx1/TrxR1 redox system in the neutrophils of ASD subjects, which may play a role in the progression of ASD

Auranofin Modulates Thioredoxin Reductase/Nrf2 Signaling in Peripheral Immune Cells and the CNS in a Mouse Model of Relapsing–Remitting EAE

Multiple sclerosis (MS) is one of the most prevalent chronic inflammatory autoimmune diseases. It causes the demyelination of neurons and the subsequent degeneration of the central nervous system (CNS). The infiltration of leukocytes of both myeloid and lymphoid origins from the systemic circulation into the CNS triggers autoimmune reactions through the release of multiple mediators. These mediators include oxidants, pro-inflammatory cytokines, and chemokines which ultimately cause the characteristic plaques observed in MS. Thioredoxin reductase (TrxR) and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling plays a crucial role in the regulation of inflammation by modulating the transcription of antioxidants and the suppression of inflammatory cytokines. The gold compound auranofin (AFN) is known to activate Nrf2 through the inhibition of TrxR; however, the effects of this compound have not been explored in a mouse model of relapsing–remitting MS (RRMS). Therefore, this study explored the influence of AFN on clinical features, TrxR/Nrf2 signaling [heme oxygenase 1 (HO-1), superoxide dismutase 1 (SOD-1)] and oxidative/inflammatory mediators [IL-6, IL-17A, inducible nitric oxide synthase (iNOS), myeloperoxidase (MPO), nitrotyrosine] in peripheral immune cells and the CNS of mice with the RR type of EAE. Our results showed an increase in TrxR activity and a decrease in Nrf2 signaling in SJL/J mice with RR-EAE. The treatment with AFN caused the amelioration of the clinical features of RR-EAE through the elevation of Nrf2 signaling and the subsequent upregulation of the levels of antioxidants as well as the downregulation of oxidative/pro-inflammatory mediators in peripheral immune cells and the CNS. These data suggest that AFN may be beneficial in the treatment of RRMS