Association between coffee and green tea intake and pneumonia among the Japanese elderly: a case-control study.

A large prospective cohort study in the United States examined the association between coffee intake and overall and cause-specific mortality and showed a inverse association between pneumonia and influenza deaths and coffee intake. In Japan, the mortality rate of pneumonia in elderly people is high, and its prevention is an important issue. The present study investigated the association between coffee and green tea intake and pneumonia among the elderly. The design was a hospital-based case control study. The cases were patients over 65 years old newly diagnosed as pneumonia. As a control, patients with the same sex and age (range of 5 years) who visited the same medical institution around the same time (within 2 months after examination of the case) for a disease other than pneumonia were selected. There were two controls per case. Odds ratio (OR) and 95% confidence interval (CI) for pneumonia of coffee and green tea intake during the past month were calculated using a conditional logistic regression model. A total of 199 cases and 374 controls were enrolled. When compared to those who do not drink coffee, the OR for pneumonia of those who drink less than one cup of coffee per day was 0.69 (95% CI 0.39-1.21), OR of those who drink one cup was 0.67 (0.38-1.18), and OR of those who drink two or more cups was 0.50 (0.28-0.88) (Trend p = 0.024). No association was found between pneumonia and green tea consumption. This study suggested a preventive association between coffee intake over 2 cups per day and pneumonia in the elderly.

Deep Negative Deflection in Unipolar His-Bundle Electrogram as a Predictor of Excellent His-Bundle Pacing Threshold Postimplant.

Background His-bundle pacing (HBP) is a physiological form of pacing. Although high capture thresholds are common, few predictors of low HBP threshold have been determined. We aimed to identify electrophysiological predictors. Methods Fifty-one patients (53% with atrioventricular block) underwent HBP for bradycardia with an intrinsic QRS duration of <120 ms. Attempts to anchor the HBP lead were guided by unipolar His-bundle electrograms (HB EGMs) recorded with an electrophysiology recording system. Patients were followed-up for >6 months. Results In total, 153 attempts at anchoring the HBP lead were made, of which, 45 achieved acceptable HBP thresholds (≤2.5 V at 1 ms). The amplitude of negative deflection in HB EGM and the selective HBP form at fixation were independently associated with achieving an acceptable threshold. A negative amplitude of ≥0.060 mV in HB EGM was determined as the optimal value for identifying the acceptable threshold. This deep negative HB EGM was recorded with an HBP threshold of 1.4±1.3 V (in 34 attempts), significantly lower than that of positive HB EGM without deep negative deflection (2.8±1.3 V, in 31 trials; or >5 V, in 38 trials). The permanent HBP lead remained with deep negative (≥0.060 mV) or positive HB EGMs in 28 and 14 patients, respectively, and with positive or negative HB injury current in 19 and 23 patients, respectively. During follow-up, increased HBP threshold of >1 V was significantly more prevalent in the positive HB EGM group. The HBP thresholds of deep negative HB EGM and HB injury current, but not of the selective HBP group, were significantly lower than the other subgroups during follow-up. Conclusions Deep negative HB EGM at fixation was associated with an excellent short-term HBP threshold, similar to HB injury current. Analysis of unipolar HB EGM postfixation may enable prediction of permanent HBP threshold.

Modeling Retinal Diseases Using Genetic Approaches in Mice.

Genetic mouse models mimicking human diseases have been developed and utilized for retinal research in various topics, involving anatomy, physiology, biochemistry, and pathology. The main reasons why mouse models are important for retinal research include that rodents share a key retinal homology with humans and that genetic manipulation is relatively easily applicable for mice. Here, we describe genetic mouse models, which are categorized with functions in the retina and relationship with human diseases.

Docosahexaenoic acid promotes differentiation of photoreceptor cells in three-dimensional neural retinas.

Retinal tissues generated from human pluripotent stem cells can be an excellent tool for investigating pathogenesis of retinal diseases and developing new pharmacologic therapies. Moreover, patient derived retinal tissues could allow for retinal transplantation therapy for degenerative retinal diseases. However, obtaining retinal tissues with matured photoreceptor outer segments, which are essential for photoreceptor functions, is currently challenging. Here we investigated the effects of docosahexaenoic acid (DHA) for maturation of photoreceptor outer segments at the late stage and visual chromophore analog, 9-cis-retinal for the early stage of differentiation to three-dimensional (3D)-retinal tissues from human embryonic stem cells (hESCs), respectively. In the presence of DHA, differentiated 3D-retinal tissues demonstrated improved maturation of photoreceptor outer segments and increased number of photoreceptor cells compared with tissues without DHA. Increased mRNA expression of mature photoreceptor markers was additionally documented in retinal tissues cultured with DHA. Conversely supplementation with 9-cis-retinal failed to improve differentiation of retinal tissues perhaps due to chronic aldehyde toxicity. The current study demonstrated that the addition of DHA to culture medium can help promote differentiation of photoreceptor outer segments in vitro and utilization of this methodology may lead to future therapies for patients with blinding diseases.

Investing in nursing and midwifery enterprise to empower women and strengthen health services and systems: An emerging global body of work.

In September of 2014, the Institute of Medicine (IOM) convened a global Rockefeller Bellagio Center workshop focusing on the largely overlooked area of investment in nursing and midwifery enterprise as a means for both empowering women and strengthening health systems and services. The report of this meeting, Empowering Women and Strengthening Health Systems and Services Through Investing in Nursing and Midwifery Enterprise: Lessons from Lower-Income Countries: Workshop Summary, was released in February, 2015. This report represents a pivotal point in a growing body of work begun in 2012, providing insights and perspectives of global experts that have resulted in subsequent global discussions and are paving the way for the future. This three-part article summarizes the initial exploration leading to the IOM workshop and report, followed by highlights and insights from the report and related meetings, and authors concluding discussion of implications for the future and next steps.

Manganese-Enhanced MRI for Preclinical Evaluation of Retinal Degeneration Treatments.

PURPOSE: Apply manganese-enhanced magnetic resonance imaging (MEMRI) to assess ion channel activity and structure of retinas from mice subject to light-induced retinal degeneration treated with prophylactic agents. METHODS: Abca4(-/-)Rdh8(-/-) double knockout mice with and without prophylactic retinylamine (Ret-NH2) treatment were illuminated with strong light. Manganese-enhanced MRI was used to image the retina 2 hours after intravitreous injection of MnCl2 into one eye. Contrast-enhanced MRIs of the retina and vitreous humor in each experimental group were assessed and correlated with the treatment. Findings were compared with standard structural and functional assessments of the retina by optical coherence tomography (OCT), histology, and electroretinography (ERG). RESULTS: Manganese-enhanced MRI contrast in the retina was high in nonilluminated and illuminated Ret-NH2-treated mice, whereas no enhancement was evident in the retina of the light-illuminated mice without Ret-NH2 treatment (P < 0.0005). A relatively high signal enhancement was also observed in the vitreous humor of mice treated with Ret-NH2. Strong MEMRI signal enhancement in the retinas of mice treated with retinylamine was correlated with their structural integrity and function evidenced by OCT, histology, and a strong ERG light response. CONCLUSIONS: Manganese-enhanced MRI has the potential to assess the response of the retina to prophylactic treatment based on the measurement of ion channel activity. This approach could be used as a complementary tool in preclinical development of new prophylactic therapies for retinopathies.

Supplementation with vitamin a derivatives to rescue vision in animal models of degenerative retinal diseases.

The perception of light begins when photons reach retinal tissue located at the back of the eye and photoisomerize the visual chromophore 11-cis-retinal to all-trans-retinal within photoreceptor cells. Isomerization of 11-cis-retinal activates the protein rhodopsin located in photoreceptor outer segments, thereby inducing a phototransduction cascade leading to visual perception. To maintain vision, 11-cis-retinal is regenerated in the retinal pigmented epithelium (RPE) via the visual cycle and delivered back to the photoreceptor cells where it may again bind to rhodopsin. Distinct pathological mechanisms have been observed to contribute to inherited retinal degenerative diseases including severe delay in 11-cis-retinal regeneration and delayed clearance of all-trans-retinal, which leads to the accumulation of harmful retinoid by-products. In the last decade, our group has conducted several proof-of-concept (POC) studies with retinoid derivatives aimed at developing treatments for retinal degenerative diseases caused by an impaired visual cycle. Here, we will introduce experimental procedures, which have been developed for POC studies involving retinoid biology.

Systems pharmacology identifies drug targets for Stargardt disease-associated retinal degeneration.

A systems pharmacological approach that capitalizes on the characterization of intracellular signaling networks can transform our understanding of human diseases and lead to therapy development. Here, we applied this strategy to identify pharmacological targets for the treatment of Stargardt disease, a severe juvenile form of macular degeneration. Diverse GPCRs have previously been implicated in neuronal cell survival, and crosstalk between GPCR signaling pathways represents an unexplored avenue for pharmacological intervention. We focused on this receptor family for potential therapeutic interventions in macular disease. Complete transcriptomes of mouse and human samples were analyzed to assess the expression of GPCRs in the retina. Focusing on adrenergic (AR) and serotonin (5-HT) receptors, we found that adrenoceptor α 2C (Adra2c) and serotonin receptor 2a (Htr2a) were the most highly expressed. Using a mouse model of Stargardt disease, we found that pharmacological interventions that targeted both GPCR signaling pathways and adenylate cyclases (ACs) improved photoreceptor cell survival, preserved photoreceptor function, and attenuated the accumulation of pathological fluorescent deposits in the retina. These findings demonstrate a strategy for the identification of new drug candidates and FDA-approved drugs for the treatment of monogenic and complex diseases.

Evaluation of 9-cis-retinyl acetate therapy in Rpe65-/- mice.

PURPOSE: Mice lacking retinal pigment epithelium-specific 65-kDa protein (RPE65) develop retinopathy and blindness resembling Leber congenital amaurosis. Effects of 9-cis-retinyl acetate (9-cis-R-Ac) on visual function and retinopathy progression were tested in Rpe65(-/-) mice. METHODS: Young C57Bl/6 mice were given 9-cis-R-Ac in each of four different oil-based vehicle solutions by gastric gavage to identify the vehicle most suitable for drug delivery by measuring retinoid levels in plasma. Then doses of 9-cis-R-Ac ranging from 1 to 100 mg/kg were administered to 5- to 12-week-old Rpe65(-/-) mice by different treatment regimens, including single doses and either intermittent or daily doses for various periods up to 8 weeks. Retinoid effects on visual function were evaluated by electroretinography, retinoid analyses, histologic methods, and vision-dependent behavioral testing. RESULTS: Soybean oil vehicle provided the highest 9-cis-R-Ac metabolite levels in plasma. Single doses of 9-cis-R-Ac (6.25-50 mg/kg) provided significant dose-dependent improvement in electroretinographic responses. Well-tolerated daily doses (1-12.5 mg/kg) for 2 weeks induced remarkable improvement of retinal function. Significant dose-dependent improvement of electroretinographic responses was observed 6 days after administration of 9-cis-R-Ac daily for 3 days at 1 to 12.5 mg/kg. Mice given either daily or intermittent 9-cis-R-Ac treatment at 1 and 4 mg/kg and evaluated 8 weeks later displayed dose-dependent improvement of retinal function and morphology, whereas retinal function deteriorated in control animals. Treated mice also performed better than control animals in vision-dependent behavioral tests. CONCLUSIONS: Treatment with 9-cis-R-Ac improves visual function and preserves retinal morphology in Rpe65(-/-) mice.

Co-administration of l-cystine and l-theanine enhances efficacy of influenza vaccination in elderly persons: nutritional status-dependent immunogenicity.

AIM: The immune response to influenza vaccine is attenuated in elderly persons, though they are at greatest risk for morbidity and mortality by influenza virus infection. Experimental studies demonstrate that co-administration of l-cystine and l-theanine enhanced antigen-specific production of immunoglobulin in aged mice infected with influenza virus. We thus investigated the effect of l-cystine and l-theanine on antibody induction by influenza vaccines in elderly persons. METHODS: Residents in a nursing home were randomly allocated to l-cystine and l-theanine (n = 32) or placebo (n = 33). The test substances were administered p.o. for 14 days before immunization. Serum influenza virus antibody titers were measured before and 4 weeks after vaccination. RESULTS: Vaccination significantly elevated hemagglutination inhibition (HI) titers for all the three strains of influenza viruses (A/New Caledonia [H1N1], A/New York [H3N2] and B/Shanghai) in both groups. HI titers after vaccination were not significantly different between the two groups for either strain. Also, the seroconversion rate was not significantly different between the two groups in the aggregate. A stratified analysis showed that the rate of seroconversion was significantly greater in the l-cystine and l-theanine group compared with the placebo group for influenza virus A (H1N1) among subjects with low serum total protein (63% vs 10%, P < 0.05) or low hemoglobin (71% vs 9%, P < 0.05). CONCLUSION: Co-administration of l-cystine and l-theanine before vaccination may enhance the immune response to influenza vaccine in elderly subjects with low serum total protein or hemoglobin.

Role of photoreceptor-specific retinol dehydrogenase in the retinoid cycle in vivo.

The retinoid cycle is a recycling system that replenishes the 11-cis-retinal chromophore of rhodopsin and cone pigments. Photoreceptor-specific retinol dehydrogenase (prRDH) catalyzes reduction of all-trans-retinal to all-trans-retinol and is thought to be a key enzyme in the retinoid cycle. We disrupted mouse prRDH (human gene symbol RDH8) gene expression by targeted recombination and generated a homozygous prRDH knock-out (prRDH-/-) mouse. Histological analysis and electron microscopy of retinas from 6- to 8-week-old prRDH-/- mice revealed no structural differences of the photoreceptors or inner retina. For brief light exposure, absence of prRDH did not affect the rate of 11-cis-retinal regeneration or the decay of Meta II, the activated form of rhodopsin. Absence of prRDH, however, caused significant accumulation of all-trans-retinal following exposure to bright lights and delayed recovery of rod function as measured by electroretinograms and single cell recordings. Retention of all-trans-retinal resulted in slight overproduction of A2E, a condensation product of all-trans-retinal and phosphatidylethanolamine. We conclude that prRDH is an enzyme that catalyzes reduction of all-trans-retinal in the rod outer segment, most noticeably at higher light intensities and prolonged illumination, but is not an essential enzyme of the retinoid cycle.

Essential role of Ca2+-binding protein 4, a Cav1.4 channel regulator, in photoreceptor synaptic function.

CaBP1-8 are neuronal Ca(2+)-binding proteins with similarity to calmodulin (CaM). Here we show that CaBP4 is specifically expressed in photoreceptors, where it is localized to synaptic terminals. The outer plexiform layer, which contains the photoreceptor synapses with secondary neurons, was thinner in the Cabp4(-/-) mice than in control mice. Cabp4(-/-) retinas also had ectopic synapses originating from rod bipolar and horizontal cells tha HJt extended into the outer nuclear layer. Responses of Cabp4(-/-) rod bipolars were reduced in sensitivity about 100-fold. Electroretinograms (ERGs) indicated a reduction in cone and rod synaptic function. The phenotype of Cabp4(-/-) mice shares similarities with that of incomplete congenital stationary night blindness (CSNB2) patients. CaBP4 directly associated with the C-terminal domain of the Ca(v)1.4 alpha(1)-subunit and shifted the activation of Ca(v)1.4 to hyperpolarized voltages in transfected cells. These observations indicate that CaBP4 is important for normal synaptic function, probably through regulation of Ca(2+) influx and neurotransmitter release in photoreceptor synaptic terminals.