A correlation of 5-hydroxytriptamine and cerebral vasoreactivity in patients with migraine

Cerebral haemodynamics and the level of serum 5-hydroxytriptamine (5-HT) were analysed in 21 migraine patients (8 with and 13 without aura) during the headache-free period as well as the attack. Cerebral vasoreactivity was evaluated by acetazolamide test and Transcranial Doppler ultrasonography (TCD). TCD findings were within normal ranges in the majority of migraine patients. Patients with migraine without aura had higher blood flow velocities (BFV) than patients with aura. Comparison of BVF and pulsatility index (PI) data patterns in migraine with and in migraine without aura during the attack revealed differences indicating cerebral hypoperfusion. It was noticed that systolic BFV decreased in migraine with aura on the headache side while PI increased. In migraine without aura, both systolic BFV and PI increased. 5-HT findings were heterogeneous. Reduction of cerebral vasoreactivity was observed especially in migraine with aura. Our results suggest different pathogenic mechanisms between migraine with and without aura, supporting the neurogenic inflammation theory.     

An experimental study of pathomorphology in the iris and ciliary body after intraocular lens implantation]

Recent studies have suggested that cytokines play a critical role in the pathophysiology of alopecia areata; however, no information is available regarding the difference in cytokine profiles in these patients. Serum levels of cytokines, including interferon gamma (IFN-gamma), tumor necrosis factor alpha, interleukin 1 alpha (IL-1 alpha), IL-2, IL-4, and IL-6, were measured using radioimmunoassay or enzyme-linked immunosorbent assay techniques in patients with the localized form and the extensive form (alopecia universalis). The serum levels of IL-1 alpha and IL-4 were significantly elevated in patients with the localized form. In contrast, the serum levels of IFN-gamma and IL-2 were significantly elevated in patients with the extensive form. These results indicate that immune responses in the localized form and the extensive form of alopecia areata are regulated by Th2 cytokines and Th1 cytokines, respectively.     

Metal contamination in illicit samples of heroin

During TB cytokines play a role in host defence. To determine the cytokine pattern during various disease stages of TB, serum levels of IL-12, interferon-gamma (IFN-gamma), IL-4, IL-6 and IL-10 were measured in 81 patients with active TB, 15 patients during therapy and 26 patients after anti-tuberculous therapy as well as in 16 persons who had been in close contact with smear-positive TB and in 17 healthy controls. IFN-gamma was elevated during active TB when compared with healthy controls, declining during and after treatment. IL-12 (p40 and p70) serum levels were not significantly higher in patients with active TB compared with any of the other groups. IL-4 levels were low in all groups. IL-6 and IL-10 serum levels were elevated in patients with active TB and during treatment. In patients with active TB serum levels of IFN-gamma and IL-6 were higher in patients with fever, anorexia and malaise. IL-12 levels were higher in patients with a positive smear. Cytokine levels did not correlate with localization of TB (pulmonary versus extrapulmonary), or skin test positivity. Cytokines directing a Th1 response (IL-12) or a Th2 response (IL-4) were not elevated in sera of this large group of patients with pulmonary and extrapulmonary TB. In patients with active TB, cytokines that were elevated in serum were IFN-gamma, IL-6 and IL-10.     

Cytokine production regulating Th1 and Th2 cytokines in hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is caused by the hyperactivation of T cells and macrophages. The clinical characteristics associated with this disease result from overproduction of Th1 cytokines including interferon-gamma (IFN-gamma), interleukin-2 (IL-2), and tumor necrosis factor-alpha (TNF-alpha). In this study, we analyzed the production of IL-12 and IL-4, which determine Th1 and Th2 response, respectively, and IL-10, which antagonizes Th1 cytokines, in 11 patients with HLH. IL-12 was detected in plasma in all patients (mean peak value, 30.0 +/- 5.0 pg/mL), while IFN-gamma was massively produced in nine patients (mean peak value, 79.2 +/- 112.0 U/mL). IL-4 was not detected in any of the patients. Plasma IL-10 levels were elevated in all patients (mean peak value, 2,698.0 +/- 3,535.0 pg/mL). There was a positive correlation between the levels of IFN-gamma and IL-10 (P < .01). The plasma concentrations of these cytokines were initially high, before decreasing after the acute phase. However, the decrease in IL-10 levels was slower than that of IFN-gamma. Although the concentration of IL-12 was high at the acute phase, in some patients, a peak in the level was delayed until the chronic phase. Thus, in HLH, production of cytokines that promote development of Th1 cells appears to be predominant over that for Th2 cell development. Overproduction of IL-10 was also observed indicating that a mechanism suppressing hyperactivation of Th1 cells and monocytes/macrophages functions in patients with this disease.     

Blood eosinophils and serum IgE as predictors for prognosis of interferon-gamma therapy in atopic dermatitis

BACKGROUND: Interferon-gamma (IFN-gamma) therapy has been reported to be effective in atopic dermatitis. However, IFN-gamma therapy in atopic dermatitis has not yet been well established. In this study, immunologic variables were evaluated as predictors for the prognosis of IFN-gamma therapy in atopic dermatitis. METHODS: Sixty-eight atopic dermatitis patients were each treated 18 times with 2 x 10(6) units/m2 IFN-gamma. Blood IgE level, eosinophil percentage, eosinophil count, and levels of IFN-gamma, interleukin-4 (IL-4), IL-5, and IL-10 were investigated. According to clinical responses, patients were classified into three groups: patients with improved clinical severity scores of over 20% were included in group A; those with improved scores of 20% or less in group B; and those with no improvement in group C. RESULTS: Serum IgE levels and blood eosinophil percentages were the lowest in group A. Most atopic dermatitis patients with an eosinophil percentage over 9% and IgE level over 1500 IU/ml did not respond to IFN-gamma therapy. Initial IL-10 levels were the highest in group A. IL-4 levels in group A, and IL-5 and IL-10 levels in all groups were significantly decreased by IFN-gamma therapy. CONCLUSIONS: IFN-gamma therapy may be recommended for atopic dermatitis patients with blood eosinophil percentages less than 9% and serum IgE levels less than 1500 IU/ml.     

Sumatriptan in the acute treatment of migraine without aura: efficacy of 50-mg dose

We conducted an open study on the efficacy of 50 mg of sumatriptan as an acute treatment for migraine without aura. We recruited 200 consecutive patients, with an established history of migraine without aura, presenting at a headache center. The patients were instructed to take half a 100-mg sumatriptan tablet for their next migraine attack, and to record details of their headache in a diary. The primary outcome of the study was headache relief from one migraine attack. Attacks were moderately intense (46%), moderate to severe (7%), or severe (47%). Total or partial benefit at 2 hours from the 50-mg dose was reported by 140 of 200 patients (70%). Thirty-six patients received no benefit from half a tablet, and 24 did not take sumatriptan, preferring their habitual medication. Side effects were few, mild, and short lasting. We conclude that the 50-mg oral dose is generally effective for migraine without aura attacks of both moderate and severe intensity and recommend this dose for all such patients. If, however, sumatriptan is ineffective at that dose it can be increased to a maximum of 100 mg.     

Migrainous disorder and its relation to migraine without aura and migraine with aura. A genetic epidemiological study

Migrainous disorder was analysed in a large population-based study of 4000 forty-year-old males and females. All interviews were conducted by one physician and the diagnostic criteria of the International Headache Society were used. Of the 48 people with migrainous disorder, 40 had migrainous disorder without aura and 9 had migrainous disorder with aura. One person had co-occurrence of migrainous disorder with and without aura. The lifetime prevalence of migrainous disorder was 2.5% with a male:female ratio of 1:1.2. The first-degree relatives of probands with migrainous disorder were blindly interviewed. Compared with the general population, first-degree relatives of probands with migrainous disorder without aura had a slightly but less increased risk of migraine without aura than first-degree relatives of probands with migraine without aura. First-degree relatives of probands with migrainous disorder with aura had no increased risk of migraine with aura. We conclude that migrainous disorder without aura in some people is a type of migraine without aura and in other people not. Migrainous disorder with aura may be unrelated to migraine with aura.     

Onchocerca volvulus-mediated keratitis: cytokine production by IL-4-deficient mice

Corneal inflammation similar to human onchocercal keratitis can be induced in mice by subcutaneous immunization of a soluble extract of Onchocerca volvulus (OvAg) followed by direct injection of OvAg into the corneal stroma. Previous studies have shown that corneal pathology is associated with increased systemic and corneal Th2 cytokine expression and that IL-4 gene knockout (IL-4-/-) mice develop less severe or no O. volvulus-mediated keratitis. The current study examined the contribution of Th2 cytokines to the diminished OvAg-induced corneal immunopathology observed in IL-4-/- mice. IL-4-/- mice (129Sv x C57B1/6), wild-type F2 littermates (IL-4+/+), and C57B1/6 mice were sensitized by repeated subcutaneous immunization with OvAg. Ten days after the final immunization, mice were sacrificed, spleens were removed, and cells were incubated with OvAg. Cells from immunocompetent C57B1/6 and IL-4+/+ mice produced IL-4 and IL-5, but no IFN-gamma, whereas cells from IL-4-/- mice had elevated IFN-gamma and no IL-4. Interestingly, cells from these animals produced levels of IL-5 protein equivalent to those of C57B1/6 and IL-4+/+ mice. To determine cytokine production in corneas during the onset of onchocercal keratitis, OvAg-immunized mice were injected intracorneally with OvAg, and cytokine gene expression in the cornea was determined by RT-PCR. Temporal analysis of cytokine gene expression in corneas of immunocompetent mice showed that the Th2-associated cytokines IL-4, IL-5, IL-10, and IL-13 were produced within 1 day of intrastromal injection, with sustained elevations for 10 days. Maximal IFN-gamma mRNA levels were not detected until Day 10. This was in contrast to IL-4-/- mice in which IFN-gamma appeared at Day 1 and remained elevated for at least 10 days. Moreover, in corneas from IL-4-/- mice, all Th2 cytokines with the exception of IL-4 were up-regulated and expressed with kinetics similar to that of IL-4+/+ littermates. Histologically, corneas from IL-4-/- mice were less edematous and contained fewer eosinophils and other inflammatory cells than those from immunocompetent controls. As there was no difference in peripheral eosinophil levels, these data indicate that the diminished severity of onchocercal keratitis in IL-4-/- mice is not due to failure to develop systemic or local Th2 cytokine responses or to produce eosinophils, but that IL-4 may be involved in recruitment of eosinophils and other inflammatory cells into the corneal stroma.     

Phospholipid vesicle binding and aggregation by four novel fish annexins are differently regulated by Ca2+

The aim of this study was to further assess the role of pooled human immunoglobulin (PHIG) on cytokine production from PBMC stimulated with a bacterial superantigen. Human PBMC were cultured with Streptococcus pyrogenic exotoxin A (SPE-A) with or without PHIG and several proinflammatory cytokine levels of culture supernatants were measured. Serum cytokine levels of KD patients before and after PHIG therapy were also examined. PHIG greatly reduced the production of IL-12, interferon-gamma (IFN-gamma) and other cytokines from SPE-A-stimulated PBMC, while exogenous IL-12, but neither IL-1 nor tumour necrosis factor-alpha (TNF-alpha), restored IFN-gamma production inhibited by PHIG. Although PHIG partially adsorbed SPE-A, its inhibitory effect on cytokine production was not played by anti-SPE-A antibody. Although purified CD4+ T cells cultured with human HLA-DR-transfected mouse L cells and SPE-A could not effectively produce IFN-gamma, they produced large amounts of IFN-gamma if exogenous IL-12 was introduced. KD patients in the acute phase had higher levels of serum IFN-gamma than did controls and patients with bacterial infection. Although IL-12 levels of children with or without KD were not significantly different, IL-12 levels of children were much higher than those of adults. However, serum levels of IL-12 of KD patients were transiently but significantly decreased by PHIG therapy and IFN-gamma amounts subsequently reverted to basal levels thereafter. These findings indicate that PHIG inhibits IL-12 production of SPE-A-activated monocytes and thereby decreases IFN-gamma synthesis by T cells and suggest that inhibition of IL-12 and IFN-gamma production is an important part of the mechanisms underlying PHIG therapy on KD.     

"Normal'' P300 amplitude predicts rapid response to ECT in melancholia

Migraine aura without headache (acephalgic migraines) is a recognized subset of migrainous phenomena in the adult population. No reports of its prevalence or characteristics in a series of children exists. Using diagnostic criteria for migraine aura without headache established by the International Headache Society, a retrospective review of a computerized database of all patients referred over a 4-year period (July 1991 to June 1995 inclusive) to a single university-based pediatric neurologist was performed. Fourteen patients were identified, representing 2% of all patients with a primary diagnosis of migraine. Nine were females and 13 had a strong family history of migraines. Age of onset of symptoms ranged from 5 to 12 years with a mean of 8 years. Symptoms were episodic in all, varying in frequency from weekly to more typically monthly, lasting generally less than 10 min. In 9 patients the aura described was that of often colorful photopsias or scintillating scotomas. Two had micropsia, one had temporal distortion (time "speeded up"), one had hyperacusis, and the final patient had a vague sense of disconnection from her surroundings. Only 2 patients had a headache occasionally associated with the described aura. In addition to the acephalgic migraines, 9 patients had either common or classical migraines, the latter typically featuring aura distinct from those observed in these patients' acephalgic episodes. Neurologic examination, electrophysiologic investigation (EEG/evoked potentials), and neuroimaging were noncontributory in all instances. Migraine aura without headache is a recognizable benign migraine syndrome of late childhood.     

Anti-CD4 monoclonal antibody-induced tolerance to MHC-incompatible cardiac allografts maintained by CD4+ suppressor T cells that are not dependent upon IL-4

Anti-CD4 mAb-induced tolerance to transplanted tissues has been proposed as due to down-regulation of Thl cells by preferential induction of Th2 cytokines, especially IL-4. This study examined the role of CD4+ cells and cytokines in tolerance to fully allogeneic PVG strain heterotopic cardiac allografts induced in naive DA rats by treatment with MRC Ox38, a nondepleting anti-CD4 mAb. All grafts survived >100 days but had a minor mononuclear cell infiltrate that increased mRNA for the Thl cytokines IL-2, IFN-gamma, and TNF-beta, but not for Th2 cytokines IL-4 and IL-6 or the cytolytic molecules perforin and granzyme A. These hosts accepted PVG skin grafts but rejected third-party grafts, which were not blocked by anti-IL-4 mAb. Cells from these tolerant hosts proliferated in MLC and produced IL-2, IFN-gamma, and IL-4 at levels equivalent to naive cells. Unfractionated and CD4+ T cells, but not CD8+ T cells, transferred specific tolerance to irradiated heart grafted hosts and inhibited reconstitution of rejection by cotransferred naive cells. This transfer of tolerance was associated with normal induction of IL-2 and delayed induction of IFN-gamma, but not with increased IL-4 or IL-10 mRNA. Transfer of tolerance was also not inhibited by anti-IL-4 mAb. This study demonstrated that tolerance induced by a nondepleting anti-CD4 mAb is maintained by a CD4+ suppressor T cell that is not associated with preferential induction of Th2 cytokines or the need for IL-4; nor is it associated with an inability to induce Th1 cytokines or anergy.     

Cytokines in leprosy, II. Effect of treatment on serum cytokines in leprosy

BACKGROUND: Leprosy is a chronic infectious disease characterized by a broad spectrum of clinical forms depending on the patient's immune response, in particular cell-mediated immune response. METHODS: Cytokines can play a role in the cell-mediated immune response. Serum levels of interferon-gamma (IFN-gamma), interleukin-2 (IL-2), interleukin-2 receptor (IL-2R), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1beta (IL-1beta) were measured by enzyme-linked immunosorbent assay (ELISA) in 55 untreated leprosy patients and 35 reactional leprosy patients, in addition to 20 age- and sex-matched healthy controls. RESULTS: Leprosy patients showed significantly higher serum levels of the studied cytokines (except IL-2) compared with healthy controls. When the two poles were compared, tuberculoid leprosy (TT) patients showed significantly higher levels of IFN-gamma and TNF-alpha with significant negative correlations with the bacterial index (BI), whereas lepromatous leprosy (LL) patients showed significantly higher serum levels of IL-2R, IL-10, and IL-1beta with significant positive correlations with the BI. Both type I and type II reactional patients showed significantly higher serum IFN-gamma, IL-2R, and IL-1beta, in addition to IL-10 in type II reactional patients, compared with nonreactional leprosy patients. When compared with each other, type I reactional patients showed increased levels of IFN-gamma, whereas type II reactional patients showed increased levels of IL-10. CONCLUSIONS: In leprosy patients, both IFN-gamma and TNF-alpha are immunoprotective, whereas IL-2R, IL-10, and IL-1beta are immunosuppressive. Our results indicate that type I reaction, with increased levels of IFN-gamma, is a cell-mediated immune response, whereas type II reaction, with increased levels of IL-10, is essentially an immune complex disease.     

Disruption of the murine IL-4 gene blocks Th2 cytokine responses

Murine T-helper clones are classified into two distinct subsets (Th1 and Th2) on the basis of their patterns of lymphokine secretion. Th1 clones secrete interleukin-2 (IL-2), tumour necrosis factor-beta (TNF-beta) and interferon-gamma (IFN-gamma), whereas Th2 clones secrete IL-4, IL-5 and IL-10 (ref. 1). These subsets are reciprocally regulated by IL-4, IL-10 and IFN-gamma and differentially promote antibody or delayed-type hypersensitivity responses. To evaluate whether IL-4 is required for mounting Th2 responses, we generated IL-4-mutant mice (IL-4-/-) and assessed the cytokine secretion pattern of T cells both from naive and Nippostrongylus brasiliensis infected mice. CD4+ T cells from naive IL-4-/- mice failed to produce Th2-derived cytokines after in vitro stimulation. The levels of Th2 cytokines IL-5, IL-9 and IL-10 from CD4+ T cells obtained after nematode infection were significantly reduced. The reduced IL-5 production in IL-4-/- mice correlated with reduced helminth-induced eosinophilia, which has been shown to be dependent on IL-5 in vivo. We conclude that IL-4 is required for the generation of the Th2-derived cytokines and that immune responses dependent on these cytokines are impaired.     

Increased serum concentrations of interleukin-10 in patients with hepatosplenic candidiasis

Hepatosplenic candidiasis (HSC) becomes clinically overt in cancer patients upon recovery from neutropenia. HSC may be a consequence of a Th1-Th2 imbalance, characterized by increased serum levels of one or more cytokines. Serum levels of two immunosuppressive cytokines, markers of the Th2 pathway, interleukin (IL)-4 and IL-10 were measured by ELISA in 10 patients with HSC (22 samples) and compared with 19 healthy blood donors, 13 patients with cancer but no infection (23 samples), and 11 patients with cancer and various bacterial infections (17 samples). IL-4 was undetectable in all controls and patients. By contrast, levels of IL-10 were increased in HSC patients compared with levels in healthy donors and cancer patients without infection (P < .001) or with bacterial infections (P < .01). These findings indicate that IL-10 but not IL-4 is increased in patients with HSC and suggest that IL-10 plays a role in the pathogenesis of this infection.     

Type 1- and type 2-like lesional skin-derived Mycobacterium leprae-responsive T cell clones are characterized by coexpression of IFN-gamma/TNF-alpha and IL-4/IL-5/IL-13, respectively

In an earlier study, we generated a large number of Mycobacterium leprae-responsive and M. leprae-nonresponsive T cell clones (TCC) from the lesional skin of immunologic unstable borderline leprosy patients. In that study, we divided TCC into type 1- and type 2-like on the basis of their IFN-gamma and IL-4 expression. To explore whether other cytokines are coproduced along with IFN-gamma and IL-4, we investigated the secretion of a panel of other cytokines (TNF-alpha, IL-5, IL-6, IL-10, and IL-13) by a large number of these TCC. Upon analysis of 139 M. leprae-responsive TCC, we observed a positive correlation in the coproduction of IFN-gamma/TNF-alpha (r = 0.81), and in that of IL-4/IL-5 (r = 0.83), IL-4/IL-13 (r = 0.80), and IL-5/IL-13 (r = 0.82). Polarized type 1-like TCC produced dominantly IFN-gamma/TNF-alpha, and polarized type 2-like TCC predominantly IL-4/IL-5/IL-13. Most type 0-like TCC produced both sets of cytokines. In contrast, type 1- and type 2-like subsets of M. leprae-nonresponsive TCC (n = 58) did not show the same coexpression of these cytokines. Furthermore, when the differential expression of a broad panel of cytokines by individual M. leprae-responsive TCC is considered, it appeared that additional phenotypes could be recognized. These results suggested that distinct isotypes of type 1- and type 2-like T cells, based on the secretion of a panel of cytokines, may reflect M. leprae-specific characteristics.     

Patterns of cytokine production in psoriatic synovium

OBJECTIVE: To determine patterns of cytokine production and mRNA expression in synovium from patients with psoriatic arthritis (PsA) and to compare the profile of cytokine production in PsA explants with those derived from rheumatoid (RA) and osteoarthritic (OA) synovia and psoriatic skin. METHODS: Cytokine levels were measured in supernatants from synovial and dermal explant cultures at Day 10 by ELISA. Cytokine mRNA expression in PsA whole tissue was determined by multi-gene assay. Cytokine levels in explant supernatants were compared between PsA, RA and OA, and psoriatic skin. Synovial tissues were scored histologically by a pathologist blinded to the clinical diagnosis. RESULTS: PsA explants released elevated levels of interleukin (IL)-1beta, IL-2, IL-10, interferon (IFN)-gamma, and tumor necrosis factor (TNF)-alpha, but not IL-4 or IL-5. A similar pattern of gene expression was detected in whole synovial tissue. These cytokine levels were greater in PsA than RA, despite higher histopathologic scores in RA explants. Production of IL-1beta, IFN-gamma, and IL-10 were strongly correlated. Levels of IFN-gamma, IL-1beta, and IL-10 were higher in psoriatic synovium than psoriatic dermal plaques. CONCLUSION: The cytokine profile in PsA is characterized by the presence of Th1 cytokines and the monokines TNF-alpha and IL-1beta and very elevated levels of IL-10. The higher levels of these cytokines in PsA compared to RA suggest the presence of different underlying mechanisms.     

Light-induced discomfort and pain in migraine

Quantitative thresholds for discomfort and pain with monocular and binocular light stimuli were measured in 67 controls and 67 migraine patients (37 migraine with aura and 30 migraine without aura). Patients were more photophobic during attack than outside attack (p < 0.03), and they were more sensitive to light than controls even between attacks (p < or = 0.0001). We found no differences in light sensitivity between migraine with aura and migraine without aura (p > or = 0.93). Unilateral pain affected light sensitivity on both sides. When asked with a questionnaire, 74% of patients answered that they were sensitive to light outside attack and 100% were sensitive during attack. Pain thresholds were generally lower among sensitive than non-sensitive patients (p = 0.004), indicating some agreement between subjective opinion and objective measurements of photophobia. Photophobia seems to be an intrinsic property of migraineurs. It is increased by migraine pain, but seems to be unrelated to migraine characteristics such as nausea, severity of attacks, pain character and pain laterality.