Molecular Pharmacology of Vitamin C and Relevance to Health and Obesity-A Narrative Review.

The role of food constituents as pharmacological agents is an important consideration in health and obesity. Vitamin C acts as a small molecule antioxidant but is also a co-factor for numerous transition metal-dependent enzymes involved in healthy weight and energy metabolism. Vitamin C cannot be manufactured by humans and is mainly obtained from the dietary intake of fresh fruit and vegetables. There is great variability between different nutritional guidelines in the recommended daily allowance of vitamin C. Vitamin C deficiency results from an inadequate intake of vitamin C-containing foods and also increased utilization by oxidative and carbonyl stress. Risk factors for vitamin C deficiency include cigarette smoking, malnutrition, obesity, type 2 diabetes mellitus, age, race, sex, social isolation, major surgery, and Western-type diets. Despite the common belief that vitamin C deficiency is rare in affluent countries, surveys of large populations and specific patient groups suggest otherwise. Patients with obesity typically consume highly processed, energy-dense foods which contain inadequate micronutrients. As obesity increases, larger amounts of oral vitamin C are required to achieve adequate plasma and tissue concentrations, as compared to persons with a healthy weight. This is important in the control of oxidative stress and the maintenance of homeostasis and organ function. In this narrative review, the dosage, absorption, distribution, excretion, and catabolism of vitamin C are reviewed, together with the latest findings on vitamin C pharmacology in patients with obesity.

Cellular Senescence and Extracellular Vesicles in the Pathogenesis and Treatment of Obesity-A Narrative Review.

This narrative review explores the pathophysiology of obesity, cellular senescence, and exosome release. When exposed to excessive nutrients, adipocytes develop mitochondrial dysfunction and generate reactive oxygen species with DNA damage. This triggers adipocyte hypertrophy and hypoxia, inhibition of adiponectin secretion and adipogenesis, increased endoplasmic reticulum stress and maladaptive unfolded protein response, metaflammation, and polarization of macrophages. Such feed-forward cycles are not resolved by antioxidant systems, heat shock response pathways, or DNA repair mechanisms, resulting in transmissible cellular senescence via autocrine, paracrine, and endocrine signaling. Senescence can thus affect preadipocytes, mature adipocytes, tissue macrophages and lymphocytes, hepatocytes, vascular endothelium, pancreatic ß cells, myocytes, hypothalamic nuclei, and renal podocytes. The senescence-associated secretory phenotype is closely related to visceral adipose tissue expansion and metaflammation; inhibition of SIRT-1, adiponectin, and autophagy; and increased release of exosomes, exosomal micro-RNAs, pro-inflammatory adipokines, and saturated free fatty acids. The resulting hypernefemia, insulin resistance, and diminished fatty acid ß-oxidation lead to lipotoxicity and progressive obesity, metabolic syndrome, and physical and cognitive functional decline. Weight cycling is related to continuing immunosenescence and exposure to palmitate. Cellular senescence, exosome release, and the transmissible senescence-associated secretory phenotype contribute to obesity and metabolic syndrome. Targeted therapies have interrelated and synergistic effects on cellular senescence, obesity, and premature aging.

ADOPTERs of Innovation in a Crisis: The History of Vera Gedroits, Kanehiro Takaki and the Russo-Japanese War of 1904-1905.

The 1904-1905 Russo-Japanese War was the first "modern" conflict, using rapid-firing artillery and machine guns, fought over imperial ambitions in Korea and Manchuria. During the war, Princess Vera Gedroits pioneered early laparotomy for penetrating abdominal wounds with unprecedented success. Her techniques were then adopted by the Russian Society of Military Doctors. However, Allied forces took 10 years to adopt operative management of penetrating abdominal wounds over conservative management. Gedroits was later appointed in Kyiv as the world's first female Professor of Surgery. Kanehiro Takaki, a Japanese Naval surgeon, showed in 1884 a diet of barley, meat, milk, bread, and beans, rather than polished white rice, eliminated beriberi in the Japanese Navy. Despite this success, the Japanese Army failed to change the white rice rations until March 1905. During the 1904-1905 Russo-Japanese War, an estimated 250,000 Japanese soldiers developed beriberi, of whom 27,000 died. Japan's 1905 defeat of Russia sowed the seeds of discontent with Tsar Nicholas' rule, culminating in the 1917 Russian Revolution. Although the Russian Navy was destroyed, Japan ceded North Sakhalin Island to Russia in peace negotiations, and Russia seized Manchuria, South Sakhalin, and the Kuril Islands in 1945. We highlight the contributions of Gedroits and Takaki, 2 intellectual prodigies who respectively pioneered rapid triage and surgical management of trauma and a cure for beriberi. We aim to show how both these surgeons challenged entrenched dogma and the cultural and political zeitgeist, and risked their professional reputations and their lives in being ADOPTERs of innovation during a crisis.

Molecular Mechanisms of Western Diet-Induced Obesity and Obesity-Related Carcinogenesis-A Narrative Review.

The present study aims to provide a narrative review of the molecular mechanisms of Western diet-induced obesity and obesity-related carcinogenesis. A literature search of the Cochrane Library, Embase and Pubmed databases, Google Scholar and the grey literature was conducted. Most of the molecular mechanisms that induce obesity are also involved in the twelve Hallmarks of Cancer, with the fundamental process being the consumption of a highly processed, energy-dense diet and the deposition of fat in white adipose tissue and the liver. The generation of crown-like structures, with macrophages surrounding senescent or necrotic adipocytes or hepatocytes, leads to a perpetual state of chronic inflammation, oxidative stress, hyperinsulinaemia, aromatase activity, activation of oncogenic pathways and loss of normal homeostasis. Metabolic reprogramming, epithelial mesenchymal transition, HIF-1α signalling, angiogenesis and loss of normal host immune-surveillance are particularly important. Obesity-associated carcinogenesis is closely related to metabolic syndrome, hypoxia, visceral adipose tissue dysfunction, oestrogen synthesis and detrimental cytokine, adipokine and exosomal miRNA release. This is particularly important in the pathogenesis of oestrogen-sensitive cancers, including breast, endometrial, ovarian and thyroid cancer, but also 'non-hormonal' obesity-associated cancers such as cardio-oesophageal, colorectal, renal, pancreatic, gallbladder and hepatocellular adenocarcinoma. Effective weight loss interventions may improve the future incidence of overall and obesity-associated cancer.

Risks and Prevention of Surgical Site Infection After Hernia Mesh Repair and the Predictive Utility of ACS-NSQIP.

AIM: The aim of this paper was to provide a narrative review of surgical site infection after hernia surgery and the influence of perioperative preventative interventions. METHODS: The review was based on current national and international guidelines and a literature search. RESULTS: Mesh infection is a highly morbid complication after hernia surgery, and is associated with hospital re-admission, increased health care costs, re-operation, hernia recurrence, impaired quality of life and plaintiff litigation. The American College of Surgeons National Surgical Quality Improvement Program is a particularly useful resource for the study and evidence-based practise of abdominal wall hernia repair. DISCUSSION: The three major modifiable patient comorbidities significantly associated with postoperative surgical site infection in hernia surgery are obesity, tobacco smoking and diabetes mellitus. Preoperative optimization includes weight loss, cessation of smoking, and control of diabetes. Intraoperative interventions relate, in particular, to the control of fomite mediated transmission in the operating theatre and prevention of mesh contamination with S. aureus CFUs. Risk management strategies should also target the niche ecological conditions which enable bacterial survival and subsequent biofilm formation on an implanted mesh. Outcomes of mesh infection after hernia surgery are closely related to mesh type and porosity, patient smoking status, presence of MRSA, bacterial adhesion and biofilm production. The use of suction drains and the timing of drain removal are controversial and discussed in detail. Finally, the utility of the ACS-NSQIP Surgical Risk Calculator in predicting complications and outcomes in individual patients and the importance of quality improvement initiatives in surgical units are emphasized.

Pathophysiology, prevention, and treatment of beriberi after gastric surgery.

Beriberi is a nutritional complication of gastric surgery, caused by deficiency of vitamin B1, or thiamine. Thiamine deficiency leads to impaired glucose metabolism, decreased delivery of oxygen by red blood cells, cardiac dysfunction, failure of neurotransmission, and neuronal death. This review describes the history and pathophysiology of beriberi as well as the relationship between beriberi and nutritional deficiencies after gastric surgery. A literature review of the history and pathophysiology of beriberi and the risk factors for thiamine deficiency, particularly after gastric resection or bariatric surgery, was performed. Recommendations for nutritional follow-up post gastric surgery are based on current national guidelines. Patients may have subclinical thiamine deficiency after upper gastrointestinal surgery, and thus beriberi may be precipitated by acute illness such as sepsis or poor dietary intake. This may occur very soon or many years after gastrectomy or bariatric surgery, even in apparently well-nourished patients. Prompt recognition and administration of supplemental thiamine can decrease morbidity and mortality in patients with beriberi. Dietary education post surgery and long-term follow-up to determine nutritional status, including vitamin and mineral assessment, is recommended for patients who undergo gastric surgery.

Morpheus and the Underworld-Interventions to Reduce the Risks of Opioid Use After Surgery: ORADEs, Dependence, Cancer Progression, and Anastomotic Leakage.

BACKGROUND: Perioperative pain management is a key element of enhanced recovery after surgery (ERAS) programs. A multimodal approach to analgesia as part of a coordinated ERAS includes the reduction of opioid use. This review aims to discuss opioid-related adverse events, strategies to reduce opioid use after surgery, and the relevance to the present "opioid crisis" in North America. METHODS: A literature review of the pharmacology of opioid drugs, perioperative opioid reduction strategies, and the potential public health benefit was performed. This included current ERAS guidelines on multimodal analgesia, randomized controlled trials on perioperative analgesia, and intervention studies to decrease opioid use, misuse, and diversion in North America. RESULTS: Reduction of perioperative opioid usage has been endorsed by joint clinical practice guidelines on the management of postoperative pain from the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists. Interventions as part of an "opioid bundle" that can be incorporated into ERAS protocols include multimodal analgesia, regional anesthesia, opioid sparing drugs, carbon dioxide humidification during laparoscopy, changing opioid prescription practices, patient and physician education, and proper disposal of unused opioid medications. CONCLUSION: There are substantial benefits in incorporating opioid reduction strategies into ERAS and clinical practice guidelines. These include faster return of function and mobility, and decreased opioid-related adverse drug events (ORADEs), postoperative morbidity and mortality, and length of hospital stay. Improved oncological outcomes after cancer surgery may be an additional benefit. Evidence-based interventions can also reduce opioid abuse and diversion in the community.

Hypoxia, cytokines and stromal recruitment: parallels between pathophysiology of encapsulating peritoneal sclerosis, endometriosis and peritoneal metastasis.

Peritoneal response to various kinds of injury involves loss of peritoneal mesothelial cells (PMC), danger signalling, epithelial-mesenchymal transition and mesothelial-mesenchymal transition (MMT). Encapsulating peritoneal sclerosis (EPS), endometriosis (EM) and peritoneal metastasis (PM) are all characterized by hypoxia and formation of a vascularized connective tissue stroma mediated by vascular endothelial growth factor (VEGF). Transforming growth factor-ß1 (TGF-ß1) is constitutively expressed by the PMC and plays a major role in the maintenance of a transformed, inflammatory micro-environment in PM, but also in EPS and EM. Persistently high levels of TGF-ß1 or stimulation by inflammatory cytokines (interleukin-6 (IL-6)) induce peritoneal MMT, adhesion formation and fibrosis. TGF-ß1 enhances hypoxia inducible factor-1α expression, which drives cell growth, extracellular matrix production and cell migration. Disruption of the peritoneal glycocalyx and exposure of the basement membrane release low molecular weight hyaluronan, which initiates a cascade of pro-inflammatory mediators, including peritoneal cytokines (TNF-α, IL-1, IL-6, prostaglandins), growth factors (TGF-α, TGF-ß, platelet-derived growth factor, VEGF, epidermal growth factor) and the fibrin/coagulation cascade (thrombin, Tissue factor, plasminogen activator inhibitor [PAI]-1/2). Chronic inflammation and cellular transformation are mediated by damage-associated molecular patterns, pattern recognition receptors, AGE-RAGE, extracellular lactate, pro-inflammatory cytokines, reactive oxygen species, increased glycolysis, metabolomic reprogramming and cancer-associated fibroblasts. The pathogenesis of EPS, EM and PM shows similarities to the cellular transformation and stromal recruitment of wound healing.