Role of renin angiotensin system inhibitors and metformin in Glioblastoma Therapy: a review.

Glioblastoma multiforme (GBM) is a highly aggressive and incurable disease accounting for about 10,000 deaths in the USA each year. Despite the current treatment approach which includes surgery with chemotherapy and radiation therapy, there remains a high prevalence of recurrence. Notable improvements have been observed in persons receiving concurrent antihypertensive drugs such as renin angiotensin inhibitors (RAS) or the antidiabetic drug metformin with standard therapy. Anti-tumoral effects of RAS inhibitors and metformin have been observed in in vitro and in vivo studies. Although clinical trials have shown mixed results, the potential for the use of RAS inhibitors and metformin as adjuvant GBM therapy remains promising. Nevertheless, evidence suggest that these drugs exert multimodal antitumor actions; by particularly targeting several cancer hallmarks. In this review, we highlight the results of clinical studies using multidrug cocktails containing RAS inhibitors and or metformin added to standard therapy for GBM. In addition, we highlight the possible molecular mechanisms by which these repurposed drugs with an excellent safety profile might elicit their anti-tumoral effects. RAS inhibition elicits anti-inflammatory, anti-angiogenic, and immune sensitivity effects in GBM. However, metformin promotes anti-migratory, anti-proliferative and pro-apoptotic effects mainly through the activation of AMP-activated protein kinase. Also, we discussed metformin's potential in targeting both GBM cells as well as GBM associated-stem cells. Finally, we summarize a few drug interactions that may cause an additive or antagonistic effect that may lead to adverse effects and influence treatment outcome.

Roles of Angiotensin III in the brain and periphery.

Angiotensin (Ang) III, a biologically active peptide of the renin angiotensin system (RAS) is predominantly known for its central effects on blood pressure. Our understanding of the RAS has evolved from the simplified, classical RAS, a hormonal system regulating blood pressure to a complex system affecting numerous biological processes. Ang II, the main RAS peptide has been widely studied, and its deleterious effects when overexpressed is well-documented. However, other components of the RAS such as Ang III are not well studied. This review examines the molecular and biological actions of Ang III and provides insight into Ang III's potential role in metabolic diseases.

A review of primary care referrals for patients with dizziness and vertigo: prevalence and demographics.

BACKGROUND: International studies show that dizziness and vertigo are a significant burden on the general population, with 20-30% experiencing symptoms over a lifetime. There are no Irish studies indicating prevalence. The aim of this study was to review primary care referrals for patients with dizziness and vertigo to an otolaryngology tertiary centre. METHODS: A review of an out-patient department waiting list was performed on primary care referrals for dizziness and vertigo to an otolaryngology tertiary centre. Demographic information was recorded on all patients referred between May 2017 and August 2019. RESULTS: Two hundred fifteen patients out of 901 patients (24%) referred to an otologist between May 2017 and August 2019 were referred with dizziness as a presenting complaint. The average age was 51 years. F/M ratio was 3:2. The average waiting time was 441 days. The most common associated otological symptom was tinnitus (42%). Relevant comorbidities included anxiety, depression, migraine/headaches and cardiac disease. CONCLUSION: This study demonstrates that a significant number of patients referred to an otologist from primary care are referred with dizziness and vertigo and supports the need for the establishment of multi-disciplinary vestibular/balance centres to address and manage these patients.

Utilization Trends and Disparities in Adolescent Bariatric Surgery in the United States 2009-2017.

Background: Current reports of adolescent bariatric surgery underutilization for treating severe obesity do not comprehensively assess the extent of existing disparities. We sought to describe national trends in adolescent bariatric surgery over a 9-year period and investigate previously described ethnoracial-, insurance-, income-, and geographic-based disparities. Methods: A cross-sectional analysis of adolescents aged 10-19 years who underwent bariatric surgery from 2009 to 2017 was conducted using Healthcare Cost and Utilization Kids' Inpatient Database and National Inpatient Sample Databases. Annual rates and types of bariatric surgery were assessed using trend analysis and stratified by patient, hospital, and regional characteristics. Results: The rate of bariatric surgeries per 1,000,000 adolescents with severe obesity increased over time (227 cases in 2009 to 331cases in 2017). Roux-en-Y gastric bypass and gastric band significantly decreased (p < 0.001), while sleeve gastrectomy became the most commonly performed bariatric surgery (p < 0.001). Surgeries were increasingly performed in urban teaching hospitals (77.9%) and most commonly in the Northeast (34.4%) and South (40.9%). The proportion of black patients (12.1%-15.8%) undergoing bariatric surgery increased, although was not significant and remained below that of white patients (p = 0.06). The proportion of publicly insured patients undergoing bariatric surgery significantly increased (17.0% to 30.7%, p < 0.001), although no changes were observed based on median household income. Conclusions: Over the study period, utilization of adolescent bariatric surgery has increased. Yet, vulnerable populations, who have the highest rates of severe obesity, continue to undergo bariatric surgery at disproportionately lower rates. Further efforts to address disparities and barriers to care are urgently needed to care for these children.

15-Deoxy-Δ-12,14-prostaglandin J2 effects in vascular smooth muscle cells: Implications in vascular smooth muscle cell proliferation and contractility.

15-Deoxy-Δ-12,14-prostaglandin J2 (15d-PGJ2) is an endogenous agonist of the ligand dependent transcriptional factor, peroxisome proliferator-activated receptor -gamma (PPAR-γ). Although PPAR-γ mediates some actions of 15d-PGJ2, many actions of 15d-PGJ2 are independent of PPAR-γ. The PPAR-γ signaling pathway has beneficial effects on tumor progression, inflammation, oxidative stress, and angiogenesis in numerous studies. In this review, various studies were analyzed to understand the effects of 15d-PGJ2 in vascular smooth muscle cells (VSMC)s. 15d-PGJ2 inhibits proliferation of VSMCs during vascular remodeling and it alters the expression of contractile proteins and inflammatory components within these cells as well. However, the effects of 15d-PGJ2 as well as its ability to induce PPAR-γ activation remains controversial as contradictory effects of this prostaglandin in VSMCs exist. Understanding the mechanisms by which 15d-PGJ2 elicit beneficial actions whether by PPAR-γ activation or independently, will aid in developing new therapeutic strategies for diseases such as hypertension with an inflammatory component. Although great advances are being made, more research is needed to reach definitive conclusions.

FDG PET-CT imaging in head and neck paragangliomas: A centre experience.

Head and neck paragangliomas (HNPGLs) are rare tumours with ~ 30% genetic mutations, mainly in succinate dehydrogenase (SDHx) genes. The utility of FDG PET-CT in HNPGLs is questioned by recent developments in novel radiotracers. We therefore performed a retrospective study in a single tertiary referral centre to address the utility of FDG PET/CT in HNPGLs. METHODS: Clinical data on genetic testing and follow-up were collected for patients who had FDG PET-CT scans from 2004 to 2016. Receiver operator characteristic (ROC) analysis was used to compare standardized uptake values (SUVs), metabolic tumour volume (MTV) and total lesion glycolysis (TLG) between lesions in patients who had a clinically related event: event (+) and those who did not: event (-). Similarly, we compared PET parameters between SDHx+ patients and a control group with low probability of mutation. RESULTS: Of 153 HNPGL patients, 73 (29 SDHx+) with 93 FDG-positive lesions were identified: 53.8% of lesions were assessed in a pre-therapeutic setting. In comparison with a reference extracted from clinicoradiological database, FDG PET-CT showed good performance to detect HNPGLs (96.6% accuracy). In this study population, 16 disease progression, 1 recurrence and 1 death were recorded and event (+) patients had lesions with higher SUVmax (p = .03 and p = .02, respectively). Conversely, there were no differences in PET parameters between lesions in SDHx+ patients and controls with low probability of SDHx+ mutations. CONCLUSIONS: FDG PET-CT has clinical utility in HNPGLs, mostly before local treatment. There were no significant differences in PET parameters between SDHx patients and a sporadic HNPGL population. However, regardless of SDHx mutation status, a high SUVmax was associated with more clinical events and prompts to a closer follow-up.

Displaced Gastrostomy Tube in the Pediatric Emergency Department: Implementing an Evidence-based Algorithm and Quality Improvement Project.

INTRODUCTION: ED visits for gastrostomy tube-related complications are common, and many are related to tube displacement. Evidence-based practices can provide standardized care. METHODS: This study was an evidence-based project to develop and implement an algorithm for the care of patients with a displaced gastrostomy tube in the emergency department. Providers were educated on the algorithm, and clinical practice change was evaluated. Provider knowledge was assessed using pretest and posttest; analyses included paired t test. Descriptive statistics of electronic medical record data on confirmation method, documentation, and referral were reported. RESULTS: Provider knowledge was improved after the education (n = 22; t(21) = -3.80; P = 0.001). After the education, procedure notes were used and completed in 95% of the cases. Appropriate use of the confirmation method was present in 95% of the cases, and all cases were referred to the gastrostomy/specialty clinic. DISCUSSION: Educating providers regarding care for displaced gastrostomy tubes increased their knowledge. A standardized algorithm improved care by decreasing the use of contrast studies, improving documentation, and referring patients to the gastrostomy/specialty clinic. This evidence-based algorithm offered health care providers a protocol to ensure consistent care for children in the emergency department and support for families.

Effect of digestion on stability of palivizumab IgG1 in the infant gastrointestinal tract.

BACKGROUND: Potentially, orally administered antibodies specific to enteric pathogens could be administered to infants to prevent diarrheal infections, particularly in developing countries where diarrhea is a major problem. However, to prevent infection, such antibodies would need to resist degradation within the gastrointestinal tract. METHODS: Palivizumab, a recombinant antibody specific to respiratory syncytial virus (RSV), was used in this study as a model for examining the digestion of neutralizing antibodies to enteric pathogens in infants. The survival of this recombinant IgG1 across digestion in 11 infants was assayed via an anti-idiotype ELISA and RSV F protein-specific ELISA. Concentrations were controlled for any dilution or concentration that occurred in the digestive system using mass spectrometry-based quantification of co-administered, orally supplemented, indigestible polyethylene glycol (PEG-28). RESULTS: Binding activity of Palivizumab IgG1 decreased (26-99%) across each phase of in vivo digestion as measured by both anti-idiotype and RSV F protein-specific ELISAs. CONCLUSION: Antibodies generated for passive protection of the infant gastrointestinal tract from pathogens will need to be more resistant to digestion than the model antibody fed to infants in this study, or provided in higher doses to be most effective. IMPACT: Binding activity of palivizumab IgG1 decreased (26-99%) across each phase of in vivo infant digestion as measured by both anti-idiotype and RSV F protein-specific ELISAs. Palivizumab was likely degraded by proteases and changes in pH introduced in the gut. Antibodies generated for passive protection of the infant gastrointestinal tract from pathogens will need to be more resistant to digestion than the model antibody fed to infants in this study, or provided in higher doses to be most effective. The monoclonal antibody IgG1 tested was not stable across the infant gastrointestinal tract. The observation of palivizumab reduction was unlikely due to dilution in the gastrointestinal tract. The results of this work hint that provision of antibody could be effective in preventing enteric pathogen infection in infants. Orally delivered recombinant antibodies will need to either be dosed at high levels to compensate for digestive losses or be engineered to better resist digestion. Provision of enteric pathogen-specific recombinant antibodies to at-risk infants could provide a new and previously unexplored pathway to reducing the infection in infants. The strategy of enteric recombinant antibodies deserves more investigation throughout medicine as a novel means for treatment of enteric disease targets.

CDC Deployments to State, Tribal, Local, and Territorial Health Departments for COVID-19 Emergency Public Health Response - United States, January 21-July 25, 2020.

Coronavirus disease 2019 (COVID-19) is a viral respiratory illness caused by SARS-CoV-2. During January 21-July 25, 2020, in response to official requests for assistance with COVID-19 emergency public health response activities, CDC deployed 208 teams to assist 55 state, tribal, local, and territorial health departments. CDC deployment data were analyzed to summarize activities by deployed CDC teams in assisting state, tribal, local, and territorial health departments to identify and implement measures to contain SARS-CoV-2 transmission (1). Deployed teams assisted with the investigation of transmission in high-risk congregate settings, such as long-term care facilities (53 deployments; 26% of total), food processing facilities (24; 12%), correctional facilities (12; 6%), and settings that provide services to persons experiencing homelessness (10; 5%). Among the 208 deployed teams, 178 (85%) provided assistance to state health departments, 12 (6%) to tribal health departments, 10 (5%) to local health departments, and eight (4%) to territorial health departments. CDC collaborations with health departments have strengthened local capacity and provided outbreak response support. Collaborations focused attention on health equity issues among disproportionately affected populations (e.g., racial and ethnic minority populations, essential frontline workers, and persons experiencing homelessness) and through a place-based focus (e.g., persons living in rural or frontier areas). These collaborations also facilitated enhanced characterization of COVID-19 epidemiology, directly contributing to CDC data-informed guidance, including guidance for serial testing as a containment strategy in high-risk congregate settings, targeted interventions and prevention efforts among workers at food processing facilities, and social distancing.

Partial Degradation of Recombinant Antibody Functional Activity During Infant Gastrointestinal Digestion: Implications for Oral Antibody Supplementation.

Oral administration of engineered immunoglobulins has the potential to prevent enteric pathogen-induced diarrhea in infants. To prevent infection, these antibodies need to survive functionally intact in the proteolytic environment of the gastrointestinal tract. This research examined both ex vivo and in vivo the functional survival across infant digestion of palivizumab, a model FDA-approved recombinant antibody against respiratory syncytial virus (RSV) F protein. Palivizumab-fortified feed (formula or human milk), infant gastric, and intestinal samples were incubated to simulate in vivo digestion (ex vivo digestion). Palivizumab-fortified human milk was also fed to infants, followed by collection of gastric and intestinal samples (in vivo digestion). Palivizumab was purified from the samples of digestate using protein G spin columns followed by filtration through molecular weight cut-off membranes (30 kDa). Palivizumab functional survival across ex vivo and in vivo digestion was determined via an anti-idiotype ELISA and an RSV plaque reduction neutralization test. Palivizumab concentration and RSV neutralization capacity both decreased when incubated in intestinal samples (ex vivo study). The concentration and neutralization activity of orally-supplemented palivizumab also decreased across infant digestion (in vivo study). These results indicate that if recombinant IgGs were selected for oral supplementation to prevent enteric infections, appropriate dosing would need to account for degradation occurring in the digestive system. Other antibody formats, structural changes, or encapsulation could enhance survival in the infant gastrointestinal tract.

Angiotensin II induces cyclooxygenase 2 expression in rat astrocytes via the angiotensin type 1 receptor.

We previously showed that Angiotensin (Ang) II stimulated pro-inflammatory and mitogenic actions in astrocytes suggesting that astrocytes are emerging as key players in neuroinflammation. Evidence suggests that neuroinflammation may contribute to central sympathetic overactivity and elevated blood pressure. Further, cyclooxygenase (Cox)-derived prostanoids were implicated in Ang II-dependent hypertension. Cox2 is one of two Cox isoenzymes that is responsible for the formation of prostanoids from arachidonic acid. Constitutively expressed Cox2 has a protective and homeostatic role in the cardiovascular and renal systems. Inducible Cox2 has been associated with pathogenic stimuli resulting in inflammatory conditions and cancers. In this study, we investigated the effect of Ang II on Cox2 protein and mRNA expression in brainstem and cerebellum astrocytes, and determined whether any differences in Cox2 expression exist in spontaneously hypertensive rat (SHR) astrocytes compared to their normotensive control Wistar rats. We demonstrated that Ang II increased Cox2 protein and mRNA levels relative to untreated controls in a time-dependent manner, in Wistar and SHR brainstem and cerebellum astrocytes. Increases in Cox2 protein expression were evident within 4 h, with subsequent sustained elevation for several hours followed by a decline at 48 h. Ang II-induced Cox2 protein levels were higher in Wistar compared to SHRs in both brainstem and cerebellum astrocytes for the majority of time points examined. The Ang II-induced Cox2 mRNA levels increased within 8 h followed by a rapid decline to almost basal levels at later time points. At the earlier time points, Cox2 mRNA elevation were higher in SHR compared to Wistar rat astrocytes. These Ang II actions were mediated by the Ang type I receptor. Our results corroborate previous reports of Ang II's ability to stimulate neuroinflammatory mediators in astrocytes. Cox2-derived prostaglandins might play a role in brain-renin angiotensin system associated hypertension, and astrocytes could be significant players.

Addressing Childhood Obesity for Type 2 Diabetes Prevention: Challenges and Opportunities.

IN BRIEF Addressing the problem of childhood obesity is an important component of preventing type 2 diabetes. Although children and their families ultimately make decisions about diet, physical activity, and obesity management, many groups have a role in making these choices easier. They do this by providing families with tools and resources and by implementing policies and practices that support a healthy diet and physical activity in the places where children and their families spend their time. Diabetes educators are an important part of the solution.

CDC's Active People, Healthy NationSM: Creating an Active America, Together.

Physical activity can reduce the risk of at least 20 chronic diseases and conditions and provide effective treatment for many of these conditions. Yet, physical activity levels of Americans remain low, with only small improvements over 20 years. The Centers for Disease Control and Prevention (CDC) considered what would accelerate progress and, as a result, developed Active People, Healthy NationSM, an aspirational initiative to improve physical activity in 2.5 million high school youth and 25 million adults, doubling the 10-year improvement targets of Healthy People 2020. Active People, Healthy NationSM will implement evidence-based guidance to improve physical activity through 5 action steps centered on core public health functions: (1) program delivery, (2) partnership mobilization, (3) effective communication, (4) cross-sectoral training, and (5) continuous monitoring and evaluation. To achieve wide-scale impact, Active People, Healthy NationSM will need broad engagement from a variety of sectors working together to coordinate activities and initiatives.

Astrocytes and the Renin Angiotensin System: Relevance in Disease Pathogenesis.

The presence of a brain renin angiotensin system (RAS) is well documented. An overactive brain RAS contributes to the development and progression of cardiovascular and renal disorders among other conditions. In hypertension, an augmented brain RAS leads to an increase in sympathetic nervous system activity. In addition, impaired baroreceptor reflex function, increased vasopressin activity and neuroinflammation are important contributors as well. The relevance of angiotensins in central and peripheral systems, such as neurons and vascular smooth muscle cells, in cardiovascular disease pathogenesis is fairly understood. However, the role of astrocytes is less well studied. Astrocytes are a major contributor to neuroinflammation by increased synthesis and secretion of inflammatory mediators, dysregulated astrogliosis and impaired astrocyte proliferation. Astrocytes may also contribute to impaired neuromodulation. The precise molecular mechanisms by which astrocytes mediate these effects are still not fully understood. Here, we summarize the role of astrocytes in RAS -mediated pathogenesis of hypertension and other cardiovascular diseases.

Bioaccumulation of Polychlorinated Biphenyls (PCBs) in Atlantic Sea Bream (Archosargus rhomboidalis) from Kingston Harbour, Jamaica.

Multiple sizes of Sea bream were collected from Kingston Harbour, Jamaica, to assess steady state bioaccumulation of polychlorinated biphenyls (PCBs) in a tropical fish. Sea beam fork lengths ranged from 7.3 to 21.5 cm (n = 36 fish) and tissue lipids decreased with body length. Larger fish had lower δ13C isotopes compared to smaller fish, suggesting a change in diet. Linear regressions showed no differences in lipid equivalent sum PCB concentrations with size. However, differences in individual congener bioaccumulation trajectories occurred. Less hydrophobic PCBs decreased with increasing body length, intermediate PCBs showed no trend, whereas highly hydrophobic (above log KOW of 6.5) PCBs increased. The different congener patterns were interpreted to be a result of decreases in overall diet PCB concentrations with increased fish length coupled with differences in PCB toxicokinetics as a function of hydrophobicity yielding dilution, pseudo-steady state and non-steady state bioaccumulation patterns.

Physical Inactivity Among Adults Aged 50 Years and Older - United States, 2014.

Physical activity can help delay, prevent, or manage many of the chronic diseases for which adults aged ≥50 years are at risk (1-3). These diseases can impact the length and quality of life, as well as the long-term ability to live independently.* All adults aged ≥50 years, with or without chronic disease, gain health benefits by avoiding inactivity (2,3). To examine the prevalence of inactivity by selected demographic characteristics and chronic disease status in mid-life and older adults, CDC analyzed data on adults aged ≥50 years from the 2014 Behavioral Risk Factor Surveillance System (BRFSS). Overall, 27.5% of adults aged ≥50 years reported no physical activity outside of work during the past month. Inactivity prevalence significantly increased with increasing age and was 25.4% among adults aged 50-64 years, 26.9% among those aged 65-74 years, and 35.3% among those aged ≥75 years. Inactivity prevalence was significantly higher among women than men, among Hispanics and non-Hispanic blacks than among non-Hispanic whites, and among adults who reported ever having one or more of seven selected chronic diseases than among those not reporting one. Inactivity prevalence significantly increased with decreasing levels of education and increasing body mass index. To help adults with and without chronic disease start or maintain an active lifestyle, communities can implement evidence-based strategies, such as creating or enhancing access to places for physical activity, designing communities and streets to encourage physical activity, and offering programs that address specific barriers to physical activity.

Staged imaging pathway for the evaluation of pediatric appendicitis.

PURPOSE: Despite significant radiation exposure involved with computed tomography (CT) in evaluation of pediatric appendicitis, its use is still widespread. The goal of this study was to assess the effect of a staged imaging pathway for appendicitis to significantly decrease CT use while maintaining diagnostic accuracy. METHODS: Chart review was performed for patients evaluated for appendicitis over a 12-month period prior to and after pathway implementation. RESULTS: There was a significant decrease in CT use as initial imaging after implementation of the pathway; 87.1-13.4 % for evaluations positive for appendicitis (decrease 84.6 %, p < 0.0001) and 82.6-9.2 % for evaluations negative for appendicitis (decrease 88.9 %, p < 0.0001). Use of CT during any point in the evaluation decreased from 91.7 to 25.1 % (decrease 72.6 %, p < 0.0001). The negative appendectomy rate was similar; 5.4 % prior, 4.9 % post (p = 0.955). The missed appendicitis rate did not statistically change; 1.1 % prior, 3.7 % post (p = 0.523). The perforation rate was not statistically altered; 6.5 % prior; 9.8 % post (p = 0.421). 350 less patients underwent CT during the year following the pathway. CONCLUSIONS: The staged imaging pathway resulted in a marked decrease in children exposed to CT without compromising diagnostic accuracy.

Conclusion and future directions: CDC Health Disparities and Inequalities Report - United States, 2013.

The reports in this supplement document persistent disparities between some population groups in health outcomes, access to health care, adoption of health promoting behaviors, and exposure to health-promoting environments. Some improvements in overall rates and even reductions in some health disparities are noted; however, many gaps persist. These finding highlight the importance of monitoring health status, outcomes, behaviors, and exposures by population groups to assess trends and target interventions. In this report, disparities were found between race and ethnic groups across all of the health topics examined. Differences also were observed by other population characteristics. For example, persons with low socioeconomic status were more likely to be affected by diabetes, hypertension, and human immunodeficiency virus (HIV) infection and were less likely to be screened for colorectal cancer and vaccinated against influenza.

Catheter associated blood stream infections in patients receiving parenteral nutrition: a prospective study of 850 patients.

BACKGROUND: Data was prospectively collected on 850 consecutive patients undergoing central venous catheterisation (CVC) to receive total parenteral nutrition (TPN) in a major university teaching hospital over a 46 months period. METHODS: Data included information about CVC insertion and clinical outcomes, most notably, suspected catheter-related blood stream infections (CRBSI). RESULTS: The internal jugular vein was the most common site (n = 882, 68%), followed by the subclavian vein (n = 344, 24.6%) and femoral vein (n = 95, 6.5%). The CRBSI rate per 100 line feeding days was 0.93% in patients cared for in a non ICU setting versus 1.98% for ICU managed patients. The mean number of line days preceding a pyrexial spike was 13.1. CRBSI was commonest in patients with femoral lines (n = 21/95, 22.1%), especially those cared for in a non-ICU setting (29.6% versus 14.5% for those in the ICU group). Preference should be given to internal jugular or subclavian-sited CVCs in ICU and non-ICU patients to reduce the risk of CRBSI. If femoral catheterisation is unavoidable, strict attention to aseptic technique is mandatory. CONCLUSION: The aim of this study was to investigate the rate and pattern of CRBSI and to recommend changes in protocol, technique and equipment as deemed necessary from these findings.