Mucosal immunosenescence: new developments and vaccines to control infectious diseases.

Infection of the aero-digestive tract represents a major disease burden of the elderly, and despite recent advances in our understanding of the mucosal immune system, its immunosenescence remains poorly defined. Age-associated alterations of the intestinal and respiratory immune systems occur at distinct times and in a distinct manner. A reduction in gut-associated lymphoreticular tissues, intestinal antigen-specific IgA antibody responses and lack of oral tolerance induction are all associated with aging. By contrast, nasopharyngeal-associated lymphoreticular tissue function remains intact during aging with notable signs of immunosenescence seen only in the elderly. The distinct timing of mucosal immunosenescence seen between the gut and respiratory system suggests the nasal route of vaccination might be preferable for effective mucosal vaccines in the elderly.

Trends Immunol. 2009 Jul;30(7):334-43

Mucosal adjuvants for vaccines to control upper respiratory infections in the elderly.

Influenza virus and Streptococcus pneumoniae are two major pathogens that lead to significant morbidity and mortality in the elderly. Since both pathogens enter the host via the mucosa, especially the upper respiratory tract (URT), it is essential to elicit pathogen-specific secretory IgA (SIgA) antibody (Ab) responses at mucosal surfaces for defense of the elderly. However, as aging occurs, alterations in the mucosal immune system of older individuals result in a failure to induce SIgA Abs for protection from these infections. To overcome mucosal immunosenescence, we have developed a mucosal dendritic cell targeting, novel double adjuvant system which we show to be an attractive and effective immunological modulator. This system induces a more balanced Th1- and Th2-type cytokine response which supports both mucosal SIgA and systemic IgG1 and IgG2a Ab responses. Thus, adaptation of this adjuvant system to nasal vaccines for influenza virus and S. pneumoniae could successfully provide protection by supporting pathogen-specific SIgA Ab responses in the URT in the mouse model of aging. In summary, a double adjuvant system is considered to be an attractive and potentially important strategy for the future development of mucosal vaccines for the elderly.

Exp Gerontol. 2014 Jun;54:21-6

Regulation of IgA synthesis at mucosal surfaces.

Immunoglobulin A is the main element of the humoral immune response that has been selected through evolution, together with innate mucosal defences, to provide protection against microbial antigens at mucosal surfaces. IgA responses are initiated in organized inductive structures, such as Peyer's patches and nasal-associated lymphoid tissues, as well as diffuse effector tissues, such as gut lamina propria and nasal mucosa. Hypermutated secretory IgAs play a critical role in regulating the composition of the intestinal microflora. Dysregulation of gut homeostasis in IgA-deficient gut causes a continuous activation of the immune cells and induces inflammatory processes leading to lymphoneogenesis. Recent advances in this field include new insights into the role of IgA in the maintenance of gut homeostasis and the proposal of an updated model for the induction of IgA responses in the gut.

Curr Opin Immunol. 2004 Jun;16(3):277-83

The IgA system: a comparison of structure and function in different species.

The predominant immunoglobulin isotype on most mucosal surfaces is secretory immunoglobulin A (SIgA), a polypeptide complex comprising two IgA monomers, the connecting J chain, and the secretory component. The molecular stability and strong anti-inflammatory properties make SIgA particularly well suited to provide protective immunity to the vulnerable mucosal surfaces by preventing invasion of inhaled and ingested pathogens. In contrast to SIgA, IgA in serum functions as an inflammatory antibody through interaction with FcalphaR on immune effector cells. Although IgA appears to share common features and protective functions in different species, significant variations exist within the IgA systems of different species. This review will give an overview of the basic concepts underlying mucosal IgA defence which will focus on the variations present among species in structure, antibody repertoire development, pIgR-mediated transport, colostral IgA content, hepatobiliary transport, and function with particular emphasis on the IgA system of the pig and dog. These interspecies variations emphasise the importance of elucidating and analysing the IgA system within the immune system of the species of interest rather than inferring roles from conclusions made in human and mouse studies.

Vet Res. 2006 May-Jun;37(3):455-67

Bacillus probiotics.

Bacterial spore formers are being used as probiotic supplements for use in animal feeds, for human dietary supplements as well as in registered medicines. Their heat stability and ability to survive the gastric barrier makes them attractive as food additives and this use is now being taken forward. While often considered soil organisms this conception is misplaced and Bacilli should be considered as gut commensals. This review summarises the current use of Bacillus species as probiotics, their safety, mode of action as well as their commercial applications.

Food Microbiol. 2011 Apr;28(2):214-20

Multi-faceted functions of secretory IgA at mucosal surfaces.

Secretory IgA (SIgA) plays an important role in the protection and homeostatic regulation of intestinal, respiratory, and urogenital mucosal epithelia separating the outside environment from the inside of the body. This primary function of SIgA is referred to as immune exclusion, a process that limits the access of numerous microorganisms and mucosal antigens to these thin and vulnerable mucosal barriers. SIgA has been shown to be involved in avoiding opportunistic pathogens to enter and disseminate in the systemic compartment, as well as tightly controlling the necessary symbiotic relationship existing between commensals and the host. Clearance by peristalsis appears thus as one of the numerous mechanisms whereby SIgA fulfills its function at mucosal surfaces. Sampling of antigen-SIgA complexes by microfold (M) cells, intimate contact occurring with Peyer's patch dendritic cells (DC), down-regulation of inflammatory processes, modulation of epithelial, and DC responsiveness are some of the recently identified processes to which the contribution of SIgA has been underscored. This review aims at presenting, with emphasis at the biochemical level, how the molecular complexity of SIgA can serve these multiple and non-redundant modes of action.

Front Immunol. 2013 Jul 12;4:185

Influence of the oral administration of lactic acid bacteria on iga producing cells associated to bronchus.

Intestinal, respiratory and genitourinary mucosal surfaces are the most important routes of entry for microbial pathogens. The stimulus of the mucosal immunity is not easy because the trigger keys for the activation do not follow the ones of the systemic immune response. In previous works we have demonstrated that some Lactic Acid Bacteria (LAB), when orally administered, can induce an enhance of the gut immune response. Taking into account the concept of a common mucosal response, we studied the effect of orally administered mice with Lactobacillus casei, L. acidophilus, L. rhamnosus, L. delbrueckii subsp. bulgaricus, Streptococcus salivarius subsp. thermophilus and Lactococcus lactis on the IgA secreting cells associated to bronchus. As shown before, oral immunostimulation with LAB induced an increase of the IgA* cells at intestinal level by a dose depending effect. In this study it is also showed that the LAB assayed, with exception of L. acidophilus, were able to enhance IgA+ cells at bronchial level, being also this effect dose dependent. The increment induced by some LAB in the number of IgA+ cells on the mucosa surface of the lower respiratory tract may be very important to prevent bronchus diseases.

Int J Immunopathol Pharmacol. 1999 May-Aug;12(2):97-102

Effect of long term consumption of probiotic milk on infections in children attending day care centres: double blind, randomised trial.

OBJECTIVE: To examine whether long term consumption of a probiotic milk could reduce gastrointestinal and respiratory infections in children in day care centres. DESIGN: Randomised, double blind, placebo controlled study over seven months. SETTING: 18 day care centres in Helsinki, Finland. ARTICIPANTS: 571 healthy children aged 1-6 years: 282 (mean (SD) age 4.6 (1.5) years) in the intervention group and 289 (mean (SD) age 4.4 (1.5) years) in the control group. INTERVENTION: Milk with or without Lactobacillus GG. Average daily consumption of milk in both groups was 260 ml. MAIN OUTCOME MEASURES: Number of days with respiratory and gastrointestinal symptoms, absences from day care because of illness, respiratory tract infections diagnosed by a doctor, and course of antibiotics. RESULTS: Children in the Lactobacillus group had fewer days of absence from day care because of illness (4.9 (95% confidence interval 4.4 to 5.5) v 5.8 (5.3 to 6.4) days, 16% difference, P=0.03; age adjusted 5.1 (4.6 to 5.6) v 5.7 (5.2 to 6.3) days, 11% difference, P=0.09). There was also a relative reduction of 17% in the number of children suffering from respiratory infections with complications and lower respiratory tract infections (unadjusted absolute % reduction -8.6 (-17.2 to -0.1), P=0.05; age adjusted odds ratio 0.75 (0.52 to 1.09), P=0.13) and a 19% relative reduction in antibiotic treatments for respiratory infection (unadjusted absolute % reduction -9.6 (-18.2 to -1.0), P=0.03; adjusted odds ratio 0.72 (0.50 to 1.03), P=0.08) in the Lactobacillus group. CONCLUSIONS: Lactobacillus GG may reduce respiratory infections and their severity among children in day care. The effects of the probiotic Lactobacillus GG were modest but consistently in the same direction.

BMJ. 2001 Jun 2;322(7298):1327

Cimetidine: an immunomodulator.

Suppressor T lymphocytes possess histamine2 (H2) receptors and contribute significantly to the function of the immune system. Experimentally, cimetidine, an H2-receptor antagonist, has been shown to enhance a variety of immunologic functions both in vivo and in vitro because of its inhibitory effects on suppressor-cell function. Successful tumor immunotherapy, as well as some protection from infection, has been reported in experimental animals. Patients receiving cimetidine have been shown to exhibit enhanced cell-mediated immunity as evaluated by increased response to skin-test antigens, restoration of sensitivity following development of acquired tolerance, and increased responses of lymphocytes to mitogen stimulation. Preliminary reports also indicate that cimetidine may offer therapeutic benefits for patients with Varicella zoster and Herpes simplex infections, as well as those suffering from mucocutaneous candidiasis and common variable hypogammaglobulinemia. These immunoregulatory effects are dose-related but are not always consistent. Because of its inhibitory effect on suppressor function, cimetidine treatment may be deleterious in patients with organ transplant and autoimmune disorders. Cimetidine should be used as an immunomodulator on an experimental basis only.

DICP. 1990 Mar;24(3):289-95

Antimicrobial properties of Allium sativum (garlic).

Although garlic has been used for its medicinal properties for thousands of years, investigations into its mode of action are relatively recent. Garlic has a wide spectrum of actions; not only is it antibacterial, antiviral, antifungal and antiprotozoal, but it also has beneficial effects on the cardiovascular and immune systems. Resurgence in the use of natural herbal alternatives has brought the use of medicinal plants to the forefront of pharmacological investigations, and many new drugs are being discovered. This review aims to address the historical use of garlic and its sulfur chemistry, and to provide a basis for further research into its antimicrobial properties.

Appl Microbiol Biotechnol. 2001 Oct;57(3):282-6

Colds and influenza: a review of diagnosis and conventional, botanical, and nutritional considerations.

The common cold is the leading cause of doctor visits in the United States and annually results in 189 million lost school days. In the course of one year the U.S. population contracts approximately 1 billion colds. Influenza infection is still a leading cause of morbidity and mortality, accounting for 20-25 million doctor visits and 36,000 deaths per year in the United States. Conventional therapies for colds and flu focus primarily on temporary symptom relief and include over-the-counter antipyretics, anti-inflammatories, and decongestants. Treatment for influenza also includes prescription antiviral agents and vaccines for prevention. This article reviews the common cold and influenza viruses, presents the conventional treatment options, and highlights select botanicals (Echinacea spp., Sambucus nigra, larch arabinogalactan, Astragalus membranaceous, Baptisia tinctoria, Allium sativa, Panax quinquefolium, Eleutherococcus senticosus, Andrographis paniculata, olive leaf extract, and Isatis tinctoria) and nutritional considerations (vitamins A and C, zinc, high lactoferrin whey protein, N-acetylcysteine, and DHEA) that may help in the prevention and treatment of these conditions.

Altern Med Rev. 2007 Mar;12(1):25-48

Male lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH).

Male lower urinary tract symptoms, benign prostatic hyperplasia, enlargement of the prostate, and bladder outlet obstruction are common among aging men and will increase in socioeconomic and medical importance at a time of increased life expectancy and aging of the baby boomer generation. This article reviews the epidemiology, management, and therapeutic options for these conditions. In patients bothered by moderate to severe symptoms, providers can make educated and differential choices between several classes of drugs, alone or in combination, to treat effectively and improve the symptoms in most men. Despite the efficacy of medical therapy, there will be patients who require referral to a urologist either early, to rule out prostate cancer and other conditions, or later, after initial medical therapy and lifestyle management has failed. Perhaps as many as 30% of patients fail to achieve sufficient symptom improvement with medication, lifestyle adjustment, and fluid management, and may require more invasive or surgical treatment options.

Med Clin North Am. 2011 Jan;95(1):87-100

Management of the complications of BPH/BOO.

Most men will develop histological BPH if they live long enough. Approximately, half will develop benign prostatic enlargement (BPE) and about half of these will get BOO with high bladder pressures and low flow, this in turn leads to detrusor wall hypertrophy. Many of these men will only have lower urinary tract symptoms (LUTS) but a significant number will also suffer the other complications of BPH. These include urinary retention (acute and chronic), haematuria, urinary tract infection, bladder stones, bladder wall damage, renal dysfunction, incontinence and erectile dysfunction. Recognition of the complications of BPH/BOO early allows more effective management of these complications. This is particularly important for the more serious urinary infections and also for high-pressure chronic retention (HPCR). Complications of LUTS/BPH are very rare in clinical trials because of their strict inclusion and exclusion criteria but are more common in real life practice.

Indian J Urol. 2014 Apr;30(2):208-13

The effect of short sleep duration on coronary heart disease risk is greatest among those with sleep disturbance: a prospective study from the Whitehall II cohort.

STUDY OBJECTIVES: Short sleep duration is associated with increased CHD (coronary heart disease) mortality and morbidity, although some evidence suggests that sleep disturbance is just as important. We investigated whether a combination of short sleep duration and sleep disturbance is associated with a higher risk of CHD than their additive effects. SETTING: The Whitehall II study. PATIENTS OR PARTICIPANTS: The Whitehall II study recruited 10,308 participants from 20 civil service departments in London, England. Participants were between the ages of 35 and 55 years at baseline (1985-1988) and were followed up for an average of 15 years. INTERVENTIONS: N/A.MEASUREMENTS: Sleep hours and sleep disturbance (from the General Heath Questionnaire-30) were obtained from the baseline survey. CHD events included fatal CHD deaths or incident nonfatal myocardial infarction or angina (ICD-9 codes 410-414 or ICD-10 120-25). RESULTS: Short sleep duration and sleep disturbance were both associated with increased hazards for CHD in women as well as in men, although, after we adjusted for confounders, only those reporting sleep disturbance had a raised risk. There was some evidence for an interaction between sleep duration and sleep disturbance. Participants with short sleep duration and restless disturbed nights had the highest hazard ratios (HR) of CHD (relative risk:1.55, 95% confidence interval:1.33-1.81). Among participants who did not report any sleep disturbance, there was little evidence that short sleep hours increased CHD risk. CONCLUSION: The effect of short sleep (< or = 6 hours) on increasing CHD risk is greatest among those who reported some sleep disturbance. However, among participants who did not report any sleep disturbance, there was little evidence that short sleep hours increased CHD risk.

Sleep. 2010 Jun;33(6):739-44

Sleep duration as a risk factor for cardiovascular disease- a review of the recent literature.

Sleep loss is a common condition in developed countries, with evidence showing that people in Western countries are sleeping on average only 6.8 hour (hr) per night, 1.5 hr less than a century ago. Although the effects of sleep deprivation on our organs have been obscure, recent epidemiological studies have revealed relationships between sleep deprivation and hypertension (HT), coronary heart disease (CHD), and diabetes mellitus (DM). This review article summarizes the literature on these relationships. Because sleep deprivation increases sympathetic nervous system activity, this increased activity serves as a common pathophysiology for HT and DM. Adequate sleep duration may be important for preventing cardiovascular diseases in modern society.

Curr Cardiol Rev. 2010 Feb;6(1):54-61

Identification, pharmacologic considerations, and management of prostatitis.

BACKGROUND: Prostatitis is a collection of signs and symptoms that occur as a result of inflammation or swelling of the prostate gland. There are many different causes for prostatitis, including infection; occasionally no clear etiology for the inflammation is found. Effective treatment often depends on identification of the cause, but a microbiologic organism is not always detectable, especially in cases of chronic prostatitis. OBJECTIVE: The aim of this article was to review identification and treatment options for prostatitis, including pharmacologic and nonpharmacologic interventions. METHODS: Relevant information was identified through a search of MEDLINE (1966-June 2010), International Pharmaceutical Abstracts (1970-June 2010), and EMBASE (1947-June 2010). Randomized, controlled trials that examined prostate cancer, benign prostatic hypertrophy, or procedures related to the prostate (ie, biopsies) were excluded. RESULTS: A working classification system for prostatitis was developed in 1999, but there are few randomized controlled trials that distinguish between the various treatment options. Bacterial prostatitis can be acute or chronic but always requires some degree of antimicrobial therapy. Pharmacologic features of fluoroquinolones make them the preferred agents for most patients. These antibiotics can become trapped in a chronically inflamed prostate due to pH differences between prostatic tissue and serum. Many fluoroquinolones have penetration ratios (prostate level:serum level) of up to 4:1. A study in European men (N = 117) who received levofloxacin 500 mg/d with a diagnosis of chronic bacterial prostatitis demonstrated clinical success rates of 92% (95% CI 84.8%-96.5%), 77.4% (95% CI, 68.2-84.9%), 66.0% (95% CI, 56.2%-75.0%), and 61.9% (95% CI, 51.9%-71.2%) at 5-12 days, 1 month, 3 months, and 6 months after treatment. Additionally, there have been numerous randomized, placebo-controlled trials in patients with chronic prostatitis that have studied a-blockers, steroid inhibitors, anti-inflammatory agents, and bioflavonoids. Treatment responses to a-blockers appear to be greater with longer durations of therapy in a-blocker-naïve patients (National Institutes of Health-Chronic Prostatitis Symptom Index [NIH-CPSI] score reduction of at least 3.6 points after 6 weeks of tamsulosin therapy [P = 0.04] and up to 14.3 and 9.9 point NIH-CPSI score reductions with 14 weeks of terazosin and 24 weeks of alfuzosin therapy, respectively [P = 0.01 for both]). Combination therapy with an a-blocker, an anti-inflammatory, and a muscle relaxant does not appear to offer significant advantages over monotherapy (12.7 vs 12.4 point reduction in NIH-CPSI scores) and a stepwise approach to therapy involving antibiotics followed by bioflavonoids and then a-blockers appears to effectively reduce symptoms for up to 1 year in patients with chronic prostatitis (mean NIH-CPSI point reduction of 9.5 points compared with baseline, P < 0.0001). Patients who have had multiple unsuccessful treatment regimens may benefit from direct stimulation of the pelvic muscles through electromagnetic or electroacupuncture therapy. CONCLUSIONS: Prostatitis can resemble various other medical conditions but proper classification and an understanding of the pharmacologic features and expectations of the medications used to treat it can help identify effective treatment strategies. Fluoroquinolones are the preferred agents for treating bacterial causes of prostatitis and have demonstrated efficacy in some cases of chronic prostatitis when an organism has not been identified. However, the use of agents with anti-inflammatory or antiadrenergic properties may be necessary in combination with or after trying antimicrobial agents.

Am J Geriatr Pharmacother. 2011 Feb;9(1):37-48

Symptomatic diagnosis of prostate cancer in primary care: a structured review.

BACKGROUND: Prostate cancer has the second highest cancer incidence and mortality in European men. Most prostate cancers are diagnosed after lower urinary tract symptoms (LUTS) are presented to primary care, but such symptoms more often have a benign cause. A general practitioner (GP) has to try and identify which of these patients have prostate cancer. AIMS: To review the presenting features of symptomatic prostate cancer. DESIGN OF STUDY: Structured review. METHOD: We searched Medline from 1980 to 2003 for symptoms, signs, and investigations reported in prostate cancer. This list was then expanded by secondary searches of reference lists. We excluded studies on post-diagnostic topics, such as staging, treatment, and prognosis; studies on non-Western patients; and studies on investigations that are not available in primary care. A second cycle of exclusions removed studies whose results would not guide a GP in deciding whether a patient has prostate cancer. RESULTS: No studies from primary care compared prostate cancer patients directly with controls. Two secondary care studies had enough information to allow a comparison of symptoms in cases compared with controls. In these studies, symptoms were generally more prevalent in cases, but the differences were small. Screening and secondary care studies suggest that early prostate cancer is symptomless, and that locally advanced cancer has LUTS that are similar to those for benign prostatic hypertrophy. CONCLUSION: There is a very weak evidence base for the primary care diagnosis of prostate cancer in men with lower urinary tract symptoms.

Br J Gen Pract. 2004 Aug;54(505):617-21

With alpha blockers, finasteride and nettle root against benign prostatic hyperplasia. Which patients are helped by conservative therapy?

Symptomatic benign prostatic hyperplasia (BPH), which a man has a 50% chance of developing during the course of his lifetime, should receive stage-related treatment. While Vahlensieck stage I disease requires no therapy, stages II and III are indications for medication. Established medications for the treatment of BPH in current use are alpha-blockers, finasteride, and the phytotherapeutic agents pumpkin seed (cucurbitae semen), nettle root (urticae radix), the phytosterols contained in Hypoxis rooperi, rye pollen and the fruits of saw palmetto (sabalis serrulati fructus). If the patient responds, these medicaments can be given life-long, or intermittently. The hard criterion for the rational use of drug treatment of BPH is, over the long term, the reduction in the number of prostate operations. In stage IV disease surgical measures--after prior compensation of renal function--are to the fore.

MMW Fortschr Med. 2002 Apr 18;144(16):33-6

Epidemiology of benign prostatic syndrome. Associated risks and management data in German men over age 50.

In Germany, the condition of lower urinary tract symptoms (LUTS)/benign prostatic hypertrophy (BPH) is referred to as benign prostatic syndrome (BPS), reflecting the vast variation and interdependency of symptom severity, prostate volume, and micturition parameters. BPS is a progredient disease with distinguished risk factors for progression: age, symptom severity, prostate volume, and degree of obstruction. Therapy in Germany is provided by general practitioners and urologists. From a representative survey in Germany (the Herner BPS study), it can be calculated that among 11,674,900 men over 50 years of age, 3,230,000 have an enlarged prostate (benign prostatic enlargement, with prostate volume >25 ml). Moreover, 1,500,000 men with significant symptoms [International Prostate Symptom Score (IPSS) >7] have a prostate volume >40 ml, representing BPS with a high risk of progression, and 2,080,000 men show signs of obstruction (defined as Qmax <10 ml/s). Thirty percent of men with significant symptoms (IPSS >7) are treated medically, and an additional 20% have been prescribed medication for LUTS at least once. Ten percent of men in Germany are treated without evidence of symptoms. Based on published parameters of progression, 18.5% of men over 50 years of age will experience symptomatic progression (IPSS increase above four score points). Overall progression (symptomatic, surgery, or urinary retention) was 27% in 5 years. These findings show that BPS is a disease with substantial future effects on the German healthcare system.

Urologe A. 2008 Feb;47(2):141-8

Risk factors for lower urinary tract symptoms suggestive of benign prostatic hyperplasia in a community based population of healthy aging men: the Krimpen Study.

PURPOSE: We explored risk factors for lower urinary tract symptoms suggestive of benign prostatic hyperplasia in the open population. MATERIALS AND METHODS: A longitudinal, population based study with a followup of 6.5 years was done in 1,688 men who were 50 to 78 years old. Data were collected on transrectal ultrasound of prostate volume, urinary flow rate, ultrasound estimated post-void residual urine volume, generic and disease specific quality of life, and symptom severity based on the International Prostate Symptom Score. Lower urinary tract symptoms suggestive of benign prostatic hyperplasia were defined as an International Prostate Symptom Score of greater than 7 after a report of a score of less than 7 in the previous round. A multivariate Cox proportional hazard model was constructed to determine risk factors for clinical benign prostatic hyperplasia after correcting for patient age. RESULTS: Total followup was 4,353 person-years. During followup 180 events of attaining an International Prostate Symptoms Score of greater than 7 occurred. Multivariate analysis showed that functional bladder capacity, post-void residual urine volume, treatment for cardiac diseases, education level, antidepressant use, calcium antagonist use, erectile function or dysfunction, prostate specific antigen and a family history of prostate cancer were determinants with a significant HR. CONCLUSIONS: In addition to age, we established 9 significant determinants for lower urinary tract symptoms suggestive of benign prostatic hyperplasia. However, not all risk factors for lower urinary tract symptoms suggestive of benign prostatic hyperplasia are accounted for since we can conclude that 1 of 3 men without these risk factors will still be diagnosed with lower urinary tract symptoms suggestive of benign prostatic hyperplasia between ages 50 and 80 years.

J Urol. 2009 Feb;181(2):710-6

Pathogenic mechanisms linking benign prostatic hyperplasia, lower urinary tract symptoms and erectile dysfunction.

INTRODUCTION: Erectile dysfunction (ED) and lower urinary tract symptoms (LUTS) caused by benign prostatic hyperplasia (BPH) are clinical entities very prevalent in men aged over 50 years. There is evidence that both may have a common pathophysiology. OBJECTIVE: The objective of this study was to conduct a literature review aiming to show theories and hypotheses that justify a single pathophysiology for ED and LUTS/BPH. METHODS: A search in Medline using the keywords of the Medical Subject Headings (MESH) 'erectile dysfunction' and 'lower urinary tract symptoms' in all fields of the database up to 15 December 2012. This search found 198 relevant articles that were analyzed. RESULTS: The data and articles were divided according to the type of evidence found. There are strong epidemiological data showing that LUTS/BPH is a risk factor for developing ED. Several experimental models demonstrated partial obstruction of the bladder in animals causes voiding disorders as well as a negative impact on erectile function of the operated animals. The increased adrenergic tonus in animals leads to prostate growth and urodynamic conditions similar to those found in men with LUTS and ED. Arteriosclerosis may lead to loss of vesical complacency, urinary tract obstruction and fibrosis of the cavernous bodies. The use of phosphodiesterase type 5 inhibitors (PDE-5i) and/or alpha-adrenergic blockers to treat ED and LUTS/BPH reinforces the hypothesis that, at least in some patients, both clinical pictures may have the same pathophysiology.

Ther Adv Urol. 2013 Aug;5(4):211-8

A comparative randomized prospective study to evaluate efficacy and safety of combination of tamsulosin and tadalafil vs. tamsulosin or tadalafil alone in patients with lower urinary tract symptoms due to benign prostatic hyperplasia.

INTRODUCTION: Lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) and erectile dysfunction are common disorders of advancing age. AIM: To evaluate the efficacy and safety of tamsulosin and tadalafil in patients with LUTS due to BPH. METHODS: In this prospective randomized study, 133 men complaining of LUTS due to BPH were included. Forty-five patients received tamsulosin 0.4 mg/day alone (Group A), 44 patients received tadalafil 10 mg/day (Group B), and combination therapy (tamsulosin and tadalafil both) was instituted in 44 patients (Group C). After a 2-week medication free run-in period, they were evaluated for International Prostatic Symptom Score (IPSS), International Index of Erectile Function score (IIEF5), quality of life (IPSS QoL), maximum urinary flow rate (Qmax), post-void residual urine (PVR) volume, and safety parameters before and at 3 months of treatment. MAIN OUTCOME MEASURES: There were primary (IPSS, IPSS QoL index, Qmax, and PVR) and secondary (erectile function [EF] domain scores from IIEF5) efficacy end points. Safety assessment included laboratory tests and patient's reporting of adverse event. RESULTS: A significant improvement in IPSS score was observed in all the 3 groups A, B, and C (-50.90%, P < 0.05; -33.50%, P < 0.05; and -53.90%, P < 0.05, respectively). IIEF5 score increased significantly in these three groups (+39.28%, P < 0.05; +45.96%, P < 0.05; and +60.23%, P < 0.05, respectively). A significant increase in Qmax and decrease in PVR were also observed (33.99%, P < 0.05; 29.78%, P < 0.05; and 37.04%, P < 0.05) and (-60.90%, P < 0.05; -49.45%, P < 0.05; and -62.97%, P < 0.05, respectively). The QoL scores improved significantly (-73.35%, P < 0.05; -70.26%, P < 0.05; and -79.65%, P < 0.05, respectively). Side effects were dyspepsia, heartburn, headache, flushing, myalgia, and backache. Adverse effect dropout was 3.7%. No participant experienced any severe or serious adverse events. CONCLUSIONS: In patients with LUTS due to BPH, tamsulosin and tadalafil alone or in combination cause a significant improvement in patients with LUTS. Their EF also improves with these medications. The improvement is better with combination therapy compared with single agent alone.

J Sex Med. 2014 Jan;11(1):187-96

The efficacy of PDE5 inhibitors alone or in combination with alpha-blockers for the treatment of erectile dysfunction and lower urinary tract symptoms due to benign prostatic hyperplasia: a systematic review and meta-analysis.

INTRODUCTION: Erectile dysfunction (ED) and lower urinary tract symptoms (LUTS) are both highly prevalent in aging men. Alpha-blockers and PDE-5 inhibitors are widely used for the treatment of LUTS/benign prostatic hyperplasia (BPH) and ED. AIM: The purpose of this meta-analysis was to evaluate the efficacy of phosphodiesterase type 5 (PDE5) inhibitors alone or in combination with alpha-blockers for the treatment of ED and LUTS. METHODS: The databases MEDLINE, EMBASE, PubMed, the Cochrane Controlled Trial Register of Controlled Trials, and the Chinese Biological Medical Database were searched to identify randomized controlled trials that referred to the use of a combination of PDE5 inhibitors and alpha-blockers for the treatment of ED and LUTS associated with BPH. A systematic review and meta-analysis was conducted. MAIN OUTCOME MEASURES: International Prostate Symptom Score (IPSS), the maximum flow rate (Qmax), and International Index of Erectile Function-Erectile Function (IIEF-EF) domain score were used in this meta-analysis. RESULTS: Seven publications involving 515 patients were included in the meta-analysis. In the analysis, we found significantly improved IIEF, IPSS, and Qmax values in the combination use group compared with the use of PDE5 inhibitors alone (P = 0.04, 0.004, 0.007, respectively). CONCLUSIONS: The combined use of PDE5 inhibitors and alpha-blockers results in additive favorable effects in men with ED and LUTS suggestive of BPH compared with PDE5 inhibitor monotherapy. The alpha-blockers may enhance the efficacy of the PDE5 inhibitors, which is beneficial for the treatment of ED and LUTS.

J Sex Med. 2014 Jun;11(6):1539-45

Glaucoma and its association with obstructive sleep apnea: A narrative review.

SA) is one of the systemic risk factors for glaucoma which causes irreversible visual field (VF) damage. We reviewed the published data of all types of studies on the association between these two conditions and papers regarding functional and structural changes related to glaucomatous damage using Scopus, web of science, and PubMed databases. There is evidence that the prevalence of glaucoma is higher in OSA patients, which independent of intraocular pressure (IOP). Studies have reported thinning of retinal nerve fiber layer (RNFL), alteration of optic nerve head, choroidal and macular thickness, and reduced VF sensitivity in patients of OSA with no history glaucoma. A negative correlation of apnea-hypopnea index with RNFL and VF indices has been described in some studies. Raised IOP was noted which is possibly related to obesity, supine position during sleep, and raised intracranial pressure. Diurnal fluctuations of IOP show more variations in OSA patients before and after continuous positive airway pressure (CPAP) therapy when compared with the normal cases. The vascular factors behind the pathogenesis include recurrent hypoxia with increased vascular resistance, oxidative stress damage to the optic nerve. In conclusion, comprehensive glaucoma evaluation should be recommended in patients with OSA and should also periodically monitor IOP during CPAP treatment which may trigger the progression of glaucomatous damage.

Oman J Ophthalmol. 2016 Sep-Dec;9(3): 125-134

Genetics and genetic testing for glaucoma.

PURPOSE OF REVIEW: In recent decades, investigators have identified numerous genes and genetic factors that cause or contribute risk for glaucoma. These findings have increased our understanding of disease mechanisms, provided us with new diagnostic tools, and may allow for development of improved therapies for glaucoma. However, genetic testing is most useful when it is reserved for appropriate patients. The purpose of this article is to review key points and recent developments regarding the genetics and genetic testing for glaucoma and to provide recommendations for when genetic testing may be warranted. RECENT FINDINGS: Large genome-wide association studies have identified multiple new susceptibility loci associated with primary open angle glaucoma and primary angle closure glaucoma. SUMMARY: Several glaucoma-causing genes and genetic risk factors for glaucoma have been discovered. As a result, there are specific clinical scenarios in which genetic testing is warranted. In select cases (i.e., familial juvenile open angle glaucoma), genetic testing can serve as a powerful tool to improve diagnostic accuracy, efficiency of disease surveillance, and selection of treatment, enabling physicians to better optimize care for their patients.

Curr Opin Ophthalmol. 2017 Mar;28(2):133-138

Presence and Risk Factors for Glaucoma in Patients with Diabetes.

Diabetes mellitus represents a growing international public health issue with a near quadrupling in its worldwide prevalence since 1980. Though it has many known microvascular complications, vision loss from diabetic retinopathy is one of the most devastating for affected individuals. In addition, there is increasing evidence to suggest that diabetic patients have a greater risk for glaucoma as well. Though the pathophysiology of glaucoma is not completely understood, both diabetes and glaucoma appear to share some common risk factors and pathophysiologic similarities with studies also reporting that the presence of diabetes and elevated fasting glucose levels are associated with elevated intraocular pressure-the primary risk factor for glaucomatous optic neuropathy. While no study has completely addressed the possibility of detection bias, most recent epidemiologic evidence suggests that diabetic populations are likely enriched with glaucoma patients. As the association between diabetes and glaucoma becomes better defined, routine evaluation for glaucoma in diabetic patients, particularly in the telemedicine setting, may become a reasonable consideration to reduce the risk of vision loss in these patients.

Curr Diab Rep. 2016 Dec;16(12):124

Impact of Drugs on Glaucoma and Intraocular Pressure.

Purpose Systemic drugs may have unfavourable effects on intraocular pressure, glaucoma and the efficacy of glaucoma drugs. Material and Methods The article provides a review of the literature from PubMed and clinical experience. Results Topical and systemic corticosteroids induce complex changes inside the trabecular meshwork. New genetic results improve the understanding of pathogenetic processes, although many questions are still open. Arterial hypertension and antihypertonic drugs may influence the risk of glaucoma, intraocular pressure and ocular perfusion pressure. Intravitreal anti-VEGF therapy may be associated with the risk of sustained intraocular pressure elevation. Systemic drugs with parasympaticolytic activity (e.g. psychopharmaceuticals) are able to induce acute angle block glaucoma. Conclusion New insights into the interactions between drugs (e.g. antihypertensives, corticosteroids) and glaucomatous optic neuropathy affect large patient groups and may improve understanding of the underlying pathogenetic processes in open angle glaucoma. There is a great need for further clinical and experimental research.

Klin Monbl Augenheilkd. 2017 Feb;234(2): 179-184

Configuration of the drainage angle, intraocular pressure, and optic disc cupping in subjects with chronic angle-closure glaucoma.

OBJECTIVE: To investigate the relationship between drainage angle configuration with untreated intraocular pressure (IOP) and optic disc cupping in subjects with chronic angle-closure glaucoma (CACG). DESIGN: Prospective, observational study. PARTICIPANTS: Two hundred seventy-five Asian subjects with CACG who participated in a randomized controlled trial that investigated the IOP-reducing effect of latanoprost and timolol. METHODS: Chronic angle-closure glaucoma was defined as the presence of glaucomatous optic neuropathy (with or without a visual field defect), an anterior chamber angle in which the pigmented trabecular meshwork was not visible for at least 180 degrees on gonioscopy, and evidence of peripheral anterior synechiae (PAS) in association with elevated IOP of 21 mmHg or more. Static and dynamic gonioscopy were performed, the angles were graded in each quadrant according to the Shaffer scheme, and the number of clock hours of PAS was recorded. The untreated IOP and vertical cup-to-disc ratio were correlated with mean angle width and extent of PAS. MAIN OUTCOME MEASURES: Mean angle width, clock hours of PAS, IOP, and vertical cup-to-disc ratio. RESULTS: Most subjects were female (75%), and the mean age was 62.9+/-9.4 years. The mean angle width was 0.77+/-0.53 and the mean number of clock hours of PAS was 4.77+/-3.2 hours. Untreated IOP correlated with angle width (r = -0.23; P<0.001) and clock hours of PAS (r = 0.22; P<0.001). Vertical cup-to-disc ratio also correlated with angle width (r = -0.17; P = 0.004) and PAS (r = 0.28; P<0.001). Performing a multiple linear regression using baseline IOP as the outcome variable with age, gender, clock hours of PAS, and angle width as predictors, there was a 0.39-mmHg (95% confidence interval, 0.15-0.63) increase in baseline untreated IOP for each unit increase in clock hours of PAS (P = 0.002). CONCLUSIONS: In subjects with CACG, the e of the drainage angle were associated with higher untreated IOP and a larger vertical cup-to-disc ratio.

Ophthalmology. 2005 Jan;112(1):28-32

The progress in optic nerve regeneration, where are we?

Optic nerve regeneration is an important area of research. It can be used to treat patients suffering from optic neuropathy and provides insights into the treatment of numerous neurodegenerative diseases. There are many hurdles impeding optic regeneration in mammals. The mammalian central nervous system is non-permissive to regeneration and intrinsically lacks the capacity for axonal regrowth. Any axonal injury also triggers a vicious cycle of apoptosis. Understanding these hurdles provides us with a rough framework to appreciate the essential steps to bring about optic nerve regeneration: enhancing neuronal survival, axon regeneration, remyelination and establishing functional synapses to the original neuronal targets. In this review article, we will go through current potential treatments for optic nerve regeneration, which includes neurotrophic factor provision, inflammatory stimulation, growth inhibition suppression, intracellular signaling modification and modeling of bridging substrates.

Neural Regen Res. 2016 Jan;11(1):32-6

Disease progression and the need for neuroprotection in glaucoma management.

Glaucoma, the second leading cause of worldwide blindness, is a progressive optic neuropathy characterized by a loss of retinal ganglion cells and their axons beyond typical age-related baseline loss. Diagnosis is defined by optic disc and visual field changes, and the primary goal of glaucoma treatment is to preserve vision. Proven existing therapies (ie, pharmacotherapy, laser, and surgical) focus on reduction of intraocular pressure (IOP), although elevated IOP is no longer a diagnostic feature of glaucoma. New neuroprotectant drugs are being investigated, with the goal of reducing retinal ganglion cell loss, either prophylactically or after the insult has occurred. Various treatment strategies are being evaluated, and include a neuroprotectant only, or a complete therapy approach comprised of both a neuroprotectant supplemented by an IOP-lowering therapy. Dually targeted complete therapy may directly preserve the optic nerve, decrease the risk factors that cause glaucoma damage, and reduce glaucoma-related morbidities. Neuroprotectant therapy outcomes should include functional and structural effects of disease progression and neuroprotectant therapies, as well as patient functioning and economic impact.

Am J Manag Care. 2008 Feb;14(1 Suppl):S15-9

Neuroprotection in glaucoma - Is there a future role?

In glaucoma, the major cause of global irreversible blindness, there is an urgent need for treatment modalities that directly target the RGCs. The discovery of an alternative therapeutic approach, independent of IOP reduction, is highly sought after, due to the indirect nature and limited effectiveness of IOP lowering therapy in preventing RGC loss. Several mechanisms have been implicated in initiating the apoptotic cascade in glaucomatous retinopathy and numerous drugs have been shown to be neuroprotective in animal models of glaucoma. These mechanisms and their potential treatment include excitotoxicity, protein misfolding, mitochondrial dysfunction, oxidative stress, inflammation and neurotrophin deprivation. All of these mechanisms ultimately lead to programmed cell death with loss of RGCs. In this article we summarize the mechanisms involved in glaucomatous disease, highlight the rationale for neuroprotection in glaucoma management and review current potential neuroprotective strategies targeting RGCs from the laboratory to the clinic.

Exp Eye Res. 2010 Nov;91(5):554-66

Open-angle glaucoma.

Glaucoma is the second most common cause of legal blindness in the United States. Open-angle glaucoma is an asymptomatic, progressive optic neuropathy characterized by enlarging optic disc cupping and visual field loss. Patients at increased risk for open-angle glaucoma include blacks older than 40 years, whites older than 65 years, and persons with a family history of glaucoma or a personal history of diabetes or severe myopia. Elevated intraocular pressure is a strong, modifiable risk factor for open-angle glaucoma, but it is not diagnostic. Some patients with glaucoma have normal intraocular pressure (i.e., normal-pressure glaucoma), and many patients with elevated intraocular pressure do not have glaucoma (i.e., glaucoma suspects). Routine measurement of intraocular pressure by primary care physicians to screen patients for glaucoma is not recommended. Open-angle glaucoma usually is discovered during an adult eye evaluation performed for other indications. Final diagnosis and treatment occur in collaboration with ophthalmologists and optometrists. Formal visual field testing (perimetry) is a mainstay of glaucoma diagnosis and management. Eye drops, commonly nonspecific beta-blocker or prostaglandin analog drops, generally are the first-line treatment to reduce intraocular pressure. Laser treatment and surgery usually are reserved for patients in whom medical treatment has failed. Without treatment, open-angle glaucoma can end in irreversible vision loss.

Am Fam Physician. 2003 May 1;67(9):1937-44

Protective effects of bilberry (Vaccinium myrtillus L.) extract against endotoxin-induced uveitis in mice.

Endotoxin-induced uveitis (EIU), a useful animal model of ocular inflammation, is induced by injection of lipopolysacharide (LPS). These experiments showed that the nitric oxide (NO) level significantly increased in the whole eye homogenate of BALB/C mice 24 h after footpad injection of LPS at a dosage of 100 mg/mouse. However, the elevated NO level was significantly reduced by oral administration of bilberry extract (containing 42.04% anthocyanins) at dosages of 50, 100, and 200 mg/kg/day for 5 days before the LPS injection. In addition, bilberry extract decreased malondialdehyde (MDA) level and increased oxygen radical absorbance capacity (ORAC) level, glutathione (GSH) level, vitamin C level, and total superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities. Moreover, bilberry extract increased expression of copper/zinc superoxide dismutase (CuZnSOD), manganese superoxide dismutase (MnSOD), and GPx mRNA. Taken together, bilberry extract showed protective effects against EIU, whereas the effects of bilberry extract (100 and 200 mg/kg/day, 5 days) were dose-dependent. In conclusion, these results provide new evidence to elucidate the beneficial effects of bilberry extract on eye health.

J Agric Food Chem. 2010 Apr 28;58(8):4731-6

Bilberry (Vaccinium myrtillus) anthocyanins modulate heme oxygenase-1 and glutathione S-transferase-pi expression in ARPE-19 cells.

PURPOSE: To determine whether anthocyanin-enriched bilberry extracts modulate pre- or posttranslational levels of oxidative stress defense enzymes heme-oxygenase (HO)-1 and glutathione S-transferase-pi (GST-pi) in cultured human retinal pigment epithelial (RPE) cells. METHODS: Confluent ARPE-19 cells were preincubated with anthocyanin and nonanthocyanin phenolic fractions of a 25% enriched extract of bilberry (10(-6)-1.0 mg/mL) and, after phenolic removal, cells were oxidatively challenged with H(2)O(2). The concentration of intracellular glutathione was measured by HPLC and free radical production determined by the dichlorofluorescin diacetate assay. HO-1 and GST-pi protein and mRNA levels were determined by Western blot and RT-PCR, respectively. RESULTS: Preincubation with bilberry extract ameliorated the intracellular increase of H(2)O(2)-induced free radicals in RPE, though H(2)O(2) cytotoxicity was not affected. By 4 hours, the extract had upregulated HO-1 and GST-pi protein by 2.8- and 2.5-fold, respectively, and mRNA by 5.5- and 7.1-fold, respectively, in a dose-dependent manner. Anthocyanin and nonanthocyanin phenolic fractions contributed similarly to mRNA upregulation. CONCLUSIONS: Anthocyanins and other phenolics from bilberry upregulate the oxidative stress defense enzymes HO-1 and GST-pi in RPE, suggesting that they stimulate signal transduction pathways influencing genes controlled by the antioxidant response element.

Invest Ophthalmol Vis Sci. 2007 May;48(5): 343-9