Evaluation of cerebrospinal fluid S 100 B protein concentration in patients with purulent, bacterial meningitis - own observations - Epidemiological Review

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Department of Infectious Diseases, Medical University of Silesia in Bytom

ABSTRACT

7+($,0RIWKHVWXG\ZDVHYDOXDWLRQRIXVHIXOQHVVRIFHUHEURVSLQDOIOXLG&6)6%SURWHLQFRQFHQWUDWLRQ DVVHVVPHQWLQDGXOWVZLWKSXUXOHQWEDFWHULDOPHQLQJRHQFHSKDOLWLV

0$7(5,$/$1'0(7+2'67KHLQYHVWLJDWLRQZDVSHUIRUPHGLQVXEMHFWVKRVSLWDOL]HGDWWKH'HSDUWPHQW RI,QIHFWLRXV'LVHDVHVRI0HGLFDO8QLYHUVLW\RI6LOHVLDLQ%\WRPLQ±GXHWRSXUXOHQWEDFWHULDOPH-ningoencephalitis. All patients were divided into two groups according to the severity of their clinical condition: I group – very severe course of the disease, II group – moderate and mild course of the disease. In all individuals &6)6%SURWHLQFRQFHQWUDWLRQZDVHYDOXDWHGGXULQJWKHILUVWKRXUVRIKRVSLWDOL]DWLRQ

5(68/76. Mean CSF S100 B protein concentration in patients in very severe clinical condition (group I) was SJP/FRPSDUHGWRSJP/LQVXEMHFWVRIJURXS,,ZLWKPRGHUDWHDQGPLOGFRXUVHRIGLVHDVH 7KHGLIIHUHQFHEHWZHHQ&6)PHDQFRQFHQWUDWLRQRIWKLVSURWHLQZDVVWDWLVWLFDOO\VLJQLILFDQWS1RFRU-UHODWLRQVZHUHDVVHVVHGEHWZHHQ&6)6%SURWHLQFRQFHQWUDWLRQVDQGRWKHU&6)LQIODPPDWRU\SDUDPHWHUV &RQWURODVVD\VSHUIRUPHGLQSDWLHQWVIURPJURXS,UHYHDOHGRQO\VOLJKWO\GHFUHDVHRI&6)6%SURWHLQOHYHO in fatal course of the disease. In survivals with recovery CSF concentration of this protein was evident decreased compared to initial level.

&21&/86,216.7KHREWDLQHGUHVXOWVLQGLFDWHWKHXVHIXOQHVVRI&6)6%SURWHLQFRQFHQWUDWLRQDVVHVVPHQW in estimation of severity of the patient’s clinical condition. The level of this protein concentration also seems to EHKHOSIXODVSURJQRVWLFPDUNHULQSXUXOHQWEDFWHULDOPHQLQJRHQFHSKDOLWLV

.H\ZRUGVS100 B protein, cerebrospinal fluid, purulent, bacterial meningoencephalitis INTRODUCTION

Bacterial infections of the central nervous system &16 UHPDLQ D VHULRXV SUREOHP RI FRQWHPSRUDU\ medicine. Despite advances of pharmacotherapy and LQWHQVLYHFDUHEDFWHULDOSXUXOHQWPHQLQJRHQFHSKDOLWLV remain the disease of an uncertain prognosis and rela-tively high mortality rate and in many cases it leads to permanent, neurological sequelae (1). The results of URXWLQHO\SHUIRUPHGFHUHEURVSLQDOIOXLG&6)WHVWVLH CSF leukocyte count and cytogram, concentration of protein, glucose, chloride and, rarely, lactic acid do not DOZD\VVHHPWRIXOO\UHIOHFWWKHDFWXDOLQWHQVLW\RIEUDLQ WLVVXHLQIODPPDWRU\SURFHVVLQWKHVHGLVHDVHV7KH aim of this study was to evaluate the usefulness of CSF S100 B protein levels determination, for the diagnosis RISXUXOHQWEDFWHULDOPHQLQJRHQFHSKDOLWLVLQDGXOWV

MATERIAL AND METHOD

The study was conducted in group of 16 patients hospitalized at the Department of Infectious Diseases of 0HGLFDO8QLYHUVLW\RI6LOHVLDLQ%\WRPLQ $WRWDORIPDOHVDQGIHPDOHV were included, the youngest patient was 19 years old, WKHROGHVWDQGPHDQDJHZDV\HDUV3DWLHQWV were admitted to the Department with suspected me-QLQJRHQFHSKDOLWLV,QDOOFDVHVEDVHGRQWKH&6)WHVW UHVXOWV SXUXOHQW EDFWHULDO PHQLQJRHQFHSKDOLWLV ZDV diagnosed. The following etiological factors of disease were identified: Streptococcus pneumoniae in 5 patients Neisseria meningitidisLQFDVHV LQWKHUHPDLQLQJQLQHSDWLHQWVWKHHWLRORJLFDO agent of meningoencephalitis was not determined.

Due to clinical severity of the condition assessed on the day of admission to the Department, the patients were divided into two groups:

1) Group I - 9 patients in very severe conditions (6 men and 3 women, mean age 55 years) with altered conscious-ness, focal neurological deficits, generalized seizures (in the period prior to hospitalization or at the first day), *ODVJRZ&RPD6FDOHVFRUH*&6GLGQRWH[FHHG etiological factors were: Streptococcus pneumoniae in 4 cases, Neisseria meningitidis in one case, in the remain-LQJIRXUFDVHVWKHHWLRORJ\ZDVQRWHVWDEOLVKHG

 *URXS,,SDWLHQWVLQPLOGWRPRGHUDWHO\VHYHUH FRQGLWLRQPHQDQGZRPHQPHDQDJH\HDUV ZKRKDGQRVLJQLILFDQWGLVWXUEDQFHVRIFRQVFLRXVQHVV no focal neurological deficits or seizures, Glasgow &RPD6FDOHVFRUHH[FHHGHWLRORJLFDOIDFWRUVRIPH-ningioencephalitis were: Streptococcus pneumoniae (1 case), Neisseria meningitidis (1 case), in the other ILYHFDVHVWKHHWLRORJ\ZDVQRWHVWDEOLVKHG

,QDOOSDWLHQWVOXPEDUSXQFWXUHDQG&6)H[DPLQD-tion were made at the day of admission, including leu-kocyte count and cytogram, concentration of proteins, glucose, lactic acid and S100 B protein (S100 B). To measure the concentration of S100 B, enzyme immuno-assay kits was used : Human S100B ELISA, BioVendor, 5HVHDUFKDQG'LDJQRVWLF3URGXFWV*PE+*HUPDQ\

Furthermore, at the 10 th day of treatment in seven patients in group I control CSF tests were made . Of these, four people were successfully treated, in one deafness oc-curred as a consequence of disease and two patients died. The comparison of average count of leukocytes, concentrations of protein, glucose, lactic acid and protein S100 B in the two groups of patients were per-formed using Student’s t test. Significance was defined DVSĮ”DQGSĮ7KHFRUUHODWLRQEHWZHHQ WKHSDUDPHWHUVRI&6)LQERWKJURXSVXVLQJ3HDUVRQ¶V correlation coefficient was also evaluated.

RESULTS

Results of CSF examination in patients with puru- OHQWEDFWHULDOPHQLQJRHQFHSKDOLWLVREWDLQHGRQDGPLV-VLRQGD\DUHVKRZQLQ7DEOH,

In group I, the average pleocytosis was 663 cells / mm LQDOOSDWLHQWVLQF\WRJUDP310VSUHYDLOHGIURPWR RIWKHFHOOVWKHPHDQSURWHLQFRQFHQWUDWLRQPJ/ JOXFRVHPPRO/ODFWLFDFLGPPRO/ DQGFRQFHQWUDWLRQRISURWHLQ6%SJP/

The condition of these patients assessed on the admission day and course of the disease was very VHYHUH,QWKUHHFDVHVWKHUHZDVDQ$5'6LQWXEDWLRQ or a tracheotomy was necessary, patients were treated with mechanical ventilation on the Intensive Care Unit, two of them died. Overall, three patients of this group died, one had a persistent neurological sequelae as a deafness, 5 patients were cured. The highest CSF concentration of protein, lactic acid, and protein S100 %ZDVREVHUYHGLQIDWDOFDVHV

,QJURXS,,WKHDYHUDJHSOHRF\WRVLVZDVFHOOV /mm3, in all patients’ cytogram also PNMs prevailed IURPWRRIDOOFHOOV0HDQ&6)OHYHOVRI other parameters were as follows: protein 906 mg / L, JOXFRVHPPRO/ODFWLFDFLGPPRO/DQG the concentration of protein S100 B - 419.56 pg / mL. Condition of the patients and course of disease in this group was moderately-severe or mild, and outcomes FRPSDUHGZLWKWKHJURXS,ZHUHGHILQLWHO\EHWWHU&RP-plete recovery was achieved in 6 cases, in one patient hearing loss occured as a consequences of neuroinfec-tions. There was no respiratory distress in this group, none of the patients died.

Results of CSF control examinations performed in seven patients in group I were as follows: in 4 patients who were cured, there was a marked reduction of the concentration of S100 B protein. In all cases reduction in the average count of leukocytes, CSF protein and lactic acid in comparison to the initial results were REVHUYHG,QDSDWLHQWZLWKDGHDIQHVVDVDFRQVHTXHQFH decrease of S100 B protein concentration in control examination was less pronounced.

Whereas in two patients who died, there was in-significant decrease in the concentration of S100 B SURWHLQLQ&6),QERWKFDVHVWKHUHZDVDSHUVLVWHQWO\ high PNMs pleocytosis, a high CSF protein and lactic acid concentration. Results of control determinations of CSF S100 B protein in the course of disease in patients RIJURXS,DUHVKRZQLQ7DEOH,,

7DEOH 7KHUHVXOWVRI&6)H[DPLQDWLRQLQSDWLHQWVZLWKSXUXOHQWEDFWHULDOPHQLQJRHQFHSKDOLWLVRQWKHGD\RIDGPLVVLRQ to the ward

Patient group Pleocytosis (cell/mm3₎ Protein (mg/L)* Glucose (mmol/L) Lactic acid (mmol/L)** S100B protein (pg/mL)** Group I Q  ±“ ±“ “(0 – 1.4) “ ± ±“ Group II Q  (69 – 533)“ “ ± “± “± ±“ 7KHWDEOHVKRZVWKHPHDQYDOXHVRIH[DPLQHGSDUDPHWHUV 6WDWLVWLFDOO\VLJQLILFDQWGLIIHUHQFHS 6WDWLVWLFDOO\VLJQLILFDQWGLIIHUHQFHS

Cerebrospinal fluid S 100B protein 

No 3

7DEOH,, &6)6%SURWHLQOHYHOVLQWKHFRXUVHRIWKH disease in group I

Patient S100 B protein (pg/mL) Outcome I examination II examination 1.   recovery    „ -3.  611.19 „ -4.   „ -5. 1149.55  deafness 6.   decease    „

-Differences in average count of leukocytes and CSF JOXFRVHFRQFHQWUDWLRQVEHWZHHQWKHWZRJURXSVRISD-tients were not statistically significant. However, there were statistically significant differences in mean CSF FRQFHQWUDWLRQVRISURWHLQSODFWLFDFLGS DQG6%SURWHLQSEHWZHHQ*URXS,DQG,,

DISCUSSION

7KHEDVLFWHVWLQWKHGLDJQRVLVRI&16LQIHFWLRQV LVDQDO\VLVRIWKHFHUHEURVSLQDOIOXLG,QPRVWODERUDWR-ries CSF is routinely examined for count and types of leukocytes, protein concentration, glucose and chloride OHYHOVUDUHO\ODFWLFDFLG

For many years, attempts were made to extend the scope of CSF parameters for diagnosis of the CNS infections. The following parameters were determined, LDWKHFRQFHQWUDWLRQRIO\VR]\PHLPPXQRJOREXOLQV inflammatory cytokines, chemokines, arachidonic acid GHULYDWLYHV SURVWDJODQGLQV WKURPER[DQHV OHXNRW-rienes), procalcitonin (PCT), lactate dehydrogenase (LDH), creatine kinase (CK), neuron-specific enolase (NSE) and ciliary neurotrophic factor (CNTF).These tests allowed for a more accurate assessment of the actual intensity and course of inflammatory processes LQSDWLHQW¶VVXEDUDFKQRLGVSDFHEXWWKHLUSHUIRUPLQJ often requires significant financial outlays and a well-HTXLSSHGODERUDWRU\

6%SURWHLQEHORQJVWRDFDOFLXPELQGLQJSURWHLQ family. It occurs in the CNS, mainly in the astroglia, oligodendrocytes and Schwann cells, in the cytosol RUDWWDFKHGWRFHOOPHPEUDQHV,WLVV\QWKHVL]HGDQG VHFUHWHGSULPDULO\E\DVWURF\WHVRIWKHEUDLQ

S100 B protein is a regulatory protein modulating activity of effector cells and is involved in maintaining calcium homeostasis and the regulation of proteins phosphorylation. S100 B intracellular activity involve regulatory effect on cell growth, differentiation, model- LQJDQGHQHUJ\PHWDEROLVP$QGH[WUDFHOOXODUO\VWLPX-lates neuronal survival and differentiation, astrocyte SUROLIHUDWLRQQHXURQDOGHDWKE\DSRSWRVLVVWLPXODWHRU LQKLELWWKHDFWLYLW\RILQIODPPDWRU\FHOOV

Depending on the concentration protein S100 B H[KLELWVDQHXURWURSKLFDQGWURSKLFRUWR[LFWREUDLQWLV-sue. At physiological concentrations it has neurotrophic effects on development and regeneration of nerves, in high concentrations is neurotoxic and participates in neurodegenerative disorders. S100 B protein concentra-WLRQLVWKHUHIRUHFRQVLGHUHGWREHRQHRIWKHELRFKHPLFDO PDUNHUVRIEUDLQGDPDJH

Depending on the concentration protein S100 B H[KLELWVDQHXURWURSKLFDQGWURSKLFRUWR[LFWREUDLQWLV-sue. At physiological concentrations it has neurotrophic effects in development and regeneration of nerves, in high concentrations is neurotoxic and participates in neurodegenerative disorders. S100 B protein concentra-WLRQLVWKHUHIRUHFRQVLGHUHGWREHRQHRIWKHELRFKHPLFDO PDUNHUVRIEUDLQGDPDJH

Experimental studies revealed that S100 B protein is involved in various disease processes of CNS, in-cluding meningitis and encephalitis. In the course of meningoencephalitis damage to the nerve and glial cells occurs, which leads to the release of specific intracel-lular proteins into the extracelintracel-lular space and CSF. 7KHFRQFHQWUDWLRQRI6%SURWHLQLQ&6)PD\EHD PDUNHURIJOLDODFWLYDWLRQDQGGDPDJHLQFHUHEUDOZKLWH PDWWHU

S100 B levels in serum and CSF were tested in vari-RXV&16GLVHDVHVLQSDUWLFXODUYDVFXODUEUDLQGLVHDVHV In ischemic stroke the increased serum concentration of this protein was shown (14,15) and the extent of S100B elevation may help to identify patients with an increased risk of specific early neurological complications (16). ,QSDWLHQWVZLWKFHUHEUDOKHPRUUKDJHWKHHOHYDWHG6 %OHYHOVLQVHUXPZHUHDOVRREVHUYHG

There was also elevated serum and CSF levels of 6%LQWKHFRXUVHRIWUDXPDWLFEUDLQLQMXU\$F-cording to Vos et al extent of S100 B elevation in the VHUXPFDQEHFRQVLGHUHGDVDVLQJOHVWURQJHVWSUHGLFWRU of poor outcome of disease (19).

Studies in patients with neurodegenerative diseases, including Alzheimer’s disease have shown elevated lev-HOVRI6SURWHLQ%LQ&6)DQGVHUXP0HDVXULQJ of S100 B concentration demonstrated its usefulness in WKHGLDJQRVLVRIWKHVFKL]RSKUHQLDDQGGHSUHVVLRQ

7KHUHLVUHODWLYHO\OLWWOHUHSRUWVDERXWWKHUHVHDUFK RI6%UROHLQWKHFRXUVHRISXUXOHQWEDFWHULDOPH-QLQJRHQFHSKDOLWLV ,Q  SDWKRSK\VLRORJ\ RI EDFWHULDO &16LQIHFWLRQVLVFKHPLDDQGK\SR[LDRIEUDLQWLVVXHLV an important issue.

,QWKHFRXUVHRILQIODPPDWLRQLQWKHVXEDUDFKQRLG space initially activation occurs and then - the dam-age and death of glial cells. Glial cells and CNS resi-dent macrophages are involved in the inflammatory UHVSRQVHWKHQDSRSWRVLVLQGXFWLRQQHUYHDQGJOLDO FHOOVDQGGDPDJHWREUDLQWLVVXHRFFXUV5HIOHFWLRQRI these processes is the release of S100B from glial cells

and neuron-specific enolase (NSE) from neurons into WKH&6)7KHFOLQLFDOFRXUVHDQGRXWFRPHRIEDFWHULDO meningoencephalitis depend on severity and extent of QHXURQDODQGJOLDOGDPDJH

6WXGLHVLQFKLOGUHQZLWKEDFWHULDOPHQLQJRHQFHSKD-litis showed an increase the concentration of S100B in VHUXPDQG&6)7KHFRQFHQWUDWLRQERWKLQ&6)DQGLQ the serum, in the early stage of the disease correlated with the clinical severity, as well as with occurrence neu-rological complications after disease. Elevated levels of this protein in serum and CSF in the acute phase of the disease were reduced in control tests in successfully WUHDWHGFDVHV/LQVHWDOSRLQWWKHXVHIXOQHVVRI 6%LQVHUXPLQPRQLWRULQJRIWKHFRXUVHRIEDFWHULDO PHQLQJRHQFHSKDOLWLVZKLFKPD\EHRIJUHDWSUDFWLFDO importance in case of contraindications for performing FRQWUROOXPEDUSXQFWXUH

7KHUHZDVQRFOHDUUHODWLRQEHWZHHQFRQFHQWUDWLRQ RI6%SURWHLQLQWKH&6)DQGWKHHWLRORJ\RIEDFWHULDO PHQLQJRHQFHSKDOLWLV:HDOVRKDYHQRW found such relation in patients involved in the study .

7KHUHKDVQRWDOVREHHQVKRZQFOHDUFRUUHODWLRQ EHWZHHQWKHFRQFHQWUDWLRQRIWKHSURWHLQLQ&6)DQG others routinely tested CSF parameters. In success-IXOO\WUHDWHGFDVHVZHUHREVHUYHGUHGXFWLRQVRI6 B levels in control tests parallel with the normalization of other CSF parameters (pleocytosis, proteins and JOXFRVH

$SRVLWLYHFRUUHODWLRQEHWZHHQFRQFHQWUDWLRQVRI S100B and lactic acid level in CSF was found in Group ,RIREVHUYHGSDWLHQWVZKHUHDVWKHUHZDVQRFRUUHODWLRQ EHWZHHQ6%DQG301VFRXQWSURWHLQDQGJOXFRVH OHYHOV,QWKHVHFRQGJURXSDFRUUHODWLRQEHWZHHQFRQ-centrations of S100B and other parameters of CSF was QRWREVHUYHG

$QLQWHUHVWLQJLVVXHLVUHODWLRQEHWZHHQFRQFHQWUD-tion of S100B in CSF and clinical severity in patients ZLWKEDFWHULDOSXUXOHQWPHQLQJRHQFHSKDOLWLV7KHKLJK-HVWFRQFHQWUDWLRQVRI6%LQ&6)ZDVREVHUYHGLQ patients with the most severe clinical course.

7KLVVHHPVWRLQGLFDWHWKHVXEVWDQWLDOGDPDJHRI EUDLQ WLVVXH ZKLWH PDWWHU JOLDO FHOOV UHVXOWLQJ IURP EDFWHULDOLQIHFWLRQ+RZHYHUFKDQJHVLQFRQFHQWUDWLRQ RI6%LQWKHFRXUVHRIEDFWHULDOPHQLQJRHQFHSKDOLWLV have a certain relationship with the further progression and course of the disease. Control tests performed dur-ing hospitalization showed significantly reduced levels of S100 B protein in CSF in patients with clinical im-provement and normalization of routine CSF tests. In patients whose clinical condition did not improve, the concentration of this protein in CSF remained high, FRPSDUDEOHWRWKDWRIWKHILUVWWHVW

,QRXUVWXGLHVZHREVHUYHGWKHKLJKHVWFRQFHQWUD-tions of S100B in the CSF in patients in a very severe clinical condition (group I). There were no statistically

significant differences in average PMNs count and JOXFRVHLQ&6)EHWZHHQWKHJURXSV,DQG,,+RZHYHU the highest mean concentrations of protein and lactic DFLGREVHUYHGLQSDWLHQWVZLWKPRVWVHYHUHFRXUVHSDU-ticularly those who died.

The results indicate that concentration of S100 B protein clearly correlated with the clinical severity on admission to the Department and with the further course RIWKHGLVHDVH&RQWUROWHVWVVKRZHGDUHDOWLRQEHWZHHQ concentration of S100 B protein in CSF and outcome of the disease. In successfully treated cases S100 B levels ZHUHGHFUHDVHGLQPRVWFDVHVEHIRUHFOLQLFDOLPSURYH-ment and normalization of other CSF parameters.

In contrast, in patients who died, the concentration of S100B virtually were not reduced compared to the first examination. At the same time maintained a high CSF inflammatory parameters and clinical condition GLGQRWLPSURYH5HODWLYHO\VPDOOQXPEHURIVWXGLHG patients hampers a more detailed statistical analysis of results and to draw unequivocal, far-reaching conclu-VLRQVEXWMXVWLILHVWKHGHVLUDELOLW\RIIXUWKHUUHVHDUFK

SUMMARY

Concentration of S100B protein in CSF seems ODUJHO\UHIOHFWWKHLQWHQVLW\RIEUDLQGDPDJHFDXVHGE\ EDFWHULDOLQIHFWLRQ(OHYDWHGOHYHOVRI6%LQ&6)LQL-tially points to the activation of glial cells in the course of meningoencephalitis, and then - the white matter of EUDLQGDPDJH6%SURWHLQLVFRQVLGHUHGDQLQGLFDWRU RIGDPDJHWRZKLWHPDWWHULQDQXPEHURISDWKRORJL-cal processes of the central nervous system, including EDFWHULDOPHQLQJRHQFHSKDOLWLV

Determination of S100 B in CSF in patients with SXUXOHQWEDFWHULDOPHQLQJRHQFHSKDOLWLVPD\WKHUHIRUHEH LPSRUWDQWERWKLQDVVHVVLQJWKHDFWXDOLQWHQVLW\RIJOLDO damage, which are relevant to the course and outcome of the disease, as well as to predict fatal outcome. This FDQEHXVHIXOLQPRQLWRULQJWKHFRXUVHDQGWUHDWPHQW of purulent meningoencephalitis and have some prog-nostic value.

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16. Dassan P, Keir G, Brown MM. Criteria for a clinically LQIRUPDWLYHVHUXPELRPDUNHULQDFXWHLVFKDHPLFVWURNHD UHYLHZRI6%&HUHEURYDVF'LV -DPHV0/%OHVVLQJ53KLOOLSV%XWH%*LLQ6%DQG EUDLQQDWULXUHWLFSHSWLGHSUHGLFWIXQFWLRQDOQHXURORJLFDO RXWFRPHDIWHULQWUDFHUHEUDOKDHPRUUKDJH%LRPDUNHUV  *RQoDOYHV&$/HLWH0&1RUGLQ3%LRORJLFDODQGPHWK-odological features of the measurement of S100B, a puta-WLYHPDUNHURIEUDLQLQMXU\&OLQ%LRFKHP  9RV3(-DFREV%$QGULHVVHQ70LLQ*)$3DQG6% DUHELRPDUNHUVRIWUDXPDWLFEUDLQLQMXU\DQREVHUYDWLRQDO FRKRUWVWXG\1HXURORJ\ 6WHLQHU-%RJHUWV%6FKURHWHU0/LLQ6%SURWHLQ LQQHXURGHJHQHUDWLYHGLVRUGHUV&OLQ&KHP/DE0HG  5RWKHUPXQGW0$KX-1-|UJHQV66%LQVFKL]R-SKUHQLDDQXSGDWH*HQ3K\VLRO%LRSK\V)  ,QIDQWH-50DUWLQHV$2FKRD-LLQ&HUHEURVSLQDOIOXLG s100 protein levels in neurological pathologies. J Physiol %LRFKHP

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Department of Infectious Diseases Silesian Medical University