3. Bleeker SE, Moll HA, Steyerberg EW, Donders AR, Derksen-Lubsen G, Grobbee DE, Moons KG. External validation is necessary in predic- tion research: a clinical example. J Clin Epidemiol 2003;56:826–832. Effect of Vitamin D on Tuberculosis and HIV Replication Depends on Conversion to Calcitriol and Concentration To the Editor: Dr. Wejse and colleagues reported results of a randomized controlled trial of cholecalciferol supplementation in patients on treatment for tuberculosis and found no effect on clinical outcome or mortality (1). The authors used 25 hydroxy chol- ecalciferol for supplementary treatment and did not report on its effect on levels of the active form of vitamin D, which is 1,25 dihydroxy cholecalciferol. The distinction between 25 hydroxy cholecalciferol and its active form 1,25 dihydroxy cholecalci- ferol (calcitriol) is important because inflammatory stimuli associated with increased tumor necrosis factor (TNF) concen- trations can block the stimulatory effect of parathyroid hor- mone (PTH) on the renal 1-a-hydroxylase generating calcitriol (2). TNF appears to down-regulate PTH receptors. TNF is a key mediator in the immune response to Mycobacterium tuberculosis, and in HIV infection there was a strong negative correlation of TNF and calcitriol levels (3). It may therefore be important to give 1,25 dihydroxy cholecalciferol and not 25 hydroxy cholecalciferol to achieve an effect on immunity against tuberculosis. The authors specu- lated that the dose of vitamin D used may not have been sufficient to generate a clinical effect but did not discuss the potential implications of the choice of a high dose of vitamin D for the immune response in patients with tuberculosis and on viral replication in HIV infection. The calcitriol effect is concentration dependent. In supra- physiological concentrations calcitriol acts as an immune sup- pressant. It inhibits the production of a wide range of cytokines including IFN-g. IFN-g is a key cytokine involved in antimyco- bacterial immunity, and calcitriol concentrations above 10 nmol/L have been shown to reduce IFN-g production in vitro in peripheral blood mononuclear cells (4). Subsequent investiga- tions found that calcitriol suppressed IFN-g production in response to live M. tuberculosis in human peripheral blood mononuclear cells (PBMC) with a maximum suppression at a concentration of 100 nmol/L (5). Wejse and coworkers observed a trend for increased mortality in HIV positive vitamin D supplemented patients (1). Recent experiments in HeLa, U937 and Cos-1 cells revealed that the vitamin D receptor is able to stimulate HIV-1 long terminal repeat transactivation increasing HIV gene expression (6). Future trials need to use calcitriol to avoid potential prob- lems with lack of activation of the applied vitamin D prepara- tion due to systemic inflammation. Dose regimes need to avoid high doses leading to immune suppression associated with plasma levels greater than 10 nmol/L to optimize its effect against M. tuberculosis infection. Conflict of Interest Statement: The author has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. MICHAEL EISENHUT Luton & Dunstable Hospital NHS Foundation Trust Luton, United Kingdom References 1. Wejse C, Gomes VF, Rabna P, Gustafson P, Aaby P, Lisse IM, Andersen PL. Glerup H, Sodemann M. Vitamin D as supplementary treatment for tuberculosis: a double-blind randomized placebo-controlled trial. Am J Respir Crit Care Med 2009;179:843–850. 2. Ebert R, Jovanovic M, Ulmer M, Schneider D, Meissner-Weigl J, Adamski J, Jakob F. Downregulation by nuclear factor kappa-B of human 25 hydroxyvitamin D3 1-hydroxylase promoter-1. Mol Endo- crinol 2004;18:2440–2450. 3. Haug CJ, Aukrust P, Haug E, Morkrid L, Mueller F, Froland SS. Severe deficiency of 1,25-dihydroxyvitamin D3 in human immunodeficiency virus infection: association with immunological hyperactivity and only minor changes in calcium homeostasis. J Clin Endocrinol Metab 1998;83:3832–3838. 4. Manolagas SC, Provvedini DM, Tsoukas CD. Interactions of 1, 25- dihydroxyvitamin D 3 and the immune system. Mol Cell Endocrinol 1985;43:113–122. 5. Vidyarani M, Selvaraj P, Jawahar MS, Narayanan PR. 1,25 dihydroxyvi- tamin D3 modulated cytokine response in pulmonary tuberculosis. Cytokine 2007;40:128–134. 6. Nevado J, Tenbaum SP, Castillo AJ, Sanchez-Pacheco A, Aranda A. Activation of the human immunodeficiency virus type 1 long terminal repeat by 1a 25-dihydroxy vitamin D3. J Mol Endocrinol 2007;38:587– 601. From the Authors: Dr. Eisenhut in his letter points out that 1,25-dihydroxycholecalci- ferol (calcitriol) is the active form of vitamin D and suggests that we should have used calcitriol instead of 25-OH-cholecalciferol (25-OH-D 3 ) in our study (1). 25-OH-D 3 is the storage form of vitamin D (half life 2–3 wk), and consequently we determined s-25- OH-D 3 levels to be a measure of the vitamin D status. Measure- ment of s-calcitriol often gives very confusing results due to the short half life (12–24 h), and in severe vitamin D deficiency, low to normal and even raised levels of s-calcitriol have been reported. Dr. Eisenhut ignores the important local autocrine 1-a- hydroxylase activity in the monocytes and macrophages (2). Holick and Chen recently reviewed the calcemic and noncalce- mic effects of vitamin D (3). The PTH-stimulated renal 1-a- hydroxylase activity appears to be important for the calcemic actions of vitamin D, and maintains stable serum levels of calcium. The noncalcemic actions of vitamin D seem primarily to be mediated through autocrine 1-a-hydroxylase activity. Local calcitriol synthesis is not dependent on PTH stimulation, but is dependent on the substrate 25-OH-D 3 , and seems to be maximal with serum concentrations of 25-OH-D 3 greater than 75 nmol/L. The use of calcitriol as suggested by Dr. Eisenhut would demand a close monitoring of serum levels of calcitriol to avoid supraphysiological concentrations, which could result in immu- nosuppression or even hypercalcemia. We believe in the use of vitamin D 3 , as it is safer and easier to use. Correction of vitamin D deficiency ensures a sufficient intracellular level of calcitriol due to local autocrine 1-a-hydroxylase activity. Conflict of Interest Statement: Neither author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript. CHRISTIAN WEJSE Aarhus University Hospital Skejby, Denmark HENNING GLERUP Aarhus University Hospital Silkeborg, Denmark References 1. Wejse C, Gomes VF, Rabna P, Gustafson P, Aaby P, Lisse IM, Andersen PL, Glerup H, Sodemann M. Vitamin D as supplementary treatment for tuberculosis: a double-blind randomized placebo-controlled trial. Am J Respir Crit Care Med 2009;179:843–850. 2. Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, Ochoa MT, Schauber J, Wu K, Meinken C, et al. Toll-like receptor triggering of a Correspondence 795
Correspondence
3. Bleeker SE, Moll HA, Steyerberg EW, Donders AR, Derksen-Lubsen G,
Grobbee DE, Moons KG. External validation is necessary in prediction research: a clinical example. J Clin Epidemiol 2003;56:826–832.
Effect of Vitamin D on Tuberculosis and HIV
Replication Depends on Conversion to
Calcitriol and Concentration
795
2.
3.
To the Editor:
Dr. Wejse and colleagues reported results of a randomized
controlled trial of cholecalciferol supplementation in patients
on treatment for tuberculosis and found no effect on clinical
outcome or mortality (1). The authors used 25 hydroxy cholecalciferol for supplementary treatment and did not report on
its effect on levels of the active form of vitamin D, which is 1,25
dihydroxy cholecalciferol. The distinction between 25 hydroxy
cholecalciferol and its active form 1,25 dihydroxy cholecalciferol (calcitriol) is important because inflammatory stimuli
associated with increased tumor necrosis factor (TNF) concentrations can block the stimulatory effect of parathyroid hormone (PTH) on the renal 1-a-hydroxylase generating calcitriol
(2). TNF appears to down-regulate PTH receptors. TNF is a key
mediator in the immune response to Mycobacterium tuberculosis,
and in HIV infection there was a strong negative correlation of
TNF and calcitriol levels (3).
It may therefore be important to give 1,25 dihydroxy
cholecalciferol and not 25 hydroxy cholecalciferol to achieve
an effect on immunity against tuberculosis. The authors speculated that the dose of vitamin D used may not have been
sufficient to generate a clinical effect but did not discuss the
potential implications of the choice of a high dose of vitamin D
for the immune response in patients with tuberculosis and on
viral replication in HIV infection.
The calcitriol effect is concentration dependent. In supraphysiological concentrations calcitriol acts as an immune suppressant. It inhibits the production of a wide range of cytokines
including IFN-g. IFN-g is a key cytokine involved in antimycobacterial immunity, and calcitriol concentrations above 10 nmol/L
have been shown to reduce IFN-g production in vitro in
peripheral blood mononuclear cells (4). Subsequent investigations found that calcitriol suppressed IFN-g production in
response to live M. tuberculosis in human peripheral blood
mononuclear cells (PBMC) with a maximum suppression at a
concentration of 100 nmol/L (5). Wejse and coworkers observed
a trend for increased mortality in HIV positive vitamin D
supplemented patients (1). Recent experiments in HeLa, U937
and Cos-1 cells revealed that the vitamin D receptor is able to
stimulate HIV-1 long terminal repeat transactivation increasing
HIV gene expression (6).
Future trials need to use calcitriol to avoid potential problems with lack of activation of the applied vitamin D preparation due to systemic inflammation. Dose regimes need to avoid
high doses leading to immune suppression associated with plasma
levels greater than 10 nmol/L to optimize its effect against M.
tuberculosis infection.
4.
5.
6.
for tuberculosis: a double-blind randomized placebo-controlled trial.
Am J Respir Crit Care Med 2009;179:843–850.
Ebert R, Jovanovic M, Ulmer M, Schneider D, Meissner-Weigl J,
Adamski J, Jakob F. Downregulation by nuclear factor kappa-B of
human 25 hydroxyvitamin D3 1-hydroxylase promoter-1. Mol Endocrinol 2004;18:2440–2450.
Haug CJ, Aukrust P, Haug E, Morkrid L, Mueller F, Froland SS. Severe
deficiency of 1,25-dihydroxyvitamin D3 in human immunodeficiency
virus infection: association with immunological hyperactivity and only
minor changes in calcium homeostasis. J Clin Endocrinol Metab
1998;83:3832–3838.
Manolagas SC, Provvedini DM, Tsoukas CD. Interactions of 1, 25dihydroxyvitamin D3 and the immune system. Mol Cell Endocrinol
1985;43:113–122.
Vidyarani M, Selvaraj P, Jawahar MS, Narayanan PR. 1,25 dihydroxyvitamin D3 modulated cytokine response in pulmonary tuberculosis.
Cytokine 2007;40:128–134.
Nevado J, Tenbaum SP, Castillo AJ, Sanchez-Pacheco A, Aranda A.
Activation of the human immunodeficiency virus type 1 long terminal
repeat by 1a 25-dihydroxy vitamin D3. J Mol Endocrinol 2007;38:587–
601.
From the Authors:
Dr. Eisenhut in his letter points out that 1,25-dihydroxycholecalciferol (calcitriol) is the active form of vitamin D and suggests that
we should have used calcitriol instead of 25-OH-cholecalciferol
(25-OH-D3) in our study (1). 25-OH-D3 is the storage form of
vitamin D (half life 2–3 wk), and consequently we determined s-25OH-D3 levels to be a measure of the vitamin D status. Measurement of s-calcitriol often gives very confusing results due to the
short half life (12–24 h), and in severe vitamin D deficiency, low to
normal and even raised levels of s-calcitriol have been reported.
Dr. Eisenhut ignores the important local autocrine 1-ahydroxylase activity in the monocytes and macrophages (2).
Holick and Chen recently reviewed the calcemic and noncalcemic effects of vitamin D (3). The PTH-stimulated renal 1-ahydroxylase activity appears to be important for the calcemic
actions of vitamin D, and maintains stable serum levels of
calcium. The noncalcemic actions of vitamin D seem primarily
to be mediated through autocrine 1-a-hydroxylase activity. Local
calcitriol synthesis is not dependent on PTH stimulation, but is
dependent on the substrate 25-OH-D3, and seems to be maximal
with serum concentrations of 25-OH-D3 greater than 75 nmol/L.
The use of calcitriol as suggested by Dr. Eisenhut would
demand a close monitoring of serum levels of calcitriol to avoid
supraphysiological concentrations, which could result in immunosuppression or even hypercalcemia. We believe in the use of
vitamin D3, as it is safer and easier to use. Correction of vitamin
D deficiency ensures a sufficient intracellular level of calcitriol
due to local autocrine 1-a-hydroxylase activity.
Conflict of Interest Statement: Neither author has a financial relationship with a
commercial entity that has an interest in the subject of this manuscript.
CHRISTIAN WEJSE
Aarhus University Hospital
Skejby, Denmark
HENNING GLERUP
Aarhus University Hospital
Silkeborg, Denmark
Conflict of Interest Statement: The author has no financial relationship with a
commercial entity that has an interest in the subject of this manuscript.
MICHAEL EISENHUT
Luton & Dunstable Hospital NHS Foundation Trust
Luton, United Kingdom
References
1. Wejse C, Gomes VF, Rabna P, Gustafson P, Aaby P, Lisse IM, Andersen
PL. Glerup H, Sodemann M. Vitamin D as supplementary treatment
References
1. Wejse C, Gomes VF, Rabna P, Gustafson P, Aaby P, Lisse IM, Andersen
PL, Glerup H, Sodemann M. Vitamin D as supplementary treatment
for tuberculosis: a double-blind randomized placebo-controlled trial.
Am J Respir Crit Care Med 2009;179:843–850.
2. Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, Ochoa MT,
Schauber J, Wu K, Meinken C, et al. Toll-like receptor triggering of a
Keep reading this paper — and 50 million others — with a free Academia account
This text provides an overview of the role and authority of the European Court of Human Rights which celebrated its 20th anniversary as a full-time court in November 2018. After providing a short description of the Court’s role in Europe’s changing legal architecture, emphasis is placed on the authority that the Court’s case-law has acquired as well as the challenges that it faces, principally from the ‘new democracies,’ after the fall of the Berlin Wall. Focus is then placed on the responsibility of states to consolidate and reinforce the effectiveness of the European Convention on Human Rights and the Strasbourg Court’s authority.
To be published in No.1 Arabic Review of International Humanitarian Law and Human Rights Education (new on-line publication, December 2018, https://acihl.org/news.htm).
Belâgat ilmi, Arap edebiyatında önemli bir yere sahiptir. Belagât sözün tekellüf ve
yapmacıktan uzak olup yorumlamaya ihtiyaç duymaksızın kolay anlaşılır bir şekilde yerinde
ve muhatabına göre söylenmesidir. Böylece belâgat ilmi konuşmanın düzgün, pürüzsüz ve
adamına göre söylenmesini öğretir. Belagât; meâni ve beyân ilimleri ile birlikte muhassinat
(lafzı ve manayı güzelleştiren sanatlar) olarak incelenen konular, zaman içerisinde bedi‘
ilmini oluşturmuştur. Klasik Arap şiirinin vazgeçilmez unsurlarından olan edebî sanatlar,
şairin ve şiirin belâgatini ortaya koyması açısından önemli bir rol oynar. Bundan dolayı şairler
belagât ilminin bir kısmı olan bedii ilminde yer alan sanatlara çokça başvurup konuşmalarını
bu sanatlara göre irad etmeye çalışmışlardır. Bu çalışma, Arap edebiyatında bedîî sanatların
muhassinat-ı lafziye (lafzı güzelleştirenler) başlığı altında ele alınan Hüsn-i İbtida sanatı ile
ilgilidir. Bir kitap, makale veya konuşma gibi yazılı eserlerde olduğu gibi, şiirde de girişin
dikkat çekici olması okuyucunun ilgisini çekmesi ve değerini artırması için konuşmacılar bu
sanata önem vermişlerdir. Zira başlangıç bu tür sanatlardan yoksun olduğunda şiir vb. ilgisiz
kalır ve itibar görmezdi. Hatta bu sanata başvurmayan şairler zaman zaman eleştirildiği
olmuştur. Çalışmanın giriş bölümünden sonra, fesâhat, kelime, kelam ve mütekellimin
fesahati, belâgat, kelam ve mütekellimin belagâtı ve belâgat ilminin kısımları olan beyan,
meani ve bedi kavramlarından kısaca bahsedilmiştir. Ardından, detaylıca hüsn-i ibtidâ ve
berâat-i istihlâl kavramları ele alınarak aralarındaki farka değinilmiştir. Son kısımda ise,
konuya dair klasik şiirlerden örnekler getirilerek konu izaha kavuşturulmuştur.
Anahtar Kelimeler: Arap Dili ve Belâgatı, Klasik Arap Şiiri, husn-i ibtidâ.
Introdução: A COVID-19 foi responsável por milhares de óbitos no Brasil e no mundo. Diante disto, investigar as determinantes sociais e a localização geográfica são estratégias que podem contribuir para que determinadas populações fiquem menos expostas à determinadas condições, sobretudo num contexto de pandemia. Objetivo: Analisar os municípios com maior incidência de óbitos por COVID-19 no Brasil no período de abril a agosto de 2021. Metodologia: Trata-se de um estudo transversal e analítico de dados secundários disponibilizados pelo Diagnósticos da América S.A (DASA) - DASA ANALYTICS (dadoscoronavirus.dasa.com.br). Foram selecionados os 15 municípios de médio e grande porte de todo o território nacional com maiores taxas de óbitos por COVID-19 ao final de cada mês no período de abril a agosto de 2021. Em seguida, foram levantadas informações a respeito da população e índice de desenvolvimento humano municipal (IDH-M). Resultados e discussão: A região do país que mais teve municíp...
The COVID-19 outbreak has resulted in public fear of transmitting infection. Nurses in dealing with the COVID-19 outbreak also obtained stigmatized due to discrimination received by COVID-19 sufferers. The objective of the study is to identify the dominant factor to determine the occurrence of stigma experienced by nurses when caring for COVID-19 patients. The research design was qualitative and quantitative, with a sample of 121 Primary Health Center nurses who were performed by convenience sampling. Data analysis with Multiple Linear Regression presented that overall, there was a significant correlation between knowledge in preventing COVID-19, Personal Ability and Organizational Ability to stigma from society experienced by nurses with ANOVA or F test results (229.427) with p = 0.000. Morever, there is a strong and significant relationship between knowledge, self-efficacy and organizational ability to community stigma (R Square = 0.964). The dominant factor that affects stigma as...
Este artigo estabelece uma estrutura abrangente para detectar design. Ao elucidar as características e processos que significam o design inteligente, demonstramos por que a dicotomia entre design e não design abrange todos os mecanismos de origem possíveis. Esta distinção clara é essencial para a compreensão da intencionalidade, precisão e complexidade inerentes aos sistemas concebidos de forma inteligente.