TGF-ß1 in plasma and cerebrospinal fluid can be used as a biological indicator of chronic pain in patients with osteoarthritis.

INTRODUCTION: Previous studies have demonstrated that cytokines, transforming growth factor (TGF-ß1), and brain-derived neurotrophic factor (BDNF) can impact the intensity of pain in rodents. However, the roles of cytokines, TGF-ß1 and BDNF in humans with chronic pain in osteoarthritis remains unclear, and no comparison between plasma and central cerebral spinal fluid (CSF) has been conducted. METHODS: Patients with osteoarthritis who were scheduled to receive spinal anesthesia were enrolled. The intensity of pain was evaluated with a visual analogue scale (VAS). In addition, patients with genitourinary system (GU) diseases and without obvious pain (VAS 0-1) were included as a comparison (control) group. The levels of TGF-ß1, BDNF, tumor necrosis factor-α (TNF-α), and interleukin (IL)-8 within the CSF and plasma were collected and evaluated before surgery. RESULTS: The plasma and CSF TGF-ß1 levels were significantly lower in the osteoarthritis patients with pain (VAS ≥ 3) than in the GU control patients. Downregulation of plasma BDNF was also found in osteoarthritis patients with pain. The Spearman correlation analysis showed that the VAS pain scores were significantly negatively correlated with the levels of TGF-ß1 in the CSF of patients with osteoarthritis. However, there was no significant correlations between the pain scores and the levels of BDNF, TNF-α, and IL-8 in either the CSF or plasma. CONCLUSIONS: TGF-ß1 but not BDNF, TNF-α, or IL-8 may be an important biological indicator in the CSF of osteoarthritis patients with chronic pain.

uPA alleviates kaolin-induced hydrocephalus by promoting the release and activation of hepatocyte growth factor in rats.

Urokinase-type plasminogen activator (uPA) was demonstrated to alleviate kaolin-induced communicating hydrocephalus via inhibiting subarachnoid space fibrosis, but the exact mechanism remains elusive. Thus, this study was designed to investigate if hepatocyte growth factor (HGF), which plays a vital role in uPA-triggered inhibiting of fibrosis in multiple systems, is involved in this process in hydrocephalus. There were 2 parts in this study. First, hydrocephalus was induced in rats by basal cistern injection of kaolin. Then rats were treated with saline or uPA and brain tissue and CSF were collected for Western blot and enzyme-linked immuno sorbent assay (ELISA) four days later. Second, kaolin-induced hydrocephalus rats were treated with saline, uPA, uPA + PHA665752 (antagonist of HGF) or PHA665752. Some animals received MRI four weeks later and brains were used for immunofluorescence. The others were euthanized four days later for ELISA. Both levels of total and activated HGF in the CSF was increased after uPA injections, but related mRNA expression of HGF showed no statistical significance when compared with the control group. Further, the effects of uPA that alleviating ventricular enlargement, subarachnoid fibrosis and reactive astrocytosis were partially reversed by PHA665752. Moreover, PHA665752 partially abolished uPA-induced reduction of transforming growth factor- ß1(TGF- ß1) level in CSF. Our data suggest that uPA effectively inhibited subarachnoid fibrosis and restricted the development of communicating hydrocephalus in rats in part by promoting HGF release and activation, which may further regulate the TGF-ß1 expression in CSF.

Cerebrospinal fluid biomarkers implicated in the pathogenesis of anti-neutrophil cytoplasmic antibody-related hypertrophic pachymeningitis.

OBJECTIVE: Hypertrophic pachymeningitis (HP) related to anti-neutrophil cytoplasmic antibody (ANCA) is the most frequently seen immune-mediated HP. We investigated cerebrospinal fluid (CSF) biomarkers related to the pathogenesis of ANCA-related HP (ANCA-HP). METHODS: The levels of B cell activation factor of the tumor necrosis factor family (BAFF), a proliferation-inducing ligand (APRIL), and transforming growth factor beta 1 (TGF-ß1) in the CSF were compared between patients with ANCA-HP (n = 12), other types of immune-mediated HP (other HP; n = 12), multiple sclerosis (MS; n = 14), and non-inflammatory neurological disorders (NIND; n = 10). In addition, we evaluated whether ANCA would be detected in CSF. RESULTS: CSF levels of BAFF, APRIL, and TGF-ß1 were significantly increased in ANCA-HP and other HP. In particular, BAFF and APRIL levels were significantly correlated with the IgG index in ANCA-HP. In other HP, BAFF and APRIL levels were significantly correlated with cell counts and protein levels in CSF. Of 12 patients with ANCA-HP, the CSF of 7 patients (58%) tested positive for myeloperoxidase (MPO)- or proteinase 3 (PR3)-ANCA, while none of the CSF samples from other HP, MS, or NIND patients tested positive. CONCLUSION: The levels of BAFF, APRIL, and TGF-ß1 may serve as useful CSF biomarkers for assessing the disease activity of immune-mediated HP. Moreover, BAFF and APRIL in the CSF may be implicated in the pathogenesis of ANCA-HP via promoting autoreactive B cells, while detecting MPO- or PR3-ANCA in the CSF may be found in some patients with ANCA-HP.Key Points• CSF BAFF, APRIL, and TGF-ß1 levels increase significantly in immune-mediated HP.• CSF BAFF and APRIL levels are significantly correlated with IgG index in ANCA-HP.• Detection of MPO- or PR3-ANCA in the CSF is found in some patients with ANCA-HP.• BAFF, APRIL, and ANCA in the CSF may be implicated in the pathogenesis of ANCA-HP.

Protective effects of quercetin against brain injury in a rat model of lipopolysaccharide-induced fetal brain injury.

Maternal exposure to lipopolysaccharide (LPS), a bacterial endotoxin produced during infection, leads to disruption in fetal brain development and causes newborn brain injury. Quercetin (QR) is a multipotent flavonoid that functions as an antioxidant and protects against inflammation and neurodegeneration. In this study, we explored the potential functions of QR in alleviating maternal LPS exposure induced fetal brain damage. Pregnant rats at late gestational stages were treated with saline, LPS, QR, LPS and QR. Brain injury biomarker TGF-1ß was assessed in cerebrospinal fluid (CSF) and brain tissue of newborn rats. Pro-inflammatory cytokines, apoptosis markers and oxidative stress indicators were evaluated. We found that LPS treatment induced an increased production of TGF-1ß which was suppressed by QR administration. LPS enhanced pro-apoptotic Bax and inhibited anti-apoptotic Bcl-2 expression. QR reduced that ratio of Bax and Bcl-2 that was high in LPS treated brain tissue. Additionally, QR suppressed oxidative stress induced by LPS. Finally, QR reduced the levels of pro-inflammatory cytokines that were produced as a result of LPS exposure. In summary, our study indicates that QR potently alleviates maternal LPS exposure induced fetal brain injury in rats, making it a potential therapeutic for suppressing infant brain damage as a result of maternal infection.

Transforming growth factor-ß1 in the cerebrospinal fluid of patients with distinct neurodegenerative diseases.

A chronic inflammatory condition may underlie neurodegenerative disorders, including Parkinson's disease (PD) and Alzheimer's disease (AD). For example, both PD and AD patients show an increase in transforming growth factor-ß1 (TGF-ß1) levels in their cerebrospinal fluid (CSF). TGF-ß1 is a cytokine that inhibits inflammation. In the present study, using an enzyme-linked immunosorbent assay, we tested the hypothesis that the level of TGF-ß1 in the CSF of patients with amyotrophic lateral sclerosis (ALS), spinocerebellar degeneration (SCD), or multiple system atrophy-cerebellar subtype (MSA-C) would be elevated compared with that of normal controls. We found that TGF-ß1 levels in the CSF were not significantly different between these patients and normal controls. Our data suggest that the level of TGF-ß1 in the CSF is an unreliable biomarker of ALS, SCD, and MSA-C.

Does the Cerebrospinal Fluid Reflect Altered Redox State But Not Neurotrophic Support Loss in Parkinson's Disease?

Alteration in neurotrophic factors support and antioxidant defenses in the central nervous system (CNS) along with deficit of ferritin have been associated with idiopathic Parkinson's disease (PD). The objectives were to analyze in the cerebrospinal fluid (CSF) of patients with PD and controls the following: (i) the levels of the neuroprotectant factors glial cell line-derived neurotrophic factor, persephin, neurturin, and brain-derived neurotrophic factor, (ii) the levels of transforming growth factor-ß1 (TGFß1) and transforming growth factor-ß2 (TGFß2), proinflammatory factors, (iii) the activity of the antioxidant enzymes glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-S-transferase (GST), catalase, superoxide dismutases (SODs), and peroxiredoxins (PRDxs), and (iv) ferritin levels. The study revealed that, among neurotrophic factors, only TGFß1 levels were found to be enhanced in patients with PD (early, p < 0.05; advanced, p < 0.02). Regarding antioxidant enzymes, the activity of GPx, catalase, and PRDxs, all hydrogen peroxide scavengers, was found to be significantly reduced in patients (GPx, p < 0.001; catalase, p < 0.01; PRDxs, p < 0.01, one-way analysis of variance). Finally, ferritin content in CSF was significantly diminished over time in patients (early, p < 0.01, -49%; advanced, p < 0.001, -80.7%). Our observations lead to the hypothesis that parkinsonian patients suffer from a serious disturbance of redox state in the CNS, as evaluated through the CSF, characterized by reduced hydrogen peroxide scavenging and iron storage.

Altered cerebrospinal fluid concentrations of TGFß1 in patients with drug-resistant epilepsy.

Transforming growth factor beta (TGFß) signaling participates in pathogenesis of epilepsy. TGFß1, as a transmitter of TGFß signaling, might be a useful marker for predicting the prognosis of patients with epilepsy. The present study aimed to measure TGFß1 level in the cerebrospinal fluid (CSF) of patients with drug-resistant epilepsy and non-resistant epilepsy. A total of 43 patients with epilepsy were recruited, 28 were non-resistant epilepsy subgroup, 15 drug-resistant epilepsy subgroup. 11 patients with intracranial infection and 11 individuals with primary headache were used as controls. The concentration of CSF and serum TGFß1 was measured by enzyme-linked immunosorbent assay. The concentration of CSF-TGFß1 was 209.26 ± 81.07 pg/ml in the drug-resistant epilepsy subgroup, 121.80 ± 40.32 pg/ml in the non-resistant epilepsy subgroup, 552.17 ± 456.20 pg/ml in intracranial infection control, 133.80 ± 68.55 pg/ml in headache control, respectively. TGFß1 level was significantly increased in the drug-resistant epilepsy subgroup compared to the non-resistant epilepsy subgroup. TGFß1 level in intracranial infection control was higher than that in the non-resistant epilepsy subgroup. There was no statistically difference of CSF-TGFß1 between the non-resistant epilepsy subgroup and headache controls, between the resistant epilepsy subgroup and intracranial infection controls. TGFß levels are increased in the CSF of patients with drug-resistant epilepsy. High CSF-TGFß1 levels may be a potential screening biomarker of antiepileptic drug resistance in patients with epilepsy.

[Changes in CD4(+)CD25(+) regulatory T cells in patients with spontaneous subarachnoid hemorrhage].

OBJECTIVE: To explore the role of CD4(+)CD25(+) regulatory T cells (Treg) in the occurrence of spontaneous subarachnoid hemorrhage (SAH). METHODS: Fifteen patients with spontaneous SAH, 15 with traumatic SAH, and 15 with headache without organic pathologies as confirmed by lumbar puncture (control group) were examined with flow cytometry for Treg in the peripheral blood and cerebrospinal fluid and intracellular cytokine interleukin-10 (IL-10) and transforming growth factor beta1 (TGF-ß1) levels. The Glasgow score (GCS), neurological deficit score (NIHSS), headache, visual analog scale (VAS) and hospitalization time were compared between the two SAH groups. RESULTS: Spontaneous SAH patients showed significantly lowered peripheral blood Treg, IL-10, and TGF-ß1 in the cerebrospinal fluid compared with the patients with traumatic SAH and the control group (P<0.05), and the 3 measurements were comparable between the latter two groups (P>0.05). After administration of treatment, of Treg content in spontaneous SAH patients increased progressively and became comparable with those in the other two groups at the third and fourth lumbar punctures. Spontaneous SAH patients showed significantly lower GCS, NIHSS, and VAS with shorter hospital stay than the traumatic SAH patients. Correlation analysis showed that Treg, IL-10 and TGF-ß1 were all inversely correlated with NIHSS, VAS, and duration of hospitalization but positively correlated with GCS (the absolute r values were all greater than 0.6, P<0.05). CONCLUSION: Treg deficiency can be an important mechanism for the occurrence of spontaneous SAH, and a higher level of Treg indicates a better outcome of the patients.

TGF beta1 and TGF beta2 and their role in posthemorrhagic hydrocephalus following SAH and IVH.

OBJECTIVE: Posthemorrhagic hydrocephalus (pHC) is a serious complication following subarachnoid hemorrhage (SAH) and intraventricular hemorrhage (IVH). Besides known clinical predictors, different cytokines have drawn attention to the development of chronic hydrocephalus. Transforming growth factor (TGF) ß1 and TGF ß2 are involved in fibrogenesis, scar formation, cell survival, and tissue differentiation and may play a role in the occurrence of pHC. TGF ß1 is stored in platelets in large amount and is released in the cerebrospinal fluid (CSF) after SAH and IVH. Both TGF ß1 and TGF ß2 can be expressed by various intracranial cells. METHODS: TGF ß1 and ß2 were measured in CSF and blood samples of 42 patients with SAH or IVH with acute hydrocephalus during the first 10 days after ictus. Furthermore, albumin was measured in CSF as an indicator for the amount of blood. Patients were categorized as developing pHC requiring shunt treatment or not-developing pHC within 6 months. RESULTS: After adjusting for age, SAH resulted significantly more often in pHC than did IVH. Plasma levels of TGF ß1 showed a marked increase over time, whereas CSF levels of TGF ß1 constantly decreased. The time course of TGF ß1 and albumin in CSF was paralleled and did not correlate with the development of shunt dependent pHC. Also, TGF ß1 plasma concentrations did not correlate with shunt dependent pHC. TGF ß2 concentrations in plasma showed stable values over time without any variations. TGF ß2 in CSF described a parabolic course with a peak at day 6 after ictus. No correlation was found concerning TGF ß2 in plasma or CSF and shunt dependent pHC. CONCLUSION: TGF ß1 in CSF is derived by platelets from the cisternal or ventricular clot. TGF ß2 in CSF is derived as a general reaction of traumatized brain tissue. These data do not confirm a crucial role of TGF ß1 and TGF ß2 release in the development of pHC.

[Association of chronic hydrocephalus after aneurysmal subarachnoid hemorrhage with transforming growth factor-ß1 levels and other risk factors].

OBJECTIVE: To study the role of transforming growth factor-ß1 (TGF-ß1) levels and other risk factors in the occurrence of chronic hydrocephalus after aneurysmal subarachnoid hemorrhage (aSAH). METHODS: Patients treated for aSAH in our hospital between January, 2007 and June, 2012 were divided into non-hydrocephalus group and hydrocephalus group. TGF-ß1 levels in the cerebrospinal fluid (CSF) were compared between the two groups at different time points. A retrospective analysis was conducted to identify the potential risk factors for chronic hydrocephalus, which were subsequently confirmed by Logistic regression analysis. RESULTS: Of the 129 patients enrolled, 16 (12.4%) developed chronic hydrocephalic with an average diagnosis time of 31.6∓17.0 days. In patients with chronic hydrocephalus, TGF-ß1 level in the CSF increased significantly on the 13th day following aSAH (P<0.05). Retrospective analysis showed that the patients with hydrocephalus and those without had significant differences in history of hypertension, times of SAH, Hunt-Hess classification, ventricular expansion, aneurysm position, Fisher classification, ventricular hemorrhage score and intracranial infections (P<0.05). Logistic regression analysis identified ventricular expansion, aneurysm position, Fisher classification, ventricular hemorrhage score and postoperative intracranial infections as significant risk factors for the occurrence of chronic hydrocephalus (P<0.05). CONCLUSIONS: In adult patients with aSAH, the risk factors for chronic hydrocephalus include ventricular expansion, aneurysm position, Fisher classification, ventricular hemorrhage score and postoperative intracranial infections. These risk factors can have greater clinical value than TGF-ß1 levels in the CSF in predicting the occurrence of chronic hydrocephalus following aSAH.

Interleukin-6, vascular endothelial growth factor and transforming growth factor beta 1 in canine steroid responsive meningitis-arteritis.

BACKGROUND: Steroid Responsive Meningitis-Arteritis (SRMA) is a common cause of inflammation of the canine central nervous system (CNS). To investigate if transforming growth factor beta 1 (TGF-ß1), interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) are involved in the production of excessive immunoglobulin A (IgA), the induction of acute phase proteins and in the development of a systemic necrotizing vasculitis, characteristic of SRMA, these three signalling proteins were evaluated. RESULTS: Cerebrospinal fluid (CSF) and serum samples of dogs during the acute phase of SRMA (SRMA) were tested for IL-6, VEGF and TGF- ß1. Results were compared to those of dogs affected with SRMA during treatment (SRMA Th) and during relapse (SRMA R), to dogs with other meningoencephalomyelitides (ME), with miscellaneous non-inflammatory diseases of the CNS (CNS-Mix), with idiopathic epilepsy (IE), with systemic inflammatory diseases (Syst. Infl.) and with healthy dogs (Healthy). Concentrations of IL-6 and VEGF in CSF were significantly elevated in the SRMA group compared to the other disease categories (p<0.05). The CSF concentrations of TGF-ß1 were increased in SRMA group, but statistically significant differences were found only in comparison with Healthy and CNS-Mix groups. No differences were detected in the serum concentrations of TGF-ß1 between the different groups. In untreated SRMA patients, a positive correlation (rSpear = 0.3549; P=0.0337) between concentrations of TGF-ß1 and IgA concentration was found in CSF, while concentrations of IL-6 and VEGF in CSF positively correlated with the degree of pleocytosis (rSpear=0.8323; P<0.0001 and rSpear=0.5711; P=0.0166, respectively). CONCLUSIONS: Our results suggest that these three signalling proteins are biomarkers of disease activity in SRMA. VEGF might play an important role in the development of a systemic arteritis. TGF-ß1 is considered to be involved in the excessive IgA production, while IL-6 in the pleocytosis. The combined intrathecal increase of TGF-ß1 and IL-6 detected in SRMA could possibly force CD4 progenitors to differentiate towards the newly described Th17 lymphocyte subset and enhance the autoimmune response.

Expression of HGF, MMP-9 and TGF-ß1 in the CSF and cerebral tissue of adult rats with hydrocephalus.

OBJECT: The hepatocyte growth factor (HGF), matrix metallopeptidase-9 (MMP-9) and transforming growth factor-ß1 (TGF-ß1) are important cytokines with modulatory actions in the nervous system. In this study, we attempted to investigate the role and expression of HGF, MMP-9 and TGF-ß1 in the cerebral tissue and cerebrospinal fluid (CSF) of adult rats with hydrocephalus induced via intraventricular kaolin injection. METHODS: Adult male Sprague-Dawley rats were randomly divided into two groups: control group (n = 12) and experimental group (n = 20). Kaolin was injected into the lateral ventricle of experimental animals. Control rats underwent the same procedure but received sterile saline injection instead of kaolin. Magnetic resonance imaging was used to assess ventricle size. The CSF was studied by enzyme-linked immunosorbent assay and the excised brains were studied by reverse-transcription polymerase chain reaction and immunohistochemical analyses to measure the messenger RNA and protein expression level of HGF, MMP-9 and TGF-ß1. RESULTS: Hydrocephalus was induced in all the rats after kaolin injection into the lateral ventricle. After 2 weeks, the expressions of HGF, MMP-9 and TGF-ß1 in the CSF and cerebral tissue were significantly increased in the experimental group compared with the control group. CONCLUSIONS: This results indicated that HGF, MMP-9 and TGF-ß1 may participate in the formation and prognosis of hydrocephalus after kaolin induction.

Comparison of cerebrospinal fluid biomarkers between idiopathic normal pressure hydrocephalus and subarachnoid hemorrhage-induced chronic hydrocephalus: a pilot study.

BACKGROUND: We examined the cerebrospinal fluid (CSF) markers of subarachnoid hemorrhage (SAH)-induced and idiopathic normal pressure hydrocephalus (INPH) to investigate the pathophysiology and mechanism of communicating hydrocephalus compared to obstructive hydrocephalus. MATERIAL/METHODS: We obtained CSF samples from 8 INPH, 10 SAH-induced hydrocephalus, and 6 unmatched patients with non-hemorrhagic obstructive hydrocephalus during their ventriculoperitoneal shunt operations. Transforming growth factor (TGF)-ß1, tumor necrosis factor (TNF)-α, vascular endothelial growth factor (VEGF), and total tau in the CSF were analyzed via enzyme-linked immunosorbent assay. RESULTS: The mean VEGF levels in the CSF of patients with SAH-induced hydrocephalus, INPH, and obstructive hydrocephalus were 239 ± 131, 239 ± 75, and 163 ± 122 pg/mL, respectively. The total tau concentrations in the CSF of the groups were 1139 ± 1900, 325 ± 325, and 1550 ± 2886 pg/mL, respectively. TNF-α values were 114 ± 34, 134 ± 38, and 55 ± 16 pg/mL, respectively. TGF-ß1 values were 953 ± 430, 869 ± 447, and 136 ± 63 pg/mL, respectively. A significant difference in TNF-α and TGF-ß1 levels was observed only between SAH-induced and chronic obstructive hydrocephalus, and between INPH and chronic obstructive hydrocephalus (p<0.01). CONCLUSIONS: No significant differences in the 4 CSF biomarker levels were observed between INPH and SAH-induced hydrocephalus, whereas CSF TNF-α and TGF-ß1 levels were increased compared to those in patients with chronic obstructive hydrocephalus. Post-SAH hydrocephalus and INPH are probably more destructive to neural tissues, and then stimulate the inflammatory reaction and healing process, compared with obstructive hydrocephalus.

Biomarkers in neonatal posthemorrhagic hydrocephalus.

Posthemorrhagic hydrocephalus (PHH) is a rare but serious outcome among premature babies in the NICU, with consequences including mortality and severe neurodevelopmental disabilities. The causes of PHH are still not entirely understood, and its prevention and treatment are controversial. Various cerebrospinal fluid biomarkers have been studied in infants with PHH in order to recognize the causes, diagnose brain injury, and predict neurodevelopmental outcomes. This systematic review summarizes studies on biomarkers of extracellular matrix activity, fibrinolysis/coagulation, hypoxia/cell death, and inflammation in the cerebrospinal fluid of infants with PHH.

Relation between TGF-beta 1 levels in cerebrospinal fluid and ETV outcome in premature newborns with posthemorrhagic hydrocephalus.

OBJECT: Therapy of posthaemorrhagic hydrocephalus (PHH) by using ventriculo-peritoneal drainage bears considerable rate of complications and remains a challenge in premature newborns. The role of endoscopic third ventriculostomy (ETV) in these patients is unclear, through obstruction is proven in some patients with PHH. Transforming growth factor beta 1 (TGF-beta1) release into the cerebrospinal fluid (CSF) in time of primary bleeding is suggested as one of the possible pathophysiologic reasons of PHH formation. Relation between TGF-beta1 levels and ETV success rate has not been reported yet. The aim of our study is to detect group of patients, according to the levels of TGF-beta1, who have magnetic resonance imaging (MRI)-proven obstruction hydrocephalus without participation of hyporesorption-so that we can expect success of ETV. METHODS: We followed 29 premature newborns with PHH during 2005-2007, all of them treated by Ommaya reservoir implantation and repeated taps with TGF-beta1 levels examination. In case of persisting hydrocephalus, MRI was performed. In 16 patients with proven obstruction, ETV was performed. We were successful in six patients (37,5%). We evaluated pathophysiological type of hydrocephalus and ETV succes rate and their relation to TGF-beta1 CSF levels. RESULTS: We have proven statistically relevant probability in diagnosis of hyporesorptive hydrocephalus based on TGF-beta1 level in CSF. Value exceeding 3,296 pg/ml means 81,3% probability of present hyporesorption. Success rate of ETV in patients with MRI-verified obstruction and TGF-beta1 level lower than 3,296 pg/ml was 100% in our series. CONCLUSION: TGF-beta1 level indicates participation of hyporesorption in hydrocephalus development and its level may influence decision making in ETV for premature newborns with PHH.

Cerebrospinal fluid cytokine levels in migraine, tension-type headache and cervicogenic headache.

Cytokines have been measured in cerebrospinal fluid (CSF) from headache patients [infrequent episodic tension-type headache (TTH) and migraine with or without aura, all during attack, and cervicogenic headache] and compared with levels in pain-free individuals. Both proinflammatory [interleukin (IL)-1beta, tumour necrosis factor-alpha and monocyte chemoattractant protein-1 (MCP-1)] and anti-inflammatory cytokines [IL-1 receptor antagonist (IL-1ra), IL-4, IL-10 and transforming growth factor-beta1 (TGF-beta1)] were included. There were significant group differences in IL-1ra, TGF-beta1 and MCP-1 in episodic TTH and migraine compared with controls, and a significant difference in MCP-1 between cervicogenic headache and migraine with aura. Intrathecal MCP-1 correlated with IL-1ra, IL-10 and TGF-beta1 in episodic TTH, and MCP-1 with IL-10 in migraine with aura. Cytokine increases were modest compared with those often accompanying serious neurological conditions, and may represent a mild response to pain. We believe this to be the first comparative study of CSF cytokine levels in connection with headache.

High CSF transforming growth factor beta levels after subarachnoid haemorrhage: association with chronic communicating hydrocephalus.

BACKGROUND: Chronic communicating hydrocephalus is a common sequela of subarachnoid haemorrhage and develops when the flow and drainage of CSF are impaired after fibrosis in the subarachnoid space. Released by platelets into the CSF after subarachnoid haemorrhage, transforming growth factor (TGF)beta1/beta2 are potent fibrogenic agents that may promote post-haemorrhagic fibrosis and chronic communicating hydrocephalus. METHODS: Temporal changes in total (latent plus active) TGFbeta1/beta2 CSF levels of post-haemorrhage patients developing acute hydrocephalus were measured using ELISA to discover if titres were higher in patients that subsequently developed chronic communicating hydrocephalus, compared with those that did not. RESULTS: Mean (SD) CSF levels of total TGFbeta1 were 97 (42) pg/ml and total TGFbeta2 were 395 (39) pg/ml in control patients with (non-haemorrhagic) hydrocephalus. For days 1-5 post-subarachnoid haemorrhage (dph), levels of 1427 (242) pg/ml and 976 (191) pg/ml were seen for total TGFbeta1 and TGFbeta2, respectively. Beyond 5 dph, total TGFbeta1/beta2 levels declined but remained significantly elevated (p<0.01) above control patient values for at least 19 dph. Haemorrhagic patients that went on to develop chronic communicating hydrocephalus had significantly higher levels of total TGFbeta1 (p<0.01) and TGFbeta2 (p<0.05) between 1 and 9 dph, compared with those of haemorrhagic patients that did not. CONCLUSIONS: Acutely measured levels of TGFbeta1/beta2 in the CSF of patients with subarachnoid haemorrhage are thus potential prognostic biomarkers for the subsequent development of chronic communicating hydrocephalus, indicating likely dependency on CSF shunting.

Expression of TGF-betas and TGF-beta type II receptor in cerebrospinal fluid of patients with idiopathic normal pressure hydrocephalus.

We investigated cerebrospinal fluid (CSF) samples from 21 patients with idiopathic normal pressure hydrocephalus (INPH) and 14 controls without neurological disease. The concentrations of leucine-rich alpha-2-glycoprotein (LRG), transforming growth factor (TGF)-beta1, 2, 3 and TGF-beta type II receptor (TbetaR-II) in CSF were measured using ELISA. TGF-beta1, TbetaR-II and LRG CSF levels of patients with INPH were significantly higher than controls, whereas no significant differences in TGF-beta2 levels were found between INPH patients and controls. The present study suggests that TGF-betas expressions may be modulated differently in patients with INPH. These results also indicate that the CSF level assay of TGF-beta1, TbetaR-II and LRG is useful for the diagnosis of patients with INPH, and TGF-beta1, TbetaR-II and LRG may be involved in the pathogenesis of the disease.

Cerebrospinal fluid obstruction and malabsorption in human neonatal hydrocephaly.

INTRODUCTION: The pathophysiology involved in human neonatal high-pressure hydrocephalus (HC) includes both cerebrospinal fluid (CSF) malabsorption and obstruction. OBJECTIVE: The aim was to estimate the relative contribution between CSF malabsorption and obstruction in three different etiological groups of neonatal high-pressure HC by assessment of specific CSF biomarkers indicative of growth factor- and fibrosis-related CSF malabsorption (transforming growth factor beta-1 (TGF beta-1), aminoterminal propeptide of type 1 collagen (PC1NP)]. MATERIALS AND METHODS: Patients were subdivided into three groups. Group A: spina bifida HC (n=12); group B: non-haemorrhagic triventricular HC (n=4); and group C: posthaemorrhagic HC (n=6). To exclude for confounding differences in pro-inflammatory state between the three groups, interleukin-6 (IL-6) CSF concentrations were assessed. Consecutively, the CSF concentrations of TGF beta-1 and PC1NP were compared between the different groups. RESULTS: Median CSF concentrations of IL-6 were low and did not differ between groups. Median CSF concentrations of PC1NP were significantly lower in group A (median: 180 ng/ml, range 90-808) than in group C (median: 1,060, range 396-1194; p=0.002). TGF beta-1 concentrations were significantly higher in group C (median 355 pg/ml, range 129-843) than in groups A (median 103, range 78-675 pg/ml) and B (median 120 pg/ml, range 91-188; p=0.01 and 0.03, respectively). CONCLUSIONS: In neonatal posthaemorrhagic HC, high concentrations of malabsorption-related biomarkers contrast with lower concentrations in SB and non-haemorrhagic triventricular HC. During the early development of high pressure HC in SB neonates, CSF biomarkers strongly indicate that CSF obstruction contributes more to the development of HC than malabsorption.