Replete State Research Articles

Candida albicans Oropharyngeal Infection Is an Exception to Iron-Based Nutritional Immunity.

Candida albicans is a commensal of the human gastrointestinal tract and a common cause of human fungal disease, including mucosal infections, such as oropharyngeal candidiasis and disseminated infections of the bloodstream and deep organs. We directly compared the in vivo transcriptional profile of C. albicans during oral infection and disseminated infection of the kidney to identify niche specific features. Overall, 97 genes were differentially expressed between the 2 infection sites. Virulence-associated genes, such as hyphae-specific transcripts, were expressed similarly in the 2 sites. Genes expressed during growth in a poor carbon source (ACS1 and PCK1) were upregulated in oral tissue relative to kidney. Most strikingly, C. albicans in oral tissue shows the transcriptional hallmarks of an iron replete state while in the kidney it is in the expected iron starved state. Interestingly, C. albicans expresses genes associated with a low zinc environment in both niches. Consistent with these expression data, strains lacking transcription factors that regulate iron responsive genes (SEF1, HAP5) have no effect on virulence in a mouse model of oral candidiasis. During microbial infection, the host sequesters iron, zinc, and other metal nutrients to suppress growth of the pathogen in a process called nutritional immunity. Our results indicate that C. albicans is subject to iron and zinc nutritional immunity during disseminated infection but not to iron nutritional immunity during oral infection. IMPORTANCE Nutritional immunity is a response by which infected host tissue sequesters nutrients, such as iron, to prevent the microbe from efficiently replicating. Microbial pathogens subjected to iron nutritional immunity express specific genes to compensate for low iron availability. By comparing the gene expression profiles of the common human fungal pathogen Candida albicans in 2 infection sites, we found that C. albicans infecting the kidney has the transcriptional profile of iron starvation. By contrast, the C. albicans expression profile during oropharyngeal infection indicates the fungus is not iron starved. Two transcription factors that activate the transcriptional response to iron starvation are not required for C. albicans virulence during oral infection but are required for disseminated infection of the kidney. Thus, our results indicate that C. albicans is subject to nutritional iron immunity during disseminated infection but not during oropharyngeal infection, and highlight niche specific differences in the host-Candida albicans interaction.

Combined Pulsed Electron Double Resonance EPR and Molecular Dynamics Investigations of Calmodulin Suggest Effects of Crowding Agents on Protein Structures.

Calmodulin (CaM) is a highly dynamic Ca2+-binding protein that exhibits large conformational changes upon binding Ca2+ and target proteins. Although it is accepted that CaM exists in an equilibrium of conformational states in the absence of target protein, the physiological relevance of an elongated helical linker region in the Ca2+-replete form has been highly debated. In this study, we use PELDOR (pulsed electron–electron double resonance) EPR measurements of a doubly spin-labeled CaM variant to assess the conformational states of CaM in the apo-, Ca2+-bound, and Ca2+ plus target peptide-bound states. Our findings are consistent with a three-state conformational model of CaM, showing a semi-open apo-state, a highly extended Ca2+-replete state, and a compact target protein-bound state. Molecular dynamics simulations suggest that the presence of glycerol, and potentially other molecular crowding agents, has a profound effect on the relative stability of the different conformational states. Differing experimental conditions may explain the discrepancies in the literature regarding the observed conformational state(s) of CaM, and our PELDOR measurements show good evidence for an extended conformation of Ca2+-replete CaM similar to the one observed in early X-ray crystal structures.

Associations between non-anaemic iron deficiency and outcomes following elective cardiac surgery (IDOCS): a prospective cohort study

One in two adults undergoing cardiac surgery are iron deficient, best practice guidelines and consensus statements recommend routine investigation and treatment of iron deficiency before elective cardiac surgery, even in the absence of anaemia; however, it is not clear if non-anaemic iron deficiency is associated with worse outcomes in this patient population. We hypothesised that iron deficiency would be associated with worse postoperative outcomes than an iron replete state in adults without anaemia undergoing elective cardiac surgery. We performed a prospective, cohort study at two hospitals in Australia. We recruited adults (ie, people 18 years and older) undergoing elective cardiac surgery without anaemia (defined as a haemoglobin of less than 130 g/L for men and less than 120 g/L for women), concomitant haemoglobinopathy, bone marrow pathology, haemochromatosis, or end-stage renal failure requiring dialysis. Participants were stratified as iron deficient or iron replete on the basis of preoperative testing. Iron deficiency was defined as a serum ferritin of less than 100 μg/L or 100-300 μg/L if transferrin saturation was less than 20% or C-reactive protein was more than 5 mg/L. The primary endpoint was days alive and at home at postoperative day 30. The primary analysis included all patients with data available for the primary endpoint and was adjusted for risk measured using EuroSCORE-II and body surface area. The study was prospectively registered with the Australian and New Zealand Clinical Trials Registry, ACTRN12618000185268. We conducted the study between Feb 21, 2018, and May 7, 2021. We assessed 1171 patients for eligibility and 691 were ineligible; therefore, we enrolled and followed up 480 participants. 240 (50%) were iron deficient and 240 (50%) were iron replete, 95 (20%) were women, 385 (80%) were men, and 453 (94%) were White. Complete data was available for 479 individuals (240 in the iron deficient group and 239 in the iron replete group) for the primary endpoint. The iron deficient group had a median of 22·87 days (IQR 20·65 to 24·06) alive and at home at postoperative day 30, and the iron replete group had a median of 23·18 days (IQR 20·69 to 24·70). The unadjusted difference in medians between the groups was -0·18 days (95% CI -0·73 to 0·36; p=0·51) and the adjusted difference in medians between the groups was -0·11 days (95% CI -0·66 to 0·45; p=0·70). In non-anaemic adults undergoing elective cardiac surgery, our findings suggest that patients with iron deficiency do not have a reduction in days alive and at home at postoperative day 30 compared with patients who have a normal iron status. Routine preoperative investigation for iron deficiency in patients without anaemia undergoing elective cardiac surgery using the definitions we tested might be low-value care. Australian and New Zealand College of Anaesthetists Foundation.

Imitation and aspiration dynamics bring different evolutionary outcomes in feedback-evolving games

Feedback-evolving games characterize the interplay between the evolution of strategies and environments. Rich dynamics have been derived for such games under the premise of the replicator equation, which unveils persistent oscillations between cooperation and defection. Besides replicator dynamics, here we have employed aspiration dynamics, in which individuals, instead of comparing payoffs with opposite strategies, assess their payoffs by self-evaluation to update strategies. We start with a brief review of feedback-evolving games with replicator dynamics and then comprehensively discuss such games with aspiration dynamics. Interestingly, the tenacious cycles, as perceived in replicator dynamics, cannot be observed in aspiration dynamics. Our analysis reveals that a parameter θ —which depicts the strength of cooperation in enhancing the environment—plays a pivotal role in comprehending the dynamics. In particular, with the symmetric aspiration level, if replete and depleted states, respectively, experience Prisoner's Dilemma and Trivial games, the rich environment is achievable only when θ > 1. The case θ < 1 never allows us to reach the replete state, even with a higher cooperation level. Furthermore, if cooperators aspire less than defectors, then the enhanced state can be achieved with a relatively lower θ value compared with the opposite scenario because too much expectation from cooperation can be less beneficial.

Potential role of Vitamin D as an antiviral agent

Vitamin D has potential antimicrobial activity, the deficiency of which has deleterious effects on the general well-being and longevity, predisposing major public health problem worldwide. About 1 billion people have Vitamin D deficiency, which is prevalent among all ethnicities and age groups throughout the world. In addition, the incidence of antimicrobial resistance has emerged as a major threat to public health, and it is estimated to cause 10 million deaths annually by 2050 throughout the world. Vitamin D, as a mighty antimicrobial agent, may decrease the occurrence of infection through numerous pathways. Vitamin D strengthens innate immunity by modulating the production of various anti-microbial peptide (AMPs), cytokine, chemokines and interleukin responses. Vitamin D is responsible for the regulation of >200 genes, including cell proliferation, differentiation, and apoptotic genes. It acts as the key holder for modulating systemic inflammation, oxidative stress, and mitochondrial respiratory functions. Thus, a Vitamin D replete state appears to benefit most infections. As an antiviral agent, Vitamin D may constitute an inexpensive prophylactic option either by itself or as a synergistic agent during the treatment of different viral infections. The present review stipulates the importance of Vitamin D and its possible mechanisms against treating any kind of viruses. Relevant published articles were summarized by performing computerized literature searches (searches were made in PubMed/Medline, EMBASE, ScienceDirect, and Scirus) of different authentic databases using the following keywords: Vitamin D, VDR, infections, antimicrobial peptides, viruses, and COVID-19. The future for the sunshine vitamin as an antiviral agent looks brighter. More scientific proposition entailing in vitro, in vivo, or genomic studies are required to understand how important Vitamin D is against viral infections.

Metabolic and Transcriptional Profiles of Dunaliella viridis Supplemented With Ammonium Derived From Glutamine

Algal biofuel production requires an input of synthetic nitrogen fertilizer. Fertilizer synthesized via the Haber-Bosch process produces CO2 as a waste byproduct and represents a substantial financial and energy investment. Reliance on synthetic fertilizer attenuates the environmental significance and economic viability of algae production systems. To lower fertilizer input, the waste streams of algal production systems can be recycled to provide alternative sources of nitrogen such as amino acids to the algae. The halophytic green alga Dunaliella viridis can use ammonium (NH4+) derived from the abiotic degradation of amino acids, and previously, supplementation of NH4+ from glutamine degradation was shown to support acceptable levels of growth and increased neutral lipid production compared to nitrate. To understand the effect of glutamine-released NH4+ on algae growth and physiology, metabolite levels, growth parameters, and transcript profiles of D. viridis cultures were observed in a time course after transition from media containing nitrate as a sole N source to medium containing glutamine, glutamate, or a N-depleted medium. Growth parameters were similar between glutamine (NH4+) and nitrate supplemented cultures, however, metabolite data showed that the glutamine supplemented cultures (NH4+) more closely resembled cultures under nitrogen starvation (N-depleted and glutamate supplementation). Neutral lipid accumulation was the same in nitrate and glutamine-derived NH4+ cultures. However, glutamine-derived NH4+ caused a transcriptional response in the immediate hours after inoculation of the culture. The strong initial response of cultures to NH4+ changed over the course of days to closely resemble that of nitrogen starvation. These observations suggest that release of NH4+ from glutamine was sufficient to maintain growth, but not high enough to trigger a cell transition to a nitrogen replete state. Comparative transcript profiling of the nitrogen-starved and nitrate-supplied cultures show an overall downregulation of fatty acid synthesis and a shift to starch synthesis and accumulation. The results indicate that a continuous, amino acid derived slow release of NH4+ to algae cultures could reduce the amount of synthetic nitrogen needed for growth, but optimization is needed to balance nitrogen starvation and cell division.

Five Nights of Sleep Restriction Attenuates Microvascular Endothelial Function

Adequate sleep is requisite for optimal physiological function, including microvascular endothelial function. Short‐term sleep restriction (5 hours/night) negatively alters glucose metabolism and may also impair microvascular endothelial function via increased sympathetic nervous system activity and inflammatory pathways. The cutaneous microvasculature represents an accessible, well‐described vascular bed to non‐invasively assess the effects of sleep restriction on microvascular function. Our objective was to evaluate cutaneous microvascular endothelial function during baseline sleep replete conditions (10 hours/night time in bed), after 5 nights of sleep restriction (5 hours/night), and again after 2 nights of recovery sleep repletion. This was part of the Sleep Restriction Study (PI: Chang), an 11‐day inpatient study that took place in the Penn State University Clinical Research Center, during which diet and physical activity were controlled. Eight young, healthy men (23.3 ± 3.4 years) participated in the study. Cutaneous microvascular function was measured utilizing a standardized local skin heating protocol to induce endothelial nitric oxide‐synthase‐dependent vasodilation during all three study phases (baseline, sleep restricted, recovery). Red cell flux (laser Doppler flowmetry) was continuously measured on the ventral forearm at thermoneutral temperature (33 °C) and throughout local heating 0.5°C·5 s−1 to 42 °C until a stable (20 min) plateau had been reached. Red cell flux was normalized to cutaneous vascular conductance (CVC: flux·MAP−1) and expressed as a percentage of maximum CVC (43°C: %CVCmax). Compared to the baseline sleep replete state, the response to local heating was attenuated by 10% after 5 nights of sleep restriction (baseline: 89.2 ± 2.0, restricted: 80.4 ± 3.0 %CVCmax; p=0.045) and fully recovered after 2 nights of recovery sleep (88.7 ± 1.8 %CVCmax; p=0.99 compared to baseline). Maximum CVC was not affected by sleep restriction (all p>0.05). These results suggest that 5 nights of sleep restriction impairs microvascular endothelial function, likely through attenuated nitric oxide‐dependent vasodilation, but that 2 nights of recovery sleep restores microvascular endothelial function in young, healthy men.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

DIETARY PROTEIN INTAKE PATTERN AND SOURCES AND THEIR ASSOCIATIONS WITH MUSCLE AND PHYSICAL FUNCTION MEASURES IN OLDER CHINESE ADULTS WITH SARCOPENIA IN HONG KONG

Background: Protein intake is a major risk factor of sarcopenia. To combat sarcopenia, strategies focused on providing sufficient high quality dietary protein are required. Objectives: We aimed to identify the pattern of dietary protein intake and its association with muscle and physical functions among community-dwelling sarcopenic Chinese older adults in Hong Kong. Design: Baseline data of a randomized controlled trial in sarcopenia were analyzed. Setting: Participants who were ambulant and could travel to the assessment centre at a regional hospital in Hong Kong were recruited in nearby community elderly centers, nursing homes and other institutional settings. Participants: A total of 113 Chinese older adults aged 65 or above who had sarcopenia defined using The Asia Working Group Criteria for Sarcopenia were recruited. Measurements: Dietary data and muscle function tests were measured. Results: Although the energy intake (mean + standard deviation: 1491.7±338.6 kcal/d in female, 1738.1±392.9 kcal/d in male) was lower than the recommended daily energy requirement, protein intake averaged 1.6±0.5 g/kg body weight/day, which was high compared to the current Recommended Daily Allowance (RDA, 0.8 g/kg body weight/day for older people). Animal and plant sources contributed to 62% and 38% respectively of the total protein intake. Dietary protein intake was not evenly distributed throughout the day. Physical Activity Scale for the Elderly (PASE) score was more predictive of muscle mass and functions compared to protein intake and sources. Conclusions: Our findings showed that PASE was more predictive of muscle mass and functions compared to protein intake and sources, and there was a minimal association between protein intake and muscle performance measures in our community-dwelling sacropenic older adults. The protein replete state of our study population may explain these findings. The observations that an uneven distribution of protein intake throughout a day may suggest the need to increase protein intake at breakfast among Chinese sarcopenic older adults.

A test of the optimal iron hypothesis among breastfeeding Ariaal mothers in northern Kenya.

The optimal iron hypothesis posits a trade-off in iron nutrition-iron deficiency restricts iron available to infectious agents, protecting against severe infection, but also compromises immune defense-such that mild-to-moderate iron deficiency may be more adaptive than either iron-replete or severe deficiency in environments with high infectious disease load. This hypothesis has not been tested among adults. A secondary analysis of data and specimens from 220 lactating mothers in northern Kenya was conducted. Elevated serum C-reactive protein (CRP > 2 or >5 mg/l) was utilized to identify prevalent subclinical infection/inflammation. Iron deficiency was identified with transferrin receptor in archived dried blood spots (TfR > 5.0 mg/l). The absence of iron deficiency or anemia (Hemoglobin < 12 g/l) defined the iron replete state. Iron-deficient erythropoiesis (IDE, mild-to-moderate iron deficiency) was defined as iron deficiency without anemia; iron deficiency anemia (IDA, severe iron deficiency) as iron deficiency with anemia; and noniron-deficiency anemia (NIDA) as anemia without iron deficiency. The prevalence of elevated inflammation (subclinical infection) was lowest in IDE. In logistic regression, IDE was inversely associated with inflammation (for CRP > 2 mg/l: adjusted odds ratio, aOR = 0.30; p = 0.02; for CRP > 5 mg/l: aOR = 0.27; p = 0.10), compared to the iron replete state. The protective effect of IDE differed in the presence of vitamin A deficiency or underweight. We interpret these patterns as tentative support for the optimal iron hypothesis in breastfeeding women in the infectious disease ecology of northern Kenya. Iron deficiency may interact in important ways with other forms of malnutrition that are known to affect immune protection.

An oscillating tragedy of the commons in replicator dynamics with game-environment feedback

A tragedy of the commons occurs when individuals take actions to maximize their payoffs even as their combined payoff is less than the global maximum had the players coordinated. The originating example is that of overgrazing of common pasture lands. In game-theoretic treatments of this example, there is rarely consideration of how individual behavior subsequently modifies the commons and associated payoffs. Here, we generalize evolutionary game theory by proposing a class of replicator dynamics with feedback-evolving games in which environment-dependent payoffs and strategies coevolve. We initially apply our formulation to a system in which the payoffs favor unilateral defection and cooperation, given replete and depleted environments, respectively. Using this approach, we identify and characterize a class of dynamics: an oscillatory tragedy of the commons in which the system cycles between deplete and replete environmental states and cooperation and defection behavior states. We generalize the approach to consider outcomes given all possible rational choices of individual behavior in the depleted state when defection is favored in the replete state. In so doing, we find that incentivizing cooperation when others defect in the depleted state is necessary to avert the tragedy of the commons. In closing, we propose directions for the study of control and influence in games in which individual actions exert a substantive effect on the environmental state.

Abstract 119: Anti-hypertensive Effect of Thiazides Shifts From Salt Excretion to Vasorelaxation During Salt Restriction or Volume Depletion

Thiazide derivatives, including hydrochlorothiazide (HCTZ), are specific inhibitors of the Na+-Cl- Co-transporter (NCC) in the kidney distal tubules, and the most commonly used diuretic for the treatment of mild to moderate hypertension. Both renal (natriuretis) and extra renal (vasorelaxation) mechanisms have been proposed as major mediators of blood pressure reduction by HCTZ but the circumstances under which the renal or extra renal mechanism predominates remain unknown . To address these issues, systemic blood pressure was monitored by intra-arterial catheter and computerized tail cuff in transgenic mice lacking NCC under varying conditions. For comparison, mice with pendrin ablation or double deletion of pendrin and NCC were used to ascertain the compensatory role of pendrin in salt reabsorption in response to HCTZ. Pendrin KO mice were the only group which showed enhanced salt excretion in response to HCTZ, with salt excretion increasing by ~30% in pendrin KO vs. WT mice (p&lt;0.05). In mice lacking NCC, HCTZ significantly reduced the systemic blood pressure only during salt restriction and without enhancing salt excretion. In volume depleted but not in volume resuscitated NCC/pendrin dKO mice, HCTZ caused dramatic reduction in systemic blood pressure, with systolic blood pressure decreasing from 72.13± 5.1 at baseline to 51.06 ± 6.6 mm Hg in dKO mice within 20 minutes of HCTZ administration (p&lt;0.01 vs. baseline) with no significant effect in WT mice (p&gt;0.5 vs. baseline) or in salt resuscitated NCC/pendrin dKO mice. There was no enhancement in salt excretion and no reduction in echocardiography-monitored cardiac output in pendrin/NCC dKO mice in response to HCTZ. The antihypertensive effects of HCTZ were abrogated in the presence of paxilline, a specific blocker of BK channel, which is upregulated in arterial vasculature of volume depleted mutant mice. We propose that thiazides reduce blood pressure predominantly via vasorelaxation during salt restriction/volume depletion; whereas, they enhance salt excretion during salt replete state and specifically in conditions associated with pendrin downregulation/inactivation.

The influence of mandatory iodine fortification on the iodine status of Australian school children residing in an iodine sufficient region.

To counter emerging iodine deficiency mandatory iodine fortification of bread was introduced throughout Australia in 2009. This study investigated the impact of iodine fortification on the iodine status of school aged children living in the iodine replete state of Queensland, and investigated which foods had greatest influence on overall iodine status. A convenience sample of 30 children aged 8.0-10.9 years living in south east Queensland, Australia, provided spot morning and afternoon urine samples on two consecutive days. Iodine status was categorised by the World Health Organization criterion. Semiquantitative food questionnaires (FFQ) completed by carers were used to investigate which foods were having the greatest influence on UIC. Analysis of variance was used to reduce the within person variation observed in urinary iodine concentrations (UIC) and the data were log transformed before statistical analysis. Adjusted median UIC was 144 ug/L (IQR 120-210 ug/L) indicating iodine sufficient status. No samples were above the cut off for excessive UIC. Bread was the only statistically significant contributor to UIC (standardized β=0.37, p=0.04) with 14% of variation in UIC explained by bread consumption. UIC increased by 8.7% for each additional serve of bread. Iodine fortification of bread has increased the iodine status of school aged children in this Queensland cohort. Despite the small sample size in this study, improvements in methodology allowed its findings to be comparable to other, larger surveys.

Vitamin D Status and Monitoring in Female Veterans

An increasing number of women are serving in the military. We initiated a retrospective study to evaluate vitamin D status and monitoring in female veterans, and to examine the potential link between vitamin D status, age, race, post-traumatic stress disorder (PTSD), health care costs, and utilization. Approximately 44 percent of the 3,608 female veterans evaluated between 2001 and 2010 were vitamin D deficient (25(OH)D < 20 ng/ml), a rate substantially higher than that of the general population. While younger (<55 years) and older (55+ years) women did not differ significantly in initial vitamin D status, older women had significantly more vitamin D monitoring and follow-up testing than younger women. Approximately 44 percent of vitamin D deficient women did not receive follow-up vitamin D testing. Minority female veterans were most likely to be vitamin D deficient. Female veterans with PTSD did not differ from others regarding their initial vitamin D status; those that were initially deficient were significantly more likely to receive follow-up testing and were more likely to achieve a replete state. Vitamin D deficiency in female veterans was also associated with increased health-care costs. Appropriate monitoring and replacement of vitamin D should be offered to all female veterans.

New Insights Into Androgen and Estrogen Receptor Regulation of the Male Skeleton.

Beginning with the report in 1994 that an adult male with homozygous loss of estrogen receptor α (ERα) had unfused epiphyses and osteopenia,(1) there is now considerable evidence from observational and interventional studies (summarized in Khosla and colleagues(2)) that estrogen is the dominant regulator of bone metabolism in men. Indeed, a legitimate argument can be made that testosterone is largely a prohormone for the skeleton, with its effects on bone mediated principally via aromatization to estrogen, although it remains likely that testosterone contributes to bone size via effects on periosteal apposition and perhaps indirectly to bone mass by increasing muscle mass.

Assessing fluid status with the vascular pedicle width: relationship to IVC diameter, IVC variability and lung comets

This study attempts to determine a vascular pedicle width (VPW) cutoff value that identifies a fluid replete state defined as an IVC diameter ≥2 cm and ≤15% respiratory variation.

Functional coupling of renal K+ and Na+ handling causes high blood pressure in Na+ replete mice

A network of kinases, including WNKs, SPAK and Sgk1, is critical for the independent regulation of K+ and Na+ transport in the distal nephron. Angiotensin II is thought to act as a key hormone in orchestrating these kinases to switch from K+ secretion during hyperkalaemia to Na+ reabsorption during intravascular volume depletion, thus keeping disturbances in electrolyte and blood pressure homeostasis at a minimum. It remains unclear, however, how K+ and Na+ transport are regulated during a high Na+ intake, which is associated with suppressed angiotensin II levels and a high distal tubular Na+ load. We therefore investigated the integrated blood pressure, renal, hormonal and gene and protein expression responses to large changes of K+ intake in Na+ replete mice. Both low and high K+ intake increased blood pressure and caused Na+ retention. Low K+ intake was accompanied by an upregulation of the sodium-chloride cotransporter (NCC) and its activating kinase SPAK, and inhibition of NCC normalized blood pressure. Renal responses were unaffected by angiotensin AT1 receptor antagonism, indicating that low K+ intake activates the distal nephron by an angiotensin-independent mode of action. High K+ intake was associated with elevated plasma aldosterone concentrations and an upregulation of the epithelial sodium channel (ENaC) and its activating kinase Sgk1. Surprisingly, high K+ intake increased blood pressure even during ENaC or mineralocorticoid receptor antagonism, suggesting the contribution of aldosterone-independent mechanisms. These findings show that in a Na+ replete state, changes in K+ intake induce specific molecular and functional adaptations in the distal nephron that cause a functional coupling of renal K+ and Na+ handling, resulting in Na+ retention and high blood pressure when K+ intake is either restricted or excessively increased.

Role of endothelin-1 in renal regulation of acid-base equilibrium in acidotic humans

Endothelin-1 inhibits collecting duct sodium reabsorption and stimulates proximal and distal tubule acidification in experimental animals both directly and indirectly via increased mineralocorticoid activity. Diet-induced acid loads have been shown to increase renal endothelin-1 activity, and it is hypothesized that increased dietary acid-induced endothelin-1 activity may be a causative progression factor in human renal insufficiency and that this might be reversed by provision of dietary alkali. We sought to clarify, in normal human volunteers, the role of endothelin-1 in renal acidification and to determine whether the effect is dependent on dietary sodium chloride. Acid-base equilibrium was studied in seven normal human volunteers with experimentally induced metabolic acidosis [NH(4)Cl 2.1 mmol·kg body weight (BW)(-1)·day(-1)] with and without inhibition of endogenous endothelin-1 activity by the endothelin A/B-receptor antagonist bosentan (125 BID p.o./day) both during dietary NaCl restriction (20 mmol/day) and NaCl repletion (2 mmol NaCl·kg BW(-1)·day(-1)). During NaCl restriction, but not in the NaCl replete state, bosentan significantly increased renal net acid excretion in association with stimulation of ammoniagenesis resulting in a significantly increased plasma bicarbonate concentration (19.0 ± 0.8 to 20.1 ± 0.9 mmol/l) despite a decrease in mineralocorticoid activity and an increase in endogenous acid production. In pre-existing human metabolic acidosis, endothelin-1 activity worsens acidosis by decreasing the set-point for renal regulation of plasma bicarbonate concentration, but only when dietary NaCl provision is restricted.

Intravenous iron replacement for persistent iron deficiency anemia after Roux-en-Y gastric bypass

BackgroundIron deficiency is a major postoperative complication of Roux-en-Y gastric bypass surgery. Oral replacement can fail to correct the deficiency. Thus, recourse to parenteral iron administration might be necessary. Our objective was to evaluate the effectiveness and safety of a standardized 2 g intravenous iron dextran infusion in the treatment of iron deficiency after Roux-en-Y gastric bypass surgery. The setting was a university-affiliated community hospital in the United States. MethodsWe reviewed the medical records of 23 patients at our institution who had received 2 g of iron dextran intravenously for recalcitrant iron deficiency after Roux-en-Y gastric bypass surgery. We obtained the demographic data and the complete blood count and serum iron studies obtained before treatment and at outpatient visits after infusion. ResultsBefore treatment, all 23 patients were iron deficient (average ferritin 6 ng/mL) and anemic (average hemoglobin 9.4 g/dL). By 3 months, the average ferritin and hemoglobin had increased to 269 ng/mL and 12.3 g/dL, respectively. The hemoglobin levels remained stable throughout the follow-up period. The iron stores were adequately replaced in most patients. Four patients required a repeat infusion by 1 year, because the ferritin levels had decreased to <15 ng/mL. The probability of remaining in an iron replete state was 84.6% (95% confidence interval 78–91.2%). One patient required warm compresses for superficial phlebitis. No other significant adverse events were reported. ConclusionIntravenous administration of 2 g of iron dextran corrects the anemia and repletes the iron stores for ≥1 year in most patients. This therapy is safe, tolerable, efficient, and effective.

Abstract P245: Relationship of Vitamin D Status to Cardiac Valvular Disease in Veterans

Vitamin D deficiency has reached pandemic proportions and has been closely linked to coronary and peripheral vascular disease. Moreover, vitamin D replacement may play a role in improving ejection fraction with the potential to influence cardiac valvular function. To investigate this relationship further we studied 32 veterans without a diagnosis of coronary artery disease. A retrospective study evaluated veterans with both a 25(OH) D determination and an echocardiogram. The echocardioraphic parameters were identified through chart review. Vitamin D deficiency was significantly “(P&lt; 0.05)” associated with mitral insufficiency, aortic sclerosis and pulmonary hypertension as shown in the table below. Mitral Regurgitation % Vitamin D deficient Absent 23 Present * 56 Aortic Sclerosis % Vitamin D deficient Absent 32 Present * 61 Pulmonary Hypertension % Vitamin D deficient Absent 32 Present * 67 * is P&lt;0.05. To our knowledge, this represents a novel association between vitamin D deficiency, cardiac valvular function and pulmonary Hypertension. The possibility of modulating cardiac valvular structure and function through achieving a vitamin D replete state is an exciting area for future research. Affiliation Mountain Home VA and ETSU Departments of Internal Medicine and Family Medicine.

Antimicrobial implications of vitamin D

Evidence exists that vitamin D has a potential antimicrobial activity and its deficiency has deleterious effects on general well-being and longevity. Vitamin D may reduce the risk of infection through multiple mechanisms. Vitamin D boosts innate immunity by modulating production of anti-microbial peptides (AMPs) and cytokine response. Vitamin D and its analogues via these mechanisms are playing an increasing role in the management of atopic dermatitis, psoriasis, vitiligo, acne and rosacea. Vitamin D may reduce susceptibility to infection in patients with atopic dermatitis and the ability to regulate local immune and inflammatory responses offers exciting potential for understanding and treating chronic inflammatory dermatitides. Moreover, B and T cell activation as well as boosting the activity of monocytes and macrophages also contribute to a potent systemic anti-microbial effect. The direct invasion by pathogenic organisms may be minimized at sites such as the respiratory tract by enhancing clearance of invading organisms. A vitamin D replete state appears to benefit most infections, with the possible noteworthy exception of Leishmaniasis. Antibiotics remain an expensive option and misuse of these agents results in significant antibiotic resistance and contributes to escalating health care costs. Vitamin D constitutes an inexpensive prophylactic option and possibly therapeutic product either by itself or as a synergistic agent to traditional antimicrobial agents. This review outlines the specific antimicrobial properties of vitamin D in combating a wide range of organisms. We discuss the possible mechanisms by which vitamin D may have a therapeutic role in managing a variety of infections.