Association of the MIC-A gene and HLA-B51 with Behçet's disease in Arabs and non-Ashkenazi Jews in Israel.

BACKGROUND: Behçet's disease is known to be strongly associated with HLA-B51 in many different ethnic groups. Recently, it was suggested that MIC-A (major histocompatibility complex class I related gene A) is the pathogenic gene after strong association was found between the MIC-A A6 allele of the transmembrane region and the disease in Japanese and Greek patients, although in Greek patients this association was found to be due to linkage disequilibrium with HLA-B51. OBJECTIVES: To investigate microsatellite polymorphism in Arab and non-Ashkenazi Jewish (NAJ) patients in Israel, to determine whether this association occurs in these groups with Behçet's disease, and elucidate the associated HLA allele of the disease. METHODS: Forty four Israeli patients with Behçet's disease, including 20 Arabs and 24 NAJ, and 130 ethnically matched healthy controls were examined for MIC-A microsatellite polymorphism of the transmembrane region using polymerase chain reaction, autoradiography, and sequence analysis. RESULTS: The MIC-A A6 allele was significantly more frequent in the Arab patient group (19/20 (95%)) than in healthy Arab controls (25/42 (60%)) (p(corr)=0.015, OR=12.92), but not in the NAJ patients (16/24 (67%)) compared with NAJ healthy controls (48 /88 (55%)) (p(corr)=1.02, OR=1.667). In stratification analysis of the Arab subgroup, on the confounding effect of MIC-A A6 on HLA-B51 association and vice versa, Behçet's disease was distinctly associated only with HLA-B51. CONCLUSIONS: These results imply strong association between the MIC-A A6 allele and the disease in Israeli Arabs, but not in Israeli NAJ patients. The stratification analysis indicates that this association results secondarily from a strong linkage disequilibrium with HLA-B51, and the real disease susceptibility gene which plays a part in the development of Behçet's disease is most probably the HLA-B51 allele itself.

Arthritis related to ileal pouchitis following total proctocolectomy for ulcerative colitis.

OBJECTIVE: To draw attention to arthritis that developed in patients who underwent total proctocolectomy with ileal pouch construction for ulcerative colitis (UC). METHODS: The course of 4 patients who developed arthritis for the first time after ileal-anal pouch anastomosis is described. In addition, the relationship to the chronic inflammation of the pouch-pouchitis-is discussed. RESULTS: The clinical manifestations were very similar to seronegative arthritis affecting mainly the joints of the lower extremities. It was accompanied by enthesopathy (2 patients) and by sacroiliitis (2 patients). All had active pouchitis. The abnormal laboratory test results were nonspecific, indicating chronic inflammation. All 4 patients tested negative for human leukocyte antigen (HLA) B27, and none had other concomitant extraintestinal manifestations. Steroids rapidly improved both the arthritis and pouchitis; however, disease-modifying antirheumatic drugs were required to maintain remission with minimal daily steroids. Flares of the arthritis were always associated with active pouchitis, but the opposite was not necessarily true. CONCLUSIONS: Arthritis related to ileal pouchitis after total colectomy for UC has many similarities to the arthritis associated with inflammatory bowel disease and should be added to the list of enteropathic arthropathies.

Efficacy and safety of diacerein in osteoarthritis of the knee: a double-blind, placebo-controlled trial. The Diacerein Study Group.

OBJECTIVE: To evaluate the efficacy and safety of diacerein, a drug with interleukin-1beta--inhibitory activity in vitro, in patients with knee osteoarthritis (OA). METHODS: A total of 484 patients fulfilling the American College of Rheumatology criteria for knee OA were enrolled in this 16-week, randomized, double-blind, placebo-controlled, parallel study group with 3 diacerein dosages of 50 mg/day, 100 mg/day, and 150 mg/day (administered twice daily). RESULTS: In the intent-to-treat population, 100 mg/day diacerein (50 mg twice daily) was significantly superior (P < 0.05) to placebo using the primary criterion (visual analog scale [VAS] assessment of pain on movement). Significant improvement (P < 0.05) was also observed for the secondary criteria, which included the Western Ontario and McMaster Universities OA Index (WOMAC), the WOMAC subscores, and the VAS assessment of handicap. In patients treated with diacerein dosages of 50 mg/day and 150 mg/day, favorable but not significant results were observed for the primary criterion. The best daily dosage of diacerein, calculated from the effect on the VAS assessment of pain on movement, was 90.1 mg. In the per-protocol population, the analysis of the primary criterion showed significant dose-dependent differences (P < 0.05) between each of the 3 diacerein dosages and the placebo. No differences were observed among the 3 diacerein groups. A significantly higher incidence (P < 0.05) of adverse events (AEs), as well as a higher rate of dropoout due to AEs, was observed in patients treated with 150 mg/day diacerein versus those treated with placebo, 50 mg/day diacerein, or 100 mg/day diacerein. Mild-to-moderate transient changes in bowel habits were the most frequent AEs, increasing with the dosage. CONCLUSION: Diacerein, a drug for the treatment of OA, was shown to be an effective treatment for symptoms in patients with knee OA. Taking into account both efficacy and safety, the optimal daily dosage of diacerein for patients with knee OA is 100 mg/day (50 mg twice daily).

Preservation of fertility and ovarian function and minimizing gonadotoxicity in young women with systemic lupus erythematosus treated by chemotherapy.

BACKGROUND: Premature ovarian failure (POF) is a common long-term consequence of chemotherapy. Whereas the cytotoxic-induced damage is reversible in other tissues of rapidly dividing cells such as bone marrow, gastrointestinal tract and thymus, it appears to be progressive and irreversible in the ovary, where the number of germ cells is limited, fixed since the fetal life, and cannot be regenerated. The gonadal toxicity of cyclophosphamide is well known. In patients with lupus nephritis, premature ovarian failure (POF) was reported in half of all treated women after cyclophosphamide pulse therapy, affecting 100% of those older than 30 y, about 50% of the patients between the ages of 20-30y and only 13% of the patients younger than 20y of age. Following our preliminary encouraging experience in women with lymphoma, whereby the temporary induction of a prepubertal hormonal milieu, during chemotherapy, has significantly decreased the risk of POF, we have administered a monthly injection of gonadotropin-releasing hormone agonistic analogue (GnRH-a) to eight young women in parallel to alkylating agent chemotherapy. MATERIALS AND METHODS: A monthly intramuscular depot injection of 3.75 mg D-TRP6-GnRH-a (Decapeptyl C.R.) was administered after informed consent to eight women with autoimmune, severe connective tissue diseases (seven SLE patients and one woman with nephrotic syndrome) in parallel to chemotherapy, for up to six months. The institutional committee for human experimentation approved the protocol. The concentrations of FSH, LH, progesterone, and 17-beta-estradiol (E2) were measured before, during and after the GnRH-a/chemotherapy treatment. A transvaginal (or transabdominal) sonography (TVS) was performed on each patient before and after treatment. These eight treated patients (study group) were compared to a group of nine women similarly treated by cyclophosphamide pulses (CPT) or chlorambucil for SLE/connective tissue disease but were not referred for the GnRH-a adjuvant treatment. RESULTS: Whereas none of the eight women receiving GnRH-a in parallel to alkylating agent chemotherapy (cyclophosphamide (7) or chlorambucil (1)) suffered POF and hypergonadotropic amenorrhea, five of the nine ( > 50%) patients treated by alkylating agents (cyclophosphamide (8) or chlorambucil (1)) experienced POF. Whereas two of these five women were 35 y old, the other three were < or = 23 y old at the time of the chemotherapeutic insult. CONCLUSIONS: Our present results, extrapolating this encouraging experience from hematological malignant diseases to severe connective tissue diseases, such as SLE associated nephropathy or others, suggests that the beneficial effect of GnRH-a co-treatment may be exploited towards preservation of future fertility and ovarian function in every young woman of reproductive age, exposed to alkylating agents, such as cyclophosphamide and chlorambucil.

A randomized trial of the efficacy and tolerability of the COX-2 inhibitor rofecoxib vs ibuprofen in patients with osteoarthritis. Rofecoxib/Ibuprofen Comparator Study Group.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). It is not known whether a specific inhibitor of COX-2 will provide efficacy in osteoarthritis (OA) comparable with NSAIDs. Therefore, we compared the efficacy and safety of the rofecoxib, which specifically inhibits COX-2, with those of the NSAID ibuprofen in patients with OA. OBJECTIVE: To compare the clinical efficacy and tolerability of rofecoxib (12.5 and 25 mg once daily) with ibuprofen (800 mg 3 times daily). METHODS: A randomized, double-blind trial of 809 adults with OA was conducted. Patients with OA in whom the knee or hip was the primary source of pain were randomized to 1 of 4 treatment groups on demonstration of disease activity: placebo; rofecoxib, 12.5 or 25 mg once daily; or ibuprofen, 800 mg 3 times daily. Clinical efficacy and safety were monitored during a 6-week treatment period. RESULTS: Both doses of rofecoxib demonstrated efficacy clinically comparable with ibuprofen as assessed by 3 primary end points (pain walking on a flat surface [Western Ontario and McMaster Universities Osteoarthritis Index], patient global assessment of response to therapy, and investigator global assessment of disease status) according to predefined comparability criteria. Both rofecoxib doses and the ibuprofen dose provided significantly (P<.001) greater efficacy than placebo on all primary end points. Results from secondary end points were consistent with those of the primary end points. All treatments were well tolerated; the overall incidence rates of clinical adverse experiences were not significantly different (P>.05) among the treatment groups. CONCLUSION: Rofecoxib was well tolerated and provided clinical efficacy comparable with a high dose of the NSAID ibuprofen.

Acute myocardical infarction due to delirium tremens.

A 36-year-old patient with normal-appearing coronary arteries suffered an acute Q-wave myocardial infarction during acute alcohol withdrawal and delirium tremens. Sympathetic hyperactivity with coronary spasm and increased platelet reactivity are probably the underlying mechanisms.

Diffuse narrowing of coronary arteries in diabetic patients: the earliest phase of coronary artery disease.

Coronary arteries in diabetic patients appear to be narrower than in normal subjects, but this has not been examined systematically. To investigate this hypothesis we reviewed the data of 711 consecutive patients with angiographically 'normal coronary arteries'. Excluded were patients with valvular, myocardial or pericardial disease, and patients with hypertension or hyperlipidemia. Thirteen diabetic patients (10 men) and 22 nondiabetic persons (8 men) constituted the study and control groups, respectively. The diameters of the coronary arteries and their branches were measured and adjusted for body surface area. The sum of the proximal left anterior descending (LAD), circumflex and right coronary arteries (RCA) was calculated and defined as total coronary diameter (TCD). The sum of the distal LAD, first diagonal, first marginal and distal RCA was calculated and defined as total distal coronary diameter (dTCD). The clinical data of both groups were comparable. Adjusted TCD for body surface area was 5.4 +/- 1.1 and 6.5 +/- 1.1 mm/m2 (p < 0.05) in diabetics and nondiabetics, respectively, and adjusted dTCD was 4.9 +/- 1.2 and 6.1 +/- 1.2 mm/m2 (p = 0.01) in diabetics and normal subjects, respectively. Specific arteries and branches that were significantly smaller in diabetics included: left main coronary artery, distal LAD, first diagonal, proximal RCA, distal RCA, right ventricular branch, and posterolateral and posterior descending artery of RCA origin. Gender was not a confounding factor since the control group had a larger proportion of women and still larger arteries than the diabetic group. In conclusion, coronary arteries and their branches in diabetic patients have smaller diameters than normal subjects. This may be due to increased coronary tone, diffuse mild atherosclerosis or both.

Citrus fruit supplementation reduces lipoprotein oxidation in young men ingesting a diet high in saturated fat: presumptive evidence for an interaction between vitamins C and E in vivo.

To determine the effects of vitamin C on cardiovascular risk factors, we studied dietary vitamin C enrichment in 36 healthy male students consuming a diet high in saturated fatty acids. After a 1-mo run-in period during which the subjects consumed approximately 50 mg ascorbic acid/d (low-C diet), half of the subjects were randomly assigned to receive 500 mg ascorbic acid/d for an additional 2 mo (high-C diet). Plasma ascorbic acid increased from 13.5 micromol/L with the low-C diet to 51.7 micromol/L with the high-C diet. Plasma cholesterol increased slightly with the high-C diet, but not above baseline concentrations. This increase was offset by an increase in the lag period of in vitro LDL oxidation, which correlated with plasma ascorbic acid concentrations (r = 0.735, P = 0.0012). Lipoprotein vitamin E concentrations were unchanged with the two diets. There were no effects on concentrations of fibrinogen or factor VII. The fact that ascorbic acid reduced the in vitro susceptibility of lipoproteins to oxidation provides presumptive evidence for an interaction between aqueous and lipophilic antioxidants (vitamins C and E ) in maintaining the integrity of LDL particles.

Yellow nail syndrome.

The yellow nail syndrome was defined as a clinical entity in the 1960s. Although nail abnormalities were the first sign to be noticed, this syndrome is now known to involve multiple organ systems and its association with other diseases is well described. A review of the medical literature is provided.

A late retroperitoneal hematoma mimicking acute appendicitis--an unusual complication of coronary angioplasty.

Peripheral vascular complications following coronary angiography and angioplasty are well established. They consist of arterial bleeding, occlusion, false aneurysm, and a-v fistula. Bleeding and thrombosis are usually evident within the twelve hours after the procedure. A case of acute right lower quadrant abdominal pain five days following thrombolytic therapy and percutaneous transluminal coronary angioplasty is presented. A computerized tomography was compatible with a periappendiceal inflammation, and the patient underwent laparotomy. A large retroperitoneal hematoma was the only positive finding on operation. A late complication of coronary angioplasty, such as retroperitoneal hematoma, presenting as an acute abdomen, should be a part of the differential diagnosis in such cases.

Coexistence of familial antiphospholipid syndrome and factor V Leiden: impact on thrombotic diathesis.

Two young siblings who presented with an unusual recurrent severe thromboembolic phenomenon were found to have familial anti-phospholipid syndrome and were heterozygous for the factor V R506Q mutation. The coexistence of hereditary and acquired APC-resistance may explain the severity of thromboembolism.

Ultrastructural changes in mitochondria of the adrenal cortex of iron-deficient rats.

Male Sprague-Dawley rats aged 3 weeks that were maintained on an iron-deficient diet for 4-5 weeks developed severe anemia with markedly reduced hemoglobin levels (4.11 +/- 0.20 Hb g% versus controls 12.74 +/- 0.15 Hb g%). On sacrifice, the adrenal glands were removed and processed for light and transmission electron microscopy and enzyme cytochemistry. The major histological and ultrastructural changes in the adrenal cortex in response to the iron deficiency were seen in cells of the zona fasciculata, especially in its outer region, and to a lesser degree in cells of the zona reticularis. Structural changes were seen in the mitochondria of these cells, which often became grossly enlarged and developed unusual electron-dense inclusions. In addition, the lipid droplets in the iron-deficient cells of these regions were much less developed and less prominent compared with controls. Quantitative cytochemical localization of succinic dehydrogenase (SDH) activity in the adrenal glands showed that in iron-deficient rats there was an increase in SDH activity in the zona fasciculata (46%) and in the zona reticularis (74%), whereas there was a reduction of approximately 41% in SDH activity in the zona glomerulosa. Serum corticosterone levels were significantly raised in the iron-deficient rats compared with the control rats. Our results indicate that severe nutritional iron deficiency in rats causes ultrastructural and cytochemical changes in the mitochondria of the adrenal cortex accompanied by increased secretion of corticosterone.

Ultrastructural and cytochemical changes in the heart of iron-deficient rats.

Male Sprague-Dawley rats aged 3 weeks that were maintained on an iron-deficient diet for 4-5 weeks developed severe anemia with markedly reduced hemoglobin levels (3.94 +/- 0.14 Hb g% versus controls 12.9 +/- 0.11 Hb g%). Iron-deficiency resulted in marked cardiac hypertrophy (cardiomegaly). On sacrifice, the hearts were processed for light and transmission electron microscopy. The major ultrastructural changes were found in the hypertrophied left ventricle and left papillary muscles. Iron-deficiency caused marked edema in myocytes, sarcomeres were out of register, and degeneration and discontinuities in myofilaments were common. Iron-deficiency resulted in the enlargement of the interfibrillar mitochondria, changes in the matrix and the formation of electron-dense amorphous bodies. The ultrastructural changes in myocytes in response to experimental iron-deficiency were similar to those described by others in cases of experimental ischemia or hypoxia. Mitochondrial changes were also found in the atria of iron-deficient rats. Quantitative cytochemical measurement of succinate dehydrogenase activity was determined and was shown to be substantially reduced in the iron-deficient heart. In severely iron-deficient rats restored to a normal iron-sufficient diet for two weeks, hemoglobin levels recovered, however the myocytes of the hypertrophied left ventricles and papillary muscles continued to show severe degenerative changes.

Actigraphic measurements of sleep in rheumatoid arthritis: comparison of patients with low back pain and healthy controls.

Actigraphic recordings during sleep were carried out in patients with rheumatoid arthritis (RA), in patients with chronic low back pain, and in healthy controls for 4 consecutive nights. All derived measures of sleep quality showed that the sleep of patients with RA was significantly poorer than controls, while patients with chronic low back pain had sleep quality not significantly different from either group. Polysomnographically defined periodic movements in sleep were significantly related to sleep efficiency in patients with RA. Clinical status in these patients was significantly related to several actigraphic sleep measures.

Nonsteroidal antiinflammatory drug therapy in rheumatoid arthritis patients. Lack of association between clinical improvement and effects on sleep.

Thirteen patients with rheumatoid arthritis (mean +/- SD age 55.8 +/- 10.5 years) received 20 mg of tenoxicam daily for 90 days following a 3-7 day "washout" period and 4 days of placebo treatment. Clinical evaluations were conducted at the end of the washout period and at monthly intervals thereafter. All-night polysomnography was performed in a sleep laboratory during the last 2 days of placebo treatment and on days 13, 14, 89, and 90 of tenoxicam treatment. Although there was improvement in the patients' clinical condition, there were no treatment-related changes in any of the sleep parameters. Eight of the 13 patients, however, were found to have primary sleep disorders. Four had periodic leg movements during sleep, 3 had sleep apneas, and 1 had a combination of both disorders. The implications of these findings in the treatment of sleep disorders in patients with rheumatoid arthritis are discussed.