Life Extension Magazine®

Issue: Feb 2017

Uric acid, Proton pump inhibitor, Immune defense, and Esophageal acidity

Uric acid

Epidemiology of hyperuricemia and gout.

Gout is an increasingly common medical problem. The traditional risk factors of male sex and high red meat or alcohol consumption have been joined by a wave of newer risk factors, such as increased longevity, the metabolic syndrome (hypertension, diabetes, dyslipidemia, truncal obesity, increased cardiovascular disease risk), use of diuretics, low-dose aspirin, or cyclosporine, and end-stage renal disease. Atypical presentations of gout in the elderly can mimic osteoarthritis and rheumatoid arthritis. There is a resurgence of interest in hyperuricemia as an independent and potentially modifiable cardiovascular risk factor. The pharmacologic management of gout in general practice suffers from a number of quality-control issues. This article reviews these and other new epidemiologic data on this ancient disease.

Am J Manag Care. 2005 Nov;11(15 Suppl):S435-42; quiz S465-8

Increasing prevalence of gout and hyperuricemia over 10 years among older adults in a managed care population.

OBJECTIVE: To determine whether the prevalence of gout and/or clinically significant hyperuricemia increased in a managed care population over 10 years. METHODS: The study was a descriptive analysis utilizing an administrative claims database to ascertain 10-year trends in prevalence of gout and/or hyperuricemia. Prevalence rates were calculated cross-sectionally for each year (1990-99) and expressed/compared as rates per 1000 enrollees. RESULTS: The prevalence of gout and/or hyperuricemia in the overall population increased by about 2 cases per 1000 enrollees over 10 years. In the > 75 year age group, rates increased from 21 per 1000 persons in 1990 to 41 per 1000 in 1999. In the 65-74 year age group, prevalence increased from between 21 and 24 per 1000 persons in the years 1990-92 to over 31 per 1000 during the years 1997-99. Prevalence rates in younger age groups (< 65 years) stayed consistently low during the years under study. There were sex differences in most age groups, with men having the greater burden of disease at every time point. CONCLUSION: Prevalence of gout and/or hyperuricemia in the overall study population increased during the 10-year period. When stratified by age, there were increases in prevalence among groups over age 65 in both sexes. Although gout prevalence increased in both sexes over the 10-year period, men still had most of the burden of disease. In ages younger than 65, men had 4 times higher prevalence than women (4:1 ratio), but in the older age groups (> 65), the gender gap narrowed to 1 woman to every 3 men with gout and/or hyperuricemia (3:1 ratio).

J Rheumatol. 2004 Aug;31(8):1582-7

Increased risk of vascular disease associated with gout: a retrospective, matched cohort study in the UK clinical practice research datalink.

OBJECTIVES: To determine whether gout increases risk of incident coronary heart disease (CHD), cerebrovascular (CVD) and peripheral vascular disease (PVD) in a large cohort of primary care patients with gout, since there have been no such large studies in primary care. METHODS: A retrospective cohort study was performed using data from the Clinical Practice Research Datalink (CPRD). Risk of incident CHD, CVD and PVD was compared in 8386 patients with an incident diagnosis of gout, and 39 766 age, sex and registered general practice-matched controls, all aged over 50 years and with no prior vascular history, in the 10 years following incidence of gout, or matched index date (baseline). Multivariable Cox Regression was used to estimate HRs and covariates included sex and baseline measures of age, Body Mass Index, smoking, alcohol consumption, Charlson comorbidity index, history of hypertension, hyperlipidaemia, chronic kidney disease, statin use and aspirin use. RESULTS: Multivariable analysis showed men were at increased risk of any vascular event (HRs (95% CIs)) HR 1.06 (1.01 to 1.12), any CHD HR 1.08 (1.01 to 1.15) and PVD HR 1.18 (1.01 to 1.38), while women were at increased risk of any vascular event, HR 1.25 (1.15 to 1.35), any CHD HR 1.25 (1.12 to 1.39), and PVD 1.89 (1.50 to 2.38)) but not any CVD. CONCLUSIONS: In this cohort of over 50s with gout, female patients with gout were at greatest risk of incident vascular events, even after adjustment for vascular risk factors, despite a higher prevalence of both gout and vascular disease in men. Further research is required to establish the reason for this sex difference.

Ann Rheum Dis. 2015 Apr;74(4):642-7

Presence of gout is associated with increased prevalence and severity of knee osteoarthritis among older men: results of a pilot study.

BACKGROUND: Gout and osteoarthritis (OA) are the most prevalent arthritides, but their relationship is neither well established nor well understood. OBJECTIVES: We assessed whether a diagnosis of gout or asymptomatic hyperuricemia (AH) is associated with increased prevalence/severity of knee OA. METHODS: One hundred nineteen male patients aged 55 to 85 years were sequentially enrolled from the primary care clinics of an urban Veterans Affairs hospital, assessed and categorized into 3 groups: gout (American College of Rheumatology Classification Criteria), AH (serum urate ≥6.8 mg/dL, no gout), and control (serum urate <6.8 mg/dL, no gout). Twenty-five patients from each group subsequently underwent formal assessment of knee OA presence and severity (American College of Rheumatology Clinical/Radiographic Criteria, Kellgren-Lawrence grade). Musculoskeletal ultrasound was used to detect monosodium urate deposition at the knees and first metatarsophalangeal joints. RESULTS: The study showed 68.0% of gout, 52.0% of AH, and 28.0% of age-matched control subjects had knee OA (gout vs control, P = 0.017). Odds ratio for knee OA in gout versus control subjects was 5.46 prior to and 3.80 after adjusting for body mass index. Gout subjects also had higher Kellgren-Lawrence grades than did the control subjects (P = 0.001). Subjects with sonographically detected monosodium urate crystal deposition on cartilage were more likely to have OA than those without (60.0 vs 27.5%, P = 0.037), with crystal deposition at the first metatarsophalangeal joints correlating most closely with OA knee involvement. CONCLUSIONS: Knee OA was more prevalent in gout patients versus control subjects and intermediate in AH. Knee OA was more severe in gout patients versus control subjects.

J Clin Rheumatol. 2015 Mar;21(2):63-71

Gout: an update.

Arthritis caused by gout (i.e., gouty arthritis) accounts for millions of outpatient visits annually, and the prevalence is increasing. Gout is caused by monosodium urate crystal deposition in tissues leading to arthritis, soft tissue masses (i.e., tophi), nephrolithiasis, and urate nephropathy. The biologic precursor to gout is elevated serum uric acid levels (i.e., hyperuricemia). Asymptomatic hyperuricemia is common and usually does not progress to clinical gout. Acute gout most often presents as attacks of pain, erythema, and swelling of one or a few joints in the lower extremities. The diagnosis is confirmed if monosodium urate crystals are present in synovial fluid. First-line therapy for acute gout is nonsteroidal anti-inflammatory drugs or corticosteroids, depending on comorbidities; colchicine is second-line therapy. After the first gout attack, modifiable risk factors (e.g., high-purine diet, alcohol use, obesity, diuretic therapy) should be addressed. Urate-lowering therapy for gout is initiated after multiple attacks or after the development of tophi or urate nephrolithiasis. Allopurinol is the most common therapy for chronic gout. Uricosuric agents are alternative therapies in patients with preserved renal function and no history of nephrolithiasis. During urate-lowering therapy, the dose should be titrated upward until the serum uric acid level is less than 6 mg per dL (355 micromol per L). When initiating urate-lowering therapy, concurrent prophylactic therapy with low-dose colchicine for three to six months may reduce flare-ups.

Am Fam Physician. 2007 Sep 15;76(6):801-8

An open-label, 6-month study of allopurinol safety in gout: The LASSO study.

OBJECTIVES: Allopurinol is the most widely prescribed serum uric acid-lowering therapy (ULT) in gout. To achieve serum uric acid (sUA) concentrations associated with clinical benefit, allopurinol is serially uptitrated with sUA monitoring. Suboptimal dosing is a key contributor to poor clinical outcomes, but few data are available on the safety and efficacy of dose-titrated allopurinol, particularly at doses > 300 mg/d. The objective of this open-label study was to investigate the safety and efficacy of allopurinol under conditions where investigators were encouraged to titrate to optimal, medically appropriate doses. METHODS: Long-term Allopurinol Safety Study Evaluating Outcomes in Gout Patients (LASSO) was a large, 6-month, multicenter study of allopurinol (NCT01391325). Adults meeting American Rheumatism Association Criteria for Classification of Acute Arthritis of Primary Gout and ≥ 2 gout flares in the previous year were eligible. Investigators were encouraged (but not required) to titrate allopurinol doses to achieve target sUA < 6.0mg/dL. The primary objective was evaluation of the safety of dose-titrated allopurinol by clinical and laboratory examinations at monthly visits. Secondary objectives included sUA-lowering efficacy and gout flare frequency. RESULTS: Of 1735 patients enrolled, 1732 received ≥ 1 allopurinol doses. The maximal daily allopurinol dose during study was < 300 mg in 14.4%, 300 mg in 65.4%, and > 300 mg in 20.2% of patients; dosing duration was 115.5, 152.0, and 159.7 days, respectively. Overall, baseline demographic characteristics and comorbidity rates were similar across these three categories, but patients receiving > 300-mg maximal dose had more severe gout. Treatment-emergent adverse events possibly related to allopurinol occurred in 15.2%, 9.5%, and 11.4% of patients in the < 300-, 300-, and > 300-mg categories, respectively. Rash incidence was low (1.5%) and allopurinol hypersensitivity syndrome was not reported. No clinically meaningful changes occurred in laboratory values. sUA < 6.0mg/dL at month 6 was achieved by 35.9% of patients overall: 22.4%, 35.0%, and 48.3% in dosing categories < 300, 300, and > 300 mg, respectively. CONCLUSIONS: This large multicenter study found that the allopurinol dose-titration strategy was well tolerated, without new safety signals emerging over 6 months. However, despite encouragement to treat to target, significant proportions of patients did not achieve target sUA.

Semin Arthritis Rheum. 2015 Oct;45(2):174-83

Safety of a Novel Botanical Extract Formula for Ameliorating Allergic rhinitis. Part II.

Abstract Each year more than 50 million Americans suffer from allergic rhinitis, which is a state of hypersensitivity or hyperimmunity. Basically, allergic rhinitis is symptomatically recognized as the inflammation and irritation of the nasal mucosal membranes; sneezing; stuffy/runny nose; nasal congestion; and itchy; watery, and swollen eyes; and defined as a state of hypersensitivity/ hyperimmunity caused by exposure to a particular allergen (antigen) that results in increased reactivity upon subsequent exposure. A novel polyherbal formulation (Aller-7/NR-A2) was developed for the treatment of allergic rhinitis using a unique combination of extracts from seven medicinal plants, including Phyllanthus emblica, Terminalia chebula, Terminalia bellerica, Albizia lebbeck, Piper nigrum, Zingiber officinale, and Piper longum. Earlier studies in our laboratories have demonstrated potent antihistaminic, anti-inflammatory, antispasmodic, antioxidant, and mast-cell stabilization activities of Aller-7 in addition to its efficacy in a clinical setting. A series of preliminary toxicological evaluations were also conducted in the past, which demonstrated its safety. In this study, we have conducted further safety studies on Aller-7, including acute oral, acute dermal, acute dermal irritation, eye irritation, and 90-day repeated dose toxicity studies. Acute oral toxicity of Aller-7 was found to be greater than 5,000 mg/kg body weight in both male and female rats and no mortality or toxicity was observed at this dose, while the acute dermal toxicity was found to be greater than 2,000 mg/kg body weight. In the acute dermal irritation study, the skin irritancy index was found to be 0.0, which classifies Aller-7 as a nonirritant to rabbit skin. In the acute eye irritation study, Aller-7 was found to have minimal irritancy to eyes of rabbits. In the repeated-dose 90-day oral toxicity study, Aller-7 was administered at dose levels of 100, 300, and 1,000 mg/kg rat body weight for 90 consecutive days by oral gavage. Aller-7 did not induce any significant change in the hematological parameters. No ocular abnormalities were observed. Some minor histopathological changes were observed, but did not reveal any significant treatment-related histopathological changes. The above findings revealed that the no observed adverse effect level (NOAEL) of Aller-7 is greater than 1,000 mg/kg body weight. Taken together, these studies demonstrate the broad spectrum safety of Aller-7.

Toxicol Mech Methods. 2005;15(3):193-204

Safety of a novel botanical extract formula for ameliorating allergic rhinitis.

Allergic rhinitis (also known as hay fever) is the most commonly occurring immunological disorder, and it affects 40 million men, women, and children in the United States. Symptomatically, it is an inflammation and irritation of the mucous membranes that line the nose. Allergy is defined as a state of hypersensitivity or hyperimmunity caused by exposure to a particular antigen (allergen) that results in increased reactivity upon subsequent exposure. A novel botanical formulation, Aller-7/NR-A2, was developed for the treatment of allergic rhinitis; it is a combination of medicinal plant extracts from Phyllanthus emblica, Terminalia chebula, Terminalia bellerica, Albizia lebbeck, Piper nigrum, Zingiber officinale, and Piper longum. This novel formulation has demonstrated potent antihistaminic, anti-inflammatory, antispasmodic, antioxidant, and mast-cell-stabilization activities. All of the doses for these toxicity studies were selected according to the guidelines of the Organization for Economic Cooperation and Development, the World Health Organization, and the Environmental Protection Agency. Acute toxicity of Aller-7 was evaluated in Swiss Albino mice at doses of 125, 250, 500, 1000, and 1500 mg/kg. After 15 days of treatment, the animals were sacrificed. No histopathological changes were observed in major vital organs. A similar study was conducted in Albino Wistar rats, which were sacrificed at the end of 15 days. No histopathological changes or toxicity was observed at up to 2 g/kg body weight. Subacute toxicity was conducted in Albino Wistar rats at a dose of 90 mg/kg body weight for 3 days, then at 180 mg/kg for the next 3 days, and then at 270 mg/kg for 3 weeks. After 28 days, the animals were sacrificed and tested; no toxicity was observed. In a subchronic toxicity study, there was no observed adverse effect level at 1 g/kg body weight in rats. In a teratological assay, at doses of 3.0 g/kg (20 times the recommended dose) and 1.8 g/kg, respectively, no visceral or skeletal anomalies were observed in the fetuses. No maternal changes were observed when Aller-7 was administered during gestation and lactation. No evidence of mutagenicity was observed at doses up to 5000 mug per plate of Aller-7 in Salmonella typhimurium cells. The present study evaluated the safety of Aller-7 by conducting several in vitro and in vivo studies. Further studies of the 90-day chronic toxicity of Aller-7 are currently in progress.

Toxicol Mech Methods. 2003;13(4):253-61

Proton pump inhibitor

Marked increase in proton pump inhibitors use in Australia.

OBJECTIVES: To examine the trends in the prescribing of subsidized proton pump inhibitors (PPIs) and histamine receptor antagonists (H2RAs), in the Australian population from 1995 to 2006 to encourage discussion regarding appropriate clinical use. PPIs and H2RAs are the second highest drug cost to the publicly subsidized Pharmaceutical Benefits Scheme (PBS). DESIGN: Government data on numbers of subsidized scripts, quantity and doses for PPIs and H2RAs were analysed by gender and age, dose and indication. MAIN OUTCOME MEASURE: Drug utilisation as DDD [defined daily dose]/1000 population/day. RESULTS: The use of combined PPIs increased by 1318%. Utilisation increased substantially after the relaxation of the subsidized indications for PPIs in 2001. Omeprazole had the largest market share but was substituted by its S-enantiomer esomeprazole after its introduction in 2002. There was considerable use in the elderly with the peak use being in those aged 80 years and over. The utilisation of H2RAs declined 72% over 12 years. CONCLUSIONS: PPI use has increased substantially, not only due to substitution of H2RAs but to expansion in the overall market. Utilisation does not appear to be commensurate with prevalence of gastro-oesophageal reflux disease (GORD) nor with prescribing guidelines for PPIs, with significant financial costs to patients and PBS. This study encourages clinical discussion regarding quality use of these medicines.

Pharmacoepidemiol Drug Saf. 2010 Oct;19(10):1019-24

Microglia, neuroinflammation, and beta-amyloid protein in Alzheimer's disease.

Compelling evidence from basic molecular biology has demonstrated the dual roles of microglia in the pathogenesis of Alzheimer's disease (AD). On one hand, microglia are involved in AD pathogenesis by releasing inflammatory mediators such as inflammatory cytokines, complement components, chemokines, and free radicals that are all known to contribute to beta-amyloid (Ab) production and accumulation. On the other hand, microglia are also known to play a beneficial role in generating anti-Ab antibodies and stimulating clearance of amyloid plaques. Ab itself, an inducer of microglia activation and neuroinflammation, has been considered as an underlying and unifying factor in the development of AD. A vicious cycle of inflammation has been formed between Ab accumulation, activated microglia, and microglial inflammatory mediators, which enhance Ab deposition and neuroinflammation. Thus, inhibiting the vicious cycle seems to be a promising treatment to restrain further development of AD. With increasing research efforts on microglia in AD, intervention of microglia activation and neuroinflammation in AD may provide a potential target for AD therapy in spite of the provisional failure of nonsteroidal antiinflammatory drugs in clinical trials.

Int J Neurosci. 2014 May;124(5):307-21

Microglia and inflammation in Alzheimer's disease.

One hundred and fifty years have elapsed since the original discovery of the microglial cell by Virchow. While this cell type has been well studied, the role of microglia in the pathology of many central nervous system diseases still remains enigmatic. It is widely accepted that microglial-mediated inflammation contributes to the progression of Alzheimer's disease (AD); however, the precise mechanisms through which these cells contribute to AD-related inflammation remains to be elucidated. In the AD brain, microglial cells are found in close association with amyloid beta (Abeta) deposits. Histological examination of AD brains as well as cell culture studies have shown that the interaction of microglia with fibrillar Abeta leads to their phenotypic activation. The conversion of these cells into a classically 'activated' phenotype results in production of chemokines, neurotoxic cytokines and reactive oxygen and nitrogen species that are deleterious to the CNS. However, microglia also exert a neuroprotective role through their ability to phagocytose Abeta particles and clear soluble forms of Abeta. These cells have been documented to play integral roles in tissue repair and inflammation, and in recent years it has been appreciated that this cell type is capable of facilitating a more complex response to pathogens by changing their activation status. A variety of new findings indicate that their role in the central nervous system is far more complex than previously appreciated. In this review we discuss the role of microglia in the normal brain and their phenotypic heterogeneity and how this may play a role in AD-related pathophysiology. We touch on what is known about their ability to recognize and clear Abeta peptides as well as more controversial topics, including various activation states of microglia and the ability of peripheral macrophages or monocytes to infiltrate the brain.

CNS Neurol Disord Drug Targets. 2010 Apr;9(2):156-67

Immune attack: the role of inflammation in Alzheimer disease.

The past two decades of research into the pathogenesis of Alzheimer disease (AD) have been driven largely by the amyloid hypothesis; the neuroinflammation that is associated with AD has been assumed to be merely a response to pathophysiological events. However, new data from preclinical and clinical studies have established that immune system-mediated actions in fact contribute to and drive AD pathogenesis. These insights have suggested both novel and well-defined potential therapeutic targets for AD, including microglia and several cytokines. In addition, as inflammation in AD primarily concerns the innate immune system - unlike in 'typical' neuroinflammatory diseases such as multiple sclerosis and encephalitides - the concept of neuroinflammation in AD may need refinement.

Nat Rev Neurosci. 2015 Jun;16(6):358-72

A Simulation Model of Periarterial Clearance of Amyloid-b from the Brain.

The accumulation of soluble and insoluble amyloid-b (Ab) in the brain indicates failure of elimination of Ab from the brain with age and Alzheimer's disease (AD). There is a variety of mechanisms for elimination of Ab from the brain. They include the action of microglia and enzymes together with receptor-mediated absorption of Ab into the blood and periarterial lymphatic drainage of Ab. Although the brain possesses no conventional lymphatics, experimental studies have shown that fluid and solutes, such as Ab, are eliminated from the brain along 100 nm wide basement membranes in the walls of cerebral capillaries and arteries. This lymphatic drainage pathway is reflected in the deposition of Ab in the walls of human arteries with age and AD as cerebral amyloid angiopathy (CAA). Initially, Ab diffuses through the extracellular spaces of gray matter in the brain and then enters basement membranes in capillaries and arteries to flow out of the brain. Although diffusion through the extracellular spaces of the brain has been well characterized, the exact mechanism whereby perivascular elimination of Ab occurs has not been resolved. Here we use a computational model to describe the process of periarterial drainage in the context of diffusion in the brain, demonstrating that periarterial drainage along basement membranes is very rapid compared with diffusion. Our results are a validation of experimental data and are significant in the context of failure of periarterial drainage as a mechanism underlying the pathogenesis of AD as well as complications associated with its immunotherapy.

Front Aging Neurosci. 2016 Feb 12;8:18.

Do Microglia Default on Network Maintenance in Alzheimer's Disease?

Although the cause of Alzheimer's disease (AD) remains unknown, a number of new findings suggest that the immune system may play a critical role in the early stages of the disease. Genome-wide association studies have identified a wide array of risk-associated genes for AD, many of which are associated with abnormal functioning of immune cells. Microglia are the brain's immune cells. They play an important role in maintaining the brain's extracellular environment, including clearance of aggregated proteins such as amyloid-b (Ab). Recent studies suggest that microglia play a more active role in the brain than initially considered. Specifically, microglia provide trophic support to neurons and also regulate synapses. Microglial regulation of neuronal activity may have important consequences for AD. In this article we review the function of microglia in AD and examine the possible relationship between microglial dysfunction and network abnormalities, which occur very early in disease pathogenesis.

J Alzheimers Dis. 2016;51(3):657-69

The proton-pump inhibitor lansoprazole enhances amyloid beta production.

A key event in the pathogenesis of Alzheimer's disease (AD) is the accumulation of amyloid-b (Ab) species in the brain, derived from the sequential cleavage of the amyloid precursor protein (APP) by b- and g-secretases. Based on a systems biology study to repurpose drugs for AD, we explore the effect of lansoprazole, and other proton-pump inhibitors (PPIs), on Ab production in AD cellular and animal models. We found that lansoprazole enhances Ab37, Ab40 and Ab42 production and lowers Ab38 levels on amyloid cell models. Interestingly, acute lansoprazole treatment in wild type and AD transgenic mice promoted higher Ab40 levels in brain, indicating that lansoprazole may also exacerbate Ab production in vivo. Overall, our data presents for the first time that PPIs can affect amyloid metabolism, both in vitro and in vivo.

PLoS One. 2013;8(3):e58837

Proton pump inhibitors: predisposers to Alzheimer disease?

The abnormal processing of amyloid-beta peptide (A beta) and resultant formation of fibrillar A beta (fA beta) are major events in the pathogenesis of Alzheimer disease (AD). Microglia as the phagocytic cells of the brain can engulf and digest fA beta within their acidic lysosomes. The lysosomes of AD patients are less acidic and therefore less capable of clearance of fA beta. Vacuolar proton pumps (V-ATPases) which are found abundantly in microglia and macrophages, acidify lysosomes by pumping protons into these structures. Proton pump inhibitors (PPIs) can inhibit V-ATPases of the lysosomes. These drugs are shown to penetrate the blood-brain barrier in animals. PPIs are consumed for long periods in conditions such as gastroesophageal reflux disease, with the resultant exposure of the human brain to the substantial amounts of PPIs. We hypothesize that by blocking the V-ATPases on microglial lysosomes, PPIs may basify lysosomes and hamper degradation of fA beta. Chronic consumption of PPIs may thus be a risk factor for AD.

J Clin Pharm Ther. 2010 Apr;35(2):125-6

Immune defense

Micronutrients at the interface between inflammation and infection--ascorbic acid and calciferol: part 1, general overview with a focus on ascorbic acid.

As elements of the antioxidant system, cofactors of enzymes, components of transcription factors, and epigenetic modulators, micronutrients, such as vitamins and trace elements, influence various metabolic processes that are directly associated with immune functions. Specifically, the vitamins C and D have been shown to have significance immune function. Therefore, the objective of this review is to elucidate interactions between micronutrients and the immune system. In the initial section of this review, we present a general overview of interactions between the immune system and micronutrients, with a focus on the immunobiologically relevant functions of vitamin C. Immune competent cells accumulate vitamin C against a concentration gradient, with a close relationship between vitamin C supply and immune cell activity, especially phagocytosis activity and T-cell function. Accordingly, one of the consequences of vitamin C deficiency is impaired resistance to various pathogens, while an enhanced supply increases antibody activity and infection resistance.

Inflamm Allergy Drug Targets. 2011 Feb;10(1):54-63

Immune-enhancing role of vitamin C and zinc and effect on clinical conditions.

Vitamin C concentrations in the plasma and leukocytes rapidly decline during infections and stress. Supplementation of vitamin C was found to improve components of the human immune system such as antimicrobial and natural killer cell activities, lymphocyte proliferation, chemotaxis, and delayed-type hypersensitivity. Vitamin C contributes to maintaining the redox integrity of cells and thereby protects them against reactive oxygen species generated during the respiratory burst and in the inflammatory response. Likewise, zinc undernutrition or deficiency was shown to impair cellular mediators of innate immunity such as phagocytosis, natural killer cell activity, and the generation of oxidative burst. Therefore, both nutrients play important roles in immune function and the modulation of host resistance to infectious agents, reducing the risk, severity, and duration of infectious diseases. This is of special importance in populations in which insufficient intake of these nutrients is prevalent. In the developing world, this is the case in low- and middle-income countries, but also in subpopulations in industrialized countries, e.g. in the elderly. A large number of randomized controlled intervention trials with intakes of up to 1 g of vitamin C and up to 30 mg of zinc are available. These trials document that adequate intakes of vitamin C and zinc ameliorate symptoms and shorten the duration of respiratory tract infections including the common cold. Furthermore, vitamin C and zinc reduce the incidence and improve the outcome of pneumonia, malaria, and diarrhea infections, especially in children in developing countries.

Ann Nutr Metab. 2006;50(2):85-94

Vitamin C supplementation slightly improves physical activity levels and reduces cold incidence in men with marginal vitamin C status: a randomized controlled trial.

The early indications of vitamin C deficiency are unremarkable (fatigue, malaise, depression) and may manifest as a reduced desire to be physically active; moreover, hypovitaminosis C may be associated with increased cold duration and severity. This study examined the impact of vitamin C on physical activity and respiratory tract infections during the peak of the cold season. Healthy non-smoking adult men (18-35 years; BMI < 34 kg/m2; plasma vitamin C < 45 µmol/L) received either 1000 mg of vitamin C daily (n = 15) or placebo (n = 13) in a randomized, double-blind, eight-week trial. All participants completed the Wisconsin Upper Respiratory Symptom Survey-21 daily and the Godin Leisure-Time Exercise Questionnaire weekly. In the final two weeks of the trial, the physical activity score rose modestly for the vitamin C group vs. placebo after adjusting for baseline values: +39.6% (95% CI [-4.5,83.7]; p = 0.10). The number of participants reporting cold episodes was 7 and 11 for the vitamin C and placebo groups respectively during the eight-week trial (RR = 0.55; 95% CI [0.33,0.94]; p = 0.04) and cold duration was reduced 59% in the vitamin C versus placebo groups (-3.2 days; 95% CI [-7.0,0.6]; p = 0.06). These data suggest measurable health advantages associated with vitamin C supplementation in a population with adequate-to-low vitamin C status.

Nutrients. 2014 Jul 9;6(7):2572-83

Immunologic modulation by vitamin C in the elderly.

Aging is associated with a decline in both humoral-mediated and cellular-mediated immunity. These aberrations may contribute to morbidity and mortality in the elderly. Since we have previously shown that vitamin C enhances in vitro and in vivo immune functions in young healthy volunteers, we studied the effects of vitamin C on certain immunologic parameters in an elderly population. In vitro lymphocyte proliferation to the mitogen concanavalin-A was significantly less when compared to a young control group. When lymphocytes from the elderly were pre-incubated overnight and cultured in the presence of 10 micrograms/ml of vitamin C, mitogen-stimulated lymphocyte proliferation was similar to that from controls without vitamin C in culture. Having demonstrated significant in vitro immunoenhancement with vitamin C, we next studied the effects of oral ingestion of 2 g of vitamin C daily on certain in vitro and in vivo immunologic parameters in the elderly. When compared with a placebo-treated group, 3 weeks of vitamin C treatment did not effect in vitro mitogen-stimulated lymphocyte proliferation or in vivo reactivity to common skin test antigens. The augmenting effects of in vitro vitamin C suggest that this essential vitamin may be an effective agent in modulating aberrant immunologic functions in the elderly. The clinical significance of these findings requires further study.

Int J Immunopharmacol. 1986;8(2):205-11

Vitamin C: is supplementation necessary for optimal health?

BACKGROUND: Consumption of vitamin C is essential for life in humans because the body does not synthesize it. Numerous studies have demonstrated that supplementation with vitamin C enhances the immune system, avoids DNA damage, and significantly decreases the risk of a wide range of pathologies, such as cancers, and degenerative and chronic diseases. Moreover, it has been demonstrated that modern crop production, transport, and food storage severely impair the quality of food and provoke a loss in micronutrients, such as vitamin C. OBJECTIVES: In this paper, we report that the Recommended Daily Allowance (RDA) in vitamin C is lower than the bodily needs. In fact, it does not seem to ensure true health protection and it appears difficult to reach an effective dose of vitamin C only through food consumption. Furthermore, the literature shows that vitamin C intake higher than the RDA is safe. Therefore, in order to achieve optimal health and avoid a number of diseases, we suggest that, in the present situation, vitamin C supplementation is required. CONCLUSIONS: According to the current literature, we would like to emphasize that to ensure an optimal allowance of vitamin C, we advise 1 g daily intake of vitamin C supplementation, accompanied by a diet rich in fruits and vegetables.

J Altern Complement Med. 2008 Dec;14(10):1291-8

On the epidemiology of influenza.

The epidemiology of influenza swarms with incongruities, incongruities exhaustively detailed by the late British epidemiologist, Edgar Hope-Simpson. He was the first to propose a parsimonious theory explaining why influenza is, as Gregg said, "seemingly unmindful of traditional infectious disease behavioral patterns." Recent discoveries indicate vitamin D upregulates the endogenous antibiotics of innate immunity and suggest that the incongruities explored by Hope-Simpson may be secondary to the epidemiology of vitamin D deficiency. We identify - and attempt to explain - nine influenza conundrums: (1) Why is influenza both seasonal and ubiquitous and where is the virus between epidemics? (2) Why are the epidemics so explosive? (3) Why do they end so abruptly? (4) What explains the frequent coincidental timing of epidemics in countries of similar latitude? (5) Why is the serial interval obscure? (6) Why is the secondary attack rate so low? (7) Why did epidemics in previous ages spread so rapidly, despite the lack of modern transport? (8) Why does experimental inoculation of seronegative humans fail to cause illness in all the volunteers? (9) Why has influenza mortality of the aged not declined as their vaccination rates increased? We review recent discoveries about vitamin D's effects on innate immunity, human studies attempting sick-to-well transmission, naturalistic reports of human transmission, studies of serial interval, secondary attack rates, and relevant animal studies. We hypothesize that two factors explain the nine conundrums: vitamin D's seasonal and population effects on innate immunity, and the presence of a subpopulation of "good infectors." If true, our revision of Edgar Hope-Simpson's theory has profound implications for the prevention of influenza.

Virol J. 2008 Feb 25;5:29

Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1,25-dihydroxyvitamin D3.

The innate immune system of mammals provides a rapid response to repel assaults from numerous infectious agents including bacteria, viruses, fungi, and parasites. A major component of this system is a diverse combination of cationic antimicrobial peptides that include the alpha- and beta-defensins and cathelicidins. In this study, we show that 1,25-dihydroxyvitamin D3 and three of its analogs induced expression of the human cathelicidin antimicrobial peptide (CAMP) gene. This induction was observed in acute myeloid leukemia (AML), immortalized keratinocyte, and colon cancer cell lines, as well as normal human bone marrow (BM) -derived macrophages and fresh BM cells from two normal individuals and one AML patient. The induction occurred via a consensus vitamin D response element (VDRE) in the CAMP promoter that was bound by the vitamin D receptor (VDR). Induction of CAMP in murine cells was not observed and expression of CAMP mRNA in murine VDR-deficient bone marrow was similar to wild-type levels. Comparison of mammalian genomes revealed evolutionary conservation of the VDRE in a short interspersed nuclear element or SINE in the CAMP promoter of primates that was absent in the mouse, rat, and canine genomes. Our findings reveal a novel activity of 1,25-dihydroxyvitamin D3 and the VDR in regulation of primate innate immunity.

FASEB J. 2005 Jul;19(9):1067-77

Respiratory epithelial cells convert inactive vitamin D to its active form: potential effects on host defense.

The role of vitamin D in innate immunity is increasingly recognized. Recent work has identified a number of tissues that express the enzyme 1alpha-hydroxylase and are able to activate vitamin D. This locally produced vitamin D is believed to have important immunomodulatory effects. In this paper, we show that primary lung epithelial cells express high baseline levels of activating 1alpha-hydroxylase and low levels of inactivating 24-hydroxylase. The result of this enzyme expression is that airway epithelial cells constitutively convert inactive 25-dihydroxyvitamin D(3) to the active 1,25-dihydroxyvitamin D(3). Active vitamin D that is generated by lung epithelium leads to increased expression of vitamin D-regulated genes with important innate immune functions. These include the cathelicidin antimicrobial peptide gene and the TLR coreceptor CD14. dsRNA increases the expression of 1alpha-hydroxylase, augments the production of active vitamin D, and synergizes with vitamin D to increase expression of cathelicidin. In contrast to induction of the antimicrobial peptide, vitamin D attenuates dsRNA-induced expression of the NF-kappaB-driven gene IL-8. We conclude that primary epithelial cells generate active vitamin D, which then influences the expression of vitamin D-driven genes that play a major role in host defense. Furthermore, the presence of vitamin D alters induction of antimicrobial peptides and inflammatory cytokines in response to viruses. These observations suggest a novel mechanism by which local conversion of inactive to active vitamin D alters immune function in the lung.

J Immunol. 2008 Nov 15;181(10):7090-9

Bioactive milk peptides: a prospectus.

Bioactive peptides have been identified within the amino acid sequences of native milk proteins. Hydrolytic reactions, such as those catalyzed by digestive enzymes, result in their release. These peptides directly influence numerous biological processes evoking behavioral, gastrointestinal, hormonal, immunological, neurological, and nutritional responses. The specific bioreactions associated with each physiological class have been well characterized. Herein, we review the scientific literature and attempt to stimulate consideration of the continued use of bioactive peptides and their expanded development as a commercial product. Several applications have already evolved. For example, phosphopeptides derived from casein fractions are currently used as both dietary and pharmaceutical supplements. Potentially, the addition of bioactive peptides to food products could improve consumer safety as a result of their antimicrobial properties. Lastly, bioactive peptides may function as health care products, providing therapeutic value for either treatment of infection or prevention of disease.

J Dairy Sci. 2000 Jun;83(6):1187-95

Esophageal acidity

Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs.

CONTEXT: Reduction of gastric acid secretion by acid-suppressive therapy allows pathogen colonization from the upper gastrointestinal tract. The bacteria and viruses in the contaminated stomach have been identified as species from the oral cavity. OBJECTIVE: To examine the association between the use of acid-suppressive drugs and occurrence of community-acquired pneumonia. DESIGN, SETTING, AND PARTICIPANTS: Incident acid-suppressive drug users with at least 1 year of valid database history were identified from the Integrated Primary Care Information database between January 1, 1995, and December 31, 2002. Incidence rates for pneumonia were calculated for unexposed and exposed individuals. To reduce confounding by indication, a case-control analysis was conducted nested in a cohort of incident users of acid-suppressive drugs. Cases were all individuals with incident pneumonia during or after stopping use of acid-suppressive drugs. Up to 10 controls were matched to each case for practice, year of birth, sex, and index date. Conditional logistic regression was used to compare the risk of community-acquired pneumonia between use of proton pump inhibitors (PPIs) and H2-receptor antagonists. MAIN OUTCOME MEASURE: Community-acquired pneumonia defined as certain (proven by radiography or sputum culture) or probable (clinical symptoms consistent with pneumonia). RESULTS: The study population comprised 364,683 individuals who developed 5551 first occurrences of pneumonia during follow-up. The incidence rates of pneumonia in non-acid-suppressive drug users and acid-suppressive drug users were 0.6 and 2.45 per 100 person-years, respectively. The adjusted relative risk for pneumonia among persons currently using PPIs compared with those who stopped using PPIs was 1.89 (95% confidence interval, 1.36-2.62). Current users of H2-receptor antagonists had a 1.63-fold increased risk of pneumonia (95% confidence interval, 1.07-2.48) compared with those who stopped use. For current PPI users, a significant positive dose-response relationship was observed. For H2-receptor antagonist users, the variation in dose was restricted. CONCLUSION: Current use of gastric acid-suppressive therapy was associated with an increased risk of community-acquired pneumonia.

JAMA. 2004 Oct 27;292(16):1955-60

Gastric acid-suppressive therapy and community-acquired respiratory infections.

BACKGROUND: Bacteria and viruses have been detected in the stomach of patients during acid-suppressive therapy. AIM: To investigate whether subjects using acid-suppressive drugs more often develop community-acquired respiratory infections when compared to those who do not use acid-suppressive drugs. METHODS: 700 study subjects were recruited during a single week in December 2002. Information on the prevalence of clinical manifestations of infections and complications in the preceding month was assessed by questionnaire. Furthermore, subjects were asked to report antibiotic therapy and physician visits related to possible infection. RESULTS: Questionnaires were returned by 405 subjects (58%). Consumption of acid-suppressive drugs was reported by 91 individuals, of whom 79 used proton-pump inhibitors (20%) and 12 H2-receptor antagonists (3%). Overall, 101 (25%) responders reported clinical manifestations of respiratory infection in the preceding month. Subjects using acid-suppressive drugs were 2.34 times [95% confidence interval (CI) 1.4-4.1] more likely to have clinical manifestations of infection than individuals not using acid-suppressive drugs. Subjects using acid-suppressive drugs visited a physician 3.72 times more often (95% CI 2.1-6.8) for an infection and received antibiotic therapy 4.19 times more often (95% CI 2.2-8.1) in comparison to individuals not using acid-suppressive drugs. CONCLUSIONS: Subjects using acid-suppressive drugs more often reported community-acquired respiratory infections in comparison to those who did not use acid-suppressive drugs.

Aliment Pharmacol Ther. 2003 Oct 15;18(8):847-51

Current understanding of the functional roles of aberrantly expressed microRNAs in esophageal cancer.

The incidence of esophageal cancer is rising, mostly because the increasing incidence of esophageal adenocarcinoma in Western countries. Despite improvements in diagnosis and treatment, the overall 5-year survival rates remain low. MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate the expression of target genes. Recently, disease specific miRNAs have been identified, which act as tumor suppressors or oncogenes. In this review, we will summarize the current knowledge about the function of aberrantly expressed miRNAs in esophageal cancer. We selected 5 miRNAs (miRNA-21, -143, -145, -196a and let-7) based on the available literature, and described their potential role in regulating pathways that are deregulated in esophageal cancer. Finally we will highlight the current achievements of using and targeting miRNAs. Because these miRNAs likely have important regulatory roles in cancer development, they open a therapeutic window for new treatment modalities.

World J Gastroenterol. 2016 Jan 7;22(1):1-7

Barrett's esophagus: Incidence, etiology, pathophysiology, prevention and treatment.

Barrett's esophagus is a metaplastic alteration of the normal esophageal epithelium that is detected on endoscopic examination and pathologically confirmed by the presence of intestinal metaplasia on biopsy. Its major significance is as a predisposing factor for esophageal adenocarcinoma, which carries a high mortality rate and a rapidly growing incidence in the United States. Detection of Barrett's esophagus allows for endoscopic surveillance in order to detect the potential development of dysplasia and early cancer before symptoms develop, and thereby significantly increases treatment options and may lower mortality from esophageal adenocarcinoma. Much current work in the field is aimed at reducing the risk of progression from Barrett's esophagus to cancer, and in the identification of biomarkers that may predict progression towards cancer. Barrett's esophagus is present in 10%-20% of patients with gastroesophageal reflux disease (GERD) and has also been detected in patients who deny classic GERD symptoms and are undergoing endoscopy for other indications. We used an evidence-based approach to describe treatment options for patients with Barrett's esophagus.

Ther Clin Risk Manag. 2007 Dec;3(6):1035-145

Use of proton pump inhibitors and the risk of community-acquired pneumonia: a population-based case-control study.

BACKGROUND: Recently, the use of proton pump inhibitors (PPIs) has been associated with an increased risk of pneumonia. We aimed to confirm this association and to identify the risk factors. METHODS: We conducted a population-based case-control study using data from the County of Funen, Denmark. Cases (n=7642) were defined as all patients with a first-discharge diagnosis of community-acquired pneumonia from a hospital during 2000 through 2004. We also selected 34 176 control subjects, who were frequency matched to the cases by age and sex. Data on the use of PPIs and other drugs, on microbiological samples, on x-ray examination findings, and on comorbid conditions were extracted from local registries. Confounders were controlled by logistic regression. RESULTS: The adjusted odds ratio (OR) associating current use of PPIs with community-acquired pneumonia was 1.5 (95% confidence interval [CI], 1.3-1.7). No association was found with histamine(2)-receptor antagonists (OR, 1.10; 95% CI, 0.8-1.3) or with past use of PPIs (OR, 1.2; 95% CI, 0.9-1.6). Recent initiation of treatment with PPIs (0-7 days before index date) showed a particularly strong association with community-acquired pneumonia (OR, 5.0; 95% 2.1-11.7), while the risk decreased with treatment that was started a long time ago (OR, 1.3; 95% CI, 1.2-1.4). Subgroup analyses revealed high ORs for users younger than 40 years (OR, 2.3; 95% CI, 1.3-4.0). No dose-response effect could be demonstrated. CONCLUSION: The use of PPIs, especially when recently begun, is associated with an increased risk of community-acquired pneumonia.

Arch Intern Med. 2007 May 14;167(9):950-5

Risk of Clostridium difficile infection with acid suppressing drugs and antibiotics: meta-analysis.

OBJECTIVES: Several studies have raised concern regarding the possible association between proton-pump inhibitors (PPIs) and Clostridium difficile infection (CDI). We aimed to perform a systematic review of incident and recurrent CDI in PPI users, and to evaluate the relative impact of concurrent antibiotic use, or switching acid suppression to histamine-2-receptor antagonists (H2RAs).

METHODS: We searched MEDLINE and EMBASE from inception to December 2011 for controlled observational studies that reported on the risk of CDI with and without PPI use. We performed random effects meta-analysis and assessed statistical heterogeneity using the I(2) statistic. RESULTS: We included 42 observational studies (30 case-control, 12 cohort) totalling 313,000 participants overall. Pooled analysis of 39 studies showed a statistically significant association between PPI use and risk of developing CDI, odds ratio (OR) 1.74 (95% confidence interval (CI) 1.47-2.85, P<0.001, I(2)=85%) compared with non-users. A pooled analysis of three studies showed a significant associated risk of recurrent CDI associated with PPIs, OR 2.51 (95% CI 1.16-5.44, P=0.005, I(2)=78%). Subgroup analysis failed to fully clarify the source of the substantial statistical heterogeneity. Adjusted indirect comparison demonstrated that use of H2RAs as an alternative carried a lower-risk OR 0.71 (95% CI 0.53-0.97) compared with PPIs. Conversely, concomitant use of PPI and antibiotics conferred a greater-risk OR 1.96 (95% CI 1.03-3.70) above that of PPIs alone. For PPI and antibiotics, the Rothman's synergy index was 1.36 and attributable proportion of risk from interaction 0.19, indicating an increased risk from interaction beyond the effects of each drug alone. CONCLUSIONS: Despite the substantial statistical and clinical heterogeneity, our findings indicate a probable association between PPI use and incident and recurrent CDI. This risk is further increased by concomitant use of antibiotics and PPI, whereas H2RAs may be less harmful.

Am J Gastroenterol. 2012 Jul;107(7):1011-9

Proton pump inhibitor use and the risk of small intestinal bacterial overgrowth: a meta-analysis.

BACKGROUND & AIMS: Use of proton pump inhibitors (PPIs) could predispose individuals to small intestinal bacterial overgrowth (SIBO) by altering the intraluminal environment and bacterial flora. There is controversy regarding the risk of SIBO among PPI users because of conflicting results from prior studies. A systematic review and meta-analysis were performed to evaluate the association between PPI use and SIBO, using objective clinical outcome measures. METHODS: Clinical studies comparing SIBO risk among adult users of PPIs vs nonusers were identified in MEDLINE/PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, and the National Institutes of Health Clinical Trials databases through July 2012. Two reviewers independently extracted data on study characteristics and outcomes. The primary metameter was the odds ratio (OR) of SIBO among PPI users vs nonusers. Subgroup analyses were performed to examine the influence of study characteristics, such as SIBO diagnostic modality, on study outcome. RESULTS: Eleven studies (n = 3134) met inclusion criteria. The pooled OR of SIBO in PPI users vs nonusers was 2.282 (95% confidence interval [CI], 1.238-4.205). No significant single large study or temporal effect was seen. Subgroup analysis revealed an association between SIBO and PPI use in studies that used duodenal or jejunal aspirate cultures to diagnose SIBO (OR, 7.587; 95% CI, 1.805-31.894), but no relationship was found between SIBO and PPI use in studies that used the glucose hydrogen breath test (OR, 1.93; 95% CI, 0.69-5.42). Funnel plot analysis identified 4 outlying studies, indicating the possible presence of publication bias. CONCLUSIONS: PPI use statistically was associated with SIBO risk, but only when the diagnosis was made by a highly accurate test (duodenal or jejunal aspirate culture). Differences in study results could arise from the use of different tests to diagnose SIBO.

Clin Gastroenterol Hepatol. 2013 May;11(5):483-90

Fracture risk and bone mineral density reduction associated with proton pump inhibitors.

Many patients receive prolonged proton pump inhibitor (PPI) therapy for upper gastrointestinal disorders, but the long-term safety of PPIs, particularly increased risk of hip and nonhip fractures, has been questioned. To summarize the current literature on the risk of bone mineral density (BMD) reduction and fracture associated with PPI therapy, we conducted a literature search to identify all pertinent studies from 1980-February 2011. A total of 14 observational studies were included in this review. Most studies evaluated the risk of fracture associated with prolonged PPI exposure. Eight studies found an increased fracture risk at the hip, and five studies found an increased fracture risk at the spine associated with PPIs. Three studies showed reduction in fracture risk associated with PPIs after discontinuation for 1 month-1 year. Three studies evaluated the risk of BMD reduction associated with PPIs but did not find consistent changes in baseline or subsequent BMD. The current data suggest a modest increase in the risk of hip fracture and vertebral fracture associated with PPIs, although some studies showed conflicting results. Further studies will be needed to determine whether the increased risk of fracture is due to PPI exposure or residual confounding.

Pharmacotherapy. 2012 Jan;32(1):67-79

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