A survey of phenotype II in familial Mediterranean fever

OBJECTIVE: Phenotype II in familial Mediterranean fever (FMF) is the onset of amyloidosis before the onset of FMF with its typical attacks, or as an isolated finding in a member of an FMF family. Its presence was investigated by looking for proteinuria among the asymptomatic relatives of patients with FMF complicated by amyloidosis and among the asymptomatic relatives of patients with juvenile chronic arthritis (JCA) complicated by amyloidosis, used as controls. METHODS: The relatives of the index patients (13 with FMF and amyloidosis) and controls (6 with JCA and amyloidosis) were screened for proteinuria. Rectal biopsies were performed when proteinuria was significant (>/=300 mg/d). RESULTS: 461 relatives were screened in the FMF group and 269 among the controls. Two of the FMF relatives and one JCA relative had no symptoms of FMF but had significant proteinuria. Rectal biopsy for amyloidosis was negative in all instances of significant proteinuria. CONCLUSION: Phenotype II is uncommon among the relatives of patients with FMF and amyloidosis.     

Opioid peptides in human plasma: evidence for multiple forms

Studies were designed to assess whether the enkephalin-containing peptides and proteins present in the chromaffin granules of the adrenal medulla and in other secretory tissues, such as the neurohypophysis, could be found circulating in human blood. We analyzed human plasma acid acetone extracts chromatographed on Sephadex G-75 in acetic acid and found evidence for the existence of opioid peptides of several different molecular weights and a large number of peptides and small proteins which generate opioid activity after tryptic digestion. These compounds are different from and present in much greater quantities than previously described opioid peptides in human plasma, and are separate from dynorphin-immunoreactive compounds, which we also report in the blood. Expressed in leucine-enkephalin equivalents on a radioreceptor assay, we found 63.2 +/- 6.5 (n = 4; mean +/- SEM) pmol/ml plasma. One active peak from the Sephadex G-75 chromatography of human plasma (apparent mol wt, 3000) was examined by reverse phase high pressure liquid chromatography, tryptic digestion, and Sephadex G-50 chromatography. The results were consistent with the notion that this opioid active peptide contains an enkephalin sequence at its N-terminal, followed by a basic residue. Mild stress (2 min of deep knee bends) produced a 2-fold elevation in overall circulating opioid activity. The possibility is considered that the large enkephalin-containing peptides may have an endocrine function, independent of a role as enkephalin precursors.     

Relationship between serum free fatty acids and thyroid hormone binding inhibitor in nonthyroid illnesses

We measured the serum concentration and relative distribution of various free fatty acids (FFA) by gas/liquid chromatography in normal subjects and nonthyroid illness (NTI) patients with or without detectable serum thyroid-hormone binding inhibitor (THBI). The mean serum concentration of total FFA was 0.72 +/- 0.08 (SE) mM in eight normal subjects; it was similar (0.63 +/- 0.12) in eight THBI-negative NTI patients, but was significantly higher (3.1 +/- 1.0; P less than 0.05) in eight THBI-positive NTI patients (THBI index, 3.9 +/- 0.3 vs. 1.0 +/- 0.05 in normal subjects). Relative distribution of FFA in THBI-negative patients did not differ significantly from that in normal subjects. In THBI-positive patients, however, serum concentrations of palmitic, palmitoleic, stearic, and oleic acids were significantly above normal. Among fatty acids with appreciable THBI activity, oleic acid was most abundant in THBI-positive patients; its concentration of 1.3 +/- 0.32 mM in patients was about 6-fold higher than the corresponding normal value (0.21 +/- 0.02; P less than 0.005). The serum concentration of THBI correlated significantly with levels of both total FFA (r = 0.69; P less than 0.005) and oleic acid (r = 0.80; P less than 0.001). Addition of 0.33 mM oleic acid to THBI-negative NTI serum or 0.66 mM oleic acid to normal serum increased THBI activity to a level greater than 2 SD above the normal mean, i.e. 1.6. The various data suggest that 1) circulating FFA contribute importantly to THBI activity in sera of NTI patients; 2) oleic acid contributes more to THBI activity of NTI sera than do other FFA.     

Decreased bone mineral density in adult familial Mediterranean fever patients: a pilot study

We investigated the association between familial Mediterranean fever (FMF) and osteoporosis (OP) in adult patients. Thirty-five attack-free FMF patients (28 females, 7 males; mean age 36.9 +/- 5.7 years) were individually matched to control subjects on the basis of age (within 2 years) and sex. All patients were taking regular colchicine. Subjects having any condition that can cause decreased bone mineral density (BMD) were excluded from the study. BMD was measured at the spine and femur by dual X-ray absorptiometry (DXA). Data was given as the median (IQR). T scores of the spine were -0.700 (-1.097 to -0.262) and -0.450 (-0.830 to 0.112) in FMF patients and healthy controls, respectively (p > 0.05). T scores of the femur neck were -0.900 (-1.480 to -0.570) and -0.430 (-1.472 to 0.247) in FMF patients and healthy controls, respectively (p > 0.05). Total femur T scores were significantly lower in FMF patients than healthy controls (-0.780 [-1.222 to -0.085] vs. -0.100 [-0.765 to 0.537], respectively, p = 0.021). Total femur T scores were significantly decreased in adult patients with FMF. Ongoing subclinical inflammation may be associated with decreased bone mineral content in those patients.     

Differences in the metabolic clearance of pituitary and serum thyrotropin (TSH) derived from euthyroid and hypothyroid rats: effects of chemical deglycosylation of pituitary TSH

We compared the MCR, volume of distribution, and rapid phase (rt1/2) and slow phase half-lives of purified pituitary rat (r) TSH, TSH from crude pituitary extracts of normal and hypothyroid rats, TSH from hypothyroid rat sera, and TSH secreted from hypothyroid rat pituitaries incubated in vitro. For 3 h after iv bolus injection into euthyroid rats, 125I-labeled rTSH was determined by acid precipitation in serum and various organs, and unlabeled TSH was measured by RIA. The MCR of TSH from normal pituitary extracts (0.53 +/- 0.02 ml/min) was similar to that of unlabeled purified rTSH (0.52 +/- 0.03), while those from hypothyroid pituitary extracts (0.32 +/- 0.03) and hypothyroid sera (0.33 +/- 0.01) were decreased. The reduced MCR of TSH from hypothyroid pituitaries was due to a decreased distribution volume (8.4 +/- 0.6 ml) compared to that from normal pituitaries (11.4 +/- 0.7) and hypothyroid sera (10.9 +/- 0.8). The decreased MCR of circulating TSH from hypothyroid sera reflected an increase in its rt1/2 (12.6 +/- 0.5 min) vs. that from both normal (5.1 +/- 0.5) and hypothyroid (5.7 +/- 0.4) pituitaries. The rt1/2 of secreted TSH from incubated hypothyroid rat pituitaries (8.5 +/- 0.9) was intermediate between those of circulating and pituitary forms of hypothyroid rTSH. The clearances of intact bovine TSH (bTSH) and deglycosylated bTSH (dg-bTSH) were compared. The dg-bTSH MCR was found to be increased (0.71 +/- 0.02 ml/min) compared to that of bTSH (0.59 +/- 0.02), primarily due to a decreased rt1/2 for dg-bTSH (3.8 +/- 0.1 min) vs. bTSH (4.7 +/- 0.2). Uptake of purified [125I]rTSH was highest in the kidney at all times, varying from 43% of the injected dose at 5 min to 54% at 180 min. We conclude that in the euthyroid rat, 1) the metabolic clearance of TSH differs between pituitary and serum forms and appears to depend on specific molecular features that vary with the physiological state of the animal from which the TSH is derived; 2) since chemical deglycosylation increased the clearance of TSH, we speculate that the chemical basis for changes in TSH clearance may be related to alterations in its carbohydrate structure; and 3) for normal pituitary TSH, the kidney is the major organ of clearance.     

The separation of neuropeptides by high performance liquid chromatography and its application to the analysis of peptides in the rat pituitary neurointermediate lobe (author's transl)

High performance liquid chromatography (HPLC) was used for the separation of many neuropeptides. Chromatography was carried out using a Hitachi Model 638 high performance liquid chromatograph. Peptides and samples from tissue dissolved in an aqueous buffer were injected into a stainless-steel column (4 X 250mm) packed with Hitachi #3053 (octadecylsilane). The aqueous buffer consisted of NaH2PO4 and H3PO4. After a loading phase (0% organic solvent) of 1 min, the peptides were sequentially eluted at room temperature using a gradient of organic solvent (acetonitrile or methanol, 0-60%). The eluted polypeptides were detected by UV absorbance at 220nm, and then they were collected for subsequent bio and radioimmunoassay using a fraction collector. The gradient of methanol or acetonitrile in 0.02M NaH2PO4, 0.1% H2PO4 was useful for separating small molecular peptides. The gradient of acetonitrile in 0.05-0.1M NaH2PO4, 0.1% H2PO4 was useful for separating many neuropeptides including ACTH related peptides. Retention times of chromatographed polypeptides showed good reproducibility. Good reproducibility was also found in peak areas of these peptides. A linear relationship was observed between the doses of peptides and their peak areas. The extracts of rat pituitary neurointermediate lobe showed several peaks of UV absorbance on PHLC; some of them coincided with AVP, oxytocin, alph-MSH, CLIP and beta-endorphin but others were unidentified. AVP immunoreactivity showed one peak which coincided with the AVP peak of UV absorbance, but ACTH immunoreactivity showed 5-6 peaks. Thus, many polypeptides were well separated using HPLC by changing the eluting condition. The simplicity, speed, good reproducibility and good quality of the separations render this technique suitable for purification and quantitative analysis of neuropeptides, and the combination of HPLC, radioimmunoassay and bioassay gives very fine analysis of neuropeptides.     

Renal cytochrome P-450-dependent metabolism of arachidonic acid in cirrhotic rats

Cirrhosis was induced in Wistar-Kyoto rats by intragastric administration of carbon tetrachloride. Microsomes were obtained from the renal cortex and outer medulla and incubated with [14C]arachidonic acid (AA) (0.2-0.4 microCi) in the presence or absence of indomethacin, NADPH, and SKF-525A. Cytochrome P-450-dependent AA metabolites (those whose formation required NADPH, were inhibited by SKF-525A, but not by indomethacin) were separated by thin-layer chromatography and high-pressure liquid chromatography (HPLC). Compared to controls, total synthesis of cytochrome P-450-dependent AA metabolites was reduced in cirrhotic rats (renal cortex: cirrhotics 380 +/- 52 vs. controls 493 +/- 68 pg/mg protein per 30 min; p less than 0.05; renal outer medulla: cirrhotics 304 +/- 57 vs. controls 387 +/- 53 pg/mg protein per 30 min; p less than 0.05). The cytochrome P-450-dependent AA metabolites were composed of three peaks separated by HPLC. Peak I, which had a retention time of 16.3 +/- 0.3 min and comigrated with 11,12-dihydroxyeicosatrienoic acid, and peak II, which had a retention time of 18.7 +/- 0.4 min and comigrated with 19- and 20-hydroxyeicosatetraenoic acid, were not different in cirrhotics and controls. Peak III, which had a retention time of 26.8 +/- 0.3 min, and comigrated with 11,12-epoxyeicosatrienoic acid, was significantly decreased in the renal cortex of cirrhotic rats compared to controls (cirrhotics 316 +/- 40 vs. controls 473 +/- 89 pg/mg protein per 30 min; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhibition of nuclear T3 binding by fatty acids

Studies were performed to evaluate a possible modulatory role of lipids on the binding of T3 to rat liver nuclear receptors in vitro. Unsaturated fatty acids were potent inhibitors of the binding of [125I] T3 to isolated rat liver nuclei. Doses (in mumol/L) causing a 50% inhibition of nuclear T3 binding were 10 for palmitoleic acid, 11 for linoleic acid, 22 for oleic acid, 24 for arachidonic acid, and 37 for linolenic acid. Other lipids had less or no inhibitory activity. Unsaturated fatty acids reduced the affinity constant (Ka) of the binding of T3 to nuclear receptors to 57.4% +/- 11.0% that of controls (mean +/- SE 1.04 +/- 0.14 v 1.97 +/- 0.23 10(9) L/M, n = 5; P less than .02) but did not affect the maximal binding capacity (MBC) (1.47 +/- 0.20 v 1.55 +/- 0.10 10(-10) M/L; NS). Evaporated ether extracts of rat liver homogenate pretreated with phospholipase A2 for five to 20 minutes (that liberates unsaturated fatty acids from phospholipids) demonstrated a progressive inhibition of nuclear T3 binding with time when compared with ether extracts of untreated rat liver homogenate (F = 16.1; P less than .01). Evaporated, fatty-acid-rich ether extracts of human sera caused a dose-dependent inhibition in the binding of [125I] T3 to nuclear T3 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Tissue factor pathway inhibitor attenuates procoagulant activity and upregulation of tissue factor at the site of balloon-induced arterial injury in pigs.

Intravenous infusion of recombinant tissue factor pathway inhibitor (rTFPI) for 24 hours decreases neointimal thickening and luminal stenosis 1 month after balloon-induced injury to the carotid arteries in minipigs. This study was designed to determine whether the effect of rTFPI is accounted for by early decreases in procoagulant activity and thrombosis on the injured vessel wall. Vascular injury was induced by balloon hyperinflations in both carotid arteries of anesthetized pigs given no anticoagulant as a control (n=16), an intravenous infusion for 24 hours of rTFPI (0.5 mg/kg bolus and 25 microg. kg(-1). min(-1), n=14), or an intravenous infusion of unfractionated heparin (100 U. kg(-1). h(-1), n=19). Accumulation of radiolabeled autologous platelets was markedly decreased over 24 hours on injured arteries from animals given rTFPI (0.6x10(6)/cm(2)) compared with controls (2.5x10(6)/cm(2), P=0.0004). Deposition of radiolabeled fibrin was also decreased in rTFPI-treated animals (269+/-266 microg/cm(2)) compared with controls (2389+/-1673 microg/cm(2), P=0.04). Similar effects were observed with heparin. However, factor Xa activity, assayed after 24 hours by incubation of the injured arterial segments with the chromogenic substrate S-2222, was decreased more markedly on arteries from rTFPI-treated animals (0.14+/-0.13 OD) than those from heparin-treated animals (0.29+/-0.18 OD) compared with controls (0. 47+/-0.24 OD, P=0.0007). In addition, arteries from rTFPI-treated animals showed a 4-fold lower induction of tissue factor protein compared with controls (P=0.0002). Attenuation of procoagulant activity and tissue factor-mediated thrombin generation in response to injury may account for the promising results with rTFPI in the porcine angioplasty model.     

Association of RNA with thymidylate synthase from methotrexate-resistant Streptococcus faecium.

Thymidylate synthase (5,10-methylenetetrahydrofolate:dUMP C-methyltransferase, EC 2.1.1.45) from methotrexate-resistant Streptococcus faecium has a UV absorbance peak at 259 nm and stains with acridine orange because of the presence of RNA on the protein. Material having an absorbance peak at 254 nm, obtained from the enzyme by phenol extraction, is degraded by treatment with pancreatic RNase, T1 RNase, and alkali but is stable to DNase. Dowex-1 chromatography of the pure enzyme yields two polynucleotide fragments in addition to the apoenzyme. As estimated from their absorbance, these fragments contain 4 and 11 mononucleotide residues per mole of enzyme, respectively. In crude extracts, thymidylate synthase is associated with rapidly sedimenting material that is sensitive to RNase. Treatment of crude extracts with RNase, as is done routinely during thymidylate synthase purification, most likely results in the formation of the small polynucleotides found on the enzyme. The RNA is not required for enzyme activity.     

Characteristics of Crimean-Congo hemorrhagic fever virus (Xinjiang strain) in China

Virus strains isolated from blood of patients during a hemorrhagic fever outbreak in 1968 in southern Xinjiang, China, from Hyalomma asiaticum and from sheep, were found to be identical or closely related to Crimean-Congo hemorrhagic fever (C-CHF) virus by complement fixation and indirect immunofluorescence tests with convalescent sera of patients and with C-CHF reference antibody. The virus was inactivated by ether and acid. Viral synthesis was not suppressed by 5-iododeoxyuridine suggesting an RNA-containing genome. The buoyant density in sucrose was 1.16-1.18 g/cm3. The particle weight was estimated at 3.26 +/- 0.46 X 10(8). The diameter of the virus particles was 85-105 nm.     

Decreased interleukin 1 activity released from circulating monocytes of patients with familial Mediterranean fever during in vitro stimulation by lipopolysaccharide.

Familial Mediterranean fever (FMF) is an inherited disorder of unknown etiology characterized by recurrent episodes of serous membrane inflammation. Interleukin 1 (IL-1) is a mediator of inflammatory processes. We hypothesized that IL-1 may play a role in acute attacks of FMF. Thus we tested IL-1 production by monocytes derived from patients with FMF. Nine patients were tested during acute attacks and 9 were asymptomatic when tested. Monocytes derived from peripheral blood of patients and controls were stimulated with lipopolysaccharide (LPS) and IL-1 activity in the supernatant was tested using a T helper cell line (D10-4G.1). IL-1 secretion during acute attacks was decreased whereas IL-1 production in asymptomatic patients was comparable to healthy controls. Followup of symptomatic patients during the recovery period revealed normalization of IL-1 secretion. Addition of indomethacin (prostaglandin E2 inhibitor) to LPS stimulated monocytes did not change IL-1 activity in patients or healthy controls. We conclude that in vitro IL-1 activity in patients with FMF is associated with the intensity of the inflammatory process.     

Circulating antiandrogenic activity in children with congenital adrenal hyperplasia during peroral flutamide treatment

CONTEXT: The degree of androgen receptor blockade achieved with peroral flutamide is unknown. OBJECTIVE: The aim of this study was to examine the contribution of flutamide to circulating antiandrogenic activity in children with congenital adrenal hyperplasia using a recombinant cell bioassay. DESIGN: We describe an open-label, prospective clinical study. SETTING: The study was conducted at the Hospital for Children and Adolescents, University of Helsinki, or the Turku University Hospital, Finland. PARTICIPANTS: Seven children, age 7.2-10.5 yr, were included. Intervention: As an experimental approach to improve control of height velocity and the rate of bone maturation, the patients received letrozole (2.5 mg/d) and flutamide (10 mg/kg.d) and were followed up at 3-month intervals for 3-12 months. Before employing the bioassay, two pools of sera (obtained before and during flutamide treatment) were supplemented with increasing amounts of testosterone, and all sera (n = 27) of individual patients were supplemented with a constant amount of exogenous testosterone. MAIN OUTCOME MEASURE: The main outcome measure was circulating antiandrogenic activity. RESULTS: Flutamide and/or its metabolites shifted the dose-response curve of testosterone, in that only the highest testosterone concentration, corresponding to 1803 ng/dl (62.5 nm) in human serum, was measurable by the bioassay. In individual sera supplemented with testosterone, flutamide treatment suppressed androgen bioactivity from 378 +/- 20 ng/dl (13.1 +/- 0.7 nm) (mean +/- sem) (pretreatment) to 110 +/- 20 ng/dl (3.8 +/- 0.7 nm) (3 months), 83.7 +/- 12 ng/dl (2.9 +/- 0.4 nm) (6 months), 46.2 +/- 6 ng/dl (1.6 +/- 0.2 nm) (9 months), and 57.7 +/- 9 ng/dl (2.0 +/- 0.3 nm) (12 months) testosterone equivalents (P < 0.01). CONCLUSIONS: A dose of flutamide less than 10 mg/kg.d appears sufficient to inhibit AR in children. The recombinant cell bioassay employed herein offers a novel means to monitor the treatment of patients receiving antiandrogens.     

Familial Mediterranean fever--an important differential diagnosis in systemic juvenile chronic arthritis

Familial Mediterranean Fever (FMF), characterized by recurring episodes of fever, serositis, arthritis, skin changes and complicated by amyloidosis in 30%-60% of cases frequently begins in childhood. Systemic juvenile rheumatoid arthritis (systemic JRA, Still's disease) is the most important differential diagnosis. In our series of 10 patients the mean age of onset was 4.9 +/- 2.2 years (range 2-9 years). The mean time period elapsed before the diagnosis was established was 4.1 +/- 2.7 years (range 1.5-10 years). Three of our 10 patients already had developed renal amyloidosis at the time of diagnosis. Essential criteria for differential diagnosis against systemic JRA were positive family history for FMF (4/10), ethnic background (9/10 of Turkish decent), typical erysipeloid skin rashes (4/10), attacks of abdominal pain accompanied by fever (10/10) and the characteristic pattern of recurrent episodes lasting only a few days each (a patient's diary monitoring the attacks may be helpful). In problematic cases the metaraminol provocative test can be helpful. If an elevated plasma dopamine beta-hydroxylase activity appears to be a specific finding in FMF patients, this may well open up new avenues in the early diagnosis of the disease. Since amyloidosis can be prevented by prophylactic long lasting treatment with colchicine, a timely diagnosis of FMF is the physician's challenge.     

Plasma interleukin-10 and interleukin-12 levels in patients with familial Mediterranean fever

Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by recurrent attacks of fever, polyserositis and arthritis. A vast array of cytokines were analysed in these patients, however, little is known about the pro-inflammatory cytokine interleukin (IL)-12. Plasma IL-12 and IL-10 were measured in 24 patients with FMF (19 active, 5 inactive) and 18 healthy controls by ELISA. From 15 active patients blood was also drawn in attack-free period. Mean plasma IL-12 levels of the FMF patients (mean ± SEM, 6.84±3.59 pg/ml) were higher than the controls (0.13±0.09 pg/ml, P<0.001). Mean IL-12 levels of active (7.02±5.23 pg/ml) and inactive patients (6.89±5.61 pg/ml) were comparable, and they were higher compared to controls (P≤0.001). Mean plasma IL-10 levels of the total FMF patients (3.01±1.53 pg/ml) were also higher than the controls (P=0.024). Patients had higher IL-10 levels in attacks (3.83±2.02 pg/ml) compared to levels when they were in remission (1.86±1.59 pg/ml, P=0.046). Significantly elevated IL-12 levels in FMF patients regardless of activity may suggest the presence of a pro-inflammatory state also in the inactive period of FMF. Significant increase in IL-10 levels in FMF group may point to the compensatory suppression of inflammation in active periods of the disease.     

Living with a child with familial Mediterranean fever: does it affect the quality of life of the parents?

OBJECTIVE: The aim of the present study was to assess the quality of life (QOL) and the psychological status of parents of children with familial Mediterranean fever (FMF). METHODS: The QOL, anxiety and depression of the parents of 35 children with FMF were evaluated and compared to the parents of 23 healthy children. RESULTS: Mothers of FMF children had lower QOL scores than mothers of healthy children: 5.5 +/- 1.1 versus 6.0 +/- 0.6 (p = 0.048). They also expressed higher levels of anxiety and depression. Within each group, mothers were more anxious and depressed than fathers. Parents with several FMF children were not significantly different from parents with only one FMF child. CONCLUSION: The QOL and psychological well being of parents with FMF children were found to be slightly impaired, especially that of the mothers.     

Th1 polarization in familial Mediterranean fever

OBJECTIVE: Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by fever and serosal inflammation accompanied with an outburst of acute phase inflammatory products and cytokines. We studied the role of T helper (Th) 1 and 2 cells in FMF to elucidate the character of the inflammation. The cytokine products of Th1 and Th2, interferon-g (IFN-g) and interleukin 4 (IL-4), respectively, were analyzed by intracellular cytokine staining and FACS analysis. METHODS: We studied 34 Turkish patients with FMF (18 asymptomatic, 8 during an attack, and 8 with amyloidosis) and 14 age matched controls, as well as 11 parents of the patients who were accepted as heterozygotes for MEFV (Familial Mediterranean gene) mutations. Peripheral blood mononuclear cells were isolated and stained with monoclonal antibodies for IFN-g and IL-4. The percentage of IL-4 positive T cells was not significantly different between the groups. However, the percentage of IFN-g positive T cells in FMF patients experiencing an attack (median 25.8%, range 8.9-50.5%) was significantly higher than asymptomatic FMF patients (median 12%, range 0.1-70.7) (p = 0.04) and age matched controls (n = 7, median 0.4%, range 0-3.9%) (p = 0.0001). The percentage of IFN-g positive T cells in asymptomatic FMF patients was also significantly higher than age matched controls (p = 0.008). Heterozygotes for FMF had significantly higher IFN-g production (median 2.6%, range 0-42.4%) compared to age matched controls (n = 7, median 0.2%, range 0-1.4) (p = 0.001). IFN-g production in FMF patients with secondary amyloidosis was also markedly increased but had a large range of variation. CONCLUSION: Inflammation in FMF shows a Th1 polarization. We suggest that in patients with FMF the IFN-g concentrations may remain higher because the defective pyrin is not able to inhibit this Th1 mediated inflammation.     

Crohn disease in patients with familial Mediterranean fever

Crohn disease and familial Mediterranean fever (FMF) are inflammatory diseases characterized by abdominal pain and fever. The concurrence of the 2 diseases (FMF-CD) may pose a challenge to diagnosis and treatment. We undertook the present study to determine the prevalence of Crohn disease in FMF and to characterize FMF-CD patients clinically and genetically. Using a computerized search, the patients of our FMF clinic were screened for a concomitant diagnosis of Crohn disease. Patients and their medical records were thoroughly examined, and their DNA was genotyped for mutations in the MEFV gene. Control groups of ethnically and sex-matched patients suffering from each of the diseases alone, either Crohn disease or FMF, were used for comparison. We identified 7 patients with concomitant Crohn disease and FMF, which is more than the expected prevalence in the general population (p = 0.03). Crohn disease presented at a significantly later age in the FMF-CD group (40.6 +/- 10.0 yr versus 26.2 +/- 11.4 yr; p < 0.004). Disease severity and other characteristics of Crohn disease were comparable to the Crohn disease control group. Contrary to the FMF control group patients, FMF in FMF-CD patients was characterized by a higher attack frequency (p < 0.05) and increased prevalence of amyloidosis (p < 0.02). The overall severity score was similar in both groups. In conclusion, Crohn disease appears to be more prevalent in FMF and presents later than in patients without FMF. FMF in this group of patients shows a higher attack frequency and is more often complicated by amyloidosis.     

Pretreatment with ibuprofen augments circulating tumor necrosis factor-alpha, interleukin-6, and elastase during acute endotoxinemia

Plasma levels of tumor necrosis factor-alpha (TNF alpha), interleukin-1 (IL-1), and interleukin-6 (IL-6) were monitored after intravenous administration of Escherichia coli endotoxin with or without ibuprofen pretreatment to healthy volunteers. Intravenous endotoxin (n = 7) resulted in elevated plasma TNF alpha concentrations with maximal levels at 90 min (369 +/- 44 pg/ml, P less than .001 vs. saline controls, n = 7). The rise in TNF-alpha was followed by a rise in plasma IL-6 (27 +/- 12.8 ng/ml), peaking 30-90 min thereafter. Pretreatment with ibuprofen (n = 6) caused a significant augmentation and temporal shift in cytokine elaboration with maximal TNF alpha levels (627 +/- 136 pg/ml) at 120 min and IL-6 peaks (113 +/- 66 ng/ml) at 180 min. In ibuprofen-treated volunteers, the additional increase in TNF alpha was paralleled by increased levels of circulating elastase. In vitro experiments suggest a causal relationship between these events. Thus, the cyclooxygenase inhibitor ibuprofen blunts the clinical response to endotoxin but augments circulating cytokine levels and leukocyte degranulation.