A new 2-pyrone derivative, 5-bromo-3-(3-hydroxyprop-1-ynyl)-2H-pyran-2-one, synergistically enhances radiation sensitivity in human cervical cancer cells

Radiation resistance can be overcome by a combination treatment with chemical modifiers. Here, we showed that treatment with 5-bromo-3-(3-hydroxyprop-1-ynyl)-2H-pyran-2-one (BHP), a new 2-pyrone derivative, in combination with ionizing radiation enhances the sensitivity of human cervical cancer cells to ionizing radiation through overproduction of reactive oxygen species (ROS). The combined treatment with BHP and ionizing radiation caused a decrease in clonogenic survival and an increase in apoptotic cell death in cervical cancer cells. The combined treatment promoted conformational activation of Bax and led to mitochondrial apoptotic cell death. The combination treatment also induced a marked increase in intracellular ROS level. Inhibition of ROS attenuated the radiosensitizing effect of BHP, concurrent with a decrease in Bax activation, a decrease in mitochondrial cell death, and an increase in clonogenic survival. These results indicate that BHP synergistically enhances sensitivity of human cervical cancer cells to ionizing radiation through elevation of intracellular ROS and that ROS-dependent Bax activation is critically involved in the increase in apoptotic cell death induced by the combined treatment with BHP and ionizing radiation.     

Abnormal liver function tests associated with severe rhabdomyolysis

Rhabdomyolysis is a syndrome of skeletal muscle injury with release of cellular constituents such as potassium,phosphate,urate and intracellular proteins such as myoglobin into the circulation,which may cause complications including acute kidney injury,electrolyte disturbance and cardiac instability.Abnormal liver function tests are frequently observed in cases of severe rhabdomyolysis.Typically,there is an increase in serum aminotransferases,namely aspartate aminotransferase and alanine aminotransferase.This raises the question of liver injury and often triggers a pathway of investigation which may lead to a liver biopsy.However,muscle can also be a source of the increased aminotransferase activity.This review discusses the dilemma of finding abnormal liver function tests in the setting of muscle injury and the potential implications of such an association.It delves into some of the clinical and experimental evidence for correlating muscle injury to raised aminotransferases,and discusses pathophysiological mechanisms such as oxidative stress which may cause actual liver injury.Serum aminotransferases lack tissue specificity to allow clinicians to distinguish primary liver injury from muscle injury.This review also explores potential approaches to improve the accuracy of our diagnostic tools,so that excessive or unnecessary liver investigations can be avoided.     

Deletion of calcineurin from GFAP-expressing astrocytes impairs excitability of cerebellar and hippocampal neurons through astroglial Na+/K+ ATPase

Astrocytes perform important housekeeping functions in the nervous system including maintenance of adequate neuronal excitability, although the regulatory mechanisms are currently poorly understood. The astrocytic Ca²⁺/calmodulin-activated phosphatase calcineurin (CaN) is implicated in the development of reactive gliosis and neuroinflammation, but its roles, including the control of neuronal excitability, in healthy brain is unknown. We have generated a mouse line with conditional knockout (KO) of CaN B1 (CaNB1) in glial fibrillary acidic protein-expressing astrocytes (a stroglial c alcin eurin KO [ACN-KO]). Here, we report that postnatal and astrocyte-specific ablation of CaNB1 did not alter normal growth and development as well as adult neurogenesis. Yet, we found that specific deletion of astrocytic CaN selectively impairs intrinsic neuronal excitability in hippocampal CA1 pyramidal neurons and cerebellar granule cells (CGCs). This impairment was associated with a decrease in after hyperpolarization in CGC, while passive properties were unchanged, suggesting impairment of K⁺ homeostasis. Indeed, blockade of Na⁺/K⁺-ATPase (NKA) with ouabain phenocopied the electrophysiological alterations observed in ACN-KO CGCs. In addition, NKA activity was significantly lower in cerebellar and hippocampal lysates and in pure astrocytic cultures from ACN-KO mice. While no changes were found in protein levels, NKA activity was inhibited by the specific CaN inhibitor FK506 in both cerebellar lysates and primary astroglia from control mice, suggesting that CaN directly modulates NKA activity and in this manner controls neuronal excitability. In summary, our data provide formal evidence for the notion that astroglia is fundamental for controlling basic neuronal functions and place CaN center-stage as an astrocytic Ca²⁺-sensitive switch.     

Heal or no heel: Outcomes of ischaemic heel ulcers following lower limb revascularization from a multi‐ethnic Asian Cohort in Singapore

Ischaemic diabetic heel ulcers are difficult to treat and prognosis is often guarded. The aim was to document our outcome of treating heel ulcers following revascularization in a predominantly diabetic Asian cohort presenting with chronic limb threatening ischaemia from Singapore. Retrospective cohort study (n = 66, 66 limbs) over a 5‐year period. Data were collected from hospital electronic health records. Outcomes included time to healing, amputation free survival (AFS), and mortality. Minimum follow‐up period was 6 months. Multivariate regression analysis was performed to look for factors associated with poor outcome. Mean age was 67.4 ± 8.8 years. 62/66 (93.9%) were diabetics. Mean wound size at presentation was 3.6 ± 2.3 cm. Mean Wound, Ischaemia, Foot Infection (WIFI) score was 5 ± 1.6. 12/66 (18%) patients had a patent posterior tibial artery pre‐operatively. Straight line flow was restored in only 31/66 (46.9) patients but 47/66 (71.2%) had successful limb salvage. Median time to wound healing was 90.0 (IQR 60‐180) days. A median of 1 (IQR 0‐2) wound debridement was required. Patients who underwent negative pressure dressing (23/66; 34.8%) required a median of 26 (IQR 13‐33) cycles to achieve healing. Amputation free survival (AFS) was 72% and 68% at 6‐ and 12‐months, respectively. Mortality rate was 16.7% and 19.7% at 6‐ and 12‐months, respectively. Low albumin level and initial Rutherford class were independent predictors of worse 6‐month AFS. Outcomes of heel ulcers post revascularisation may not be as poor as previously described. Persistent attention to wound care with multidisciplinary effort is needed for optimal healing.     

Analyzing psychological conditions of field-workers in the construction industry

The Korean construction industry has experienced poor labor productivity and high accident rates. Previous studies have reported that workers’ mental health can cause negative impacts on work performance; thus, enhancing workers’ psychological conditions would help achieve more productive and safer workplaces. This research aimed to understand the level of psychological conditions of construction field-workers using four categories: (1) stress (occupational stress and stress-coping style), (2) personal temperament, (3) emotional disturbance (depression and trait anxiety), and (4) drinking habits. This research used validated questionnaires commonly used in the field of clinical psychology, surveyed 430 respondents from road, bridge, tunnel, subway, and apartment construction sites in Korea, and analyzed the overall psychological tendency of construction workers with the collaboration of professional clinical psychologists using the Z-test, analysis of variance (ANOVA), and cross-tabulation. The research also investigated how the mental conditions differed according to different working conditions, such as demographic information, employment status, work types, work experience, and wage conditions. The results indicated that construction workers suffer from a high level of stress and showed high inclination for problem-focused coping: impulsive, cautious, and dependent on other people. Two out of five construction workers suffer from depression and experience trait anxiety. More seriously, three out of five workers show alcohol-use problems that require clinical attention. This study also revealed the particular psychological problems that occur under different working conditions. The findings can be used to promote the awareness of the importance of construction workers’ mental well-being and to help in setting targets for improvement.