IL-6, IL-8, IP-10, MCP-1 and G-CSF are significantly increased in cerebrospinal fluid but not in sera of patients with central neuropsychiatric lupus erythematosus.

OBJECTIVE: To determine whether the intrathecal concentrations of cytokines/chemokines are associated with, or influenced by, serum concentrations in patients with central neuropsychiatric systemic lupus erythematosus (NPSLE), and to ascertain whether the increased production of cytokines/chemokines intrathecally relative to serum levels is associated with the presence of central NPSLE. METHODS: 52 SLE patients (30 with central NPSLE and 22 with non-NPSLE), for whom the CSF and serum samples were obtained at the same time, were enrolled. 27 kinds of cytokine/chemokine concentrations other than IFN-α in the cerebrospinal fluid (CSF) and serum samples were measured by Bio-Plex Pro Assays. IFN-α concentration and anti-ribosomal P protein antibody (anti-P) titres in CSF and serum samples were measured by ELISA. RESULTS: The mean concentrations of IL-6, IL-8, IP-10, MCP-1, G-CSF and GM-CSF were higher in the CSF than in the sera, respectively, while the mean concentrations of other 22 cytokines/chemokines, including RANTES and IFN-α, in the CSF were much lower than those in the sera, respectively. Furthermore, the concentrations of IL-6, IL-8, IP-10, MCP-1 and G-CSF in the CSF of the 30 patients with NPSLE were significantly higher than in the 22 patients with non-NPSLE (p = 6.82 × 10(-5), p = 0.00037, p = 0.0028, p = 0.00065, and p = 0.0001, respectively), while the concentration of GM-CSF in the CSF of the 30 patients with NPSLE was not significantly higher than in the 22 patients with non-NPSLE. Most importantly, the largest difference occurred in CSF IL-6 concentrations. A significant positive correlation between CSF anti-P titres and serum anti-P titres in 52 patients with SLE (r = 0.6316, p = 6.44 × 10(-6)) was found, while no significant positive correlation was observed between CSF levels and serum levels of each cytokine/chemokine in the 52 SLE patients. CONCLUSION: In central NPSLE the production of IL-6, IL-8, IP-10, MCP-1 and G-CSF might take place in the central nervous system (CNS). These increased CSF cytokines/chemokines along with anti-P might have a prerequisite role in the pathogenesis of central NPSLE.

Coronavirus Infections in the Central Nervous System and Respiratory Tract Show Distinct Features in Hospitalized Children.

BACKGROUND/AIMS: Coronavirus (CoV) infections induce respiratory tract illnesses and central nervous system (CNS) diseases. We aimed to explore the cytokine expression profiles in hospitalized children with CoV-CNS and CoV-respiratory tract infections. METHODS: A total of 183 and 236 hospitalized children with acute encephalitis-like syndrome and respiratory tract infection, respectively, were screened for anti-CoV IgM antibodies. The expression profiles of multiple cytokines were determined in CoV-positive patients. RESULTS: Anti-CoV IgM antibodies were detected in 22/183 (12.02%) and 26/236 (11.02%) patients with acute encephalitis-like syndrome and respiratory tract infection, respectively. Cytokine analysis revealed that the level of serum granulocyte colony-stimulating factor (G-CSF) was significantly higher in both CoV-CNS and CoV-respiratory tract infection compared with healthy controls. Additionally, the serum level of granulocyte macrophage colony-stimulating factor (GM-CSF) was significantly higher in CoV-CNS infection than in CoV-respiratory tract infection. In patients with CoV-CNS infection, the levels of IL-6, IL-8, MCP-1, and GM-CSF were significantly higher in their cerebrospinal fluid samples than in matched serum samples. CONCLUSION: To the best of our knowledge, this is the first report showing a high incidence of CoV infection in hospitalized children, especially with CNS illness. The characteristic cytokine expression profiles in CoV infection indicate the importance of host immune response in disease progression.

Intranasal Delivery of Granulocyte Colony-Stimulating Factor Enhances Its Neuroprotective Effects Against Ischemic Brain Injury in Rats.

Granulocyte colony-stimulating factor (G-CSF) is a hematopoietic growth factor with strong neuroprotective properties. However, it has limited capacity to cross the blood-brain barrier and thus potentially limiting its protective capacity. Recent studies demonstrated that intranasal drug administration is a promising way in delivering neuroprotective agents to the central nervous system. The current study therefore aimed at determining whether intranasal administration of G-CSF increases its delivery to the brain and its neuroprotective effect against ischemic brain injury. Transient focal cerebral ischemia in rat was induced with middle cerebral artery occlusion. Our resulted showed that intranasal administration is 8-12 times more effective than subcutaneous injection in delivering G-CSF to cerebrospinal fluid and brain parenchyma. Intranasal delivery enhanced the protective effects of G-CSF against ischemic injury in rats, indicated by decreased infarct volume and increased recovery of neurological function. The neuroprotective mechanisms of G-CSF involved enhanced upregulation of HO-1 and reduced calcium overload following ischemia. Intranasal G-CSF application also promoted angiogenesis and neurogenesis following brain ischemia. Taken together, G-CSF is a legitimate neuroprotective agent and intranasal administration of G-CSF is more effective in delivery and neuroprotection and could be a practical approach in clinic.

The antidepressant fluoxetine protects the hippocampus from brain damage in experimental pneumococcal meningitis.

BACKGROUND: High mortality and morbidity rates are observed in patients with bacterial meningitis (BM) and urge for new adjuvant treatments in addition to standard antibiotic therapies. In BM the hippocampal dentate gyrus is injured by apoptosis while in cortical areas ischemic necrosis occurs. Experimental therapies aimed at reducing the inflammatory response and brain damage have successfully been evaluated in animal models of BM. Fluoxetine (FLX) is an anti-depressant of the selective serotonin reuptake inhibitors (SSRI) and was previously shown to be neuroprotective in vitro and in vivo. We therefore assessed the neuroprotective effect of FLX in experimental pneumococcal meningitis. METHODS: Infant rats were infected intracisternally with live Streptococcus pneumoniae. Intraperitoneal treatment with FLX (10mgkg(-1)d(-1)) or an equal volume of NaCl was initiated 15min later. 18, 27, and 42h after infection, the animals were clinically (weight, clinical score, mortality) evaluated and subject to a cisternal puncture and inflammatory parameters (i.e., cyto-/chemokines, myeloperoxidase activity, matrix metalloproteinase concentrations) were measured in cerebrospinal fluid (CSF) samples. At 42h after infection, animals were sacrificed and the brains collected for histomorphometrical analysis of brain damage. RESULTS: A significant lower number of animals treated with FLX showed relevant hippocampal apoptosis when compared to littermates (9/19 animals vs 18/23, P=0.038). A trend for less damage in cortical areas was observed in FLX-treated animals compared to controls (13/19 vs 13/23, P=ns). Clinical and inflammatory parameters were not affected by FLX treatment. CONCLUSION: A significant neuroprotective effect of FLX on the hippocampus was observed in acute pneumococcal meningitis in infant rats.

Growth factors and synaptic plasticity in relapsing-remitting multiple sclerosis.

During multiple sclerosis (MS) inflammatory attacks, and in subsequent clinical recovery phases, immune cells contribute to neuronal and oligodendroglial cell survival and tissue repair by secreting growth factors. Animal studies showed that growth factors also play a substantial role in regulating synaptic plasticity, and namely in long-term potentiation (LTP). LTP could drive clinical recovery in relapsing patients by restoring the excitability of denervated neurons. We recently reported that maintenance of synaptic plasticity reserve is crucial to contrast clinical deterioration in MS and that the platelet-derived growth factor (PDGF) may play a key role in its regulation. We also reported that a Hebbian form of LTP-like cortical plasticity, explored by paired associative stimulation (PAS), correlates with clinical recovery from a relapse in MS. Here, we explored the role of PDGF in clinical recovery and in adaptive neuroplasticity in relapsing-remitting MS (RR-MS) patients. We found a correlation between the cerebrospinal fluid (CSF) PDGF concentrations and the extent of clinical recovery after a relapse, as full recovery was more likely observed in patients with high PDGF concentrations and poor recovery in subjects with low PDGF levels. Consistently with the idea that PDGF-driven synaptic plasticity contributes to attenuate the clinical consequences of tissue damage in RR-MS, we also found a striking correlation between CSF levels of PDGF and the amplitude of LTP-like cortical plasticity explored by PAS. CSF levels of fibroblast growth factor, granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor did not correlate with clinical recovery nor with measures of synaptic transmission and plasticity.

Cytokines in CSF correlate with HIV-associated neurocognitive disorders in the post-HAART era in China.

In the current era of highly active antiretroviral therapy (HAART), the incidence of HIV dementia has declined, but the prevalence of HIV-associated neurocognitive disorder (HAND) remains high. HIV-induced systemic and localized inflammation is considered to be one of the mechanisms of HAND. Changes in cytokine levels in the cerebrospinal fluid (CSF) during HIV infection might help to identify HAND. To investigate whether the cytokine profile of the CSF during HIV infection could be used as a biomarker of HAND, we compared cytokine levels in the CSF of HIV-infected cases with and without neurocognitive impairment. Cytokine concentrations in the CSF were measured by quantification bioassays (Luminex xMAP). HIV-infected cases with neurocognitive impairment demonstrated higher levels of interleukin (IL)-8, monocyte chemotactic protein (MCP)-1, induced protein (IP)-10, and granulocyte colony-stimulating factor (G-CSF) in the CSF than those without neurocognitive impairment (G-CSF (p = 0.0003), IL-8 (p = 0.0046), IP-10 (p < 0.0001), and MCP-1 (p < 0.0001)). There was no significant impact of HAART on cytokine levels in the CSF, except for IP-10, which was higher in HAART-treated patients with impaired cognition (p = 0.0182). Findings from this preliminary study suggest that elevated levels of the cytokines IL-8, MCP-1, G-CSF, and IP-10 in the CSF are associated with neurocognitive impairment in HIV infection, and these cytokines likely represent a biomarker profile for HAND.

Protein changes in CSF of HIV-infected patients: evidence for loss of neuroprotection.

To begin to unravel the complexity of HIV-associated changes in the brain, broader, multifaceted analyses of cerebrospinal fluid (CSF) are needed that examine a wide range of proteins reflecting different functions. To provide the first broad profiles of protein changes in the CSF of HIV-infected patients, we used antibody arrays to measure 120 cytokines, chemokines, growth factors, and other proteins. CSF from HIV-infected patients with a range of cognitive deficits was compared to CSF from uninfected, cognitively normal patients to begin to identify protein changes associated with HIV infection and neurological disease progression. Uninfected patients showed relatively consistent patterns of protein expression. Highly expressed proteins in CSF included monocyte chemotactic protein-1, tissue inhibitors of metalloproteases, granulocyte colony-stimulating factor, adiponectin, soluble tumor necrosis factor receptor-1, urokinase-type plasminogen activator receptor, and insulin-like growth factor binding protein-2. Inflammatory and anti-inflammatory cytokines were expressed at low levels. HIV-infected patients showed increases in inflammatory proteins (interferon-gamma, tumor necrosis factor-alpha), anti-inflammatory proteins (IL-13), and chemokines but these correlated poorly with neurological status. The strongest correlation with increasing severity of neurological disease was a decline in growth factors, particularly, brain-derived neurotrophic factor and NT-3. These studies illustrate that HIV infection is associated with parallel changes in both inflammatory and neuroprotective proteins in the CSF. The inverse relationship between growth factors and neurological disease severity suggests that a loss of growth factor neuroprotection may contribute to the development of neural damage and may provide useful markers of disease progression.

Repeated courses of granulocyte colony-stimulating factor in amyotrophic lateral sclerosis: clinical and biological results from a prospective multicenter study.

Granulocyte colony-stimulating factor (G-CSF) induces a transient mobilization of hematopoietic progenitor cells from bone marrow to peripheral blood. Our aim was to evaluate safety of repeated courses of G-CSF in patients with amyotrophic lateral sclerosis (ALS), assessing disease progression and changes in chemokine and cytokine levels in serum and cerebrospinal fluid (CSF). Twenty-four ALS patients entered an open-label, multicenter trial in which four courses of G-CSF and mannitol were administered at 3-month intervals. Levels of G-CSF were increased after treatment in the serum and CSF. Few and transitory adverse events were observed. No significant reduction of the mean monthly decrease in ALSFRS-R score and forced vital capacity was observed. A significant reduction in CSF levels of monocyte chemoattractant protein-1 (MCP-1) and interleukin-17 (IL-17) was observed. G-CSF treatment was safe and feasible in a multicenter series of ALS patients. A decrease in the CSF levels of proinflammatory cytokines MCP-1 and IL-17 was found, indicating a G-CSF-induced central anti-inflammatory response.

Caspase-1 modulates incisional sensitization and inflammation.

BACKGROUND: Surgical injury induces production and release of inflammatory mediators in the vicinity of the wound. They in turn trigger nociceptive signaling to produce hyperalgesia and pain. Interleukin-1ß plays a crucial role in this process. The mechanism regulating production of this cytokine after incision is, however, unknown. Caspase-1 is a key enzyme that cleaves prointerleukin-1ß to its active form. We hypothesized that caspase-1 is a crucial regulator of incisional interleukin-1ß levels, nociceptive sensitization, and inflammation. METHODS: These studies employed a mouse hind paw incisional model. Caspase-1 was blocked using the selective inhibitors Ac-YVAD-CMK and VRTXSD727. Nociceptive sensitization, edema, and hind paw warmth were followed in intact animals whereas caspase-1 activity, cytokine, and prostaglandin E2 levels were assessed in homogenized skin. Confocal microscopy was used to detect the expression of caspase-1 near the wounds. RESULTS: Analysis of enzyme activity demonstrated that caspase-1 activity was significantly increased in periincisional skin. Pretreatment with Ac-YVAD-CMK significantly reduced mechanical allodynia and thermal hyperalgesia. Repeated administration of this inhibitor produced robust analgesia, especially to mechanical stimulation. Administration of VRTXSD727 provided qualitatively similar results. Caspase-1 inhibition also reduced edema and the normally observed increase in paw warmth around the wound site. Correspondingly, caspase-1 inhibition significantly reduced interleukin-1ß as well as macrophage-inflammatory protein 1α, granulocyte colony-stimulating factor, and prostaglandin E2 levels near the wound. The expression of caspase-1 was primarily observed in keratinocytes in the epidermal layer and in neutrophils deeper in the wounds. CONCLUSIONS: The current study demonstrates that the inhibition of caspase-1 reduces postsurgical sensitization and inflammation, likely through a caspase-1/interleukin-1ß-dependent mechanism.

IL-8 in cerebrospinal fluid from children with acute encephalopathy is higher than in that from children with febrile seizure.

We identify possible differences in the cytokine/chemokine profiles in cerebrospinal fluid (CSF) from children with encephalopathy and febrile seizure. Interleukin (IL)-1beta, 2, 4, 5, 6, 7, 8, 10, 12, 13, 17, interferon-gamma, tumour necrosis factor-alpha, granulocyte colony-stimulating factor, granulocyte monocyte colony-stimulating factor, monocyte chemoattractant protein-1 and macrophage inflammatory protein-1beta were measured simultaneously in CSF supernatants from children with encephalopathy (n = 8), febrile seizure (n = 16) and fever without neurological complications (n = 8). IL-8 in CSF from children with encephalopathy was significantly elevated compared to that in CSF from children with febrile seizure and fever without neurological complications. IL-8 in CSF was also higher than serum IL-8, suggesting that increased IL-8 was generated from glia cells or astrocytes, not by leakage from serum. Increased IL-8 in CSF in encephalopathy may protect against severe brain damage.

IFN-gamma at the site of infection determines rate of clearance of infection in cryptococcal meningitis.

In animal models, immunity to cryptococcal infection, as in many chronic fungal and bacterial infections, is associated with a granulomatous inflammatory response, intact cell-mediated immunity, and a Th1 pattern of cytokine release. To examine the correlates of human immunity to cryptococcal infection in vivo, we analyzed immune parameters at the site of infection over time and assessed the rate of clearance of infection by serial quantitative cerebrospinal fluid (CSF) fungal cultures in 62 patients in a trial of antifungal therapy for HIV-associated cryptococcal meningitis. CSF IL-6, IFN-gamma, TNF-alpha, and IL-8 were significantly higher in survivors compared with nonsurvivors. There were negative correlations between log TNF-alpha, IFN-gamma, and IL-6 levels and baseline cryptococcal CFU. Log IFN-gamma, G-CSF, TNF-alpha, and IL-6 were correlated positively with the rate of fall in log CFU/ml CSF/day. In a linear regression model including antifungal treatment group, baseline CFU, and these cytokines, only treatment group and log IFN-gamma remained independently associated with rate of clearance of infection. The results provide direct in vivo evidence for the importance of quantitative differences in IFN-gamma secretion in human immune control of granulomatous infections, and increase the rationale for adjunctive IFN-gamma in the treatment of refractory HIV-associated cryptococcosis.

Transient elevation of interleukin-16 levels at the initial stage of meningitis in children.

IL-16 is an immunomodulatory cytokine that is characterized by chemotactic activity and stimulation of proinflammatory cytokine expression in monocytic cells. We studied IL-16 using ELISA in children with meningitis. When meningeal symptoms existed, IL-16 levels were high in the cerebrospinal fluid (CSF) of both bacterial (939 +/- 877 ng/l, n = 20) and aseptic (341 +/- 371 ng/l, n = 23) meningitis. The values in the CSF were significantly higher than those in non-meningitis controls (29 +/- 8 ng/l, n = 22, P < 0.0001). After meningeal symptoms disappeared, IL-16 levels in bacterial (191 +/- 149 ng/l, n = 10, P = 0.0042) and aseptic (159 +/- 188 ng/l, n = 13, P = 0.0118) meningitis were lower than those during the symptomatic stage. IL-16 levels were the highest before day 5 of the illness and then gradually fell. Significant correlations were found between IL-16 levels and both G-CSF levels (r = 0.783, n = 11, p = 0.0029) and IL-6 levels (r = 0.818, n = 12, P = 0.0005) in the CSF of bacterial and aseptic meningitis. IL-16 levels in all CSF samples from non-meningitis controls were lower than those in serum. In contrast, IL-16 levels in the CSF in six of 16 samples from bacterial meningitis and two of 18 samples from aseptic meningitis were higher than those in serum. Serum levels of IL-16 did not fluctuate throughout the course of meningitis. These data indicate that IL-16 levels rise transiently in CSF at the initial stage of meningitis. We speculate that IL-16 may promote inflammatory responses during meningitis in concert with other proinflammatory cytokines.

Resistance to recombinant human granulocyte colony-stimulating factor in neonatal alloimmune neutropenia associated with anti-human neutrophil antigen-2a (NB1) antibodies.

Neonatal alloimmune neutropenia is the neutrophil counterpart of the erythrocyte disorder of hemolytic disease of the newborn. Fetal neutrophil antigens, which are inherited from the father but foreign to the pregnant mother, provoke the formation of maternal antibodies, which, on transplacental passage, cause fetal/neonatal neutropenia. Because infants with this disorder are at a higher risk of infection, recombinant hematopoietic growth factors, such as recombinant human granulocyte colony-stimulating factor, have been tried, with generally good results, to treat those with severe and prolonged neutropenia. We report a neonate who had neonatal alloimmune neutropenia associated with antibodies directed against human neutrophil antigen-2a (NB1) and initially failed to respond to even very high doses of recombinant human granulocyte colony-stimulating factor but eventually had a therapeutic response.

Interleukin-1 beta and interleukin-1 receptor antagonist levels in cerebrospinal fluid of aseptic meningitis patients.

The inflammatory process in aseptic meningitis is generally mild and self-limited. To evaluate control mechanisms underlying this process, we determined interleukin (IL)-1 beta and IL-1 receptor antagonist (IL-1ra) concentrations, using enzyme linked immunosorbent assay, in cerebrospinal fluid from patients with aseptic meningitis (n = 55, median age [range]; 5.0 [1-15] years). We cross-sectionally analyzed the relationship of IL-1 beta and IL-1ra levels to leucocyte count in terms of interval between clinical onset and lumbar puncture. IL-1 beta levels were highest in the cerebrospinal fluid obtained between 12 and 24 hours after onset (n = 23, median: 2.30 pg/ml). The IL-1 beta level was significantly correlated with leucocyte count. On the other hand, IL-1ra level tended to increase over a longer interval, reaching a plateau between 24 and 36 hours after onset (n = 13, median: 5190 pg/ml). The molar ratio of IL-1ra to IL-1 beta was thus lowest between 12 and 24 hours after onset (median: 2341), which coincided with the peak increase in leucocyte count. The results are compatible with the idea that IL-1ra should be important for the regulation of IL-1 beta activity associated with leucocyte migration in aseptic meningitis.

Production of interleukin-10 in the cerebrospinal fluid in aseptic meningitis of children.

IL-10 is a cytokine that has antiinflammatory properties. We investigated IL-10 using ELISA and a reverse-transcribed polymerase chain reaction in the cerebrospinal fluid (CSF) of children with or without aseptic meningitis. When the patients with aseptic meningitis had meningeal symptoms, IL-10 in the CSF was detectable in 14 of 22 patients (88 +/- 146 ng/L, n = 31). The IL-10 levels decreased as meningeal symptoms disappeared. In 20 of 21 control children without meningitis, CSF samples had no detectable levels of IL-10 (< 10 ng/L). Serum IL-10 levels were lower than the corresponding levels in the CSF from the same individuals with aseptic meningitis. Significant correlations were found between IL-10 levels and mononuclear cell counts in the CSF of the affected patients (r = 0.644, p < 0.001). The IL-10 mRNA was detected by reverse-transcribed polymerase chain reaction-assisted amplification in the CSF cells in four of seven patients with the disease. The culture of CSF mononuclear cells produced high levels of IL-10 (152-485 ng/L) in all of five patients. Cytokine kinetics in the CSF showed that mean IL-10 levels reached the peak on the 2nd to 3rd d of the illness, although all mean levels of IL-6, IL-8, and granulocyte colony-stimulating factor were the highest on the 1st d of the illness. In summary, IL-10 is produced in the CSF in aseptic meningitis, and may increase relatively late compared with the proinflammatory cytokines. IL-10 may play an immunoregulatory role in the meningeal inflammatory network.

Relationship of interleukin-8 and colony-stimulating factors to neutrophil migration in aseptic meningitis.

Polymorphonuclear neutrophilic leucocyte (PMNL) migration into the subarachnoid space in aseptic meningitis of probable enteroviral aetiology was evaluated in relation to cerebrospinal fluid and serum levels of interleukin-8 (IL-8), macrophage colony-stimulating factor (M-CSF) and granulocyte colony-stimulating factor (G-CSF). IL-8 levels reached a plateau within 12h of onset, while M-CSF and G-CSF levels reached a peak between 12 and 24 h after onset, corresponding to the peak increase in PMNL count. G-CSF levels had the closest correlation with PMNL count. M-CSF levels were weakly correlated with PMNL count. IL-8 levels were not correlated with PMNL count except within 12 h of onset. IL-8 and G-CSF were detected predominantly in cerebrospinal fluid, while the M-CSF levels in the two compartments were not different except between 12 and 24 h after onset. It is considered that IL-8 triggers rapid and transient migration of PMNL, and that G-CSF then promotes gradual and consistent infiltration of PMNL.

Transient elevation of granulocyte colony-stimulating factor levels in cerebrospinal fluid at the initial stage of aseptic meningitis in children.

At the early stage of aseptic meningitis, there is a transient increase in neutrophil counts in the cerebrospinal fluid. Some factors in the cerebrospinal fluid might induce migration of neutrophils into the cerebrospinal fluid. Granulocyte colony-stimulating factor (G-CSF) plays an important role, not only as a hemopoietic factor but also as a regulating factor for a biologic defense system by neutrophils in the foci of infection. To analyze the role of G-CSF on accumulating neutrophils in the cerebrospinal fluid, we have measured G-CSF levels in the cerebrospinal fluid of children with aseptic meningitis, paying particular attention to the phasal transition. Within the first 2 d from the onset, G-CSF levels in the cerebrospinal fluid were 223 +/- 97 ng/L, significantly higher than those of the patients without meningitis (p < 0.01). Beyond the second day after the onset, the G-CSF levels rapidly decreased to below the detectable level, even though the patients manifested meningeal signs and symptoms. There was a direct relationship between G-CSF levels and neutrophil counts in the cerebrospinal fluid (r = 0.763, p < 0.01). During the first 2 d after the onset, the G-CSF level in the cerebrospinal fluid in each case was remarkably higher than that in the serum. This finding suggests that the G-CSF in the cerebrospinal fluid was produced in the spinal cavity. From our results, the transient elevation of G-CSF levels might lead to the transient increase in neutrophil counts in the cerebrospinal fluid by recruiting them from the peripheral blood at the initial stage of aseptic meningitis.

Absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) from rat nasal mucosa.

Nasal absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) was examined in the rat. The relative bioavailability of rhG-CSF for subcutaneous administration was approximately 2%, as evaluated from the immunologically active rhG-CSF concentration in rat plasma and the area under the curve (AUC) of the plasma rhG-CSF concentration versus time for 8 hr. Pharmacological availability relative to subcutaneous administration was determined from the increase in total blood leukocyte numbers. The pharmacological availability was 5-10%, determined from the AUC for the increased ratio of total leukocyte numbers versus time for 48 hr; it was slightly dependent on the pH and the osmotic pressure of the dosing solution. Accordingly, the plasma concentration of rhG-CSF did not always reflect its pharmacological effects. Relative bioavailability and pharmacological availability were increased about 23 times and 3 times, respectively, by polyoxyethylene 9-lauryl ether (Laureth-9), but no increase in availability occurred with sodium glycocholate. The increase in total leukocyte numbers was maintained during multiple rhG-CSF dosing, and the addition of Laureth-9 further increased the pharmacological effects of this agent. This study indicates that nasal administration of rhG-CSF is an effective parenteral administration route.

Human macrophage colony-stimulating factor levels in cerebrospinal fluid.

Macrophage colony-stimulating factor (M-CSF) levels in the cerebrospinal fluid of 14 patients with meningitis and of 14 patients suffering from a disease other than meningitis were measured using an enzyme-linked immunosorbent assay. All four bacterial meningitis patients had M-CSF levels in the cerebrospinal fluid which exceeded 1540 U/ml, and the mean value was 3333 +/- 1481 U/ml. The mean M-CSF level in the cerebrospinal fluid of the ten aseptic meningitis patients was 393 +/- 175 U/ml, which was higher than that of patients who suffered from a disease other than meningitis (179 +/- 90 U/ml) (P < 0.01). There was no clear correlation between the M-CSF levels and the numbers of white blood cells, granulocytes, or monocytes in the cerebrospinal fluid. These elevated M-CSF levels were thought to be of a local origin, since most patients with high M-CSF levels in the cerebrospinal fluid had relatively low M-CSF levels in the serum.

Interferon-alpha in lupus psychosis.

OBJECTIVE: Since the level of interferon-alpha (IFN alpha) is increased in the sera of patients with active systemic lupus erythematosus (SLE) and is detectable in the cerebrospinal fluid (CSF) of some SLE patients with neuropsychiatric manifestations, we investigated the contribution of IFN alpha to the pathogenesis of the neuropsychiatric manifestations of SLE. METHODS: IFN alpha levels were quantitated by radio-immunoassay in CSF and serum samples from 17 SLE patients with neuropsychiatric manifestations and 28 patients with SLE alone or SLE and other neurologic disorders. RESULTS: Levels of IFN alpha were increased in the CSF of 5 of 6 patients with lupus psychosis, and in 4 of these 5 patients, the levels in CSF were higher than those in serum. IFN alpha levels decreased when the manifestation of lupus psychosis subsided. In contrast, IFN alpha levels in CSF samples from patients with seizures alone were not increased. One patient with lupus psychosis died of complications of generalized seizures resulting from the SLE. At autopsy, we investigated whether IFN alpha protein or messenger RNA was detectable in the subject's brain. IFN alpha protein was immunohistochemically demonstrated in the neurons and in the microglia (focal accumulation), features not present in the brain tissues of subjects who died of other diseases. CONCLUSION: These findings support the hypothesis that IFN alpha, possibly synthesized in the brain, is the cause of the manifestation of psychosis in patients with SLE.