Vitamin D deficiency ( plasma 25(OH)D levels
<50 nmol/L)(20 ng/ml) was ubiquitous in patients with ARDS and
present in the vast majority of patients at risk of
developing ARDS following oesophagectomy.
ABSTRACT- Disseminated cryptococcosis is generally seen in immunocompromised patients mainly associated with Human Immunodeficiency Virus. Spontaneous cryptococcal peritonitis among patients of disseminated cryptococcosis is a rare presentation, which is presented in cases with cirrhosis of liver. It can be confused with spontaneous bacterial peritonitis. Strong clinical awareness and index of suspicion in a cirrhotic patient with peritonitis as well as early diagnosis and treatment is required as it is difficult to distinguish from spontaneous bacterial peritonitis. We describe here a case of disseminated cryptococcosis with cryptococcal peritonitis in a cirrhotic male.
Key-words- Liver cirrhosis, Cryptococcosis, Cryptococcal peritonitis
Directly acting antivirals and Visceral Leishmaniasis: A case reportRxVichuZ
This presentation deals with visceral leishmaniasis induced by directly acting antivirals in a patient with Hepatitis C infection.
Case details in summary, along with case report publication details have been summarized.
References have been provided below each slide.
ABSTRACT- Disseminated cryptococcosis is generally seen in immunocompromised patients mainly associated with Human Immunodeficiency Virus. Spontaneous cryptococcal peritonitis among patients of disseminated cryptococcosis is a rare presentation, which is presented in cases with cirrhosis of liver. It can be confused with spontaneous bacterial peritonitis. Strong clinical awareness and index of suspicion in a cirrhotic patient with peritonitis as well as early diagnosis and treatment is required as it is difficult to distinguish from spontaneous bacterial peritonitis. We describe here a case of disseminated cryptococcosis with cryptococcal peritonitis in a cirrhotic male.
Key-words- Liver cirrhosis, Cryptococcosis, Cryptococcal peritonitis
Directly acting antivirals and Visceral Leishmaniasis: A case reportRxVichuZ
This presentation deals with visceral leishmaniasis induced by directly acting antivirals in a patient with Hepatitis C infection.
Case details in summary, along with case report publication details have been summarized.
References have been provided below each slide.
IOSR Journal of Pharmacy (IOSRPHR), www.iosrphr.org, call for paper, research...iosrphr_editor
IOSR Journal of Pharmacy (IOSRPHR), www.iosrphr.org, call for paper, research paper publishing, where to publish research paper, journal publishing, how to publish research paper, Call for research paper, international journal, publishing a paper, call for paper 2012, journal of pharmacy, how to get a research paper published, publishing a paper, publishing of journal, research and review articles, Pharmacy journal, International Journal of Pharmacy, hard copy of journal, hard copy of certificates, online Submission, where to publish research paper, journal publishing, international journal, publishing a paper
ABO Blood Groups and SARS-CoV-2 Infection by Fumiichiro Yamamoto, Ph.D.FumiichiroYamamoto
Scientific knowledge is depicted on the association between A and B glycan antigens of the ABO blood group system important in blood transfusion and cell/tissue/organ transplantation and infection of the SARS-CoV-2 virus responsible for the ongoing epidemic of coronavirus disease COVID-19.
Infectious diseases are the second most common cause of death in end-stage renal disease (ESRD) patients. Patients with ESRD are at high risk for several infections, due to exposure to blood products and frequent dialysis. The increased susceptibility to infections among these patients is indicative of a complex and varied state of immunodeficiency manifested by abnormal phagocytosis, T and B lymphocytes abnormalities and impaired response to T cell dependent pathogens such as hepatitis B and influenza viruses. These immunologic abnormalities are complicated by the use of immunosuppressive drugs used to treat and control underlying disease and exacerbated by nutritional deficiency and the dialysis procedure. Though many of these infections can be prevented by appropriate vaccination, the usual schedules of vaccination may be less effective.
The aim of this paper is to review the studies on the use of vaccines in ESRD patients
and summarize the vaccines required in this population.
IOSR Journal of Pharmacy (IOSRPHR), www.iosrphr.org, call for paper, research...iosrphr_editor
IOSR Journal of Pharmacy (IOSRPHR), www.iosrphr.org, call for paper, research paper publishing, where to publish research paper, journal publishing, how to publish research paper, Call for research paper, international journal, publishing a paper, call for paper 2012, journal of pharmacy, how to get a research paper published, publishing a paper, publishing of journal, research and review articles, Pharmacy journal, International Journal of Pharmacy, hard copy of journal, hard copy of certificates, online Submission, where to publish research paper, journal publishing, international journal, publishing a paper
ABO Blood Groups and SARS-CoV-2 Infection by Fumiichiro Yamamoto, Ph.D.FumiichiroYamamoto
Scientific knowledge is depicted on the association between A and B glycan antigens of the ABO blood group system important in blood transfusion and cell/tissue/organ transplantation and infection of the SARS-CoV-2 virus responsible for the ongoing epidemic of coronavirus disease COVID-19.
Infectious diseases are the second most common cause of death in end-stage renal disease (ESRD) patients. Patients with ESRD are at high risk for several infections, due to exposure to blood products and frequent dialysis. The increased susceptibility to infections among these patients is indicative of a complex and varied state of immunodeficiency manifested by abnormal phagocytosis, T and B lymphocytes abnormalities and impaired response to T cell dependent pathogens such as hepatitis B and influenza viruses. These immunologic abnormalities are complicated by the use of immunosuppressive drugs used to treat and control underlying disease and exacerbated by nutritional deficiency and the dialysis procedure. Though many of these infections can be prevented by appropriate vaccination, the usual schedules of vaccination may be less effective.
The aim of this paper is to review the studies on the use of vaccines in ESRD patients
and summarize the vaccines required in this population.
ABSTRACT- Introduction: Blood group antigens have been reported to be associated with many diseased conditions
severally. Studies have suggested that ABO blood groups have an impact on infection status of the individuals
possessing a particular blood group due to the significant associations observed when analyzed. However there is
limited information on the relationship between these blood group antigens with haemoglobin genotype and CD4 cell
count in Human Immunodeficiency Virus (HIV) infection, hence the need for this study.
Materials and Method: Exactly 240 newly enrolled seropositive patients attending the HIV Clinic of LAUTECH
Teaching Hospital, Osogbo, Nigeria and 120 healthy blood donors were recruited for this study. Antibodies to HIV
were determined using determine rapid HIV 1/HIV 2 test kit (Abbott), enzyme linked immunosorbent assay (ELISA)
(GenScreen plus HIV Ag-Ab test kit, Paris) and Western blot (New-LAV Blot 1, BioRad, France) for confirmatory test.
ABO and Rhesus blood grouping was determined by standard tile and tube techniques. Haemoglobin genotype
determined by alkaline cellulose acetate haemoglobin electrophoresis while CD4 cell count was estimated with Partec
Cyflow analyser.
Result: There is no significant association between the ABO/Rh antigens and haemoglobin genotypes of the test and
control groups (P<0.05). All participants in the control group had CD4 count >200cells/mm3 while 198 (55%) HIV
infected subjects had CD4 count ≥200cells/mm3 and 42 (11.7%) had CD4 count <200cells/mm3. A significant
association was observed between the CD4 cell count of the patients and their ABO blood group antigens (P<0.05) with
blood group A and AB having the highest CD4count.
Conclusion: The outcome of this study reiterates the fact that blood group antigens are involved in immune protection
against infectious disease. Blood group A which has been implicated to confer susceptibility in some diseased condition
has been observed to confer immunity in this study.
Key-words- CD4 cells, Blood Group Antigens, HIV and Haemoglobin Genotype
Red cell alloimmunization in blood transfusion dependent Patients with Sickle...iosrjce
IOSR Journal of Dental and Medical Sciences is one of the speciality Journal in Dental Science and Medical Science published by International Organization of Scientific Research (IOSR). The Journal publishes papers of the highest scientific merit and widest possible scope work in all areas related to medical and dental science. The Journal welcome review articles, leading medical and clinical research articles, technical notes, case reports and others.
This presentation covers a brief introduction to Diagnostic kit with its different types and examples. Also, this presentation covers examples of some common diseases with their diagnostic test.
Small Arms Lethality variables 1.6e DRAFTJA Larson
small arms lethality is a complex equation.
military operations are generally a team event.....more like football or soccer than tennis......
therefore teamwork and safety adds complexity
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
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Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
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New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
Pharynx and Clinical Correlations BY Dr.Rabia Inam Gandapore.pptx
Vit D ARDS
1. ORIGINAL ARTICLE
Vitamin D deficiency contributes directly to the
acute respiratory distress syndrome (ARDS)
Rachel C A Dancer,1
Dhruv Parekh,1
Sian Lax,1
Vijay D’Souza,1
Shengxing Zheng,1
Chris R Bassford,1
Daniel Park,1
D G Bartis,1
Rahul Mahida,1
Alice M Turner,1
Elizabeth Sapey,1
Wenbin Wei,2
Babu Naidu,1
Paul M Stewart,3
William D Fraser,4
Kenneth B Christopher,5
Mark S Cooper,6
Fang Gao,1
David M Sansom,7
Adrian R Martineau,8
Gavin D Perkins,9
David R Thickett1
▸ Additional material is
published online only. To view
please visit the journal online
(http://dx.doi.org/10.1136/
thoraxjnl-2014-206680).
For numbered affiliations see
end of article.
Correspondence to
Professor David Thickett,
Centre for Translational
Inflammation and Fibrosis
Research, Queen Elizabeth
Hospital, University
of Birmingham, Birmingham
B15 2TH, UK;
d.thickett@bham.ac.uk
RCAD and DP are joint first
author of this paper.
Received 10 December 2014
Revised 10 March 2015
Accepted 2 April 2015
Published Online First
1 May 2015
To cite: Dancer RCA,
Parekh D, Lax S, et al.
Thorax 2015;70:617–624.
ABSTRACT
Rationale Vitamin D deficiency has been implicated as
a pathogenic factor in sepsis and intensive therapy unit
mortality but has not been assessed as a risk factor for
acute respiratory distress syndrome (ARDS). Causality of
these associations has never been demonstrated.
Objectives To determine if ARDS is associated with
vitamin D deficiency in a clinical setting and to
determine if vitamin D deficiency in experimental models
of ARDS influences its severity.
Methods Human, murine and in vitro primary alveolar
epithelial cell work were included in this study.
Findings Vitamin D deficiency (plasma 25(OH)D levels
<50 nmol/L) was ubiquitous in patients with ARDS and
present in the vast majority of patients at risk of
developing ARDS following oesophagectomy. In a
murine model of intratracheal lipopolysaccharide
challenge, dietary-induced vitamin D deficiency resulted
in exaggerated alveolar inflammation, epithelial damage
and hypoxia. In vitro, vitamin D has trophic effects on
primary human alveolar epithelial cells affecting >600
genes. In a clinical setting, pharmacological repletion of
vitamin D prior to oesophagectomy reduced the
observed changes of in vivo measurements of alveolar
capillary damage seen in deficient patients.
Conclusions Vitamin D deficiency is common in
people who develop ARDS. This deficiency of vitamin D
appears to contribute to the development of the
condition, and approaches to correct vitamin D
deficiency in patients at risk of ARDS should be
developed.
Trial registration UKCRN ID 11994.
INTRODUCTION
Acute respiratory distress syndrome (ARDS) occurs
due to either direct or indirect proinflammatory
insults. However, only a proportion of at-risk
patients develop ARDS, with research suggesting
that genetic, age, social and other factors play a
role in determining who develops ARDS.1
More than 1 billion people worldwide are
believed to have vitamin D deficiency.2
Vitamin D
has important functions besides bone and calcium
homeostasis3
with cells of the innate and adaptive
immune system responding to vitamin D. Vitamin
D deficiency may therefore increase the risk of bac-
terial and viral infection.
Vitamin D deficiency is associated with an
increased risk of intensive care admission and mor-
tality in patients with pneumonia.4
Deficiency is
common in critically ill patients and associated
with adverse outcome.3
Gram-positive bacteria,
invasive pneumococcal disease and meningococcal
disease are more common when 25(OH)D3 levels
are low.5
Recent data from an Austrian study in
critically ill deficient patients suggests that when
treatment with vitamin D is successful in raising
levels >75 nmol/L there is a mortality benefit.6
Vitamin D may improve outcomes by reducing
both local and systemic inflammatory responses as a
result of modulating cytokine responses.7
In a mouse
model of lethal endotoxaemia, survival post intraven-
ous lipopolysaccharide (LPS) was significantly poorer
in the vitamin D receptor knockout mice.8
Our aim was to define the prevalence and sever-
ity of vitamin D deficiency in patients with ARDS
and to establish whether vitamin D deficiency is a
risk factor for and/or a driver of the exaggerated
and persistent inflammation that is a hallmark of
ARDS. To achieve these aims, we employed transla-
tional clinical studies and in vitro primary cell
work and murine models.
Open Access
Scan to access more
free content
Key messages
What is the key question?
▸ Is vitamin D deficiency a risk factor for the
development of acute respiratory distress
syndrome (ARDS)?
What is the bottom line?
▸ Patients with and at risk of ARDS are highly
likely to be deficient, and severity of vitamin D
deficiency relates to increased epithelial
damage, the development of ARDS and
survival.
Why read on?
▸ We present evidence that an easily treatable
vitamin deficiency may increase the risk of
ARDS in patients at risk.
Dancer RCA, et al. Thorax 2015;70:617–624. doi:10.1136/thoraxjnl-2014-206680 617
Critical care
onApril14,2020byguest.Protectedbycopyright.http://thorax.bmj.com/Thorax:firstpublishedas10.1136/thoraxjnl-2014-206680on22April2015.Downloadedfrom
2. METHODS
Patient cohorts
Patient cohort details are outlined in the online supplement but
consisted of 52 patients with ARDS, 57 patients undergoing
oesophagectomy (at risk of ARDS) and 8 patients undergoing
oesophagectomy who had high-dose vitamin D supplementation
prior to surgery.
Patients with ARDS: 52 patients who were recruited into the
first beta agonist lung injury trial (BALTI-1) study9
and the
translational sub-study of BALTI-2.10
There was no difference in
age, sex, pre-enrolment Lung Injury score or acute physiology
and chronic health evaluation (APACHE) II in these two groups
of patients. Vitamin D levels were determined from ARDS
patient plasma collected on the day of enrolment. In the oeso-
phagectomy cohort, blood was collected on the day of the oper-
ation—pre any intervention.
Aetiology of ARDS is outlined in table 1. As these cohorts of
patients were diagnosed prior to the Berlin criteria, throughout
the paper we have used ARDS to indicate patients meeting cri-
teria for acute lung injury or ARDS according to the definition
of the American European Consensus Conference.11
Pulse Contour Cardiac Output Monitoring (PiCCO)
Extravascular lung water (EVLW) was measured using the single-
indicator transpulmonary thermodilution system (PiCCO-II;
Pulsion) as described previously.12
In our study, the coefficient
of variance for this system was <7% for all parameters.
Vitamin D status: 25(OH)D3 was measured by tandem mass
spectroscopy using appropriate Vitamin D External Quality
Assessment Scheme control. 1,25(OH)2D and vitamin D binding
protein (VDBP) were measured by ELISA. Definition of vitamin
D status is controversial, with different figures used throughout
the literature, but for this study we have considered plasma
25-OH vitamin D3 levels <50 nmol/L as deficient and levels
<20 nmol/L as severe deficiency.13 14
In addition, patients in the
at-risk cohort with 25(OH) vitamin D3 <20 nmol/L had signifi-
cantly lower 1,25(OH)2 vitamin D than patients with higher
levels (<20 nmol/L 74 pmol/L vs >20 nmol/L 90 pmol/L,
p=0.029).
Murine cytokines were measured by multiplex array (R&D,
UK) or ELISA as per the manufacturer’s instruction.
ATII cell isolation and culture
ATII cells were extracted from lung resection specimens accord-
ing to the methods described previously15
(see online supple-
mentary material).
Microarray analysis is outlined in the online supplementary
material.
Wound repair, proliferation and cell death assays were per-
formed as described previously.16
Mouse methods
Wild-type (WT) C57Bl/6 mice were obtained from Harlan UK,
Oxford, UK, and maintained at BMSU, Birmingham University,
UK. Once weaned, vitamin D deficiency was induced in WT
pups by feeding them a vitamin D-deficient chow (Harlan, USA)
for 6 weeks pre-intra-tracheal (IT) LPS. 25(OH)-vitamin D was
assessed by direct ELISA (ImmunDiagnostik, Germany). The
LPS challenge model was performed as described previously.17
Briefly, mice are anaesthetised and 50 mg LPS (Sigma, UK)
instilled by IT route as a model of direct lung injury. Mice were
sacrificed at neutrophilic peak, 48 h post-LPS instillation, and
bronchoalveolar lavage (BAL) performed with two washes of
0.6 mL phosphate buffered saline (PBS)/EDTA (200 nM) instal-
lations to determine the local effects on inflammation.
Untreated controls were also analysed to determine lung para-
meters in vitamin D-deficient mice. BAL fluid (BALF) was
assessed for cellular inflammation by cell count, neutrophilia
and neutrophil apoptosis (flow cytometry), markers of epithelial
damage BALF receptor for glycosylated endpoints (BALF
RAGE), protein permeability index (ratio of BALF protein:
plasma protein) as well as cytokines by luminex array (R&D
systems, UK). Results represent mice from three separate experi-
ments with at least four replicates per group. Oxygen satura-
tions were measured at 48 h post-LPS and compared with WT
mice given PBS by MouseOx II Plus (n=8 for each condition).
All experiments were performed in accordance with UK laws
with approval of local animal ethics committee.
Statistics Data were analysed using SPSS for Windows 16.0
(SPSS, Chicago, Illinois, USA). Data were tested for normality
and analysed by unpaired t tests or Mann–Whitney U test. Data
are expressed as mean (SD) unless otherwise indicated. A χ2
or
Fisher’s exact test was used to compare proportions.
Table 1 Comparison of demographics between ARDS and at-risk patients who were undergoing oesophagectomy
ARDS (n=52) At risk (n=65) p Value
Male, n (%) 30 (57) 57 (87.6) <0.001
Age (years), mean (SD) 61.3 (16.7) 62.8 (10.8) 0.560
Predisposing condition, n (%) Pneumonia 18 (35)
Other sepsis 24 (46)
Aortic aneurysm repair 3 (6)
Chest trauma 2 (3.8)
Pancreatitis 1 (1.9)
Transfusion-related lung injury 1 (1.9)
Other 3 (6)
Oesophagectomy 65 (100) n/a
LIS, median (IQR) 2.75 (2.50–3.19) 1.5 (1.0–2.0) <0.001
APACHE II median (IQR) 24 (19–28) 12 (8–14) <0.001
Worst P/F ratio during admission, mean (SD) 14.9 (5.2) 31.5 (9.9) <0.001
Hospital survival, n (%) 16 (30.8) 62 (95.4) <0.001
Length of hospital stay for survivors (days), median (IQR) 35 (16–49) 17 (10–28) 0.025
Statistical tests used are χ2
t test where data is normally distributed and Kruskal–Wallis for non-parametric data.
APACHE, acute physiology and chronic health evaluation; ratio of arterial oxygen tension to the fraction of inspired oxygen (Pao2:Fio2), arterial oxygen tension: fractional inspired
oxygen; ARDS, acute respiratory distress syndrome; LIS, lung injury score.
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3. To test the hypothesis that low 25(OH)D levels are associated
with the development of ARDS in the at-risk oesophagectomy
cohort (N=65), we performed multivariable logistic regression
with the exposure of interest being 25(OH)D3 level <20 nmol/L
and ARDS as the outcome. Adjusted ORs were estimated by multi-
variable logistic regression models with inclusion of covariate
terms chosen, a priori, thought to be plausibly associated with
both 25(OH)D3 level and ARDS in the oesophagectomy patient
cohort. We sought to build a parsimonious model that did not
unnecessarily adjust for covariates that did not affect bias or the
causal relation between exposure and outcome. Model calibration
was assessed using the Hosmer–Lemeshow (HL) χ2
goodness-of-fit
test and the accompanying p value. Bayesian information criterion
and Akaike information criterion were also used to determine
global model fit. Covariates included in the logistic regression
model were age, gender, diagnosis, staging and pack-years
smoked. The discriminatory ability for ARDS was quantified using
the c-statistic. In all analyses, p values are two-tailed and values
below 0.05 were considered statistically significant.
RESULTS
Plasma vitamin D status in patients with or at risk of ARDS
Patients with ARDS (100%) were vitamin D-deficient (plasma
25(OH)D3 <50 nmol/L). In total, 55 (96%) out of 57
unsupplemented oesophagectomy patients at risk of ARDS were
deficient preoperatively but levels were higher than in patients
with ARDS. Both patients at risk and patients with ARDS had
significantly lower levels of 25(OH)D3 than normal controls
(see figure 1). Demographics of patients groups based on
vitamin D levels are illustrated in table 2.
In at-risk patients, preoperative median plasma levels of 25
(OH)D3 were significantly lower in those patients who were ven-
tilated with ARDS postoperatively (ARDS 16.97 nmol/L vs no
ARDS 25.46 nmol/L, p=0.014). Oesophagectomy patients with
severe vitamin D deficiency (plasma 25(OH)D3 <20 nmol/L)
had a 37.5% risk of postoperative lung injury as opposed to a
15% risk with vitamin D levels >20 nmol/L (figure 2).
In the at-risk oesophagectomy cohort, preoperative vitamin D
status was the only measure to have a significant difference in
oesophagectomy patients who develop lung injury postopera-
tively (see table 3).
The odds of ARDS in patients with 25(OH)D3 <20 nmol/L
was 3.5-fold that of patients with 25(OH)D3 ≥20 nmol/L
(OR=3.5 (95% CI 1.06 to 11.6; p=0.040)). Following adjust-
ment for gender, age, diagnosis, staging data, and pack-years,
patients with 25(OH)D3 <20 nmol/L had a 4.2-fold higher
odds of ARDS than patients with 25(OH)D <20 nmol/L
(OR=4.2 (95% CI 1.13 to 15.9; p=0.032)). The adjusted
model showed good calibration (HL χ2
11.10, p=0.20) and dis-
crimination for ARDS (area under the curve 0.73). When 25
(OH)D was analysed with logistic regression as a continuous
Figure 1 Plasma 25(OH)D3 levels in acute respiratory distress
syndrome (ARDS) versus at risk and normal controls. The horizontal bar
represents the median, and the boxes represent IQRs. Vertical lines
show minimum–maximum range. Fifty-two patients with ARDS, 57
at-risk patients undergoing oesophagectomy, 18 healthy controls.
Table 2 Comparison of demographics between patients with severe deficiency, moderate deficiency and vitamin D supplemented at-risk
patients undergoing oesophagectomy
Patients with severe
25-OH vitamin D3
deficiency (n=25)
Patients with moderate
25-OH vitamin D3
deficiency (n=32)
Patients who received
vitamin D supplementation
(n=8) p Value
Male, n (%) 21 (84) 28 (87.5) 8 (100) 0.706
Age, years
median (IQR)
60.0 (52.0–68.5) 65.5 (54.5–72.0) 68.0 (63.8–71.3) 0.122
BMI median (IQR) 24.3 (20.6–27.9) 25.4 (21.7–28.3) 24.1 (22.0–26.6) 0.698
ASA median (IQR) 2.0 (2.0–2.0) 2.0 (2.0–2.0) 2.0 (2.0–2.75) 0.950
Postoperative P/F ratio 41.0 (34.3–53.3) 39.8 (32.0–52.0) 47.8 (39.4–50.8) 0.476
Preoperative plasma 25-OH vitamin D3 level (nmol/L)
median (IQR)
13.7 (10.9–16.7) 27.6 (22.5–34.9) 66.9 (42.5–92.6) <0.001
All p values shown are Kruskal–Wallis tests from SPSS.
ASA, American Society of Anaesthesiologists physical status classification system; BMI, body mass index.
Figure 2 Risk of postoperative acute respiratory distress syndrome in
severe 25(OH)D3 deficiency versus less severe deficiency. Severe
deficiency (n=25), less severe (n=32).
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4. exposure in 1 nmol/L increments, the odds of ARDS decreases
by 17% for every 1 nmol/L decrease in 25(OH)D (OR 0.83
(95% CI 0.69 to 0.98; p=0.033)), adjusted for age, gender,
diagnosis, staging and pack-years smoked.
Plasma levels of 1,25(OH)2D are lowest in ITU non-survivors
Median plasma 1,25(OH)2D levels were also significantly lower
in patients with ARDS (35.5 pmol/L) than in at-risk patients
(85 pmol/L, p=0.0001). Plasma 1,25(OH)2D was lower at
admission to intensive therapy unit (ITU) in patients who died
than survivors (figure 3). Plasma levels of 1,25(OH)2D were
lower in oesophagectomy patients at risk of ARDS who subse-
quently went on to be ventilated for ARDS (68 pmol/L (IQR
47–91)) than those who did not get postoperative ARDS
(89 pmol/L (IQR 76–109), p=0.007).
Plasma VDBP levels are lower in patients with ARDS.
25(OH)D3 circulates tightly bound to the VDBP (also known as
Gc-actin).18
VDBP levels were 40 mg/dL in normal controls,
19 mg/dL in ARDS and 28.7 mg/mL in the at-risk patients at the
beginning of oesophagectomy (figure 4).
Vitamin D levels and perioperative changes in epithelial
integrity in patients at risk of ARDS
We measured perioperative changes in an in vivo measure of the
integrity of the alveolar–capillary barrier, namely EVLW accu-
mulation (extravascular lung water index (EVLWI)) and pulmon-
ary vascular permeability index (PVPI) using a PiCCO2
catheter19–22
and related this to the patient’s vitamin D status.
Severe vitamin D deficiency (25-(OH)D3 <20 nmol/L) was
associated with an increased accumulation of EVLW as assessed
by PiCCO EVLWI and evidence of increases of PVPI, a marker
of alveolar capillary permeability. Patients supplemented with
Table 3 Univariate analysis of predictors of postoperative ARDS in patients undergoing oesophagectomy
Patients with ARDS (n=15) Patients without ARDS (n=50) p Value
Male, n (%) 14 (93) 43 (86) 0.448
Age (years), median (IQR) 61 (53–66) 66 (56–71) 0.304
BMI (kg/cm2
), median (IQR) 25.2 (23.9–29.1) 24.8 (21.6–28.1) 0.460
FEV1 (L), median (IQR) 2.69 (2.28–3.50) 2.85 (2.38–3.3) 0.901
FVC (L), median (IQR) 4.3 (3.4–5.2) 4.1 (3.5–4.7) 0.450
Tumour type=adenocarcinoma, n (%) 12 (80) 35 (70) 0.511
Tumour stage, n (%)*
T2 4 (27) 12 (24) 0.865
T3 11 (73) 37 (76)
N0 3 (20) 12 (24) 0.719
N1–2 12 (80) 37 (76)
Smoker, n (%)
Current 6 (40) 11 (22) 0.304
Former 7 (47) 34 (68)
Never 2 (13) 5 (10)
Pack-years, median (IQR) 30 (20–40) 30 (15–45) 0.740
Plasma 25-OH vitamin D3 (nmol/L), Median (IQR) 16.97 (12.98–22.46) 25.46 (17.35–39.77) 0.014
Plasma 1,25(OH)2
vitamin D (pmol/L), median (IQR) 68 (47–91) 89 (76–109) 0.007
Only preoperative 25(OH)D3 and 1,25(OH)2D vitamin D were significantly different in univariate analysis.
*No lung function available for seven patients, pack-years not available for two patients. One patient (without lung injury) had a benign tumour—not included in staging data.
ARDS, acute respiratory distress syndrome; BMI, body mass index.
Figure 3 Plasma 1,25(OH)2D was significantly higher in patients with
acute respiratory distress syndrome who survived at least 28 days
following admission than those who died. The horizontal bar represents
the median, and the boxes represent IQRs. Vertical lines show
minimum–maximum range. Died (n=32), survived (n=20).
Figure 4 Plasma vitamin D binding protein measured by ELISA in
acute respiratory distress syndrome (ARDS) versus at risk and normal
controls. Fifty-two patients with ARDS, 57 at-risk patients undergoing
oesophagectomy, 18 healthy controls.
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5. vitamin D prior to oesophagectomy had significantly reduced
changes in PiCCO EVLWI and PVPI than unsupplemented
patients (figures 5 and 6).
Vitamin D deficiency is a determinant of inflammation and
epithelial injury in the intratracheal LPS murine model of
ALI/ARDS
We studied the response to 50 mg of IT LPS in WT or mice
made vitamin D deficient by dietary manipulation. Deficient
mice were fed a vitamin D-free diet for 6 weeks and had
median plasma vitamin 25(OH)D3 levels of 8 nmol/L (SEM
1.15 nmol/L) vs 42 nmol/L (SEM 2.17 nmol/L) in WT
(p=0.001). Untreated vitamin D-deficient mice had no observed
lung damage or inflammation (figure 7, and data not shown).
Following LPS challenge, vitamin D-deficient mice had
increased evidence of alveolar epithelial damage as measured by
BALF RAGE and BALF permeability index (figure 7A). Cellular
inflammation and neutrophil apoptosis in BALF were also ele-
vated in vitamin D-deficient mice, along with release of proin-
flammatory cytokines tumour necrosis factor-α, CXCL1/KC and
vascular endothelial growth factor (figure 7B and C, respect-
ively). These changes resulted in significantly lower oxygen sat-
uration as measured by pulse oximetry (figure 7C), which we
have previously demonstrated as a physiological measure of
murine lung function.15
Vitamin D is trophic for alveolar epithelial cells in vitro
ATII cells were treated with 100 nmol/L of 25(OH)D3 for 24 h.
Microarray analysis revealed that vitamin D treatment caused a
sustained activation or inhibition of 660 genes that included
pathways involved in vitamin metabolism as well as regulators
of cell growth, differentiation and response to wounding
(GEOSET record GSE46749). The online supplementary table
SA and SB outline the top 25 genes up-regulated and down-
regulated by vitamin D and a heat map illustrating up-regulated
and down-regulated genes. Table 4 outlines the biological pro-
cesses and molecular functions modified by vitamin D treat-
ment. Several of the identified pathways had significant
relevance to proliferation, wound repair and apoptosis, so we
tested the functional effects of vitamin D upon these important
repair/protective processes.
Effect of physiologically relevant doses of 25(OH)D3 upon
primary human alveolar type II cells
25(OH)D3 at physiologically relevant concentrations stimulated
scratch wound repair, cell proliferation and attenuated soluble
Fas ligand (sFasL)-mediated cell death (see figures 8–10).
DISCUSSION
We have assessed the vitamin D status of a large cohort of
patients with ARDS and a well-characterised group of patients
at risk of ARDS, namely patients undergoing oesophagectomy.
In ARDS cases, vitamin D deficiency was ubiquitous. Survivors
of ARDS had significantly higher levels of vitamin D than
non-survivors.
Our finding of a 30% reduction in VDBP in patients with
ARDS supports a role for either reduced production or
increased losses as an explanation for some of the degree of
deficiency seen. Equally the low observed levels of circulating
1,25(OH)2D in patients with ARDS suggests a problem with
renal metabolism as this is probably the major source of circulat-
ing 1,25(OH)2D.23
Several studies have suggested that vitamin D deficiency may
be a risk factor for adverse outcome in pneumonia24
and lower
respiratory tract infections in neonates.25
Other studies have
suggested patients with sepsis have significant vitamin D defi-
ciency.26 27
Our data suggests in the high-risk oesophagectomy
group that vitamin D status is also a pre-existing risk factor for
ARDS—especially when deficiency is severe. Patients undergo-
ing oesophagectomy with severe preoperative vitamin D defi-
ciency had greater risk of postoperative ARDS and increases in
PiCCO measures of alveolar permeability than those with less
severe deficiency.
In our animal model of LPS-induced lung injury, vitamin D
deficiency was associated with greater BALF cellular inflamma-
tion and cytokine release at 48 h. Increased epithelial damage
and accumulation of apoptotic neutrophils was also evident.
Mice that were vitamin D deficient became more hypoxic, sug-
gesting physiologically worse lung injury.
Our animal data is in keeping with recently published data in
hamsters treated with LPS.28
In contrast, Klaff et al found
reduced neutrophil chemotactic potential to the chemokine KC
ex vivo in mice deficient in vitamin D but no differences in
LPS-induced BALF neutrophilia. They used a 72 h time point
Figure 5 Changes in extravascular lung water index (EVLWI) at the
end of oesophagectomy and on the morning of postoperative day 1.
EVLWI was measured using Pulse Contour Cardiac Output Monitoring II
catheter at the end of the operation and on the morning after the
operation (day 1). Severe deficient (n=25), moderate (n=32) and
supplemented (n=8).
Figure 6 Changes in Pulse Contour Cardiac Output Monitoring
pulmonary vascular permeability index (PVPI) at the end of
oesophagectomy and the morning of postoperative day 1. Severe
deficient (n=25), moderate (n=32) and supplemented (n=8).
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6. and a much lower dose of LPS (2.5 mg), which we suggest
accounts for the differences with our study.
In both our human at-risk patients and the murine model, we
have demonstrated evidence of increased permeability of the
alveolar capillary barrier in response to one lung ventilation
(EVLWI and PVPI) and LPS challenge respectively (PPI) when
severe deficiency is present, suggesting that vitamin D might
have protective effects on the alveolar epithelium as well as
being anti-inflammatory. 1,25(OH)2D has been shown to induce
DNA incorporation in human alveolar type II cells,29
but the
effects of physiologically relevant doses of 25(OH)D have not
been addressed upon type II cells previously. To address
whether 25(OH)D3 has effects on ATII cells, we demonstrated
considerable functional activity of a physiological dose of 25
(OH)D3 by microarray analysis. Physiologically relevant doses
of 25(OH)D3 stimulated wound repair, cellular proliferation
and reduced sFasL-induced cell death. These in vitro experi-
ments suggest that 25(OH)D3 may play a trophic role on adult
human alveolar epithelial cells.
This study has limitations. First, although we obtained blood
from patients with ARDS as soon as possible following admis-
sion to ITU, we are unable to be sure that levels of 25(OH)D3
were low prior to the development of ARDS in that cohort or
whether levels fall because of the development of ARDS.
Second, our at-risk data from oesophagectomy patients has to
be divided into severe deficiency and moderate deficiency
because of the severity of vitamin D deficiency observed in that
patient group. Third, our data in oesophagectomy patients’
needs validating in an additional significant cohort as well as in
other patient groups at risk of ARDS. Finally, our comparison of
EVLWI between our patients in BALTI prevention cohort versus
our oesophagectomy patients in the open label vitamin D
replacement study is a potential limitation. However, the trans-
lational protocol of assessments and the two centres in which
those assessments were performed was the same between the
two studies. We are currently conducting a randomised placebo
controlled trial to confirm these results due to finish recruitment
in mid-2015, which should further address this question.30
Figure 7 Lung injury and inflammation was significantly higher in vitamin D-deficient mice compared with wild-type (WT) following intra-tracheal
(IT)-lipopolysaccharide (LPS). Levels of tumour necrosis factor-α and CXCL1/KC in UTCs were below the detection threshold of the assays performed.
UTC, untreated control; N.D., not detected.
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7. Taken together, these data suggest that vitamin D deficiency is
ubiquitous in patients with ARDS and relates to adverse
outcome. In patients undergoing oesophagectomy, severe pre-
operative deficiency is associated with evidence of increased
alveolar epithelial damage and EVLW accumulation as well as an
increased risk of postoperative lung injury. Novel in vitro data
further suggest a trophic and antiapoptotic role of physiologic-
ally relevant doses of 25(OH)D3 upon primary adult human
alveolar epithelial cells. Finally, preoperative restoration of
vitamin D levels in patients with oesophageal cancer who are at
risk of ARDS resulted in significantly less accumulation of
EVLW than in unsupplemented patients postoperatively.
In conclusion, we suggest that clinical strategies should be
developed to replete vitamin D levels in patients at risk of
ARDS and this approach might also have value as a treatment
for established ARDS.
Table 4 List of 30 statistically significant gene ontology (GO)
terms implicated by differential expression of genes in day 3
epithelial (type II like) cells treated with vitamin D3 100 nM relative
to untreated cells
GO
Annotated
genes Total p Value
587 2230
Immune response 48 76 0.00000
Immune system process 58 103 0.00000
Cytokine activity 25 36 0.00001
Extracellular process 45 86 0.00003
Signal transducer activity 75 173 0.00008
Molecular transducer activity 75 173 0.00008
Plasma membrane 133 356 0.00013
DNA replication 20 29 0.00015
Receptor activity 57 124 0.00015
Defence response 42 83 0.00015
Monoxygenase activity 12 13 0.00018
ATPase activity, coupled to transmembrane
movement of substances
6 107 (0.00018)
Primary active transmembrane transporter
activity
6 107 (0.00018)
Hydrolase activity, acting on acid
anhydrides, catalysing transmembrane
movement of substances
6 107 (0.00018)
P-P-bond-hydrolysis-driven transmembrane
transporter activity
6 107 (0.00018)
ATPase activity, coupled to movement of
substances
6 107 (0.00018)
Cell surface receptor linked signal
transduction
69 162 0.00025
Chemotaxis 14 17 0.00027
Taxis 14 17 0.00027
Response to external stimulus 50 108 0.00030
Response to wounding 38 76 0.00043
Heme binding 12 14 0.00060
Tetrapyrrole binding 12 14 0.00060
Cellular biosynthetic process 15 145 (0.00105)
Biosynthetic process 29 214 (0.00121)
Extracellular region part 58 137 0.00168
Nucleotide biosynthetic process 1 61 (0.00168)
Cell cycle process 44 97 0.00208
Nucleobase-containing small molecule
metabolic process
3 69 (0.00412)
Nucleotide metabolic process 3 68 (0.00466)
p values of underrepresented GO terms are denoted in parentheses.
Figure 8 Scratch wound repair response of primary human alveolar
type II cells to 25(OH)D3. Wound area after 24 h was compared with
baseline and expressed as fold change in wound area. Data represents
experiments using cells from six separate lung resection specimens.
Analysis of variance p=0.001.
Figure 9 Proliferation of primary human ATII cells in response to
physiological doses of 25(OH)D3 by bromodeoxyuridine incorporation.
Experiments were performed using cells from four donors. Analysis of
variance p=0.001.
Figure 10 Cellular response to soluble Fas ligand (sFasL) 10 ng/mL
induced cell death. Experiments were performed using ATII cells from
four donors. 100 nmol/L 25(OH)D3 was added at the time of addition
of sFasL.
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8. Author affiliations
1
Centre for Translational Inflammation and Fibrosis Research, School of Clinical and
Experimental Medicine, University of Birmingham, Birmingham, UK
2
School of Cancer Sciences, University of Birmingham, Birmingham, UK
3
Centre for Endocrinology, Diabetes and Metabolism, School of Clinical and
Experimental Medicine, University of Birmingham, Birmingham, UK
4
Norwich Medical School, University of East Anglia, Norwich, UK
5
Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston,
Massachusetts, USA
6
Department of Medicine, Concord Medical School, University of Sydney, Sydney,
New South Wales, Australia
7
Institute of Immunity and Transplantation, University College London, London, UK
8
Blizard Institute, Queen Mary University of London, London, UK
9
Warwick Clinical Trials Unit, Warwick Medical School, University of Warwick,
Coventry, UK
Correction notice This article has been corrected since it was published Online First.
The author’s name William M Fraser was incorrect and should be William D Fraser.
Acknowledgements We would like to thank the staff and patients of the Queen
Elizabeth Hospital Birmingham and Heart of England NHS trust for their help in
recruiting to and taking part in these studies. We would like to thank Teresa Melody
and Amy Bradley for trial nurse support for the study.
Contributors RCAD and DP are joint first authors. DRT, FG, ARM, PMS, MSC,
WMF and GDP designed the study. SL, VD, SZ, CRB, DP, BN, RM, AMT and ES
recruited the patients and undertook lab analysis/animal work. WW, PMS, WMF,
KBC and MSC provided expert advice in their specialist areas. All authors
contributed to the writing of the paper. DT is the guarantor of the data.
Funding These studies were funded by the Wellcome trust (DRT, PMS, MSC, SL),
QEHB charities (RCAD, VD, DRT), the Medical Research Council UK (DRT, DP, RCAD)
and the NIHR (DP, DRT, GDP). DB was funded by an ERS long-term training
fellowship and a Marie Curie Intra-European Fellowship.
Competing interests None declared.
Patient consent Obtained
Ethics approval NHS LREC West midlands and all clinical investigations were
conducted according to Declaration of Helsinki principles.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement The microarray dataset outlined in this paper is freely
available to search on PubMed GEOSET.
Open Access This is an Open Access article distributed in accordance with the
terms of the Creative Commons Attribution (CC BY 4.0) license, which permits
others to distribute, remix, adapt and build upon this work, for commercial use,
provided the original work is properly cited. See: http://creativecommons.org/
licenses/by/4.0/
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