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Biomedical subjects

A Livneh

Publications and source records attributed to A Livneh.

At least 19 recordsLinked to original sources
PubMed2001

Common MEFV mutations among Jewish ethnic groups in Israel: high frequency of carrier and phenotype III states and absence of a perceptible biological advantage for the carrier state.

Familial Mediterranean fever (FMF) is an autosomal recessive disease, characterized by recurrent attacks of fever and inflammation of serosal membranes and gradual development of nephropathic amyloidosis. The recent cloning of the FMF gene (MEFV) and identification of disease-associated mutations in most patients made the direct determination of FMF carrier frequency feasible. The aim of the present study was to investigate the carrier rate of the most common MEFV mutations among different Jewish ethnic groups in Israel. Further, an attempt was made to elucidate the possible biological advantage that the heterozygote state may confer. Three hundred Ashkenazi, 101 Iraqi, and 120 Moroccan Jews were screened for the E148Q, V726A, and M694V mutations (at least two most common mutations per group), with a resulting overall carrier frequency in the respective ethnic group of 14%, 29%, and 21%. No difference in morbidity between Ashkenazi carriers and non-carriers of MEFV mutations was discerned, although an excess of febrile episodes in carriers of the V726A and in carriers of either V726A or E148Q was evident (P < 0.02 and P < 0.05, respectively). The frequency of subjects with two MEFV mutations but not expressing FMF (phenotype III) was 1:300 in Ashkenazi Jews and 1:25 in Iraqi Jews, exceeding the reported rate of overt FMF in these ethnic groups by 40-240 fold. These results affirm the high carrier rate among the studied Jewish ethnic groups in Israel and suggest that most subjects with FMF mutations are unaffected.

Alleles↗
PubMed2001

A single mutated MEFV allele in Israeli patients suffering from familial Mediterranean fever and Behçet's disease (FMF-BD).

Although familial Mediterranean fever (FMF) is an autosomal recessive disorder, preliminary partial mutation analysis suggested that about 60% of FMF patients, who also suffer from Behçet's disease (FMF-BD), have only a single mutated FMF gene (MEFV). In this study, the possibility that patients with FMF-BD may indeed be carriers of a single mutated MEFV is further analysed. The presence of mutations in the coding region of MEFV of eight patients with FMF-BD, representing six families with 47 members, was determined by sequencing. A possible role for the non-carrier chromosome and for BD in the expression of FMF in patients with a single mutated MEFV allele was determined by analysing the association between these variables and the presence of FMF in heterozygous kin. Sequence analysis revealed that all eight patients had indeed only one mutation in the coding region of MEFV. The patients' non-carrier chromosomes converged into three different MEFV haplotypes and were shared by heterozygous unaffected kin in five of six families. BD was found in 10 of 11 carriers with FMF vs one of 16 carriers without FMF (P < 0.001). These results suggest that FMF may be expressed in individuals harbouring only one coding mutation in MEFV. The findings argue against a role for the non-carrier chromosome in the induction of FMF, and suggest that the FMF phenotype in this cohort was associated with the simultaneous presence of BD. These findings may mirror a more generalised rule, that FMF may be precipitated in carriers of a single mutated FMF gene by factors unrelated to the other MEFV allele.

Alleles↗
PubMed2001

Inhibition of the second phase of amyloidogenesis in a mouse model by a single-dose colchicine regimen.

Amyloidogenesis consists of two stages. In the first, amyloid enhancing factor (AEF) is generated, and in the second, deposition of amyloid fibrils occurs. Colchicine is a known inhibitor of amyloidosis of familial Mediterranean fever (FMF) and of mouse experimental amyloidosis, but the timing and mechanism of its effect are still unclear. The aim of this study is to determine whether colchicine inhibits the second phase of amyloidogenesis and to study the time correlate of such an effect. To that end, amyloid was induced in Swiss male mice with AEF and AgNO(3) (an inflammatory stimulus), a method that skips the first phase of amyloidogenesis. Two amyloid induction protocols were used: a standard protocol, in which AEF and AgNO(3) were administered concurrently, and a prolonged protocol, in which the administration of AgNO(3) was delayed by 24 hours or 7 days. To study the inhibitory effect of colchicine on the second phase of amyloidogenesis, a single dose of colchicine (30 microg) was injected intravenously before, during, or after administration of AgNO(3) in both the standard and prolonged amyloid induction protocols. The amount of amyloid deposition in the spleens was determined with the crush-and-smear technique and a 5-grade scale. Colchicine was found to inhibit the second phase of amyloidogenesis. Its best effect was achieved when administered 48 hours after initiation of AgNO(3) injections. The pattern of colchicine-inhibition-in-time in the standard and the prolonged amyloid induction protocols was similar, indicating that colchicine exerts inhibition through its effect on the inflammatory stimulus (AgNO(3)). These findings suggest that (1) colchicine suppresses amyloidogenesis in the late (second) stage and that (2) this suppression is possibly related to the anti-inflammatory effect of colchicine.

Amyloidosis↗
PubMed2001

Specific glycosylation of alpha(1)-acid glycoprotein characterises patients with familial Mediterranean fever and obligatory carriers of MEFV.

BACKGROUND: Familial Mediterranean fever (FMF) is a periodic febrile disorder, characterised by fever and serositis. The acute phase response during attacks of FMF results from the release of cytokines, which in turn induce increased expression and changed glycosylation of acute phase proteins. A recent study indicated that attacks in FMF are accompanied by a rise of plasma concentrations of serum amyloid A (SAA) and C reactive protein (CRP), which remain significantly raised during remission relative to healthy controls. Another study suggested that obligatory heterozygotes also display an inflammatory acute phase response. OBJECTIVE: To determine the state of inflammation in homozygotic and heterozygotic MEFV genotypes. METHODS: CRP and SAA were studied by enzyme linked immunosorbent assay (ELISA). The glycosylation of the acute phase protein, alpha(1)-acid glycoprotein (AGP), was visualised with crossed affinoimmunoelectrophoresis with concanavalin A as diantennary glycan-specific component and Aleuria aurantia lectin as fucose-specific affinity component. RESULTS: FMF attacks were associated with an increase (p<0.05) in the serum inflammation parameters CRP, SAA, and AGP. The glycosylation of AGP showed an increase (p<0.05) in fucosylated AGP glycoforms, whereas the branching of the glycans remained unaffected. The glycosylation of AGP in the MEFV carrier group, compared with that in a healthy control group, was characterised by a significant increase (p<0.05) in branching of the glycans, whereas the fucosylation remained unaffected. CONCLUSION: The findings suggest an FMF-specific release of cytokines, resulting in a different glycosylation of AGP between a homozygotic and heterozygotic MEFV genotype.

Adolescent↗
PubMed2001

Light chain amyloidosis of the urinary bladder. A site restricted deposition of an externally produced immunoglobulin.

AIMS: To identify the amyloid protein in a patient with amyloidosis localised to the urinary bladder, and to see whether subtyping of the protein by sequence analysis increases the understanding of the selection of the urinary bladder as the site of amyloid deposition. METHODS: A patient with gross haematuria and a congophilic mass in his urinary bladder was evaluated further. Characterisation of the amyloid protein was performed using conventional histological and immunohistochemical methods. Determination of the N-terminal amino acid sequence of the amyloid protein was performed using protein sequencers. RESULTS: The patient's history, physical examination, and laboratory evaluation excluded the involvement of other organs, justifying a diagnosis of amyloidosis localised to the urinary bladder. Histological and immunological studies showed that the amyloid protein deposited in the urinary bladder of the patient was probably of the amyloid light chain type. No plasma cells or lymphocytes were seen in sections of the urinary bladder and lower ureter adjacent to the amyloid deposits. Molecular analysis showed the sequence NFMLTQPHSISGSPG, which assigned the amyloid protein to either the Vlambda(I) or the Vlambda(VI) immunoglobulin (Ig) light chain families. CONCLUSIONS: The findings suggest that the amyloid protein in this patient originated outside the urinary bladder. The heterogeneity of the Ig proteins in known cases of amyloidosis of the lower urinary tract suggests that the amino acid residues, which determine the Vlambda subtyping, have no major role in restricting the deposited protein to the urinary bladder.

Amino Acid Sequence↗
PubMed2001

Anti-insulin antibodies and the natural autoimmune response in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is characterized by the finding of ample serum autoantibodies. The role and the origin of many of these antibodies are still obscure. The aim of this work was to study the occurrence of anti-insulin antibodies (AIA) in SLE, and to postulate, based on AIA determination, on the mechanisms involved in the production of some autoantibodies in SLE. IgG and lgM AIA, anti-DNA antibodies (ADA) and anti-tetanus toxoid antibodies (ATA) were determined using ELISA in sera and B-lymphocytes culture media of 24 SLE patients, 10 healthy controls and 19 insulin-dependent diabetes mellitus (IDDM) patients. B- and T-lymphocytes were isolated using Ficoll gradient, depleted of T-cells using cyclosporin A, EBV infected and grown in medium. The frequencies of IgM-AIA and IgG-ADA were higher in SLE patients than in healthy controls (P < 0.02 and P < 0.05, respectively). The rate of IgM-AIA in SLE and IDDM was comparable, while IgG-AIA was significantly less common in SLE than in IDDM (P < 0.05). The prevalence of ATA in SLE patients and healthy controls was similar. These findings increase the spectrum of the humoral autoimmune response in SLE and suggest that part of it (natural autoantibodies) is independent of antigen driven response.

Adolescent↗
PubMed2001

Abdominal CT findings in nephropathic amyloidosis of familial Mediterranean fever.

To evaluate the abdominal CT features of reactive amyloidosis, abdominal CT scans of 20 patients with amyloidosis of familial Mediterranean fever (FMF) were reviewed and compared with abdominal CT scans of 2 control groups: 22 patients with chronic renal failure (CRF) due to non-amyloidotic kidney diseases and 40 patients with normal kidney function. The kidney size of patients with amyloidosis of FMF were found to vary during the course of the disease from normal or slightly larger than normal at the proteinuric phase, to smaller than normal and comparable to kidney size in CRF, at the uremic stage. Compared to kidney disease of other causes, more patients with FMF-amyloidosis had dense kidneys with coarse parenchymal calcification and calcification in other abdominal organs. Patients with FMF-amyloidosis had fewer aortic calcifications than patients with non-amyloidotic kidney disease. These findings suggest that kidney disease of reactive amyloidosis may have abdominal CT findings distinguishing it from other types of kidney diseases.

Abdomen↗
PubMed2001

Prevalence of ischemic heart disease in patients with familial Mediterranean fever.

BACKGROUND: Familial Mediterranean fever is a genetic disorder manifested by recurrent attacks of peritonitis, pleuritis and arthritis, and characterized by clinical, histological and laboratory evidence for localized and systemic inflammation. Colchicine treatment usually prevents the attacks and the associated inflammation. Inflammation may play an important role in the initiation and progression of atherosclerosis and ischemic heart disease. OBJECTIVE: To study the effect of inflammation and its prevention on the occurrence of IHD, using FMF as a model. METHODS AND PATIENTS: We studied the presence of IHD and its risk factors in 290 FMF patients aged 40 years or more, and in two control groups--233 spouses of the FMF patients, and 126 patients with inflammatory diseases obtained from other outpatient clinics, FMF patients were also compared with age and gender-matched individuals from the population reference data of the Israel Ministry of Health. RESULTS: The prevalence of IHD in FMF patients was significantly lower than in the group of controls from other outpatient clinics (15.5% vs. 30.2%, P < 0.05) and comparable with their spouses (11.2%) and with the matched general population in Israel (16%). CONCLUSIONS: These findings suggest that despite the evidence of recurrent inflammation, colchicine-treated FMF patients are not more predisposed to IHD than the normal population.

Adult↗
PubMed2000

Familial Mediterranean fever in two Bedouin families: mutation analysis and disease severity.

Familial Mediterranean fever (FMF) is an autosomal recessive disease prevalent among non-Ashkenazi Jews, Armenians, Arabs, and Turks. The Bedouin are nomad Arab tribes residing in desert margins of the Middle East and Arabia. FMF is quite rare in Bedouins, and here we report on two Bedouin families from southern Israel suffering from this disorder. The MEFV mutations found in the Bedouin patients M694I, V726A, and E148Q are consistent with their Arab origin. The disease severity score showed a mild to moderate severity disease in six patients. The Bedouins, leading a unique nomadic life, may prove instrumental in unraveling the role of environmental factors in the course and severity of FMF.

Amino Acid Substitution↗
PubMed2000

Behçet's disease.

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Behcet Syndrome↗
PubMed2000

Behçet's disease in Familial Mediterranean fever: characterization of the association between the two diseases.

OBJECTIVES: Familial Mediterranean fever (FMF) is a genetic disease, characterized by attacks of fever and painful manifestations. Several vasculitides are more common in FMF than in the general population. The aim of the study was to define and characterize the association between FMF and Behcet's disease (BD), a form of vasculitis not previously related to FMF. METHODS: We conducted a retrospective study in which FMF patients, also suffering from BD (FMF-BD), were recruited from about 4,000 patients registered in our clinic, using a computer survey. Patients identified by the screening process were examined, and those meeting the published criteria for the diagnoses of FMF and BD were classified as FMF-BD cases and compared with unselected FMF and BD controls. RESULTS: The prevalence of BD was higher in FMF than in populations known to be rich in BD (eg, 16 per 4,000 in FMF compared with 1 per 104 in Japan, P < .001). FMF-BD cases and FMF or BD controls were comparable in most demographic, clinical, and laboratory aspects studied. However, more cases than FMF-controls were of Iraqi/Turkish origin and responded less favorably to colchicine. A higher proportion of cases than BD controls had skin, central nervous system, and gastrointestinal manifestations, originated from North Africa, and had family history of BD. In most cases, as in most respective controls, the severity of FMF was of intermediate grade and the extensiveness of BD was limited. The HLA B5 antigen was present in 53% of BD cases and 40% of BD controls. CONCLUSIONS: BD should be included among the vasculitides complicating FMF. BD and FMF in patients with FMF-BD, and in patients suffering from each of these entities alone, are clinically and demographically comparable.

Adult↗
PubMed2000

Thromboembolism in a patient with transient eosinophilia and thrombocytopenia.

A 24-year-old woman with an unremarkable medical history who developed bilateral deep venous thrombosis and pulmonary emboli is presented. Associated findings were severe eosinophilia and moderate thrombocytopenia. Since the major acquired and hereditary thrombogenic disorders were ruled out in this case (including antiphospholipid syndrome and heparin-induced thrombocytopenia), we believe that the severe eosinophilia per se could be the pro-coagulant factor leading to thrombosis and embolism in our patient. The role of eosinophilia in thrombosis is discussed.

Adult↗
PubMed2000

Diagnostic and treatment concerns in familial Mediterranean fever.

Familial Mediterranean fever (FMF) is an autosomal, recessively inherited disease, affecting people of Jewish, Arabic, Turkish and Armenian ancestry. The disease is the prototype of the periodic febrile syndromes. Its hallmark is short attacks of fever and painful manifestations in the abdomen, joints, chest, scrotum and skin. Chronic and protracted manifestations, particularly nephropathic amyloidosis, chronic arthritis, and protracted myalgia, may also occur in the disease. The diagnosis of FMF should be considered in individuals of an appropriate ethnic background who present with febrile disease of episodic nature. The differential diagnosis in this case is broad and includes a large number of infectious, inflammatory and genetic diseases. However, in most cases, the very specific general and site-restricted features of the FMF attacks on the one hand, and the absence of manifestations typical of other conditions on the other hand, determine the diagnosis of FMF. This chapter presents clues and tips that help in the diagnosis and treatment of FMF.

Amyloidosis↗
PubMed2000

Erysipelas-like erythema of familial Mediterranean fever: clinicopathologic correlation.

BACKGROUND: Familial Mediterranean fever (FMF) is an autosomal recessive disease that tends to affect certain ethnic groups. It is characterized by recurrent, self-limited attacks of peritonitis, pleuritis, and synovitis. Erysipelas-like erythema (ELE) is the pathognomonic skin manifestation. Lesions are characterized by tender erythematous plaques, usually located on the lower legs. They may be triggered by physical effort and subside spontaneously within 48 to 72 hours of bed rest. Fever and leukocytosis may accompany this condition. OBJECTIVE: The purpose of this study was to describe the histology and the immunofluorescence findings in ELE and to discuss these observations in relation to the clinical findings in FMF. METHODS: We studied 7 patients with FMF in whom ELE developed. In all patients a biopsy was performed within 18 hours from onset of the lesion. In addition to routine hematoxylin and eosin stains, immunohistochemistry to evaluate the infiltrate and direct immunofluorescence were performed. Patients were followed up for their ELE lesions. RESULTS: Histologic examination revealed edema of the superficial dermis and sparse perivascular infiltrate composed of a few lymphocytes, neutrophils, and nuclear dust. Vasculitis was not observed. Direct immunofluorescence showed, in all cases, deposits of C3 in the wall of the small vessels of the superficial vascular plexus. In some cases fibrinogen and IgM were also observed. CONCLUSION: These findings are in accordance both with those found previously in the erysipelas-like phenomenon and those in the peritoneum of patients with FMF. The sparse infiltrate and the deposition of C3 also are compatible with the clinical picture of self-resolving lesions of short duration. It also suggests that erysipelas-like erythema belongs to the spectrum of neutrophilic dermatoses and supports a pathogenesis that involves abnormal inhibition of the inflammatory cascade.

Adult↗
PubMed2000

Pregnancy and amyloidosis: II. Suppression of amyloidogenesis during pregnancy.

The observation of a deleterious effect of pregnancy on kidney function in amyloidosis of familial Mediterranean fever suggests that pregnancy may enhance amyloidogenesis. To determine whether pregnancy may indeed affect amyloidogenesis, pregnant mice were made amyloidotic by administration of amyloid-enhancing factor (AEF) and AgNO3 at different points in time from conception, and amyloid- deposition was studied with the crush-and-smear technique. A possible effect of exogenous female sex hormones (beta-estradiol and progesterone) on amyloidogenesis was studied by administration of these hormones during amyloid induction in nonpregnant female mice. Amyloidogenesis was found to be significantly suppressed in mice during pregnancy. The reduction was possibly related to the effect of pregnancy on the inflammatory stimulus (AgNO3) and not on the administered AEF. Exogenous estrogen and progesterone failed to inhibit amyloidogenesis in nonpregnant mice. These findings suggest that pregnancy may suppress amyloidogenesis in mice. The suppression is caused by an anti-inflammatory effect of pregnancy. Estrogen and progesterone are probably unrelated to this finding.

Amyloidosis↗
PubMed2000

Reply

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Journal Article↗
PubMed2000

Protracted febrile myalgia of familial Mediterranean fever. Mutation analysis and clinical correlations.

Protracted febrile myalgia (PFM) is a rare form of vasculitic disease that affects patients with familial Mediterranean fever (FMF). Mutation analysis performed in 15 patients who suffered from this disorder showed that 9 of the 15 patients were homozygous for M694V. FMF in these 9 patients was associated with more severe symptoms compared to a group of 30 M694V homozygous FMF patients without PFM.

Adolescent↗