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Genito-Thyroid Index: A Global Systems Approach to the Neutrophil-to-Lymphocyte Ratio According to the Theory of Endobiogeny Applied to Ambulatory Patients with Chronic Heart Failure

Authors:
  • Full Spectrum Health Center
  • Heal and Thrive

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Background: Chronic heart failure (CHF) is an inflammatory disorder. Elevated Neutrophil-to-Lymphocyte ratio (NLR) is associated with inflammation and increased morbidity and mortality in various disorders including CHF. NLR is a non-specific, quantitative biomarker assessment. It does not allow for a personalized approach to treatment. A global systems approach to biomarker assessment is quantitative and qualitative, contextualizing basic data into larger sets of meaning. Such a system may provide greater meaning to the NLR, increasing its clinical utility in CHF. Endobiogeny is a global systems theory. It claims to be able to model complex physiology through biomarkers, offering context-rich interpretations of data for meaningful clinical applicability. In Endobiogeny, NLR is referred to as the Genito-Thyroid index (GT).
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Journal of Cardiology & Clinical Research
Cite this article: Hedayats KM, Schuff BM, Lapraz JC, Barsotti T, Golshan S, et al. (2017) Genito-Thyroid Index: A Global Systems Approach to the Neutrophil-
to-Lymphocyte Ratio According to the Theory of Endobiogeny Applied to Ambulatory Patients with Chronic Heart Failure. J Cardiol Clin Res 5(1): 1091.
*Corresponding author
Kamyar M Hedayat, 122 S. Michigan Avenue, Ste. 1441,
Chicago, IL, USA, Tel: 858-455-9726; Fax: 858-455-9159;
Email:
Submitted: 02 December 2016
Accepted: 27 December 2016
Published: 03 January 2017
Copyright
© 2017 Hedayats et al.
OPEN ACCESS
Keywords
•Systems Biology
•Biological markers/*blood
•Hormones/*metabolism
•Heart failure/*metabolism/physiopathology
•Humans
Research Article
Genito-Thyroid Index: A Global
Systems Approach to the
Neutrophil-to-Lymphocyte
Ratio According to the Theory
of Endobiogeny Applied to
Ambulatory Patients with
Chronic Heart Failure
Kamyar M. Hedayat1*, Benjamin M. Schuff2, Jean-Claude
Lapraz1, Tiffany Barsotti3, Shahrokh Golshan4, Suzi Hong4, Barry
H. Greenberg5, and Paul J. Mills4,6
1Systems Biology Research Group, Chicago, USA
2National University of Natural Medicine, USA
3Heal and Thrive, Encinitas, USA
4Department of Psychiatry, University of California San Diego, USA
5Department of Medicine, University of California, USA
6Department of Family and Preventative Medicine, University of California, USA
Abstract
Background: Chronic heart failure (CHF) is an inammatory disorder. Elevated Neutrophil-to-Lymphocyte ratio (NLR) is associated with inammation
and increased morbidity and mortality in various disorders including CHF. NLR is a non-specic, quantitative biomarker assessment. It does not allow for a
personalized approach to treatment. A global systems approach to biomarker assessment is quantitative and qualitative, contextualizing basic data into larger
sets of meaning. Such a system may provide greater meaning to the NLR, increasing its clinical utility in CHF. Endobiogeny is a global systems theory. It claims
to be able to model complex physiology through biomarkers, offering context-rich interpretations of data for meaningful clinical applicability. In Endobiogeny,
NLR is referred to as the Genito-Thyroid index (GT).
Aim: The NLR has never been studied in ambulatory CHF patients. The rst aim of this study was to determine if NLR is elevated for ambulatory CHF
patients versus controls. The second was to determine if the endobiogenic interpretation of the NLR as the GT index is consistent with current pathophysiologic
models.
Methods: A retrospective observational case-controlled study was performed in 93 patients with New York Heart Association class II-III heart failure
patients and 104 individuals with no cardiovascular pathology as a control group. Two biomarkers, percent neutrophils and percent lymphocytes, were entered
into the Biology of Functions modeling software, from which a direct index was produced to model an aspect of the heart failure terrain. All calculations were
performed using SPSS Inc. (version 22.0) and analyzed by univariate or multivariate analysis of covariance.
Results: NLR or, GT index (normal 1.5-2.5) was elevated in CHF patients vs. control (2.81 vs 2.01, p<0.001).
Conclusions: NLR, or, GT index, when elevated reects a hyperimmune response to an aggression. CHF is associated with elevated immune activity.
Ambulatory CHF patients show signs of a hyperimmune response even when clinically stable. The endobiogenic explanation of the NLR is consistent with current
pathophysiological models of CHF. Future studies should explore if a certain cutoff value of the GT index is predictive of future deterioration in CHF patients.
Future studies should evaluate other endobiogenic indexes for their clinical relevance in CHF.
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J Cardiol Clin Res 5(1): 1091 (2017)
ABBREVIATIONS
CHF: Chronic Heart Failure; NLR: Neutrophil-to-Lymphocyte
Ratio; GT: Genito-Thyroid; BOF: Biology of Functions
INTRODUCTION
The neutrophil-to-lymphocyte ratio (NLR) has been
         
      
and mortality. It is inexpensive and often performed but remains
         
If there were a way to reinterpret the NLR as a more precise
         
in clinical practice. Biomarkers are evaluated independent
        
compensatory mechanisms within the patient. Direct ratios
     
qualitative way: one level of activity relative to another. The NRL
is one example: %Neutrophils ÷ %Lymphocytes. Other examples
include hematocrit (red blood cells/hemoglobin) and the blood
     
two or more levels of function but doesn’t address etiological or
         
“what is the clinical implication?”.
Systems theory seeks to answer these questions by
introducing the concept of upstream regulators and downstream

are downstream output from bone marrow. The question then
        

        
diminish this tendency?” Answering these questions would open
a new level of understanding of cause and effect and beyond

Endobiogeny is a global systems theory rooted in clinical
practice. It claims to assess human physiology in a manner that
      
of endobiogeny considers the neuroendocrine system as the
    
[1]. Biomarkers are considered the downstream metabolic output
of tissues that were regulated upstream by neuroendocrine
          
indirect ratios of biomarkers have been developed called the



NLR will be referred to in both ways: NLR (GT).
       
      

secondary hypothesis was that the theory of Endobiogeny could
         
currently accepted notions of the CHF terrain.
METHODS
Study Participants
A retrospective observational case-controlled study was
performed. The study sample consisted of 93 patients diagnosed
with New York Heart Association (NYHA) classes II through
III heart failure and 104 individuals with no cardiovascular
pathology as a control group. Patients were recruited from the
San Diego Veterans Affairs Medical Center Cardiology Clinic and
        
Advanced Heart Failure Program as part of a larger study on
  
in HF. We included the non-CHF control sample from the
      

Inclusion criteria for all study participants were age between
30 and 85 years. Additional inclusion criteria for CHF patients
included symptoms of CHF for at least 3 months that had been

      
fraction (LVEF) was assessed by echocardiography as part of
the patient’s routine medical evaluation. Exclusion criteria
       
      
      
than depression and co-morbid anxiety. Subjects were instructed
      
session.
The investigation conformed to the principles outlined in the
        

informed written consent.
Biochemical Analyses
Blood was drawn into ethylendiaminetetra acetic acid
      
California) for complete blood count with differential and

UCSD Medical Center.
Statistical Analyses

       
as mean ± SEM or ± SD. Results were considered statistically
           

        
analyses using the Kolmogorov-Smirnov test. We calculated
mean arterial pressure (MAP) from resting BP readings (1/3
    

Value of the NLR
In this study the normal range of NLR (GT) was considered
           

RESULTS
Sociodemographic and medical characteristics of the study
subjects are presented in Table (1). CHF patients were older
(p<0.01) and heavier (p<0.01) than non-CHF subjects and had
lower mean blood pressure (p<0.01).
Central
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3/6
J Cardiol Clin Res 5(1): 1091 (2017)
A multivariate ANCOVA examining CHF vs. control group

         
        

       
       
      


A multivariate ANCOVA was conducted on the NLR (GT) ratio
         


       

DISCUSSION
The theory of Endobiogeny considers the neuroendocrine
system to be the manager of the terrain because it regulates
metabolism. Therefore neuroendocrine activity is the primary

mechanisms of disease expression. The NLR is referred to as
the Genito-thyroid index in the BoF. It is so called because it is
      
between the gonadotropic hormone estrogen derived from the
genitals (genito-) and the thyrotropic hormone TSH (thyroid).
          
relationship to that of TSH regardless of the absolute activity of
peripheral thyroid hormones” (Figure 1).
Recall that the NLR (GT) is %Neutrophils ÷ %Lymphocytes.
       
the activity of estrogens. Estrogens (upstream) stimulate the
production of neutrophils (downstream) in the bone marrow.
      
          
 

will be.
In the denominator is lymphocytes. Estrogens in general
stimulate anabolic tissue construction [9-15]. They also stimulate
TSH to calibrate thyroid hormone output to augment production


    
the greater the relative degree of immune activity and systemic

  
the relative neutrophilia is in relationship to lymphocytosis—
         

neutrophil count) and the greater the activity of those immune
  
           
the catabolic thyrotropic activity is relative to the anabolic
        
        

         
     
       
          
      
       
factor alpha are associated with severity of CHF [30-34]. Other
aspects of neutrophil activity are also associated with CHF

        
Figure 1 Genito-Thyroid index: relationship to endocrine action on the terrain.
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Figure 2 Elevated Genito-Thyroid index: implications in the endocrine terrain.
Table 1: Sociodemographic and Medical Characteristics of the Study Subjects.
(mean ± SD) Heart Failure Non-Heart Failure p-value
N 93 104
Age (years) **   <0.01
Gender (# Women / # Men)   NS
Body Mass Index (kg/m2) **   <0.01
Mean arterial pressure (mm Hg) * 80.0 (9.5) 90.5 (10.1) <0.001
LVEF (%)  ---
Neutrophil % **   <0.01
Lymphocyte % *   <0.001
Genito-Thyroid (1.5-2.5) *   <0.001
Medications:
ACE inhibitors  0 %
Beta blockers 95 % 0 %
Calcium channel blockers 5 % 0 %
Statin  0 %
Aspirin 54 % 
Diuretics 90 % 0 %
Anti-arrhythmics 9 % 0 %
Digoxin  0 %
Abbreviations: 
        
  
disease and major cardiac events [38].
            
           
           
of the NLR is to CHF based on a global systems theory. Other
studies support the value of a qualitative analysis over a strictly
    
NLR (GT) with absolute lymphopenia were better predictors
        
           


The challenges in accepting the results of this study arise from
the binary and quantitative modalities of modern biomedical
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investigations. This approach seeks to measure output and
actions of individual actors rather than the functional activity of
multiple ones. The theory of endobiogeny describes endocrine
relationships in regulating metabolism more akin to physics or
 
         
      
prognosis of clinical conditions.
This study represents an initial step in applying global
systems theory to clinical medicine. It offers an explanation of
        
elevated NLR (GT). A limitation of this study is that it was not
able to offer insights into clinical therapies or outcomes. Future
studies should investigate this in a prospective fashion. Other

          

CONCLUSION


    

elevated in ambulatory patients with CHF. Using a global systems

factors may be related to the origin of elevated neutrophils and
diminished lymphocytes and the relevance of those factors to

inexpensive ratio may offer greater insight into the origins and
progression of chronic heart failure at the global metabolic level.
ACKNOWLEDGEMENTS
This work was supported by an unrestricted research
grant by the American Society of Endobiogenic Medicine and
  
from the National Institutes of Health and the UCSD General


The Corresponding Author has the right to grant on behalf of
    
          
Clinical Research to permit this article (if accepted) to be
        
editions and any other products and sublicenses such use and

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
5.            
      

Obstet Gynecol. 1999; 181: 408-414.
        
       


     á   
Neutrophil functions and autoimmune arthritis in the absence of
p190RhoGAP: generation and analysis of a novel null mutation in

8.    


9.         

10. 

11.    
in breast cancer: a comprehensive review of estrogen receptor
  

 

13.          
receptor variant messenger RNAs in normal and neoplastic breast

14.           

15.         
        
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       
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gene participation in the thermogenic regulation of fuel oxidation
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on hormonal and immunological factors in women with repeated
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         
between free thyroxine and TSH in the regulation of thyroid function.

     
            
        
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Cite this article

              
Thyroid hormones as modulators of immune activities at the cellular
        



count ratio predict bacteremia better than conventional infection

 
           
       


to-lymphocyte ratio as a predictor of worsening renal function in
         

    
use of biomarkers in the modeling of cancer activity based on the
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
         
        
lymphocyte ratio predicts poor clinical outcome in breast cancer

Zahorec R. Ratio of neutrophil to lymphocyte counts--rapid and simple


30.           
         
         

31.              
       
response to maximal exercise in patients with chronic heart failure.

  
      
        

33.              
       
C-reactive protein in patients with chronic stable heart failure. Heart

34.   

35.           
    
endothelial function and oxidative stress in chronic heart failure:
          

           
et al. Increased plasma neutrophil gelatinase-associated lipocalin
levels predict mortality in elderly patients with chronic heart failure.

             
Usefulness of total lymphocyte count as predictor of outcome in
          

38. 
to-Lymphocyte Ratio in Predicting Adverse Events in Elderly Patients

... Biomarkers are viewed as downstream products of cellular metabolism and thus indirect markers of upstream regulation of cell and tissue metabolism [16]. The applicability of this global systems approach in CHF patients was recently demonstrated with respect to the neutrophil-to-lymphocyte ratio, referred to as the Genito-thyroid index in Endobiogenic terminology [17]. ...
... The cortisol index formula then incorporates the bone marrow products that are increased in the numerator, and those that are diminished by cortisol in the denominator. In the context of heart disease, these changes in the CBC have already been characterized, [17,18] but not evaluated simultaneously according to a global systems perspective until now. We hypothesized that the modeling system of endobiogeny would demonstrate elevated values of the cortisol in ambulatory CHF patients versus controls. ...
... Because it models net global functional activity, it is not dependent on circadian rhythms and can be drawn at any time. It can be repeatedly performed even within hours of prior samples to evaluate the evolution of cortisol activity in acute and chronic settings [16,17]. ...
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Background: Chronic heart failure (CHF) is an inflammatory disorder in which cortisol plays an important role. Despite this, cortisol is not routinely quantitatively measured for a number of reasons. It is considered non-specific. Accuracy and validity remain in question. It is not considered convenient or cost effective. Finally, tissue level effects of cortisol do not correlate linearly to quantitative levels. If the functional, tissue level effectiveness of cortisol could be modeled, its evaluation in CHF patient may become relevant. Endobiogeny is a global systems theory that claims to be able to model complex physiology through biomarkers, offering context-rich interpretations of data for meaningful clinical applicability. Cortisol is known to alter circulating levels of elements from a complete blood count (CBC). By relating these biomarkers in a qualitative fashion, the theory of Endobiogeny posits that these elements can be contextualized to reflect the tissue level activity of cortisol, referred to as the cortisol index (CI). The algorithm derived from the theory is called the Biology of Functions (BoF). Aim: The aim of this study was to determine if the cortisol index is accurate in reflecting a greater expression of cortisol activity in ambulatory CHF patients versus controls subjects. Methods: A retrospective observational case control study was performed in 93 patients with New York Heart Association class II-III heart failure patients and 104 individuals with no cardiovascular pathology as a control group. Results from a CBC were entered into BOF modeling software, from which the cortisol index is derived. Results: The Cortisol index (3-7) was significantly elevated in CHF vs. control patients (12.8±0.91 vs. 8.48±0.74, p
... However, there are other indicators or actors in acute inflammation. For example, the neutrophil-to-lymphocyte ratio (NLR) (6)(7)(8)(9)(10) is associated with mortality on admission for patients with COVID-19 (7). It is has been referred to as the genito-thyroid index (GTi) in an attempt to describe the upstream endocrine mediators of neutrophil and lymphocyte production (6). ...
... For example, the neutrophil-to-lymphocyte ratio (NLR) (6)(7)(8)(9)(10) is associated with mortality on admission for patients with COVID-19 (7). It is has been referred to as the genito-thyroid index (GTi) in an attempt to describe the upstream endocrine mediators of neutrophil and lymphocyte production (6). Another marker is serum cortisol. ...
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Introduction Patients hospitalized with SARS-CoV-2 have an elevated risk of mortality related to a severe inflammatory response. We hypothesized that biological modeling with a complete blood count (CBC) would be predictive of mortality. Method In 2020, 81 patients were randomly selected from La Rochelle Hospital, France for a simple blinded retrospective study. Demographic, vital signs, CBC and CRP were obtained on admission, at days 2-3 and 3-5. From a CBC, two biological modeling indexes were resulted: the neutrophil-to-lymphocyte ratio (NLR) and cortisol index adjusted (CA). Results By ANOVA, in survivors vs. non-survivors there was statistical different at p < 0.01 for age (66.2 vs. 80), CRP (92 vs. 179 mg/dL, normal < 10), cortisol index adjusted (323 vs. 698, normal 3-7) and genito-thyroid indexes (7.5 vs. 18.2, normal 1.5–2.5), and at p = 0.02 creatinine (1.03 vs. 1.48, normal 0.73–1.8 mg/dL). By mixed model analysis, CA and NLR improved in those who survived across all three time points, but worsened again after 3–5 days in non-survivors. CRP continued to improve over time in survivors and non-survivors. Positive vs. Negative predictive value were: CRP (91.1%, 30.4%), NLR (94.5%, 22.7%), CA (100%, 0%). Discussion Cortisol modeling and the neutrophil-to-lymphocyte ratio were more accurate in describing the course of non-survivors than CRP. Conclusion In patients admitted for SARS CoV-2 infection, biological modeling with a CBC predicted risk of death better than CRP. This approach is inexpensive and easily repeated.
... The lower the index, the greater the tendency towards atopic disease and localized inflammation in response to an aggression [33]. We have recently described the relationship of these biomarkers to the endocrine system, and demonstrated its relationship to chronic heart failure and cancer survivors [34,35]. ...
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Living organisms are physical, chemical and biological systems organized in fractal hierarchies of structure and function. Various levels of organization may be the object of study: cell, tissue, organ or whole system. The theory of endobiogeny is a global systems approach to living systems in which the patient as a whole is the object of study. It is a global living systems theory of terrain. The essential activity of the terrain is metabolism: the continuous transformation of energy and matter. According to this theory, the neuroendocrine system is the manager of metabolism and hence the terrain. Modeling the neuroendocrine elements of regulation of the terrain is a key tool in clinical assessment of patients. There are various limits to a strictly quantitative measurement of hormone levels and metabolic activity. Therefore, a modeling system has been developed which uses downstream biomarker output from tissues to assess upstream elements of management of the terrain. This method is called the Biology of Functions. Direct and indirect ratios of biomarkers and indexes have been developed to use quantized data to generate a qualitative analysis of relative capability of the organism. The construction of two direct indexes (genital ratio and genito-thyroid), and one indirect index (evoked histamine) are discussed.
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The neutrophil-to-lymphocyte (N/L) ratio has been associated with poor outcomes in patients with cardiovascular diseases, but it has not been studied in elderly patients with chronic heart failure (CHF). In this study, we analyzed 1355 elderly patients admitted with CHF. A multivariate logistic regression model was used to assess the independent association of the N/L ratio with chronic kidney disease (CKD). The patients were then divided into tertiles according to the N/L ratios. We used Cox regression analysis to assess the association between the N/L ratio and subsequent major cardiovascular events (MCE), including cardiac death and rehospitalization for heart failure. In the multiple logistic regression analysis, the N/L ratio was identified as a risk factor for CKD in elderly patients with CHF (odds ratio [OR] = 1.170, 95% confidence interval [CI] 1.054 to 1.298, P = 0.003). The median follow-up period was 18 months. In a multivariate analysis with the lowest tertile as the reference, the highest tertile of the N/L ratio remained significantly associated with MCE (hazard ratio [HR] = 1.425, 95% CI 1.109 to 1.832, P = 0.006), cardiac death (HR = 1.747, 95% CI 1.032 to 2.958, P = 0.038), and rehospitalization for heart failure (HR = 1.461, 95% CI 1.108 to 1.927, P = 0.007). In elderly patients with CHF, the N/L ratio is one of the important risk factors for CKD and the highest tertile of the N/L ratio is associated with an increased risk for MCE.
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Polymorphonuclear neutrophils, besides their involvement in primary defense against infections - mainly through phagocytosis, generation of toxic molecules, release of enzymes, and formation of extracellular traps - are also becoming increasingly important for their contribution to the fine regulation in development of inflammatory and immune responses. These latter functions of neutrophils occur, in part, via their de novo production and release of a large variety of cytokines, including chemotactic cytokines (chemokines). Accordingly, the improvement in technologies for molecular and functional cell analysis, along with concomitant advances in cell purification techniques, have allowed the identification of a continuously growing list of neutrophil-derived cytokines, as well as the characterization of their biological implications in vitro and/or in vivo. This short review summarizes crucial concepts regarding the modalities of expression, release, and regulation of neutrophil-derived cytokines. It also highlights examples illustrating the potential implications of neutrophil-derived cytokines according to recent observations made in humans and/or in experimental animal models.
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ENDOBIOGENY AND THE BIOLOGY OF FUNCTIONS ARE BASED ON FOUR SCIENTIFIC CONCEPTS THAT ARE KNOWN AND GENERALLY ACCEPTED: (1) human physiology is complex and multifactorial and exhibits the properties of a system; (2) the endocrine system manages metabolism, which is the basis of the continuity of life; (3) the metabolic activity managed by the endocrine system results in the output of biomarkers that reflect the functional achievement of specific aspects of metabolism; and (4) when biomarkers are related to each other in ratios, it contextualizes one type of function relative to another to which is it linked anatomically, sequentially, chronologically, biochemically, etc.
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Endobiogeny is a global systems approach to human biology that may offer an advancement in clinical medicine based in scientific principles of rigor and experimentation and the humanistic principles of individualization of care and alleviation of suffering with minimization of harm. Endobiogeny is neither a movement away from modern science nor an uncritical embracing of pre-rational methods of inquiry but a synthesis of quantitative and qualitative relationships reflected in a systems-approach to life and based on new mathematical paradigms of pattern recognition.
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The neutrophil-lymphocyte count ratio (NLCR) has been identified as a predictor of bacteremia in medical emergencies. The aim of this study was to investigate the value of the NLCR in patients with community-acquired pneumonia (CAP). Consecutive adult patients were prospectively studied. Pneumonia severity (CURB-65 score), clinical characteristics, complications and outcomes were related to the NLCR and compared with C-reactive protein (CRP), neutrophil count, white blood cell (WBC) count. The study cohort consisted of 395 patients diagnosed with CAP. The mean age of the patients was 63.4±16.0 years. 87.6% (346/395) of the patients required hospital admission, 7.8% (31/395) patients were admitted to the Intensive Care Unit (ICU) and 5.8% (23/395) patients of the study cohort died. The NLCR was increased in all patients, predicted adverse medical outcome and consistently increased as the CURB-65 score advanced. NLCR levels (mean ± SD) were significantly higher in non-survivors (23.3±16.8) than in survivors (13.0±11.4). The receiver-operating characteristic (ROC) curve for NLCR predicting mortality showed an area under the curve (AUC) of 0.701. This was better than the AUC for the neutrophil count, WBC count, lymphocyte count and CRP level (0.681, 0.672, 0.630 and 0.565, respectively). Admission NLCR at the emergency department predicts severity and outcome of CAP with a higher prognostic accuracy as compared with traditional infection markers.
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Increasing evidence suggests that thyroid hormones, L-thyroxine (T(4)) and 3,3',5-triiodo-L-thyronine (T(3)), are modulators of the immune response. In monocytes, macrophages, leukocytes, natural killer cells, and lymphocytes, a wide range of immune functions such as chemotaxis, phagocytosis, generation of reactive oxygen species (ROS), and cytokine synthesis and release are altered under hypo- and hyperthyroid conditions. Hyperthyroidism decreases the proinflammatory activities of monocytes and macrophages, whereas enhancement of phagocytosis and increased levels of ROS may occur during hypothyroidism. The expression of proinflammatory molecules such as macrophage inflammatory protein-1α and interleukin-1β increases in hypothyroidism. However, in Kupffer cells, proinflammatory activities such as the respiratory burst, nitric oxide synthase activity, and tumor necrosis factor-α expression may result from increased T(3) levels. Thyroid hormones also affect natural killer cell activity and cell-mediated immune responses. Still, for many immune cells no clear correlation has been found so far between abnormally high or low T(3) or T(4) levels and the effects observed on the immune responses. In this review we outline the contributions of thyroid hormones to different aspects of innate and adaptive immune responses. The relationship between thyroid hormones and immune cells is complex and T(3) and T(4) may modulate immune responses through both genomic and nongenomic mechanisms. Future studies of the molecular signaling mechanisms involved in this cross-talk between thyroid hormones and the immune system may support development of new strategies to improve clinical immune responses.
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