Cytokines: the yin and yang of vitiligo pathogenesis

Introduction: Dysregulation of melanocyte function is associated with vitiligo, an idiopathic autoimmune hypopigmentary skin disorder, caused by the selective destruction of melanocytes. Cytokines, the key mediators of immune response, which are pivotal in maintaining immune homeostasis, are crucial in vitiligo pathogenesis. Several studies indicate that there is an imbalance between pro- and anti-inflammatory cytokines in the skin and serum of vitiligo patients.

Areas covered: In this comprehensive review, we have summarized the correlation of cytokine imbalance and vitiligo pathogenesis, its role in melanocyte biology, and its impact on vitiligo treatment. We have integrated various published reports on the levels of major cytokines from skin and serum samples of vitiligo patients. We have also discussed the role of endoplasmic reticulum and oxidative stress on cytokine imbalance and vice versa leading to destruction of melanocytes.

Expert commentary: The review reflects that dysregulation of cytokines is multifactorial, ranging from genetic predisposition to altered protein expression relevant to vitiligo pathogenesis. We emphasize that cytokine imbalance in systemic and skin microenvironment plays a crucial role in vitiligo pathogenesis and has promising potential as therapeutic targets for vitiligo.     

Blocking “don't eat me” signal of CD47-SIRPα in hematological malignancies,an in-depth review

Hematological malignancies express high levels of CD47 as a mechanism of immune evasion. CD47-SIRPα triggers a cascade of events that inhibit phagocytosis. Preclinical research supports several models of antibody-mediated blockade of CD47-SIRPα resulting in cell death signaling, phagocytosis of cells bearing stress signals, and priming of tumor-specific T cell responses. Four different antibody molecules designed to target the CD47-SIRPα interaction in malignancy are currently being studied in clinical trials: Hu5F9-G4, CC-90002, TTI-621, and ALX-148. Hu5F9-G4, a humanized anti-CD47 blocking antibody is currently being studied in four different Phase I trials. These studies may lay the groundwork for therapeutic bispecific antibodies. Bispecific antibody (CD20-CD47SL) fusion of anti-CD20 (Rituximab) and anti-CD47 also demonstrated a synergistic effect against lymphoma in preclinical models. This review summarizes the large body of preclinical evidence and emerging clinical data supporting the use of antibodies designed to target the CD47-SIRPα interaction in leukemia, lymphoma and multiple myeloma.     

A Comparison of Classical and Anatomical Total Knee Alignment Methods in Robotic Total Knee Arthroplasty : Classical and Anatomical Knee Alignment Methods in TKA

The purpose of this study was to compare the clinical and radiological outcomes achieved using classical and anatomical alignment methods in primary total knee arthroplasty (TKA). One hundred and seventeen patients were randomly assigned to undergo robotic-assisted TKA using either the classical (56 patients) or the anatomical alignment method (61 patients). Clinical outcomes including varus and valgus laxities, ROM, HSS and WOMAC scores and radiological outcomes were evaluated after a minimum follow-up of 2 years. Varus and valgus laxity assessments showed no significant inter-group differences (P > 0.05). Moreover, no significant differences were observed in ROM, HSS and WOMAC scores (P > 0.05). We could not find any significant difference in mechanical alignment of the lower limb. The results of this study show that two alignment methods provide comparable clinical and radiological outcomes after primary TKA.     

Effects of orthopaedic manual therapy in knee osteoarthritis: a systematic review and meta-analysis

Objective

This systematic review to aimed to evaluate the effects of orthopaedic manual therapy (OMT) on pain, improving function, and physical performance in patients with knee osteoarthritis (OA).

Fatigue and oxidative stress response to physical activity in type 2 diabetic patients

Physical activity (PA) and exercise is known to have a positive impact on a variety of variables pertinent to diabetes and cardiovascular disease. The aims of this study were to investigate the effects of physical activity on fatigue scores, oxidative stress, and glycemic control variables of individuals with type 2 diabetes mellitus (T2DM). Seventy-five subjects diagnosed with T2DM for more than 5 years aged 18–65 years participated in this study. The participants classified according to energy expenditure into, physically inactive [≤500 metabolic equivalents (METs)-min/week, n?=?25], moderate PA (500–2500 METs-min/week, n?=?25), and PA (≥2500 METs-min/week, n?=?25). The Global Physical Activity Questionnaire (GPAQ) version 2.0 was used to classify physical activity. The multidimensional checklist individual strength questionnaire (CIS20r) was used to measure chronic fatigue. Blood glucose was measured using a glucose oxidase and peroxidase (GOD-POD) colorimetric method. HbA1c was measured using a commercial kit. Serum insulin level was determined using an ELISA. Analysis of oxidative stress parameters including malonaldehyde (MDA) and total antioxidant capacity (TAC) was done. To test differences between severely fatigued and healthy subjects, an independent t test was performed. Spearman correlations were used to assess correlations between fatigue severity score and disease-related and psychosocial factors. A level of significance was set at p?<?0.05. The results showed a significant reduction of fasting blood sugar, glycosylated hemoglobin, fasting insulin, and MDA along with significant increase in TAC activity in the participants with moderate PA (P?<?0.05) and PA (P?<?0.01), respectively. In relation to CIS-fatigue measurements, about 33 % of the study population (n?=?25) had a CIS score above the cutoff score of 37 with 59.5 mean CIS score, and 67 % of the study population (n?=?50) had CIS score below the cutoff 37; they were classified into heightened fatigue (score 27–35) and healthy (score ≤27). There was a significant correlation between the reduction of diabetic related variables, BMI, PA status, and CIS-fatigue score analyses in T2DM patients. CIS-fatigue scores correlated positively with diabetic related variables and negatively with PA, BMI, and TAC activity. PA plays a vital role in improving CIS-fatigue score in type 2 diabetic patients via reducing oxidative stress and diabetic related variables.     

Histopathology of surgically treated renal tumours in young adults: a developing country perspective

Background  

There is no data on the histopathological characteristics of renal tumours in young adults in Pakistan.     

Phosphoinositide 3-kinase, but not mitogen-activated protein kinase, pathway is involved in hepatocyte growth factor-mediated protection against bile acid-induced apoptosis in cultured rat hepatocytes

We have previously shown that cAMP protects against hydrophobic bile acid-induced apoptosis in cultured rat hepatocytes through pathways dependent on activation of phosphoinositide 3-kinase and inhibition of mitogen activated protein kinase. Hepatocyte growth factor protects epithelial cells against apoptosis and activates both of these kinases in hepatocytes. We studied the effect of hepatocyte growth factor on glycochenodeoxycholate-induced apoptosis to determine whether hepatocyte growth factor protects hepatocytes against bile acid-induced apoptosis and whether the protective effect is mediated via phosphoinositide 3-kinase and/or mitogen-activated protein kinase pathways. Two-hour exposure of cultured rat hepatocytes to glycochenodeoxycholate resulted in apoptosis in 12.5 +/- 0.49% of the cells. Pretreatment with hepatocyte growth factor (50 ng/mL) decreased apoptosis by 50% to 70%. Hepatocyte growth factor cytoprotection was prevented by pretreatment with the phosphoinositide 3-kinase inhibitors, wortmannin (50 nmol/L) or Ly 294002 (40 micromol/L). Hepatocyte growth factor activated phosphoinositide 3-kinase dependent protein kinase B and mitogen-activated protein kinase. Pretreatment of hepatocytes with a mitogen-activated protein kinase inhibitor, U0126 (40 micromol/L) or an inhibitor of pp70(s6) kinase, rapamycin (100 nmol/L), had no effect on the growth factor's anti-apopotic effect. Treatment with hepatocyte growth factor resulted in mitogen-activated protein kinase-dependent phosphorylation of BAD on serine(112). In summary, hepatocyte growth factor protection against bile acid-induced apoptosis occurs via a phosphoinositide 3-kinase pathway and is not dependent on the mitogen-activated protein kinase pathway, phosphorylation of BAD on serine(112), or activation of p70(S6) kinase.