Modulating monocyte-derived macrophage polarization in cerebral ischemic injury with hyperglycemia.

Ischemic stroke (IS), characterized by high mortality rate, occurs owing to diminished or blocked blood flow to the brain. Hyperglycemia (HG) is a major contributor to the risk of IS. HG induces augmented oxidative stress and Blood-Brain Barrier breakdown, which increases the influx of blood-derived myeloid cells into the brain parenchyma. In cerebral ischemia, infiltrating monocytes undergo differentiation into pro-inflammatory or anti-inflammatory macrophages, having a large effect on outcomes of ischemic stroke. In addition, interleukin-4 (IL-4) and interleukin-13 (IL-13) engage in post-ischemia repair by polarizing the infiltrating monocytes into an anti-inflammatory phenotype. In this study, we aimed to determine the effect of phenotypic polarization of monocyte-derived macrophages on the prognosis of IS with HG (HG-IS). We first established a hyperglycemic mouse model using streptozotocin (150 mg/kg) and induced transient middle cerebral artery occlusion. We observed that blood-brain barrier permeability increased in HG-IS mice, as per two-photon live imaging and Evans blue staining. We also confirmed the increased infiltration of monocyte-derived macrophages and the downregulation of anti-inflammatory macrophages related to tissue remodeling after inflammation in HG-IS mice through immunohistochemistry, western blotting, and flow cytometry. We observed phenotypic changes in monocyte-derived macrophages, alleviated infarct volume, and improved motor function in HG-IS mice treated with IL-4 and IL-13. These findings suggest that the modulation of phenotypic changes in monocyte-derived macrophages following IS in hyperglycemic mice may influence ischemic recovery.

Oral Cavity Cancers: Ethnic Differences in Radiotherapy Outcomes in a Majority South Asian Leicester Community.

AIMS: Squamous cell carcinoma oral cavity cancers (SCCOCCs) have a higher reported incidence in South Asian countries. We sought to compare presenting stage and outcome by ethnicity in patients with SCCOCC treated with radical radiotherapy in a single centre in the UK. MATERIALS AND METHODS: All patients with SCCOCC treated with radical radiotherapy at an oncology department in Leicester (UK) between 2011 and 2017 were identified. Baseline demographic, clinical data and 2-year treatment outcomes were reported. RESULTS: Of the 109 patients included, 40 were South Asian and 59 were non-South Asian. South Asians had significantly poorer 2-year disease-free survival compared with non-South Asians (54.6% versus 73%, P = 0.01). CONCLUSION: Our analysis suggests that South Asians with SCCOCC have poorer outcomes despite a younger age and similar disease characteristics. Environmental, social factors and differing biology of disease may be responsible and further research is required to inform targeted interventions.

SGLT2 and DPP4 inhibitors improve Alzheimer's disease-like pathology and cognitive function through distinct mechanisms in a T2D-AD mouse model.

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2D) share common features, including insulin resistance. Brain insulin resistance has been implicated as a key factor in the pathogenesis of AD. Recent studies have demonstrated that anti-diabetic drugs sodium-glucose cotransporter-2 inhibitor (SGLT2-i) and dipeptidyl peptidase-4 inhibitor (DPP4-i) improve insulin sensitivity and provide neuroprotection. However, the effects of these two inhibitors on the brain metabolism and insulin resistance remain uninvestigated. We developed a T2D-AD mouse model using a high-fat diet (HFD) for 19 weeks along with a single dose of streptozotocin (100 mg/kg, intraperitoneally) at the fourth week of HFD initiation. Subsequently, the animals were treated with SGLT2-i (empagliflozin, 25 mg/kg/day orally [p.o.]) and DPP4-i (sitagliptin, 100 mg/kg/day p.o.) for 7 weeks. Subsequently, behavioral tests were performed, and the expression of insulin signaling, AD-related, and other signaling pathway proteins in the brain were examined. T2D-AD mice not only showed increased blood glucose levels and body weight but also insulin resistance. SGLT2-i and DPP4-i effectively ameliorated insulin sensitivity and reduced body weight in these mice. Furthermore, SGLT2-i and DPP4-i significantly improved hippocampal-dependent learning, memory, and cognitive functions in the T2D-AD mouse model. Interestingly, SGLT2-i and DPP4-i reduced the hyperphosphorylated tau (pTau) levels and amyloid ß (Aß) accumulation and enhanced brain insulin signaling. SGLT2-i reduced pTau accumulation through the angiotensin converting enzyme-2/angiotensin (1-7)/ mitochondrial assembly receptor axis, whereas DPP4-i reduced Aß accumulation by increasing insulin-degrading enzyme levels. These findings suggest that SGLT2-i and DPP4-i prevent AD-like pathology and cognitive dysfunction in T2D mice potentially through affecting brain insulin signaling via different mechanisms.

Agmatine-IRF2BP2 interaction induces M2 phenotype of microglia by increasing IRF2-KLF4 signaling.

BACKGROUND: Following central nervous system (CNS) injury, the investigation for neuroinflammation is vital because of its pleiotropic role in both acute injury and long-term recovery. Agmatine (Agm) is well known for its neuroprotective effects and anti-neuroinflammatory properties. However, Agm's mechanism for neuroprotection is still unclear. We screened target proteins that bind to Agm using a protein microarray; the results showed that Agm strongly binds to interferon regulatory factor 2 binding protein (IRF2BP2), which partakes in the inflammatory response. Based on these prior data, we attempted to elucidate the mechanism by which the combination of Agm and IRF2BP2 induces a neuroprotective phenotype of microglia. METHODS: To confirm the relationship between Agm and IRF2BP2 in neuroinflammation, we used microglia cell-line (BV2) and treated with lipopolysaccharide from Escherichia coli 0111:B4 (LPS; 20 ng/mL, 24 h) and interleukin (IL)-4 (20 ng/mL, 24 h). Although Agm bound to IRF2BP2, it failed to enhance IRF2BP2 expression in BV2. Therefore, we shifted our focus onto interferon regulatory factor 2 (IRF2), which is a transcription factor and interacts with IRF2BP2. RESULTS: IRF2 was highly expressed in BV2 after LPS treatment but not after IL-4 treatment. When Agm bound to IRF2BP2 following Agm treatment, the free IRF2 translocated to the nucleus of BV2. The translocated IRF2 activated the transcription of Kruppel-like factor 4 (KLF4), causing KLF4 to be induced in BV2. The expression of KLF4 increased the CD206-positive cells in BV2. CONCLUSIONS: Taken together, unbound IRF2, resulting from the competitive binding of Agm to IRF2BP2, may provide neuroprotection against neuroinflammation via an anti-inflammatory mechanism of microglia involving the expression of KLF4.

The Effect of Pre-operative use of Antiplatelets and Anticoagulants on Time to Surgery in Hip Fracture Patients.

Introduction: Hip fractures are a major health concern resulting in significant morbidity worldwide. They are the leading cause of fall-related injuries amongst the elderly with high risk of death, and numbers are expected to rise with the growing elderly population. Expedited surgical repair has been proven to improve patient outcomes, however there are often multiple barriers to early surgery especially in the elderly. The use of antiplatelets and anticoagulation is a significant contributory factor to surgical delay. Materials and methods: We conducted a retrospective, single centre study on hip fracture patients admitted to an acute care orthogeriatric unit over a 12-month period, aimed at determining the impact of pre-operative use of antiplatelets and anticoagulants on time to surgery (TTS) and its impact on one-year mortality rates. Results: Amongst 404 eligible patients, 102 were on antiplatelets, 23 on anticoagulants and 279 were neither on antiplatelets or anticoagulants. Our study showed that patients taking clopidogrel (p<0.001) and DOACs (p=0.001) were more likely to have delayed surgery compared to those who were not on these agents. In addition, all patients on warfarin experienced surgical delay. Warfarin group also had highest mortality rates compared to other group and 10 times more likely to die within a year (p=0.001). Conclusion: The results from this study are consistent with existing literature, suggesting that the use of clopidogrel and anticoagulants have a negative impact on TTS in hip fracture patients. Strategies should be developed for patients on these medications to enhance their TTS.

Coping with Coronavirus disease 2019: current state review and SWOT analysis to improve the urological services in Southeast Asia.

INTRODUCTION: We investigated the impact of Coronavirus Disease 2019 (COVID-19) pandemic on urological services by analyzing current attitudes and practices of urologists in the Southeast Asian (SEA) countries and create ways for improvement. MATERIALS AND METHODS: Quantitative data were used as critical indicators of workload of urological services from each country in SEA. Qualitative data analysis was done to describe the current state of attitudes of urologists against COVID-19 in the region. A strengths, weaknesses, opportunities, and threats (SWOT) analysis was performed to formulate strategic action plans. RESULTS: A total of seven urologists from six SEA countries completed the survey. Approximately 21-40% reduction in elective surgeries and outpatient visits, as stated by 42.9% and 57.1% of respondents, respectively was noted. Collectively, most respondents (71.4%) experienced <20% reduction in emergency visits. Various strategies were utilized as reaction to the pandemic. These include utilization of virtual communication platforms, pre-surgical COVID-19 screening, and limited number of accepted outpatient appointments and surgeries. Face to face patient consultations were still considered needed by many urologists although most countries had prohibited direct patient contact. The national response of countries such as Malaysia, Singapore, Thailand, and Vietnam were successful in controlling the pandemic. However, Indonesia and Philippines struggled because of the limited testing and tracing capabilities. Through the SWOT analysis, strategies were identified which can help overcome COVID-19 and any other future pandemics: (1) restarting the urological services in a safe and sustainable manner; (2) optimizing financial and infrastructural capacities; and (3) regional collaboration to strengthen the health systems. CONCLUSION: COVID-19 negatively impacted many health aspects, especially the delivery of urological services in SEA. Therefore, to ensure sustainability of urological services during the pandemic crisis, health care system should focus on safe, resilient, and adaptive approach with regional collaboration.

Role of DPP-4 and SGLT2 Inhibitors Connected to Alzheimer Disease in Type 2 Diabetes Mellitus.

Alzheimer's disease (AD) is characterized by memory loss and cognitive decline. Additionally, abnormal extracellular amyloid plaques accumulation and nerve damage caused by intracellular neurofibrillary tangles, and tau protein are characteristic of AD. Furthermore, AD is associated with oxidative stress, impaired mitochondrial structure and function, denormalization, and inflammatory responses. Recently, besides the amyloid ß hypothesis, another hypothesis linking AD to systemic diseases has been put forth by multiple studies as a probable cause for AD. Particularly, type 2 diabetes mellitus (T2DM) and its features, including hyperinsulinemia, and chronic hyperglycemia with an inflammatory response, have been shown to be closely related to AD through insulin resistance. The brain cannot synthesize or store glucose, but it does require glucose, and the use of glucose in the brain is higher than that in any other organ in the mammalian body. One of the therapeutic drugs for T2DM, dipeptidyl peptidase-4 (DPP-4) inhibitor, suppresses the degradation of incretins, glucagon-like peptides and glucose-dependent insulinotropic peptide. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, recently used in T2DM treatment, have a unique mechanism of action via inhibition of renal glucose reabsorption, and which is different from the mechanisms of previously used medications. This manuscript reviews the pathophysiological relationship between the two diseases, AD and T2DM, and the pharmacological effects of therapeutic T2DM drugs, especially DPP-4 inhibitors, and SGLT2 inhibitors.

A multi-site study on the impact of an advance care planning workshop on attitudes, beliefs and behavioural intentions over a 6-month period.

BACKGROUND: This study evaluated the impact of the adapted version of the Respecting Choices® The Living Matters Advance Care Planning (ACP) facilitator training programme on trainees' attitudes on facilitation 6 months post-training. SETTING AND PARTICIPANTS: Two hundred and twenty-one healthcare professionals consisting of doctors, nurses, medical social workers from different training venues in Singapore participated in the first phase of the study (pre- and post) of which 107 participated in the second phase 6 months later (follow-up). METHODS: Participants self-rated their attitudes, beliefs and behavioural intentions through surveys at three time points in an evaluation design that utilised repeated measures one-way ANOVA (pre-, post-, follow-up). Between-group differences were also examined using independent t-test. RESULTS: At follow-up, mean scores increased significantly in understanding, confidence, and competence. Changes in effect sizes were large. Although trainees continued to think that ACP is emotionally draining for facilitators, more than before, facilitation experience was considered pleasant for themselves with the positive change significant and moderate in effect size. Those who had experience completing/initiating ACP significantly held more positive views than those who did not. CONCLUSIONS: The ACP facilitator training programme had lasting effects on enhancing the understanding, competence, and confidence of trainees. Importantly, findings showed that experience in actual facilitation within 6 months after training was important and giving trainees opportunities to facilitate is recommended.

Maintenance of the Neuroprotective Function of the Amino Group Blocked Fluorescence-Agmatine.

Agmatine, an endogenous derivative of arginine, has been found to be effective in treating idiopathic pain, convulsion, stress-mediated behavior, and attenuate the withdrawal symptoms of drugs like morphine. In the early stages of ischemic brain injury in animals, exogenous agmatine treatment was found to be neuroprotective. Agmatine is also considered as a putative neurotransmitter and is still an experimental drug. Chemically, agmatine is called agmatine 1-(4-aminobutyl guanidine). Crystallographic study data show that positively-charged guanidine can bind to the protein containing Gly and Asp residues, and the amino group can interact with the complimentary sites of Glu and Ser. In this study, we blocked the amino end of the agmatine by conjugating it with FITC, but the guanidine end was unchanged. We compared the neuroprotective function of the agmatine and agmatine-FITC by treating them in neurons after excitotoxic stimulation. We found that even the amino end blocked neuronal viability in the excitotoxic condition, by NMDA treatment for 1 h, was increased by agmatine-FITC, which was similar to that of agmatine. We also found that the agmatine-FITC treatment reduced the expression of nitric oxide production in NMDA-treated cells. This study suggests that even if the amino end of agmatine is blocked, it can perform its neuroprotective function.

Reparative System Arising from CCR2(+) Monocyte Conversion Attenuates Neuroinflammation Following Ischemic Stroke.

Monocytes recruitment from the blood to inflamed tissues following ischemic stroke is an important immune response to wound healing and tissue repair. Mouse monocytes can be endogenously divided into two distinct populations: pro-inflammatory or classical monocytes that express CCR2highCX3CR1low and circulate in blood, and anti-inflammatory or non-classical monocytes that express CCR2lowCX3CR1high and patrol locally. In this study of transgenic mice with functional CX3CR1GFP/+ or CX3CR1GFP/+-CCR2RFP/+, we found that CCR2highCX3CR1low monocytes recruited to the injured brain were cytokine-dependently converted into CCR2lowCX3CR1high macrophages, especially under the influence of IL-4 and IL-13, thereby attenuating the neuroinflammation following sterile ischemic stroke. The overall data suggest that (1) the regulation of monocyte-switching is one of the ultimate reparative strategies in ischemic stroke, and (2) the adaptation of monocytes in a locally inflamed milieu is vital to alleviating the effects of ischemic stroke through innate immunity.

Avoiding hunger or attaining fullness? Implicit goals of satiety guide portion selection and food intake patterns.

Although implicit theories have been studied in the context of personal traits, there has been limited investigation of their role in physiological domains such as appetite. Subjective feelings and affective states can function as goals and desired end states that individuals regulate their behaviors to attain. Likewise, different conceptualizations people maintain for the subjective experience of satiety (i.e., terminating hunger or attaining fullness) may also predict individual variations in eating behavior. We examined whether portion selection and food intake were guided by such implicit goals pertaining to the nature of satiety. Across 3 studies, we observed that individuals report distinct subjective requirements (degrees of fullness) to attain different states of satiety (stop hunger, feel comfortably full, feel completely full), suggesting that these states reflect independent goals or outcomes. Importantly, personal requirements to feel completely full (compared to stop hunger or feel comfortably full) were observed to be the strongest predictor of portion sizes selected in Study 1 (B = 1.17, p < .001) and Study 2 (B = 4.26, p = .004), and the quantity of energy consumed from a meal in Study 2 (B = 3.07, p = .01). Yet, experimentally activating a situational goal to stop hunger (vs. feel full) produced the selection of smaller portion sizes, F(1, 41) = 5.64, p = .02, and personal requirements to stop hunger to become the dominant predictor of portion selection patterns in Study 3 (B = 0.43, p = .005). These findings reveal that eating behaviors of modern consumers may be guided by a predominant goal to attain the subjective experience of complete fullness, although this implicit goal may be malleable to situational demands.

An evaluation of a common elements treatment approach for youth in Somali refugee camps.

BACKGROUND: This paper reports on: (1) an evaluation of a common elements treatment approach (CETA) developed for comorbid presentations of depression, anxiety, traumatic stress, and/or externalizing symptoms among children in three Somali refugee camps on the Ethiopian/Somali border, and (2) an evaluation of implementation factors from the perspective of staff, lay providers, and families who engaged in the intervention. METHODS: This project was conducted in three refugee camps and utilized locally validated mental health instruments for internalizing, externalizing, and posttraumatic stress (PTS) symptoms. Participants were recruited from either a validity study or from referrals from social workers within International Rescue Committee Programs. Lay providers delivered CETA to youth (CETA-Youth) and families, and symptoms were re-assessed post-treatment. Providers and families responded to a semi-structured interview to assess implementation factors. RESULTS: Children who participated in the CETA-Youth open trial reported significant decreases in symptoms of internalizing (d  =  1.37), externalizing (d  =  0.85), and posttraumatic stress (d  =  1.71), and improvements in well-being (d  =  0.75). Caregivers also reported significant decreases in child symptoms. Qualitative results were positive toward the acceptability and appropriateness of treatment, and its feasibility. CONCLUSIONS: This project is the first to examine a common elements approach (CETA: defined as flexible delivery of elements, order, and dosing) with children and caregivers in a low-resource setting with delivery by lay providers. CETA-Youth may offer an effective treatment that is easier to implement and scale-up versus multiple focal interventions. A fullscale randomized clinical trial is warranted.

The role of perceived stress and gender on portion selection patterns.

Stress is linked to increased preferences and consumption of palatable energy dense foods, particularly among females. Despite the role of stress on potentially obesogenic eating habits, its effect on pre-meal planning, such as the selection of portion sizes, remain unknown. Here, we investigated the relationship between perceived stress, gender, and intended portion sizes for diverse foods. Across two studies, increased perceived stress predicted larger (higher energy) intended portion sizes across a variety of food items among females, but not males. Additionally, for females, increased perceived stress was associated with lowered expectations of the satiety of foods presented, suggesting a potential mechanism by which stress may influence decisions about portion size. These findings reveal that the potentially obesogenic effects of stress on food judgments and behaviours (particularly among females) are not only expressed within meals, but also during more deliberate stages of planning that precedes meals.

Low subjective socioeconomic status stimulates orexigenic hormone ghrelin - A randomised trial.

Recent evidence suggests that lower perceived socioeconomic status is linked to increased appetite and intake of greater calories. Yet, whether insecurity of socioeconomic resources directly influences regulatory systems of appetite and energy intake is not known. Considering psychological states, mindsets and beliefs have shown to meaningfully affect physiological responses to food, the present study tested the hypothesis that low subjective socioeconomic status (SSS) will have a direct influence on physiological responses, such as appetite-related hormones (ghrelin, pancreatic polypeptide and insulin). Forty-eight healthy males were randomly (crossover, counterbalanced) assigned, to two experimental conditions where participants were either experimentally induced to feel low SSS or not (control; CON). Feelings of low SSS resulted in an increase in active ghrelin (an orexigenic hormone) following the SSS manipulation compared with baseline, while no change in active ghrelin was observed in CON. Furthermore, participants reported lower fullness and satiety following low SSS compared with CON. Our findings demonstrate that SSS may influence hunger regulation and appetite, and suggest that physiological systems regulating energy balance (i.e. caloric resources) may also be sensitive to perceived deprivation or imbalances in critical non-food resources (socioeconomic resources).

Personal relative deprivation increases self-selected portion sizes and food intake.

Cues and experiences of the deprivation of financial/material resources have been associated with increased caloric intake and risk for overweight/obesity. Given that social comparisons may serve as a powerful reference for the adequacy of one's standing and resources, the present research tested whether subjective feelings of personal relative deprivation (PRD) or "losing out" to others stimulates calorie selection and intake. Study 1 demonstrated that self-reported chronic experiences of PRD positively predicted calories selected for a portion and consumed during an ad-libitum meal. Study 2 revealed that experimentally-induced PRD resulted in an increase in the amount of calories selected on a portion selection task and a stronger desire to consume the foods. Consequently, these findings demonstrate that chronic and acute subjective deprivation of non-food resources may contribute to socioeconomic gradients in obesity, and that perceived social inequality may have inherently obesogenic properties that promote excess calorie intake.

Complications of robotic-assisted laparoscopic surgery distant from the surgical site.

With the ever-increasing popularity of robotic-assisted laparoscopic surgery over the past decades, the literature reporting complications distant from the surgical site involving the use of this technology has also grown. The goal of this non-systematic review is to summarise these reports with a systems-based presentation of these complications. The most commonly observed complications were related to the peripheral nervous system and the most devastating occurring in cardiac and ophthalmic systems. There were no reports of patient complications directly related to the robot itself. While several of the reported complications are not unique to robotic surgery, they are included to maintain awareness of their possibility. The limitation of surgical time, judicious fluid administration, and constant vigilance of patient positioning are all recommended as possible preventative measures.

Laparoscopic radical nephrectomy with inferior vena cava thrombectomy: highlight of key surgical steps.

OBJECTIVE: Vascular involvement in the form of renal vein (RV) or inferior vena cava (IVC) thrombus can be seen in 4-10% of patients presented with RCC. In patients without presence of metastasis, surgical treatment in the form of radical nephrectomy remains the treatment of choice with 5-year survival rates of 45-70%. Open surgery is still the first treatment option of choice at the moment for RCC patients with IVC thrombus. MATERIALS AND METHODS: In our study, we are reporting a case of patient with RCC and level I IVC thrombus treated with laparoscopy. Our patient is a 72 years old man with underlying co-morbidity of hypertension and chronic kidney disease (CKD) presented with right-sided RCC. The CT scan done showed a large right renal upper pole tumor measuring 8.4x5.2cm with level I IVC thrombus (Figure-1). There were no regional lymphadenopathy and the staging scans were negative. RESULTS: The operative time was 124 minutes and blood loss was minimal. The patient was progressed to diet on POD 1 with bowel movement on POD 2. There was no significant change in the pre and post-operative glomerular filtration rate (GFR). The surgical drain was removed on POD2. The patient was discharged well on POD 5. There were no perioperative complications. The pathology was pT3bN0M0 Fuhrman grade II clear cell RCC. CONCLUSIONS: As a conclusion, laparoscopic radical nephrectomy and IVC thrombectomy is a complex and technically demanding surgery. With advancement of surgical skills as well as technology, more cases of minimally invasive laparoscopic radical nephrectomy and IVC thrombectomy can performed to improve the perioperative outcomes of carefully selected patients in a high volume center.

Rotenone Susceptibility Phenotype in Olfactory Derived Patient Cells as a Model of Idiopathic Parkinson's Disease.

Parkinson's disease is a complex age-related neurodegenerative disorder. Approximately 90% of Parkinson's disease cases are idiopathic, of unknown origin. The aetiology of Parkinson's disease is not fully understood but increasing evidence implies a failure in fundamental cellular processes including mitochondrial dysfunction and increased oxidative stress. To dissect the cellular events underlying idiopathic Parkinson's disease, we use primary cell lines established from the olfactory mucosa of Parkinson's disease patients. Previous metabolic and transcriptomic analyses identified deficiencies in stress response pathways in patient-derived cell lines. The aim of this study was to investigate whether these deficiencies manifested as increased susceptibility, as measured by cell viability, to a range of extrinsic stressors. We identified that patient-derived cells are more sensitive to mitochondrial complex I inhibition and hydrogen peroxide induced oxidative stress, than controls. Exposure to low levels (50 nM) of rotenone led to increased apoptosis in patient-derived cells. We identified an endogenous deficit in mitochondrial complex I in patient-derived cells, but this did not directly correlate with rotenone-sensitivity. We further characterized the sensitivity to rotenone and identified that it was partly associated with heat shock protein 27 levels. Finally, transcriptomic analysis following rotenone exposure revealed that patient-derived cells express a diminished response to rotenone-induced stress compared with cells from healthy controls. Our cellular model of idiopathic Parkinson's disease displays a clear susceptibility phenotype to mitochondrial stress. The determination of molecular mechanisms underpinning this susceptibility may lead to the identification of biomarkers for either disease onset or progression.