CC BY
11
/ J. Broderick, T. Brott, J. Duldner [et al.] // Stroke. -1993. - V. 24. - P. 987-993.
7. Chen Y. Overexpression of monocyte chemoattractant protein 1 in the brain exacerbates ischemic brain injury and is associated with recruitment of inflammatory cells / Y. Chen, JM. Hallenbeck, C. Ruetzler [et al.] // Journal of Cerebral Blood Flow & Metabolism - 2003.
- V. 23. - V. 748-755.
8. Craig J. Peak plasma interleukin-6 and other peripheral markers of inflammation in the first week of ischaemic stroke correlate with brain infarct volume, stroke severity and long-term outcome / J. Craig, CJ. Smith, CA Hedley [et al.] // BMC Neurology. - 2004. -V. 4. - P. 2.
9. Danton GH. Inflammatory mechanisms after ischemia and stroke // GH. Danton, WD. Dietrich // Journal of Neuropathology & Experimental Neurology. - 2003. -V. 62. - P. 127-136.
10. den Hertog HM. C-reactive protein in the very early phase of acute ischemic stroke: association with poor outcome and death / HM. den Hertog, JA. van Ros-sum, MA. van der Worp [et al.] // Journal of Neurology.
- 2009. - V. 256 (12). - P. 2003-2008
11. Gill R. Human C-reactive protein increases cerebral infarct size after middle cerebral artery occlusion in adult rats / R. Gill, JA. Kemp, C. Sabin [et al.] // Journal of Cerebral Blood Flow & Metabolism - 2004. - V. 24 (11). - P. 1214-1218.
12. Ginsberg M. Adventures in the pathophysiology of
brain ischemia: penumbra, gene expression,
neuroprotection: the 2002 Thomas Willis Lecture / M. Ginsberg // Stroke. - 2003. - V. 34. - P. 214-223.
13. Heinrich PC. Interleukin-6 and the acute phase response / PC. Heinrich, JV. Castell, T. Andus // Bio-
chemical Journal. - 1990. - V. 265 (3). - P. 621 -636.
14. Intiso D. Tumor necrosis factor alpha serum levels and inflammatory response in acute ischemic stroke patients / D. Intiso, Mm. Zarrelli, G. Lagioia [et al.] // Neurological Sciences. - 2003. - V. 24 (6). - P. 390-396.
15. Kogure K. Inflammation of the brain after ischemia / K. Kogure, Y. Yamasaki, Y. Matsuo [et al.] // Acta Neurochirurgica Supplement. - 1996. - V. 66. - P. 40 -43.
16. Ormstad H. Serum levels of cytokines and C-reactive protein in acute ischemic stroke patients, and their relationship to stroke lateralization, type, and infarct volume / H. Ormstad, HC. Aass, N. Lund-Sorensen [et al.] // Journal of Neurology. - 2011. - V. 258 (4). - P. 677-685.
17. Terao S. Inflammatory and injury responses to ischemic stroke in obese mice / S. Terao, G. Yilmaz, K. Stokes [et al.] // Stroke. - 2008. - V. 39(3). - P. 943-950.
18. Waje-Andreassen U. IL-6: an early marker for outcome in acute ischemic stroke / U. Waje-Andreassen, J. Krakenes, E. Ulvestad [et al.] // Acta Neurologica Scandinavica. - 2005. - V. 111. - P. 360-365.
19. World Health Organization: Obesity. Preventing and Managing the Global Epidemic. Report of a WHO Consultation on Obesity, Geneva 3-5 June 1997. Geneva, World Health Organization, 1998.
20. Zaremba J. Early TNF-a levels correlate with ischaemic stroke severity / J. Zaremba, J. Losy // Acta Neurologica Scandinavica. - 2001. - V. 104 (5). - P. 288-295.
English version: PECULIARITIES OF POSTISCHEMIC INFLAMMATORY RESPONSE AT ACUTE NON-LACUNAR HEMISPHERIC STROKES IN ABDOMINALLY OBESE PATIENTS
Delva M.Yu., Lytvynenko N.V.
Higher State educational if Ukraine "Ukrainian Medical Dental Academy", Poltava
We have studied the serum levels of the inflammatory interleukins, C-reactive protein, monocyte hemoattractant protein-1 in the 1st and 10 days after ischemic non-lacunar hemispheric strokes in patients with normal body weight and with abdominal obesity I-II class. Abdominally obese patients, in comparison with normal body weight patients, have enhanced postischemic inflammatory response during acute non-lacunar strokes (especially pronounced with infarcts volumes more than 20 cm3)- significant serum increase of C-reactive protein, tumor necrosis factor-а, monocyte hemoattractant protein-1, interleukin-1/3, interleukin-б. The above mentioned changes may be responsible for more severe ciini-cal course during acute stroke period and insufficient functional recovery after non-lacunar strokes in abdominally obese patients.
Key words: ischemic non-lacunar stroke, abdominal obesity, postischemic inflammatory response.
In recent years in scientific literature has been emerged a lot of scientific reports which prove the direct and significant influences of obesity on acute ischemic strokes course and outcome. In particular, in previous works we have demonstrated that abdominally obese patients I-II classes have significantly larger volumes of non-lacunar hemispheric stroke in comparison with normal weight patients [1]. Obese patients (especially with abdominal obesity (AO)) have a more severe stroke clinical course, slower regression of neurological symptoms, more frequent development of various complications and, consequently, longer hospital stay [4]. Moreover, abdominally obese patients with lacunar strokes have a worse late functional outcomes according to modified
Rankin scale (mRS) and worse a self-service according to Barthel index (BI) in comparison with normal weight patients [3].
Therefore, it’s necessary to identify the pathophysiological mechanisms underlying the peculiarities of ischemic strokes in patients with AO.
In recent years great attention is drawn to cerebral post-ischemic imuno-inflammatory processes which are responsible for modifications of stroke clinical course and functional outcome. Necrotic core tissue is eliminated by cellular, humoral, and metabolic mechanisms, which are all part of the post-ischemic cerebral inflammatory reactions [15]. However, inadequate activation (in timing, space or level) of different inflammatory processes may
To cite this English version: Delva M.Yu., Lytvynenko N.V. Peculiarities of postischemic inflammatory response at acute nonlacunar hemispheric strokes in abdominally obese patients // Problemy ekologii ta medytsyny. - 2013. - Vol 17, Ns 1-2. - P. 60 -64.
lead to the local damaging effect which exacerbates postischemic secondary neuronal death [12]. We have identified that abdominally obese patient with relatively large non-lacunar infarcts (>20 cm3) have significantly enhanced systemic inflammatory response (in the form of peripheral leukocytosis, increased blood fibrinogen concentration, increased frequencies of hyperthermia) at 1st post-stroke day in comparison with normal weight patients with similar infarct’s sizes [2]. In experiment with leptin-deficient mice (ob/ob) it has been demonstrated that obesity, as independent phenomenon, predisposes a mouse brain to enhanced inflammatory response after cerebral ischemia-reperfusion and significantly modifies and aggravates the mechanisms of post-ischemic cerebral lesions. And these pathological processes are independent of arterial hypertension, hyperglycemia, hypercholesterolemia etc [17].
In view of the above-mentioned, it’s necessary to detail peculiarities of post-ischemic cerebral inflammatory response in abdominally obese patients with acute ischemic non-lacunar strokes.
Purpose of the study was to determine of postischemic inflammatory response features among patients with AO I-II class in the acute phase of ischemic nonlacunar hemispheric strokes.
Materials and methods
In the study we have recruited subjects of both genders between the age of 56 and 65 years with acute ischemic non-lacunar (atherothrombotic and cardioem-bolic subtypes) hemispheric strokes. All patients were admitted to Poltava city hospital not later than 24 hours after stroke onset. Patients didn’t have diabetes mellitus and severe co-morbidities that could influence of neurological and functional recovery (oncological diseases, convulsive syndrome, hematological diseases, cardiac,
As table 1 demonstrates, it has been formed relatively identical groups of patients due to cerebral infarction sizes.
In hospital stroke patients received uniform therapy (antiplatelet drugs for atherothrombotic stroke, anticoagulant drugs for cardioembolic stroke, hypotensive, metabolic, nootropic drugs, etc), physiotherapy, and massage.
Venous blood samples were collected on the admission day and at 10th day from the antecubital vein in fasting state. The blood samples were centrifugated to obtain serum, which was rapidly frozen at -30° C for subsequent analysis. We used ELISA method for assessing serum concentration of tumor necrosis factor-а (TNF-a), interleukin-^ (IL-1P), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1) («Vector-Best», Russia), C-reactive protein (CRP) («Chema», Russia), according to manufacturers’ instructions.
liver, kidney and respiratory insufficiencies, progressive angina pectoris, acute myocardial infarction, vascular dementia, etc). All patients didn’t have infectious or inflammatory diseases and didn’t use anti-inflammatory drugs during 5 days before stroke onset. Moreover, patients didn’t have acute neurological episodes (according to medical records) and didn’t have neuroimaging signs of previously unrecognized non-lacunar strokes.
Patient's body weight was determined with mechanical weights during hospitalization. In severe cases, body weight was measured after patient improvement, or according to patient’s relatives. Body mass index (BMI) was calculated as weight in kilograms divided by the square of height in meters. Body weight categories were formed on the basis of BMI: normal body weight - BMI 20.0-24.9 kg/m2, obesity class I-II - BMI >30.0 kg/m2. Waist-to-hip ratio (WHR) was calculated as a measure of abdominal obesity. Waist circumference was measured with a soft tape midway between the lowest rib and the iliac crest. Hip circumference was measured over the widest part of the gluteal region. According to World Health Organization criteria, WHR >0.9 in men and >0.85 in women were denoted abdominal obesity [19].
Non-lacunar stroke subtype was verified by neurovisualization. Cerebral lesion volume was estimated by calculating the approximate volume of an ellipsoid on CT scans or T-2 weighted MRI scans [3].
We examined two patients’ groups - 28 patients with AO I-II classes and 28 normal body weight patients. It’s known that intensity of post-stroke inflammatory response significantly depends on cerebral infarction volume [5]. Therefore, within each patient’s group it has been formed two conditionally homogenous subgroups (14 patients in each one) with cerebral infarction volumes <20 cm3 and >20 cm3.
Table 1
Characteristics of cerebral infarction volumes
Table 2
Characteristics of non-lacunar stroke subtypes
Statistical analysis was performed using the statistical package Statistica 6.0 (StatSoft). Data is shown as mean (M), standard error of mean (m), probability value (p). P-value was determined by unpaired Students t test. P-value less 0,05 was taken to indicate statistical significance.
Results and discussion
Table 3 shows direct relationships between cerebral infarction volume and plasma CRP elevation during whole acute stroke period regardless of body weight category. At acute stroke CRP blood concentration directly and significantly correlates with cerebral infarction volumes (r=0,47; p=0,005) [16]. However, even with the
Patients groups normal body weight AO I-II class
Cerebral infarction sizes, cm3 <20 >20 <20 >20
Minimal size, cm3 2,9 21,8 2,1 22,5
Maximal size, cm3 19,7 48,1 19,2 45,4
M±m, cm3 10,2±1,5 31,2±2,3 12,8±1,6 32,6±2,1
Patients groups normal body weight AO I-II class
Cerebral infarction sizes, cm3 <20 >20 <20 >20
Stroke subtype atherothrombotic 9 6 7 6
cardioembolic 5 8 7 8
Totally 14 14 14 14
similar cerebral lesion volumes, abdominally obese patients have significantly increasing serum CRP at 1st and 10th post-stroke days in comparison with normal body weight patients. Possible in patients with AO, beside the volume of cerebral infarction, there are other predictors of inflammatory response intensity associated with AO (including pro-inflammatory phenotype). However, CRP
itself can directly exacerbate ischemic tissue damage in conditions of impaired blood-brain barrier due to stroke (there are experimental data that intravenous administration of exogenic CRP follows with increasing cerebral infarction size in rats) [11].
Table 3
CRP blood concentration (M±m), mg/l
Patients groups normal body weight AO I-II class
Cerebral infarction sizes, cm3 <20 >20 <20 >20
Day after stroke 1st 16,7±2,0 32,3*±3,3 29,8»±3,6 42,2*»±3,1
10® 17,7±2,5 24,7*±2,1 32,7»±3,1 33,4» ±2,3
* - difference is significant (p<0.05) in comparison with patients of identical body weight category with cerebral infarction volumes <20 cm3.
• - difference is significant (p<0.05) in comparison with normal body weight patients with the similar cerebral lesion volumes.
However, regardless of the cause-effect relationships, high CRP levels at acute stroke is independently associated with high NIHSS values during hospital stay and adverse functional outcome in 3 months after stroke accord-
ing to mRS [8, 10]. Increased CRP blood levels in acute stroke also may be due to infectious complications, but in such cases cRp starts to elevate at a later date and follows with clinical signs of infection [5].
Table 4
TNF-а blood concentration (M±m), pg/ml
Patients groups normal body weight AO I-II class
Cerebral infarction sizes, cm3 <20 >20 <20 >20
Day after stroke 1st 17,9±4,3 20,7±4,1 31,7±7,1 93,4*»±25,2
10th 8,1±1,3 11,0±1,5 15,3»±2,4 30,9*»±5,6
* - difference is significant (p<0.05) in comparison with patients of identical body weight category with cerebral infarction volumes <20 cm3.
• - difference is significant (p<0.05) in comparison with normal body weight patients with the similar cerebral lesion volumes.
Table 4 shows that abdominally obese patients have direct correlations between cerebral lesion volumes and the rates of serum CRP elevation, whereas under conditions of normal body weight this pattern is not found. In scientific literature there are different observation about relations between changes of TNF- a and cerebral infarction volume. There is report that serum TNF-a concentration in the first 24 hours after stroke was significantly correlated with the clinical severity of the disease and late outcome according to BI [20]. On the hand, it has been not detected any correlations between serum TNF-a levels and cerebral infarction sizes as well as clinical stroke severity on admission, thus authors assumed that serum TNF-a level is precise marker of the inflammatory re-
sponse intensity to the cerebral lesion that doesn’t depend on the cerebral lesion sizes [14]. In addition, abdominally obese patients I-II classes with larger strokes (> 20 cm3) have significantly increased levels of TNF-a at 1st as well at 10th day after stroke in comparison with a normal body weight patient. This phenomenon may also reflect the enhanced post-ischemic inflammatory response associated with AO. As known, TNF-a is an important factor of post-ischemic inflammatory reactions. TNF-a directly induces the expression of adhesion molecules by glial and endothelial cells, it is involved in the blood-brain barrier impairment; it increases neutrophil infiltration of cerebral parenchyma, etc [9].
Table 5
MCP-1 blood concentration (M±m), pg/ml
Patients groups normal body weight AO I-II class
Cerebral infarction sizes, cm3 <20 >20 <20 >20
Day after stroke 1st 173,5±13,0 179,4±11,7 231,4±30,0 371,4*»±58,2
10th 216,3±19,9 226,1 ±22,4 218,3±24,3 254,2±39,3
* - difference is significant (p<0.05) in comparison with patients of identical body weight category with cerebral infarction volumes <20 cm3.
• - difference is significant (p<0.05) in comparison with normal body weight patients with the similar cerebral lesion volumes.
Table 5 shows that only in patients with AO I-II classes and with larger cerebral infarction sizes (> 20 cm3) MCP-1 serum level is significantly increased. Perhaps this phenomenon is due to the necessity for some «critical» cerebral lesions volume for significant cellular activation of the post-ischemic inflammatory response. In particular, in previous studies we have shown that patients with AO I-II classes and relatively large cerebral infarction lesions (> 20 cm3) have significantly higher leukocytosis at 1st post-stroke day in comparison with normal body weight patients [2]. MCP-1 is one of the major chemokine that regulates cellular component of postischemic inflammatory response through stimulation of leukocytes (mainly monocytes) infiltration in brain paren-
chyma [7]. It has been demonstrated that leptin deficient obese mice, compared with wild-type mice, have significantly elevated MCP-1 blood level as well as significantly larger increases in leukocyte and platelet adhesion, blood-brain barrier permeability, water content, and infarct volume after middle cerebral artery occlusion-reperfusion. And, that is very important, immunoneutrali-zation of MCP-1 reduced infarct volume in obese mice [17]. Because brain tissue level of MCP-1 was similar in post-ischemic ob/ob mice compared with wild-type mice, it is unlikely that the higher plasma level was derived from the damaged brain. However, it is possible that the higher plasma MCP-1 concentration in ob/ob mice was derived from the expanded pool of adipose tissue [17].
Table 6
IL-ip blood concentration (M±m), pg/ml
Patients groups normal body weight AO I-II class
Cerebral infarction sizes, cm3 <20 >20 <20 >20
Day after stroke 1st 1,5±0,5 1,8±0,6 2,4±0,7 68,9*»±25,8
101Я 1,0±0,4 0,8±0,4 1,7±0,8 3,0»±0,7
* - difference is significant (p<0.05) in comparison with patients of identical body weight category with cerebral infarction volumes <20 cm3.
• - difference is significant (p<0.05) in comparison with normal body weight patients with the similar cerebral lesion volumes.
Table 6 shows that patients with AO I-II classes and volumes of cerebral lesions larger than 20 cm3 have dramatically increasing of IL-1 p serum level at 1st poststroke day with a subsequent significant decreasing at the 10th day. This phenomenon may reflect a hyperactivation of post-immuno-inflammatory processes in abdominally obese patients with certain cerebral lesions
sizes. It’s considered that IL-1 p has a lot of functions in post-ischemic cerebral inflammatory reactions, including induction of IL-6 synthesis by resident and circulating cells, induction of adhesion molecules’ synthesis by endothelial cells, activation of neutrophilic infiltration in brain tissue [9].
Table 7
IL-6 blood concentration (M±m), pg/ml
Patients groups normal body weight AO I-II class
Cerebral infarction sizes, cm3 <20 >20 <20 >20
Day after stroke 1st 24,5±12,5 39,4±12,4 72,2»±14,4 165,2*»±35,1
101Я 8,5±3,0 6,2±2,4 61,9»±14,5 100,1 *±31,1
* - difference is significant (p<0.05) in comparison with patients of identical body weight category with cerebral infarction volumes <20 cm3.
• - difference is significant (p<0.05) in comparison with normal body weight patients with the similar cerebral lesion volumes.
Table 7 shows that under conditions of the similar infarction volumes, abdominally obese patients have significantly elevated serum IL-6 level at 1st day after stroke as well at 10th day, compared with normal body weight patients. IL-6 - is a key regulator of post-ischemic inflammatory response. It is an endogenous pyretic that stimulates expression of acute phase proteins in the liver (CRP, fibrinogen, etc.) [13]. High serum IL-6 concentration at the first post-stroke days is associated with secondary post-ischemic cerebral lesions and is independent adverse prognostic marker of disease severity and longterm functional outcome according to mRS [8, 18]. On the analogy of MCP-1, leptin deficient obese mice, compared with wild-type mice, have significantly elevated serum IL-6 after ischemic stroke [17]. Because brain tissue level of IL-6 was decreased in post-ischemic ob/ob mice compared with wild-type mice, authors suggested that under stroke conditions just adipose tissue is a major source of serum IL-6 [17].
So, abdominally obese patients compared with normal body weight ones have enhanced post-ischemic inflammatory response (especially pronounced in cases of larger infarctions volume) at acute non-lacunar strokes. This peculiarity may be responsible for more severe acute non-lacunar strokes and worse late functional outcomes in patients with AO I-II classes.
Conclusions
1. Patients with AO I-II classes compared with normal body weight ones have enhanced post-ischemic inflammatory response (especially pronounced in cases of larger infarctions volume) at acute non-lacunar strokes.
2. The enhanced post-ischemic inflammatory response may be responsible for more severe acute nonlacunar strokes and worse late functional outcomes in patients with AO I-II classes.
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7. Chen Y. Overexpression of monocyte chemoattractant protein 1 in the brain exacerbates ischemic brain injury and is associated with recruitment of inflammatory cells / Y. Chen, JM. Hallenbeck, C. Ruetzler [et al.] // Journal of Cerebral Blood Flow & Metabolism - 2003. - V. 23. - V. 748-755.
8. Craig J. Peak plasma interleukin-6 and other peripheral markers of inflammation in the first week of ischaemic stroke correlate with brain infarct volume, stroke severity and long-term outcome / J. Craig, CJ. Smith, CA Hedley [et al.] // BMC Neurology. - 2004. - V. 4. - P. 2.
9. Danton GH. Inflammatory mechanisms after ischemia and stroke // GH. Danton, WD. Dietrich // Journal of Neuropathology & Experimental Neurology. - 2003. - V. 62. - P. 127-136.
10. den Hertog HM. C-reactive protein in the very early phase of acute ischemic stroke: association with poor outcome and death / HM. den Hertog, JA. van Rossum, MA. van der Worp [et al.] // Journal of Neurology. - 2009. - V. 256 (12). - P. 2003-2008
11. Gill R. Human C-reactive protein increases cerebral infarct size after middle cerebral artery occlusion in adult rats / R. Gill, JA. Kemp, C. Sabin [et al.] // Journal of Cerebral Blood Flow & Metabolism - 2004. - V. 24 (11). - P. 12141218.
12. Ginsberg M. Adventures in the pathophysiology of brain ischemia: penumbra, gene expression, neuroprotection:
the 2002 Thomas Willis Lecture / M. Ginsberg // Stroke. -2003. - V. 34. - P. 214-223.
13. Heinrich PC. Interleukin-6 and the acute phase response / PC. Heinrich, JV. Castell, T. Andus // Biochemical Journal. - 1990. - V. 265 (3). - P. 621 - 636.
14. Intiso D. Tumor necrosis factor alpha serum levels and inflammatory response in acute ischemic stroke patients / D. Intiso, MM. Zarrelli, G. Lagioia [et al.] // Neurological Sciences. - 2003. - V. 24 (6). - P. 390-396.
15. Kogure K. Inflammation of the brain after ischemia / K. Kogure, Y. Yamasaki, Y. Matsuo [et al.] // Acta Neurochi-rurgica Supplement. - 1996. - V. 66. - P. 40 -43.
16. Ormstad H. Serum levels of cytokines and C-reactive protein in acute ischemic stroke patients, and their relationship to stroke lateralization, type, and infarct volume / H. Ormstad, HC. Aass, N. Lund-Sorensen [et al.] // Journal of Neurology. - 2011. - V. 258 (4). - P. 677-685.
17. Terao S. Inflammatory and injury responses to ischemic stroke in obese mice / S. Terao, G. Yilmaz, K. Stokes [et al.] // Stroke. - 2008. - V. 39(3). - P. 943-950.
18. Waje-Andreassen U. IL-6: an early marker for outcome in acute ischemic stroke / U. Waje-Andreassen, J. Krakenes, E. Ulvestad [et al.] // Acta Neurologica Scandinavica. -2005. - V. 111. - P. 360-365.
19. World Health Organization: Obesity. Preventing and Managing the Global Epidemic. Report of a WHO Consultation on Obesity, Geneva 3-5 June 1997. Geneva, World Health Organization, 1998.
20. Zaremba J. Early TNF-a levels correlate with ischaemic stroke severity / J. Zaremba, J. Losy // Acta Neurologica Scandinavica. - 2001. - V. 104 (5). - P. 288-295.
Матеріал надійшов до редакції' 11.01.2013 р.
