Israel Medical Association Journal

Background: Systemic sclerosis (SSc) is a connective tissue disease that may affect the heart and the autonomic nervous system (ANS). There is little knowledge regarding the degree of ANS involvement in SSc patients with unknown cardiac disease.

Objectives: To evaluate cardiac and pupillary autonomic functions in patients before cardiac involvement has emerged.

Methods: The study comprised 19 patients with SSc and 29 healthy controls. Heart rate variability (HRV) analysis for time and frequency domains, as well as deep breathing test and Ewing maneuvers, were performed in all patients. Automated pupillometry for the evaluation of pupillary diameter and pupillary light reflex was completed in 8 SSc patients and 21 controls.

Results: Both groups had similar characteristics, except for medications that were more commonly or solely prescribed for SSc patients. Compared with control subjects, the SSc patients had significantly lower HRV parameters of NN50 (15.8 ± 24.4 vs. 33.9 ± 33.1, P = 0.03), pNN50 (4.9 ± 7.4% vs.10.8 ± 10.8%, P = 0.03), and triangular index (11.7 ± 3.4 vs. 15.7 ± 5.8, P = 0.02). Abnormal adaptive responses in heart rate changes were recorded during deep breathing tests and Ewing maneuvers. There was no significant difference in any of the pupillometric indices or other HRV parameters within groups.

Conclusions: SSc patients may manifest cardiac autonomic dysfunction, while their autonomic pupillary function is seemingly spared. The role of certain medications, the significance of differential organ involvement, as well as the prognostic value of our findings should be evaluated in future studies

Background: Postpericardiotomy syndrome (PPS) is characterized by pleuro-pericardial inflammation, which occurs in patients undergoing surgical procedures involving the pleura, pericardium, or both. The syndrome is considered to be immune mediated. However, its pathogenesis is not fully understood. It has previously been demonstrated that the Mediterranean Fever (MEFV) gene, which is associated with familial Mediterranean fever (FMF), has a role in the activation and expression of several inflammatory diseases.

Objectives: To investigate whether carriage of the MEFV mutation may precipitate PPS or affect its phenotype.

Methods: The study population included 45 patients who underwent cardiac surgery and developed PPS. The control group was comprised of 41 patients who did not develop PPS. Clinical and demographic data was collected. The severity of PPS was evaluated. Genetic analysis to determine the carriage of one the three most common MEFV gene mutations (M694V, V726A, E148Q) was performed. The carriage rate of MEFV mutations in patients with and without PPS was compared. Association between MEFV mutation carriage and severity of PPS was evaluated. 

Results: The rate of mutation carriage in the MEFV gene was similar in patients with and without PPS (15.6% in the study groups vs. 29.3% in the control group, P = 0.1937). The rate of mutation carriage in the MEFV gene was significantly lower among patients with severe PPS as compared to patients with mild-moderate PPS (4.8% vs. 25%, P < 0.05).

Conclusions: Carriage of mutations in the MEFV gene is not associated with development of PPS; however, it may affect PPS severity.

 

Abstract

Background: The relationship between autonomic nervous system (ANS) dysfunction and familial Mediterranean fever (FMF) is controversial. We recently reported normal heart rate variability (HRV), suggestive of normal ANS, in patients with uncomplicated FMF.

Objectives: To evaluate ANS function in colchicine non-responders by using the HRV tool.

Methods: The study group comprised 24 FMF patients suffering from recurrent FMF attacks despite treatment with a maximal colchicine dose. Electrocardiogram was measured under strict conditions and HRV parameters were calculated. Results were compared with age- and gender-matched unaffected controls.

Results: No statistically significant difference was found between the groups in any of the HRV parameters: maximal RR, minimal RR and average RR intervals, standard deviation of RR interval, square root of the mean squared differences of successive RR intervals, HRV triangular index, NN50, pNN50, and power spectral analysis parameters.

Conclusions: Although a small difference in HRV parameters in the current study cannot be entirely excluded, FMF patients in whom colchicine did not provide adequate symptomatic relief and who did not develop amyloidosis appear to have normal HRV parameters suggestive of normal ANS function, compared with healthy adults. 

Background: Transthyretin (TTR)-associated familial amyloid polyneuropathy (FAP) is an autosomal dominant multisystem disease with neurological and extra-neurological manifestations. It is caused by various mutations in the TTR gene leading to the formation of insoluble amyloid.

Objectives: To describe the clinical and genetic findings in patients with TTR-associated FAP in Israel.

Methods: We evaluated eight patients clinically and genetically during the years 2006 to 2011.

Results: At onset, all the patients exhibited sensory loss of the lower and upper limbs, five patients experienced muscle pain, and one patient had lower limb weakness. Five patients had autonomic nervous system manifestations, and four demonstrated evidence of amyloid cardiomyopathy. Nerve conduction studies showed sensorimotor axonal neuropathy in all patients. Sural nerve biopsies were obtained in five patients; only three biopsies revealed amyloid deposit. In four patients of Yemenite descent, genetic analysis of the TTR gene demonstrated ser77tyr mutation. One patient of Tunisian descent and one Ashkenazi patient harbored the val30met mutation. One patient of Iranian descent showed val32ala mutation, and another Ashkenazi patient showed phe33leu mutation.

Conclusions: TTR-associated FAP is a progressive and fatal disease that exists in the Israeli population and is unproportionally common among Yemenite Jews. This disease may be under-diagnosed and should be considered in the differential diagnosis of any patient with rapidly progressive neuropathy, especially with autonomic involvement or extra-neural features. The absence of amyloid in nerve biopsy should not rule out the diagnosis.  
 

Background: Familial Mediterranean fever (FMF) is a recessively inherited disease with a variety of clinical presentations. The disease is associated with mutations in the FMF gene (MEFV), which encodes for the pyrin protein. The role of the E148Q pyrin mutation in the FMF phenotype remains inconclusive, and some authors even view it as a disease-insignificant polymorphism. The calculated change, imposed by this mutation on pyrin structure, may help to understand the role of this mutation

Objectives: To calculate the relative electrochemical effect of the E148Q mutation on the structure of pyrin protein.

Methods: The electronic properties of the wild-type pyrin molecule and its common mutated forms were computed for the full-length molecule and its segments, encoded by exons 2 and 10, using the HyperChem 7.5 program with one of the molecular mechanical methods (MM+). The change in the structure of the molecule, expressed as a change in energy gain, conferred by the mutations was determined.

Results: The E148Q mutation caused deviation from the wild-type pyrin segment encoded by exon 2 by 1.15% and from the whole pyrin molecule by 0.75%, comparable to the R202Q mutation and less than the M694V mutation which caused a deviation from the wild-type structure of the whole pyrin molecule by 1.5%.

Conclusions: A quantum-chemistry based model suggests that the structural effect of the E148Q mutation is indeed low, but not zero. 
 

Background: Amyloidosis of familial Mediterranean fever (FMF) may lead to end-stage renal failure, culminating in kidney transplantation. Since amyloidosis is prompted by high serum amyloid A (SAA) levels, increased SAA is expected to persist after transplantation. However, no data are available to confirm such an assumption.

 Objectives: To determine SAA levels in kidney-transplanted FMF-amyloidosis patients and evaluate risk factors for the expected high SAA levels in this patient group.

Methods: SAA, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) values were obtained from 16 kidney-transplanted FMF-amyloidosis patients, 18 FMF patients without amyloidosis and 20 kidney-transplanted patients with non-inflammatory underlying disease. Demographic, clinical and genetic risk factors evaluation was based on data extracted from files, interviews and examination of the patients.

Results: SAA level in FMF patients who underwent kidney transplantation due to amyloidosis was elevated with a mean of 21.1 ± 11.8 mg/L (normal ≤ 10 mg/L). It was comparable to that of transplanted patients with non-inflammatory disorders, but tended to be higher than in FMF patients without amyloidosis (7.38 ± 6.36, P = 0.08). Possible risk factors for the elevated SAA levels in kidney transplant patients that were excluded were ethnic origin, MEFV mutations, gender, age and disease duration.

Conclusions: Kidney-transplanted patients with FMF-amyloidosis and with other non-FMF causes displayed mildly elevated SAA levels, possibly resulting from exposure to foreign tissue rather than from various FMF-related factors. 

Backgound: Colchicine is widely used for treating gout and familial Mediterranean fever. However, studies in animal models have reported ill effects of colchicine on the central nervous system, including cognitive function.

Objectives: To evaluate the cognitive status of elderly FMF[1] patients on long-term colchicine treatment.

Methods: The study group consisted of 55 FMF patients aged 74 ± 5, attending an FMF outpatient clinic and receiving colchicine treatment for 25.1 ± 8.9 years. The Mini-Mental State Examination was used for cognitive evaluation. Patients' scores were compared with accepted age- and education-adjusted cutoff scores, population-based norms, and scores of a matched control group of 56 subjects.

Results: Individually, all colchicine-treated FMF patients scored well above the age- and education-corrected cutoff scores. Overall, there was a large difference, 5.0 ± 1.6, from the expected cutoff points, in favor of the study group scores (P < 0.001). The individual scores of the control group were also above the cutoff points, however with a lower but still statistically significant difference (3.71 ± 1.15 points, P < 0.001). Compared to population-based norms adjusted by age and education, the study group had significantly higher mean MMSE[2] scores (27.2 ± 2.2 vs. 25.5 ± 2.4, P < 0.001). The control group’s scores were also somewhat higher than expected, but not significantly so.

Conclusions: Our results do not support the view that prolonged colchicine treatment may be associated with cognitive impairment. On the contrary, it is possible that long-term colchicine treatment may even confer protection against cognitive decline in patients with FMF.

Objectives: To report our experience with three patients who developed autoimmune disease following prostatectomy.

Patients: Three patients presented with autoimmune phenomenon soon after a prostectomy for BPH[1] or prostatic carcinoma: one had clinically diagnosed temporal arteritis, one had leukocytoclastic vasculitis, and the third patient developed sensory Guillian-Barré syndrome following prostatectomy.

Conclusions: In view of the temporal association between the removal of the prostate gland and the autoimmune process, combined with previously known immunohistologic features of BPH, a cause-effect relationship probably exists.

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[1] BPH = benign prostatic hypertrophy

Background: Heterotopic ossification is a common complication of hip surgery and musculoskeletal or brain traumas.

Objectives: To confirm by in vivo study that colchicine inhibits osteoblast cell proliferation with marked decrease in tissue mineralization.

Methods: Heterotopic ossification was induced in three groups of New Zealand white rabbits (females, 6 months old, weight 3–3.5 kg) by injecting 2 ml bone marrow drawn from the iliac crest into their right thigh muscle. To prevent heterotopic ossification, colchicine (0.25 mg/day) was administered orally for 4 weeks to two groups of adult rabbits: group A (preload group) – 1 week preceding bone marrow injection; group B – on day of injection; and group C – control group.

Results: After 4 weeks the rabbits were evaluated by radiographs and ultrasound for evidence of heterotopic ossification. At the end of the study histologic samples were taken from all the thighs. Imaging and histologic studies showed, with statistical significance, almost complete prevention of heterotopic ossification formation in group A (preload) and a marked decrease in group B, when compared with the controls in whom large new bone had formed at the injection site. These results indicated the inhibitory effects of colchicine on a bone-forming process in soft tissue such as heterotopic ossification.

Conclusions: The role of colchicine in preventing heterotopic ossification in other bone-forming conditions, such as hip arthroplasty or pelvic trauma, and after brain trauma, remains to be evaluated in a clinical setting.