Testosterone Deficiency Increases Hospital Readmission and Mortality Rates in Male Patients with Heart Failure

Background:Testosterone deficiency in patients with heart failure (HF) is associated with decreased exercise capacity and mortality; however, its impact on hospital readmission rate is uncertain. Furthermore, the relationship between testosterone deficiency and sympathetic activation is unknown.Objective:We investigated the role of testosterone level on hospital readmission and mortality rates as well as sympathetic nerve activity in patients with HF.Methods:Total testosterone (TT) and free testosterone (FT) were measured in 110 hospitalized male patients with a left ventricular ejection fraction < 45% and New York Heart Association classification IV. The patients were placed into low testosterone (LT; n = 66) and normal testosterone (NT; n = 44) groups. Hypogonadism was defined as TT < 300 ng/dL and FT < 131 pmol/L. Muscle sympathetic nerve activity (MSNA) was recorded by microneurography in a subpopulation of 27 patients.Results:Length of hospital stay was longer in the LT group compared to in the NT group (37 ± 4 vs. 25 ± 4 days; p = 0.008). Similarly, the cumulative hazard of readmission within 1 year was greater in the LT group compared to in the NT group (44% vs. 22%, p = 0.001). In the single-predictor analysis, TT (hazard ratio [HR], 2.77; 95% confidence interval [CI], 1.58–4.85; p = 0.02) predicted hospital readmission within 90 days. In addition, TT (HR, 4.65; 95% CI, 2.67–8.10; p = 0.009) and readmission within 90 days (HR, 3.27; 95% CI, 1.23–8.69; p = 0.02) predicted increased mortality. Neurohumoral activation, as estimated by MSNA, was significantly higher in the LT group compared to in the NT group (65 ± 3 vs. 51 ± 4 bursts/100 heart beats; p < 0.001).Conclusion:These results support the concept that LT is an independent risk factor for hospital readmission within 90 days and increased mortality in patients with HF. Furthermore, increased MSNA was observed in patients with LT.

Estudos sobre a alimentação mineral do cafeeiro: VI Efeitos das deficiências de micronutrientes em Coffea arabica L. var. Mundo Novo cultivado em solução nutritiva

Young coffee plants (Coffea arabica L., var. Mundo Novo) were grown in nutrient solution purified from micronutrients contaminants by the method of MUNNS & JOHNSON (1960). All plants, except those in the control treatment, wer given all macronutrients and all micronutrients except one which was omitted in order to induce its shortage. Symptoms of deficiency were obtained for all known micronutrients but chlorine. Measurements, observations and chemical analysis of leaves allowed the following main conclusions to be drawn. 1. The relative influence of micronutrients in growth-measured by the fresh weight of the entire plant - was as follows: -Fe -Zn -Cu -Mo -Mn complete = -B = -CI. that is: the omission of iron from the nutrient solution caused the severest reduction in growth; lack of B and Cl had no effect. 2. Symptoms of deficiency of B, Fe, Mn, and Zn were found to be in good agreement with those in the literature. Effects of Cu and Mo shortage, however, had not been described so far: In the case of the Cu-deficient plants, the younger leaves were distorted, having an "S" shape, due probably to lack of growth of the veins; they lost their green color and developed rather large, necrotic patches near the margins. When molybdenum was omitted from the nutrient solution yellow spots develop near the margen of subterminal (fully mature) leaves; they became necrotic; there was a characteristic downward curling of the leaf blade along the mid rib so that the opposite edges touched each other underneath. 3. The levels of micronutrients found in normal and deficient leaves are given in Table 4. It is hoped that those values will serve as a basis of judgement of micronutrient contents found in leaves of field grown plants.

Estudos sôbre alimentação mineral do cafeeiro: VIII. Estudo da absorção e da translocação do radiozinco no cafeeiro (Coffea arabica L.)

WATER-CULTURE EXPERIMENTS. Two water-culture experiments were carried out to study the absorption and the translocation of radiozinc in young coffee plants as influenced by two factors, namely, concentration of heavy metals (iron, man ganese, copper and molybdenum) and method of application. Inert zinc was supplied at an uniform rate of 0. 05 p. p. m.; the levels of iron supply were 0, 1.0, and 10.0 p. p.m.; manganese was supplied in three doses 0, 0.5, and 5.0 p. p.m.; copper- 0, 0. 02, and 0. 2 p. p. m.; molybdenum- 0, 0. 01, and 0. 1 p. p. m. When applied to the nutrient solution the activity os the radiozinc (as zinc chloride) was 0. 15 microcuries per plant. In the study of the leaf absorption, Zn65 was supplied at the level of 0. 10 microcuries per plant; in this case the radioative material was brushed either on the lower or on the upper surface or both two pairs of mature leaves. The absorption period was 8 weeks. The radioactivity assay showed the following results: 1 - Among the heavy metals herein investigated the iron concentration did not affect the uptake of the radiozinc; by raising the level of Mn, Cu and Mo ten times, the absorption dropped to 50 per cent and even more when compared with the control plants; when, however, these micronutrients were omitted from the nutrient solution, an increase in the uptake of zinc was registered in the minus Cu treatment only. The effects of high levels of Mn, Cu and Mo probably indicate an interionic competition for a same site on a common binding substance in the cell surface. 2 - The absorption of the radiozinc directly applied to the leaf surface reached levels as high as 8 times that registered when the root uptake took place. Among the three methods of application which have been tried, brushing the lower surface of the leaves proved to be the most effective; this result is easily understood since the stomatal openings of the coffee leaves an preferentially located in the lower surface - in this treatment, about 40 per cent of the activity was absorved and around 12 per cent were translocated either to the old or to the newer organs. Chemical analyses for heavy metals, were carried out only in the plants received Zn65Cl2 in the nutrient solution; the results were as follows; 1 - Control plants had, per 1,000 gm, of dry weight the following amounts in mg.: Zn- 48 in the roots and 29 in the tops; Fe- 165 in the roots and 9 in the tops; Mn- 58 in the roots and 15 in the tops, Cu- 15 in the roots and 1. 2 in the tops; Mo- 2. 8 in the roots and 0. 45 in the tops. 2 - The effect of different levels of micronutrients in the composition of the plants can be summarized as follows: Fe and Zn- when omitted from the nutrient solution, the iron and zinc contents in the roots decreased, no variation being noted in the tops; the higher dosis caused an accumulation in the roots but no apparent effect in the tops; Mn- by omitting this micronutrient a decrease in its content in the roots was noted, where as the concentration in the tops was the same; Mo- no variation in roots and tops contents when molybdenum was omitted; higher dosis of manganese and molybdenum increased the amounts formed both in the roots and in the tops. 3 - The influence of the different concentrations of micronutrients heavy metals on the zinc content of the coffee plants can be described by saying that: Fe and Mo- no marked variation; Mn- no effect when omitted, reduced amount when the high dosis was supplied; Mn- when the plants did not receive manganese the zinc content in roots and tops was the same as in the control plants; a decrease in the zinc content of the total plant occurred when the high dosis was employed; Cu -the situation is similar to that described for manganese. Hence, results showed by the chemical analyses roughly correspond to those of the radioactivity assay; the use of the tracer technique, however, gave best informations along this line. SOIL-POTS EXPERIMENTS. The two types of soils which when selected support the most extensive coffee plantations in the State of São Paulo, Brazil: "arenito de Bauru", a light sandy soil and "terra roxa legitima", a red soil derived from basalt. Besides NPK containing salts, the coffee plants were given two doses of inert zinc (65 and 130 mg ZnCl2 per pot) and radiozinc at a total activity of 10(6) counts/minute. The results of the countings can be summarized as follows: 1 - When plants were grown in "arenito de Bauru" the activity absorbed as per cent of the total activity supplied was not affected by the dosis of inert zinc. The highest value found was around 0. 1 per cent. 2 - For the "terra roxa" plants, the situation is almost the same; there was, however, a slight increase in the absorption of the radiozinc when 130 mgm of ZnClg2 was given: a little above 0. 2 per cent of the activity supplied was absorbed. The results clearly show that the young coffee plants practically did not absorb none of the zinc supplied; two reasons at least could be pointed out to explain such a fact: 1 - Zinc fixation by an exchange with magnesium or by filling holes in the octahedral layer of aluminosilicates, probably kaolinite; 2 - No need for fertilizer zinc in the particular stage of life cycle under which the experiment was set up. The data from chemical analysis are roughly parallel to the above mentioned. When one attempts to compare - by taking data herein reported zinc uptake from nutrient solution, leaf brushing or from fertilizers in the soil, a practical conclusion can be drawn: the control of zinc deficiency in coffee plants should not be done by adding the zinc salts to the soil; in other words: the soil applications used so extensively in other countries seem not to be suitable for our conditions; hence zinc sprays should be used wherever necessary.

Glucose-dependent insulinotropic polypeptide receptor deficiency leads to modifications of trabecular bone volume and quality in mice.

A role for the gastro-intestinal tract in controlling bone remodeling is suspected since serum levels of bone remodeling markers are affected rapidly after a meal. Glucose-dependent insulinotropic polypeptide (GIP) represents a suitable candidate in mediating this effect. The aim of the present study was to investigate the effect of total inhibition of GIP signaling on trabecular bone volume, microarchitecture and quality. We used GIP receptor (GIPR) knockout mice and investigated trabecular bone volume and microarchitecture by microCT and histomorphometry. GIPR-deficient animals at 16 weeks of age presented with a significant (20%) increase in trabecular bone mass accompanied by an increase (17%) in trabecular number. In addition, the number of osteoclasts and bone formation rate was significantly reduced and augmented, respectively in these animals when compared with wild-type littermates. These modifications of trabecular bone microarchitecture are linked to a remodeling in the expression pattern of adipokines in the GIPR-deficient mice. On the other hand, despite significant enhancement in bone volume, intrinsic mechanical properties of the bone matrix was reduced as well as the distribution of bone mineral density and the ratio of mature/immature collagen cross-links. Taken together, these results indicate an increase in trabecular bone volume in GIPR KO animals associated with a reduction in bone quality.

Vitamin D deficiency and a CYP27B1-1260 promoter polymorphism are associated with chronic hepatitis C and poor response to interferon-alfa based therapy

BACKGROUND: Vitamin D is an important immune modulator and preliminary data indicated an association between vitamin D deficiency and sustained virologic response (SVR) rates in patients with chronic hepatitis C. We therefore performed a comprehensive analysis on the impact of vitamin D serum levels and of genetic polymorphisms within the vitamin D cascade on chronic hepatitis C and its treatment. METHODS: Vitamin D serum levels, genetic polymorphisms within the vitamin D receptor and the 1α- hydroxylase were determined in a cohort of 468 HCV genotype 1, 2 and 3 infected patients who were treated with interferon-alfa based regimens. RESULTS: Chronic hepatitis C was associated with a high incidence of severe vitamin D deficiency compared to controls (25(OH)D3<10 ng/mL in 25% versus 12%, p<0.00001), which was in part reversible after HCV eradication. 25(OH)D3 deficiency correlated with SVR in HCV genotype 2 and 3 patients (63% and 83% SVR for patients with and without severe vitamin D deficiency, respectively, p<0.001). In addition, the CYPB27-1260 promoter polymorphism rs10877012 had substantial impact on 1-25- dihydroxyvitamin D serum levels and SVR rates in HCV genotype 1, 2 and 3 infected patients. CONCLUSIONS: Chronic hepatitis C virus infection is associated with vitamin D deficiency. Reduced 25- hydroxyvitamin D levels and CYPB27-1260 promoter polymorphism are associated with failure to achieve SVR in HCV genotype 1, 2, 3 infected patients.

The Impact of Iodine Deficiency Eradication on Schooling: Evidence from the Introduction of Iodized Salt in Switzerland

This paper examines the impact of salt iodization in Switzerland in the 1920s and 1930s on schooling outcomes. Iodine deficiency in utero causes mental retardation, and correcting the deficiency is expected to increase the productivity of a population by increasing its cognitive ability. The exogenous increase in cognitive ability brought about by the iodization program is also useful in the context of disentangling the effects of innate ability and education in later-life outcomes. I identify the impact of iodization in three ways: first, in a differences-in-differences framework, I exploit geographic variation in iodine deficiency, as well as the fact that the nationwide campaign to decrease iodine deficiency began in 1922. Second, I use spatial and temporal variation in the introduction of iodized salt across Swiss cantons, and examine whether the level of iodized salt sales at the time of one’s birth affected one’s educational attainment. Third, I employ a fuzzy regression discontinuity design and use jumps in sales of iodized salt across Swiss cantons to identify the effect of iodization, by comparing outcomes for those born right before and right after these sudden changes in the treatment environment. These approaches indicate that the eradication of iodine deficiency in previously deficient areas increased the schooling of the population significantly. The effects are larger for females than for males, which is consistent with medical evidence showing that women are more likely to be affected by iodine deficiency disorders than men.

The management of iron deficiency in inflammatory bowel disease--an online tool developed by the RAND/UCLA appropriateness method.

BACKGROUND: Iron deficiency is a common and undertreated problem in inflammatory bowel disease (IBD). AIM: To develop an online tool to support treatment choice at the patient-specific level. METHODS: Using the RAND/UCLA Appropriateness Method (RUAM), a European expert panel assessed the appropriateness of treatment regimens for a variety of clinical scenarios in patients with non-anaemic iron deficiency (NAID) and iron deficiency anaemia (IDA). Treatment options included adjustment of IBD medication only, oral iron supplementation, high-/low-dose intravenous (IV) regimens, IV iron plus erythropoietin-stimulating agent (ESA), and blood transfusion. The panel process consisted of two individual rating rounds (1148 treatment indications; 9-point scale) and three plenary discussion meetings. RESULTS: The panel reached agreement on 71% of treatment indications. 'No treatment' was never considered appropriate, and repeat treatment after previous failure was generally discouraged. For 98% of scenarios, at least one treatment was appropriate. Adjustment of IBD medication was deemed appropriate in all patients with active disease. Use of oral iron was mainly considered an option in NAID and mildly anaemic patients without disease activity. IV regimens were often judged appropriate, with high-dose IV iron being the preferred option in 77% of IDA scenarios. Blood transfusion and IV+ESA were indicated in exceptional cases only. CONCLUSIONS: The RUAM revealed high agreement amongst experts on the management of iron deficiency in patients with IBD. High-dose IV iron was more often considered appropriate than other options. To facilitate dissemination of the recommendations, panel outcomes were embedded in an online tool, accessible via http://ferroscope.com/.

Human GnRH deficiency: a unique disease model to unravel the ontogeny of GnRH neurons.

Evolutionary survival of a species is largely a function of its reproductive fitness. In mammals, a sparsely populated and widely dispersed network of hypothalamic neurons, the gonadotropin-releasing hormone (GnRH) neurons, serve as the pilot light of reproduction via coordinated secretion of GnRH. Since it first description, human GnRH deficiency has been recognized both clinically and genetically as a heterogeneous disease. A spectrum of different reproductive phenotypes comprised of congenital GnRH deficiency with anosmia (Kallmann syndrome), congenital GnRH deficiency with normal olfaction (normosmic idiopathic hypogonadotropic hypogonadism), and adult-onset hypogonadotropic hypogonadism has been described. In the last two decades, several genes and pathways which govern GnRH ontogeny have been discovered by studying humans with GnRH deficiency. More importantly, detailed study of these patients has highlighted the emerging theme of oligogenicity and genotypic synergism, and also expanded the phenotypic diversity with the documentation of reversal of GnRH deficiency later in adulthood in some patients. The underlying genetic defect has also helped understand the associated nonreproductive phenotypes seen in some of these patients. These insights now provide practicing clinicians with targeted genetic diagnostic strategies and also impact on clinical management.

Reduced Prostasin (CAP1/PRSS8) Activity Eliminates HAI-1 and HAI-2 Deficiency-Associated Developmental Defects by Preventing Matriptase Activation.

Loss of either hepatocyte growth factor activator inhibitor (HAI)-1 or -2 is associated with embryonic lethality in mice, which can be rescued by the simultaneous inactivation of the membrane-anchored serine protease, matriptase, thereby demonstrating that a matriptase-dependent proteolytic pathway is a critical developmental target for both protease inhibitors. Here, we performed a genetic epistasis analysis to identify additional components of this pathway by generating mice with combined deficiency in either HAI-1 or HAI-2, along with genes encoding developmentally co-expressed candidate matriptase targets, and screening for the rescue of embryonic development. Hypomorphic mutations in Prss8, encoding the GPI-anchored serine protease, prostasin (CAP1, PRSS8), restored placentation and normal development of HAI-1-deficient embryos and prevented early embryonic lethality, mid-gestation lethality due to placental labyrinth failure, and neural tube defects in HAI-2-deficient embryos. Inactivation of genes encoding c-Met, protease-activated receptor-2 (PAR-2), or the epithelial sodium channel (ENaC) alpha subunit all failed to rescue embryonic lethality, suggesting that deregulated matriptase-prostasin activity causes developmental failure independent of aberrant c-Met and PAR-2 signaling or impaired epithelial sodium transport. Furthermore, phenotypic analysis of PAR-1 and matriptase double-deficient embryos suggests that the protease may not be critical for focal proteolytic activation of PAR-2 during neural tube closure. Paradoxically, although matriptase auto-activates and is a well-established upstream epidermal activator of prostasin, biochemical analysis of matriptase- and prostasin-deficient placental tissues revealed a requirement of prostasin for conversion of the matriptase zymogen to active matriptase, whereas prostasin zymogen activation was matriptase-independent.

Macrophage Migration Inhibitory Factor Deficiency Is Associated With Impaired Killing of Gram-Negative Bacteria by Macrophages and Increased Susceptibility to Klebsiella pneumoniae Sepsis.

The cytokine macrophage migration inhibitory factor (MIF) is an important component of the early proinflammatory response of the innate immune system. However, the antimicrobial defense mechanisms mediated by MIF remain fairly mysterious. In the present study, we examined whether MIF controls bacterial uptake and clearance by professional phagocytes, using wild-type and MIF-deficient macrophages. MIF deficiency did not affect bacterial phagocytosis, but it strongly impaired the killing of gram-negative bacteria by macrophages and host defenses against gram-negative bacterial infection, as shown by increased mortality in a Klebsiella pneumonia model. Consistent with MIF's regulatory role of Toll-like 4 expression in macrophages, MIF-deficient cells stimulated with lipopolysaccharide or Escherichia coli exhibited reduced nuclear factor κB activity and tumor necrosis factor (TNF) production. Addition of recombinant MIF or TNF corrected the killing defect of MIF-deficient macrophages. Together, these data show that MIF is a key mediator of host responses against gram-negative bacteria, acting in part via a modulation of bacterial killing by macrophages.

Toxoplasma gondii Antigenuria in Patients with Acquired Immune Deficiency Syndrome

A longitudinal study was performed with sera and urine of patients with acquired immune deficiency syndrome (AIDS), taken before, during and after clinically Toxoplasma infection. The tested patients were followed for an average of two years. The titres of the specific IgG and IgM antibodies were measured by an indirect fluorescent antibody test (IFAT), and the appearance of circulating antigens of T. gondii was determined in 36 urine samples of 13 patients with neurotoxoplasmosis by means of the coagglutination test. The presence of T. gondii antigens in the urine of AIDS patients by this test was correlated with the immunoblot technique, with clinical symptoms and also with pathological findings. Our results indicate that the detection of T. gondii antigens in the urine of AIDS patients can be regarded as a rapid and efficient method for the diagnosis of acute toxoplasmosis