Cyclophosphamide type I hypersensitivity in systemic lupus erythematosus

Cyclophosphamide is an important immunosuppressive agent in the treatment of many rheumatic diseases. Urticaria and anaphylaxis to intravenous cyclophosphamide (i.v. CYC) have been reported in patients with haematological and solid organ malignancies. This is the first report in the rheumatology literature of a type I hypersensitivity reaction following monthly i.v. CYC. An 18-year-old girl with systemic lupus erythematosus (SLE) developed generalized urticaria (without concomitant angioedema or anaphylaxis) following i.v. CYC. She had previously developed life-threatening angioedema following a respiratory tract infection. She successfully completed regular pulse i.v. CYC with pre-medication with anti-histamine. In the absence of a severe type I hypersensitivity reaction and other suitable immunosuppressive agents, i.v. CYC may be safely continued with pre-medication and careful monitoring during each infusion.     

Cervical spine surgery in ankylosing spondylitis: Is the outcome good?

Summary Objective. To assess retrospectively, the outcome of cervical spine surgery in patients with ankylosing spondylitis (AS).Methods. A cross-sectional study of 3464 patients with identified AS, 19 patients of whom had cervical spine surgery. A self-administered questionnaire (including the use of 10 cm visual analogue scales, 0=none, 10=worst) assessing the complications of the surgery, patients' neck symptoms and post-surgery functional ability was sent to the 19 patients. Available casenotes and radiographs were reviewed. Results. The mean duration of follow-up was 10 years. One patient had two separate cervical spine operations. The types of surgery performed included cervical fusion (n=7), osteotomy (n=7) and laminectomy (n=6). Six patients had minor complications as a result of surgery. The majority of patients (93%) felt that their surgery had been successful. Most patients (81%) had a reduction in neck pain (mean pain score=3.1, SD 2.8) but increased neck stiffness (mean stiffness score=8.0, SD 2.9). Postoperative radiographs of 7 patients showed complete ankylosis of the cervical spine. Generally, few patients reported difficulty with reading/watching television (6%), sleep (19%) or driving (36%). A third of the patients were still in full time employment.Conclusions. About 1 in 200 patients with AS undergo cervical spine surgery. The surgery is often successful and complications are usually minor. Neck pain is often better after surgery and any remaining neck symptoms do not significantly affect the patient's sleep or functional activities. In this retrospective study, the long term outcome of cervical spine surgery in patients with AS appears to be good.The Arthritis and Rheumatism Council, the National Ankylosing Spondylitis Society, the Pilkington Trust and the Coates Trust. Dr Koh is supported by the Singapore government.     

Spontaneous hypoglycemia and insulin autoantibodies in a patient with Graves' disease

A 31-year-old woman with Graves' disease developed fasting hypoglycemia after treatment for 3 weeks with methimazole. Although the patient had not received exogenous insulin, high titers of insulin autoantibodies were found in serum and large amounts of total and free insulin (1550 and 82 microU/ml, respectively) and C-peptide reactivity (CPR, 22 ng/ml) were detected in serum. After glucose loading, blood glucose and total insulin levels increased abnormally. The immunoglobulin class of the autoantibodies was IgG and the light chains were of the kappa type. The titers of insulin autoantibodies, elevated serum total and free insulin, and CPR levels decreased gradually, but insulin autoantibodies and elevated insulin levels were still present in the serum 8 months after the episode of hypoglycemia. These findings suggest that the patient's fasting hypoglycemia was due to excess free insulin released from antibody-bound insulin, and that methimazole might play a role in the initiation of production of insulin autoantibodies.     

Augmentation of antitumor effects by NK cell inhibitory receptor blockade in vitro and in vivo

Subsets of natural killer (NK) cells are characterized by the expression of inhibitory and/or stimulatory receptors specific for major histocompatibility complex (MHC) class I determinants. In mice, these include the Ly49 family of molecules. One mechanism by which tumor cells may evade NK cell killing is by expressing the appropriate MHC class I and binding inhibitory Ly49 receptors. Therefore, the question of whether blocking the interaction between the Ly49 inhibitory receptors on NK and MHC class I cells on tumor cells augments antitumor activity was investigated. Blockade of Ly49C and I inhibitory receptors using F(ab')(2) fragments of the 5E6 monoclonal antibody (mAb) resulted in increased cytotoxicity against syngeneic tumors and decreased tumor cell growth in vitro. The effect of 5E6 F(ab')(2) was specific for the MHC of the tumor, as the use of F(ab')(2) of the mAb against Ly49G2 failed to increase NK activity. Treatment of leukemia-bearing mice with 5E6 F(ab')(2) fragments or adoptive transfer of NK cells treated ex vivo with the F(ab')(2) resulted in significant increases in survival. These results demonstrate that blockade of NK inhibitory receptors enhances antitumor activity both in vitro and in vivo, suggesting that NK inhibitory receptors can be responsible for diminishing antitumor responses. Therefore, strategies to block inhibitory receptors may be of potential use in increasing the efficacy of immunotherapy. (Blood. 2001;97:3132-3137)     

Comparison of Doppler ultrasonography and the hepatic venous pressure gradient in assessing portal hypertension in liver cirrhosis

BACKGROUND AND AIM: This prospective study aimed to determine whether Doppler ultrasonography can represent the hepatic venous pressure gradient (HVPG) as an assessment of the severity of portal hypertension and the response to terlipressin, which reduces the portal pressure in liver cirrhosis. METHODS: The HVPG and the Doppler ultrasonographic parameters, such as the portal venous velocity and the splenic venous velocity, the pulsatility and the resistive index of the hepatic, splenic and renal arteries were measured in 138 patients with liver cirrhosis. The changes in the HVPG and the portal venous velocity after administering terlipressin were evaluated in 43 of the 138 patients. The patients who showed a reduction in the HVPG of more than 20% of the baseline were defined as responders to terlipressin. RESULTS: None of the Doppler ultrasonographic parameters correlated with the HVPG. Both the HVPG (28.0 +/- 19.8%) and the portal venous velocity (29.7 +/- 13.2%) showed a significant reduction after terlipressin administration. However, the portal venous velocity decreased significantly, not only in the responders (31.0 +/- 12.0%) but also in the non-responders (25.2 +/- 16.4%). CONCLUSIONS: Doppler ultrasonography does not represent the HVPG, and is therefore not suitable for replacing HVPG as a means of assessing the severity of portal hypertension and the response to drugs which reduce the portal pressure in liver cirrhosis.     

Lithium therapy and cerebrospinal fluid biomarker levels in Alzheimer's disease

Recent studies suggest that lithium may retard pathological deterioration by inhibiting aberrant phosphorylation of tau in Alzheimer's disease (AD). Here, we describe three cases of AD who were treated with lithium for agitation. However, there was no obvious improvement either in global cognition, agitation or cerebrospinal fluid markers that were thought to reflect Alzheimer's pathology. Increased dosages of lithium were not tolerated by the patients because of adverse effects. It is likely that AD patients do not benefit from lithium therapy as an alternative choice of treatment.     

Gender differences in plaque characteristics of culprit lesions in patients with ST elevation myocardial infarction

There is limited research on plaque characteristics of ST elevation myocardial infarction (STEMI) patients according to the gender and age. 280 Consecutive STEMI patients who underwent VH-IVUS imaging on culprit before percutaneous coronary intervention (PCI) were enrolled in this study. Women were significantly older than men (69.8 ± 10 vs. 55.9 ± 11.3, p < 0.001). After propensity matching, men had higher plaque burden (79.7 ± 7.8 vs. 73.7 ± 13.0 %, p = 0.010), more fibro-fatty tissue (12.8 ± 9.9 vs. 9.5 ± 6.8 %, p = 0.04) and less dense calcium than women (8.4 ± 5.8 vs. 12.3 ± 8.7 %, p = 0.007). Subgroups dividing by 50, 65, 75 years old, plaque burden was higher in elderly men aged 66–75 years compared to the young men aged less than 50 (75.5 ± 9.2 vs. 68.4 ± 10.1 %, p = 0.012). And middle aged men ranged 51–65 years showed significantly more plaque burden at minimal lumen area site than matched aged women (77.5 ± 8.0 vs. 69.0 ± 17.6 %, p = 0.012). Elderly women aged 66–75 years showed significantly more necrotic core (28.6 ± 7.3 %) and dense calcium (14.9 ± 7.5 %) compared to all the younger or matched subgroups of men. These differences in plaque composition are blunted in the very elderly of men and women aged over 75 years. The findings may explain the gender differences in clinical prognosis in STEMI patients.     

Abdominal crisis in a young man with systemic lupus erythematosus

Medium-sized artery aneurysms are rare in patients with systemic lupus erythematosus (SLE). We report on a 21-year-old Chinese man with SLE and secondary antiphospholipid syndrome (APS) who presented with acute abdominal pain due to a ruptured right hepatic artery aneurysm. He was also found to have aneurysms of the left hepatic artery and splenic artery on autopsy. There have been only eight cases of hepatic artery aneurysm and one case of splenic artery aneurysm associated with SLE in the English literature. Abdominal aneurysm must be suspected in SLE patients presenting with acute abdominal pain, haemoperitoneum or occult bleeding.     

Antagonistic regulation of myogenesis by two deubiquitinating enzymes,UBP45 and UBP69

Protein modification by ubiquitin is a dynamic and reversible process that is involved in the regulation of a variety of cellular processes. Here, we show that myogenic differentiation of embryonic muscle cells is antagonistically regulated by two deubiquitinating enzymes, UBP45 and UBP69, that are generated by alternative splicing. Both enzymes cleaved off ubiquitin from polyubiquitinated protein conjugates in vivo as well as from linear ubiquitin-protein fusions in vitro. In cultured myoblasts, the level of UBP69 mRNA markedly but transiently increased before membrane fusion, whereas that of UBP45 mRNA increased as the cells fused to form myotubes. Both myoblast fusion and accumulation of myosin heavy chain were dramatically stimulated by the stable expression of UBP69 but strongly attenuated by that of the catalytically inactive form of the protease, suggesting that the mutant enzyme acts dominant negatively on the function of the wild-type protease. In contrast, stable expression of UBP45 completely blocked both of the myogenic processes but that of inactive enzyme did not, indicating that the catalytic activity of the enzyme is essential for its inhibitory effects. These results indicate that differential expression of UBP45 and UBP69 is involved in the regulation of muscle cell differentiation.     

COMP-Ang1: a designed angiopoietin-1 variant with nonleaky angiogenic activity

Angiopoietin-1 (Ang1) has potential therapeutic applications in inducing angiogenesis, enhancing endothelial cell survival, and preventing vascular leakage. However, production of Ang1 is hindered by aggregation and insolubility resulting from disulfide-linked higher-order structures. Here, by replacing the N-terminal portion of Ang1 with the short coiled-coil domain of cartilage oligomeric matrix protein (COMP), we have generated a soluble, stable, and potent Ang1 variant, COMP-Ang1. This variant is more potent than native Ang1 in phosphorylating the tyrosine kinase with Ig and epidermal growth factor homology domain 2 (Tie2) receptor and Akt in primary cultured endothelial cells, enhancing angiogenesis in vitro and increasing adult angiogenesis in vivo. Thus, COMP-Ang1 is an effective alternative to native Ang1 for therapeutic angiogenesis in vivo.