Prospective study of low-dose cyclosporine A in patients with refractory lupus nephritis

We evaluated the efficacy and safety of low-dose cyclosporine A (CsA) in patients with refractory lupus nephritis. Nine patients with systemic lupus erythematosus who had lupus nephritis resistant to previous treatment with glucocorticoids and immunosuppressants other than CsA were enrolled in a prospective, open-label study. All patients initially received 2.5 mg/kg per day of CsA; the dosage was adjusted to reach a blood trough level of 80–150 ng/ml. The urinary protein concentration decreased significantly 2 weeks after the initiation of treatment. After 30 weeks of CsA treatment, the mean urinary protein concentration was more than 50% lower than the baseline value, and urinary casts had decreased significantly. There were no significant changes in the levels of serum creatinine, serum anti-double-stranded DNA antibodies, or CH50 during any part of the study. The dose of glucocorticoids was significantly tapered by approximately 50%, without any disease flare. Hypertension developed in one patient, but was controlled with antihypertensive agents. Our results suggest that low-dose CsA therapy is an effective and less toxic alternative to conventional cyclophosphamide therapy for the management of refractory lupus nephritis.     

Synergetic antioxidant and vasodilatory action of carbon monoxide in angiotensin II - induced cardiac hypertrophy

The aim of this study was to determine the effects of carbon monoxide (CO) at a nontoxic low concentration on the cardiac and vascular hypertrophic response and reactive oxygen species generation, compared with the action of a vasodilator, hydralazine. Twelve- to 16-week-old low-density lipoprotein receptor knockout mice were subjected to angiotensin II (Ang II) infusion using osmotic minipumps (Ang II group; n=11) for 2 weeks. Controls were administered saline (n=10). Animals were exposed to CO in a chamber at 60 ppm for 2 hours per day with or without Ang II infusion (Ang II+CO group, n=10; CO group, n=9). Hydralazine was administered with Ang II infusion (n=10). Animals exhibited elevated arterial carboxyhemoglobin after CO exposure. Although the CO exposure did not affect systolic blood pressure without Ang II infusion, the hypertensive response after Ang II infusion was significantly attenuated by CO. Accordingly, the mice in the Ang II+CO group showed lesser left ventricular hypertrophy compared with those in the Ang II group. CO treatment also attenuated aortic hypertrophy. Interestingly, these changes were accompanied by the reduction of reactive oxygen species production, p47(phox) and p67(phox) subunit expressions of reduced nicotinamide-adenine dinucleotide phosphate oxidase, and Akt phosphorylation. Although hydralazine showed stronger antihypertensive action, superior inhibition on cardiac hypertrophy was obtained by CO (P<0.05). Furthermore, Ang II-dependent myocardial reactive oxygen species generation was more effectively suppressed by CO. Low-dose exogenous CO treatment attenuates Ang II-dependent reactive oxygen species generation, suggesting that appropriate CO administration alleviates hypertension and reduces organ hypertrophy mediated by Ang II.     

Inflammation and inflammatory agents activate protein kinase C epsilon translocation and excite guinea-pig submucosal neurons

BACKGROUND & AIMS: Properties of enteric neurons are transformed by inflammation and protein kinase C (PKC) isoforms are involved both in long-term changes in enteric neurons, and in transducing the effects of substances released during inflammation. We investigated roles of PKCepsilon in submucosal neurons by studying translocation in response to inflammatory mediators, effects on neuron excitability, and the changes in PKCepsilon distribution in a trinitrobenzene sulphonate model of ileitis. METHODS: Immunohistochemical detection and analysis of association with membrane and cytosolic fractions, and Western blot analysis of cytosolic and particulate fractions were used to quantify translocation. Electrophysiology methods were used to measure effects on neuron excitability. RESULTS: All submucosal neurons were immunoreactive for the novel PKC, PKCepsilon, and direct PKC activators, phorbol 12,13-dibutyrate, ingenol 3,20-dibenzoate, and the PKCepsilon-specific activator, transactivator of transduction-Psiepsilon receptor for activated C kinase, all caused PKCepsilon translocation from cytoplasm to surfaces of the neurons. Electrophysiologic studies showed that the stimulant of novel PKCs, ingenol (1 micromol/L), increased excitability of all neurons. Stimulation of protease-activated receptors caused PKCepsilon translocation selectively in vasoactive intestinal peptide secretomotor neurons, whereas a neurokinin 3 tachykinin receptor agonist caused translocation in neuropeptide Y and calretinin neurons. In all cases translocation was reduced significantly by a PKCepsilon-specific translocation inhibitor peptide. Increased PKCepsilon at the plasma membrane occurred in all neurons 6-7 days after an inflammatory stimulus. CONCLUSIONS: Major targets for PKCepsilon include ion channels near the plasma membrane. PKCepsilon is likely to have a significant role in controlling the excitability of submucosal neurons and is probably an intermediate in causing hyperexcitability after inflammation.     

Atlas of breast magnetic resonance imaging

Magnetic resonance imaging (MRI) of the breast has become important not only for assessing the extent of breast cancer for breast-conserving surgery but also for the evaluation and diagnosis of other benign and malignant pathologies. We radiologists therefore need to know the appropriate indications for performing breast MRI and understand the MRI features of breast disease. We herein review and discuss the application of current pulse sequences and the imaging strategies for MRI of breast pathologies. We will illustrate the MRI features of various breast pathologies including malignant tumors such as invasive and noninvasive ductal carcinoma, special types of invasive carcinoma (mucinous, apocrine, lobular carcinoma, spindle cell carcinoma, and so on), inflammatory carcinoma, semimalignant tumor (phyllodes tumor), benign tumors (fibroadenoma, intraductal and intracystic papilloma), inflammatory conditions, and postsurgical changes. We will also demonstrate three-dimensional fusion images of MR ductography and breast MRI of patients with nipple discharge.     

Histopathology of the tubuli recti at the start of experimental autoimmune orchitis in mice

We previously established an experimental model of autoimmune orchitis (EAO) by means of immunization with testicular germ cells (TGC) alone in mice and confirmed that the disease can be transferred to mice that had received CD4+ but not CD8+ or B lymphocytes obtained from TGC-immunized donor mice. The tubuli recti (TR) are special in that lymphocytes first accumulate around them before spreading to the peripheral seminiferous tubules in EAO. However, the minute changes in the TR remain unknown. Therefore, we investigated the histopathology of the TR before the induction of spermatogenic disturbance. The results revealed that the first infiltrating lymphocytes around the TR were not only of T-cell but also of B-cell lineage. Moreover, it was also shown that some of these infiltrating lymphocytes migrated into the TR, with resultant degeneration of the TR epithelium before damage to the seminiferous epithelium. These findings indicate that TR epithelial cells are the first targets of autoreactive T and B lymphocytes in EAO.     

A case of pathological complete response after treatment with uracil/tegafur (UFT) and folinate (Leucovorin) for liver metastasis of colon cancer

The patient is a 62-year-old female who underwent a right hemicolectomy for type-2 ascending colon cancer (moderately-differentiated adenocarcinoma, ss, n0, H0, P0, M0, stage II). Six months after the surgery, a solitary metastatic focus was expressed in the liver S3. Because schizophrenia was present concurrently, tegafur and uracil/folinate (UFT/Leucovorin) treatment was selected and performed for 3 months. Because the tumor shrank afterward, a partial hepatectomy was performed to obtain a curative resection. In a pathological examination of the resected focus, cicatricial/necrotic findings were observed, but no cancer cells were observed; hence, it was determined to be a pathological complete response (CR). In regard to chemotherapy for distant metastasis of colorectal cancer, many molecular-targeted agents are being introduced, thus resulting in more treatment options; however, depending on the patient's background, UFT/LV treatment can be an effective treatment option.     

Anti-tumor activity of the proteasome inhibitor bortezomib in gastric cancer

The prognosis of unresectable advanced gastric cancer has improved over the last decade due to advances in chemotherapy. However, molecular targeting in gastric cancer therapy has been poorly established and the 5?year survival rate is still <10%. The proteasome plays a pivotal role in the regulation of cell proliferation, apoptosis and differentiation in a variety of tumor cells. Bortezomib, a selective inhibitor of the proteasome, has prominent effects against several tumor types, including multiple myeloma. We examined the anti-tumor effects of bortezomib on gastric cancer cells in?vitro and in subcutaneously transplanted nude mice. We demonstrated that among seven types of gastric cancer cells examined, treatment with bortezomib induced both apoptotic and anti-proliferative effects, resulting in a reduction in cell survival rates. The induction of apoptosis was observed to be dependent on the inhibition of nuclear factor κB (NF-κB) activation and the subsequent production of reactive oxygen species (ROS) and c-Jun N-terminal kinase (JNK) activation. Interestingly, we observed that those cells with high levels of NF-κB activity were resistant to bortezomib treatment. Additionally, we demonstrated that the activation of the extracellular signal-regulated kinase (ERK1/2) was inhibited following bortezomib treatment, which may contribute to its anti-proliferative effects. We also observed anti?tumor effects of bortezomib in vivo. Bortezomib is a potential novel molecular targeting drug for the treatment of unresectable advanced gastric cancer.