Disseminated multiple ostial stenoses in a young woman presenting as unstable angina

A previously healthy 40-year-old woman presented as unstable angina. She had a family history of stroke as the only cardiovascular risk factor. Her blood pressure on admission was 150/90 mmHg. Laboratory study showed absolutely all negative markers of inflammation, autoimmune disorders, or atherosclerosis. Coronary angiography revealed subtotal ostial stenosis of the right coronary artery (RCA). Additionally, total occlusion of the ostium of the right subclavian artery and severe discrete ostial stenoses of left subclavian, celiac, superior mesenteric, both renal arteries were demonstrated on multidetector computed tomographic and magnetic resonance angiographies. She underwent stent implantation at the culprit lesion of RCA, and the left subclavian and both renal arteries. The fluorine-18-fluorodeoxyglucose positron-emission tomography-computed tomography showed slightly increased glucose metabolism at the proximal left subclavian artery. She is doing very well for 10 months during taking antiplatelet agents only.     

Ulnar artery vasculopathy in systemic sclerosis

Although digital ulceration frequently occurs in patients with systemic sclerosis, there have been few reports on macrovascular involvement. Macrovascular disease in systemic sclerosis has recently been described. We retrospectively reviewed the medical records and brachial angiographic findings of 19 systemic sclerosis patients, who exhibited Raynaud’s phenomenon and digital ulceration. We found that ulnar artery involvement is frequent in systemic sclerosis, although the precise mechanism is not known. There was no significant difference in risk factors of macrovascular disease between ulnar artery-involved patients and not-involved subjects. Thirteen patients underwent surgical intervention; five of the 13 patients had vascular graft performed due to ulnar artery involvement. We suggest that angiographic screening and early surgical intervention such as revascularization should be considered in patients with systemic sclerosis who manifest a severe form of Raynaud’s phenomenon and/or digital ulceration and especially in patients with diffuse sclerosis.     

Therapeutic effect of anti-vascular endothelial growth factor receptor I antibody in the established collagen-induced arthritis mouse model

Synovial angiogenesis plays an important role in the inflammation in rheumatoid arthritis (RA). Vascular endothelial growth factor (VEGF) is a key molecule in angiogenesis and binds to specific receptors, known as vascular endothelial growth factor receptor I (VEGF RI). In this study, we investigated the therapeutic efficacy of anti-VEGF RI antibody (Ab) on RA using a collagen-induced arthritis (CIA) mouse model. Twelve DBA/1 mice were divided into three groups. All mice except controls were injected with type II collagen. Mice in the anti-VEGF-RI-Ab-treated groups were injected on one posterior paw with 50 μg anti-VEGF RI Ab twice weekly for 3 weeks. Arthritis score and paw thickness were measured and histopathologic assessment of joint sections was performed by hematoxylin–eosin. The infiltration of CD45⁺ inflammatory cells and neovascularization were evaluated by immunohistochemical staining. Anti-VEGF RI Ab significantly attenuated the arthritis severity and histopathologic findings in the CIA mice model. The infiltration of CD45⁺ cells decreased in anti-VEGF-RI-Ab-treated joint tissues. Staining for CD31 revealed reduced synovial neovascularization after anti-VEGF RI Ab treatment. The data showing that in vivo administration of anti-VEGF RI Ab suppressed arthritis in established CIA mice suggest anti-VEGF RI Ab treatment may serve as a new therapeutic modality for RA.     

Induction of apoptosis by the ginsenoside Rh2 by internalization of lipid rafts and caveolae and inactivation of Akt

Background and purpose:

Lipid rafts and caveolae are membrane microdomains with important roles in cell survival signalling involving the Akt pathway. Cholesterol is important for the structure and function of these microdomains. The ginsenoside Rh2 exhibits anti-tumour activity. Because Rh2 is structurally similar to cholesterol, we investigated the possibility that Rh2 exerted its anti-tumour effect by modulating rafts and caveolae.

Experimental approach:

A431 cells (human epidermoid carcinoma cell line) were treated with Rh2 and the effects on cell apoptosis, raft localization and Akt activation measured. We also examined the effects of over-expression of Akt and active-Akt on Rh2-induced cell death.

Key results:

Rh2 induced apoptosis concentration- and time-dependently. Rh2 reduced the levels of rafts and caveolae in the plasma membrane and increased their internalization. Furthermore, Akt activity was decreased and consequently, Akt-dependent phosphorylation of Bad, a pro-survival protein, was decreased whereas the pro-apoptotic proteins, Bim and Bax, were increased upon Rh2 treatment. Unlike microdomain internalization induce by cholesterol depletion, Rh2-mediated internalization of rafts and caveolae was not reversed by cholesterol addition. Also, cholesterol addition did not restore Akt activation or rescue cells from Rh2-induced cell death. Rh2-induced cell death was attenuated in MDA-MB-231 cells over-expressing either wild-type or dominant-active Akt.

Conclusions and implications:

Rh2 induced internalization of rafts and caveolae, leading to Akt inactivation, and ultimately apoptosis. Because elevated levels of membrane rafts and caveolae, and Akt activation have been correlated with cancer development, internalization of these microdomains by Rh2 could potentially be used as an anti-cancer therapy.     

Oral Sulfasalazine as a Clinical BCRP Probe Substrate: Pharmacokinetic Effects of Genetic Variation (C421A) and Pantoprazole Coadministration

This study evaluated the utility of oral sulfasalazine as a probe substrate for Breast Cancer Resistance Protein (BCRP; ABCG2) activity by assessing the impact of genetic variation or coadministration of an inhibitor (pantoprazole) on plasma and urine pharmacokinetics of sulfasalazine and metabolites. Thirty-six healthy male subjects prescreened for ABCG2 421CC (reference activity), CA, and AA (lower activity) genotypes (N = 12 each) received a single 500 mg oral dose of enteric coated sulfasalazine alone, with 40 mg pantoprazole, or with 40 mg famotidine (gastrointestinal pH control) in a 3-period, single fixed sequence, crossover design. No significant difference in sulfasalazine or metabolite pharmacokinetics in 421AA or CA compared to 421CC subjects was found; however, high inter-subject variability was observed. Geometric mean (95% CI) sulfasalazine plasma AUC_(0–∞) values were 32.1 (13.2, 78.1), 16.8 (7.15, 39.6) and 62.7 (33.4, 118) µg h/mL, and C_max were 4.01 (1.62, 9.92), 1.70 (0.66, 4.40), and 6.86 (3.61, 13.0) µg/mL for CC, CA, and AA subjects, respectively. Pantoprazole and famotidine did not affect sulfasalazine pharmacokinetics in any genotypic cohort. These results suggest that the pharmacokinetics of oral, enteric-coated 500 mg sulfasalazine are not sufficiently sensitive to ABCG2 genetic variation or inhibitors to be useful as a clinical probe substrate of BCRP activity. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:1046–1062, 2010     

Neonatal outcome after preterm delivery in HELLP syndrome

The present study compares neonatal outcome after preterm delivery of infants in pregnancies complicated by the HELLP syndrome or severe preeclampsia (PS). The maternal and neonatal charts of 71 out of a total of 409 pregnancies that were complicated by hypertensive disorders at Severance hospital between January 1995 and December 2004 were reviewed. Twenty-one pregnancies were complicated by HELLP syndrome and 50 pregnancies were complicated by PS. Fifty normotensive (NT) patients who delivered because of preterm labor comprised the control group. Results were analyzed by the chi-square test and ANOVA. Gestational age and maternal age at delivery were matched among the three groups. The neonatal outcomes of the HELLP syndrome group were compared with the PS and NT groups. There were significant differences between the HELLP syndrome group and the PS group in the incidence of intraventricular hemorrhage (IVH) (61.9% vs. 26%, p=0.006), sepsis (85.7% vs. 44%, p =0.003) and mechanical ventilation (MV) rate (81% vs. 54%, p=0.039). There were significant differences between the HELLP syndrome group and the NT group in the incidence of neonatal death (ND) (19.5% vs. 2.0%, p=0.034), respiratory distress syndrome (RDS) (38.1% vs. 8%, p=0.0045), IVH (61.9% vs. 4%, p < 0.0001), sepsis (85.7% vs. 14%, p < 0.0001), intensive care (IC) (85.7% vs. 24%, p < 0.0001) and MV rate (80.1% vs. 14%, p < 0.0001). There were also significant differences between the PS and NT groups in the incidence of ND (20% vs. 2%, p=0.0192), RDS (30% vs. 8%, p=0.0085), IVH (26% vs. 4%, p=0.0070), sepsis (44% vs. 14%, p=0.0015), IC (78% vs. 24%, p < 0.0001), MV rate (54% vs. 14%, p < 0.0001) and low 5-min APGAR score (50% vs. 16%, p=0.0005). This study shows increased morbidity in newborns of mothers complicated with HELLP syndrome and indicates that early, regular and high quality management of these patients is essential to improve both maternal and neonatal outcome.     

Does the Tibial and Sural Nerve Transection Model Represent Sympathetically Independent Pain?

Neuropathic pain can be divided into sympathetically maintained pain (SMP) and sympathetically independent pain (SIP). Rats with tibial and sural nerve transection (TST) produce neuropathic pain behaviors, including spontaneous pain, tactile allodynia, and cold allodynia. The present study was undertaken to examine whether rats with TST would represent SMP- or SIP-dominant neuropathic pain by lumbar surgical sympathectomy. The TST model was generated by transecting the tibial and sural nerves, leaving the common peroneal nerve intact. Animals were divided into the sympathectomy group and the sham group. For the sympathectomy group, the sympathetic chain was removed bilaterally from L2 to L6 one week after nerve transection. The success of the sympathectomy was verified by measuring skin temperature on the hind paw and by infra red thermography. Tactile allodynia was assessed using von Frey filaments, and cold allodynia was assessed using acetone drops. A majority of the rats exhibited withdrawal behaviors in response to tactile and cold stimulations after nerve stimulation. Neither tactile allodynia nor cold allodynia improved after successful sympathectomy, and there were no differences in the threshold of tactile and cold allodynia between the sympathectomy and sham groups. Tactile allodynia and cold allodynia in the neuropathic pain model of TST are not dependent on the sympathetic nervous system, and this model can be used to investigate SIP syndromes.     

Langerhans cell sarcoma arising from Langerhans cell histiocytosis: a case report

Langerhans cell sarcoma (LCS) is a neoplastic proliferation of Langerhans cells that have overtly malignant cytologic features. It is a very rare disease and theoretically, it can present de novo or progress from an antecedent Langerhans cell histiocytosis (LCH). However, to our knowledge, LCS arising from an antecedent LCH has not been reported on. We present here a case of LCS arising from a pulmonary LCH. A 34 yr-old man who was a smoker, had a fever and a chronic cough. Computed tomographic (CT) scan revealed multiple tiny nodules in both lungs. The thoracoscopic lung biopsy revealed LCH. The patient quit smoking, but he received no other specific treatment. One year later, the follow up chest CT scan showed a 4 cm-sized mass in the left lower lobe of the lung. A lobectomy was then performed. Microscopic examination of the mass revealed an infiltrative proliferation of large cells that had malignant cytologic features. Immunohistochemical stains showed a strong reactivity for S-100 and CD68, and a focal reactivity for CD1a. We think this is the first case of LCS arising from LCH.