Characterization of protein folding by a Φ-value calculation with a statistical-mechanical model.

The Φ-value analysis approach provides information about transition-state structures along the folding pathway of a protein by measuring the effects of an amino acid mutation on folding kinetics. Here we compared the theoretically calculated Φ values of 27 proteins with their experimentally observed Φ values; the theoretical values were calculated using a simple statistical-mechanical model of protein folding. The theoretically calculated Φ values reflected the corresponding experimentally observed Φ values with reasonable accuracy for many of the proteins, but not for all. The correlation between the theoretically calculated and experimentally observed Φ values strongly depends on whether the protein-folding mechanism assumed in the model holds true in real proteins. In other words, the correlation coefficient can be expected to illuminate the folding mechanisms of proteins, providing the answer to the question of which model more accurately describes protein folding: the framework model or the nucleation-condensation model. In addition, we tried to characterize protein folding with respect to various properties of each protein apart from the size and fold class, such as the free-energy profile, contact-order profile, and sensitivity to the parameters used in the Φ-value calculation. The results showed that any one of these properties alone was not enough to explain protein folding, although each one played a significant role in it. We have confirmed the importance of characterizing protein folding from various perspectives. Our findings have also highlighted that protein folding is highly variable and unique across different proteins, and this should be considered while pursuing a unified theory of protein folding.

Microscopic polyangitis complicating double carcinoma of the stomach and duodenum: improvement after the resection of these carcinomas.

A 74-year-old woman developed fever, numbness of legs and glomerulonephritis. Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase (MPO-ANCA) were positive in her serum, and she presented with acute renal failure. She was also simultaneously diagnosed as having both gastric and duodenal cancers. Complete resection of both cancers and renal biopsy was performed. Some glomeruli showed cellular crescentic changes, while submucosal necrotizing vasculitis of small vessels was noted adjacent to the gastric cancer. A diagnosis of microscopic polyangitis was made. After the operation, the patient's fever, renal failure and microscopic hematuria improved and obvious reductions in her serum soluble receptors of interleukin 2 values and MPO-ANCA titer were observed without any further treatment. However, the patient's proteinuria, cylinduria, and elevated C-reactive protein persisted; these findings eventually resolved after treatment with 30 mg of prednisolone daily. An immunohistochemical analysis showed that CD8 T lymphocytes had infiltrated both the carcinomas and the renal lesions. Our case suggests that CD8 T cells induced as part of an immune response against carcinoma may play a pathologic role in ANCA-positive paraneoplastic syndrome.

Systemic lupus erythematosus complicated by recurrent pneumothorax: Case report and literature review.

Pneumothorax is a rare pleuropulmonary manifestation of systemic lupus erythematosus. We encountered a 37-year-old Japanese woman who had systemic lupus erythematosus complicated by recurrent pneumothorax during treatment for recurrent serositis with glucocorticoid therapy. She was admitted for the third episode of lupus peritonitis in December 2005. Intravenous cyclophoshamide and increased dose of oral prednisolone were administered. In early January 2006, hemoptysis was observed and bronchofiberscopy revealed hemorrhage from the left lower lobe. After intravenous methylprednisolone pulse therapy and oral cyclosporine therapy were added, pleurisy and pulmonary hemorrhage improved. On February 22nd, she suddenly developed pneumothorax on the right side, followed by pneumothorax on the left side after 2 days. This pneumothorax on the left side did not improve despite chest tube drainage for over one month. She underwent thoracoscopic partial lobectomy of lower lobe of the left lung, and her symptoms improved. Review of the literature identified 10 case reports of systemic lupus erythematosus complicated by pneumothorax. All of the patients including our case had underlying pulmonary lesions, and 9/11 patients had pleurisy. Besides 10/11 patients received glucocorticoid therapy before the occurrence of pneumothorax. Tissue fragility caused by these factors might contribute to the complication of pneumothorax in patients with systemic lupus erythematosus.

Exacerbation of adult-onset Still's disease, possibly related to elevation of serum tumor necrosis factor-alpha after etanercept administration.

Adult-onset Still's disease (AOSD) is a systemic inflammatory disease of unknown etiology. A 44-year-old male patient presented with AOSD complicated by macrophage activation syndrome after etanercept therapy. His serum tumor necrosis factor-α (TNF-α) level was increased dramatically after etanercept therapy. The clinical course of this case suggests that the increased TNF-α level by etanercept administration might cause macrophage activation syndrome in this case.

Role of mRNA expression of transcription factors in glucocorticoid sensitivity of peripheral blood mononuclear cells and disease state in rheumatoid arthritis.

OBJECTIVE: To investigate the mechanisms underlying glucocorticoid (GC) resistance in rheumatoid arthritis (RA), we evaluated the suppressive effects of prednisolone (PSL) or methylprednisolone (MPSL) on the blastogenesis of peripheral blood mononuclear cells (PBMC). We also measured the expression of mRNA for transcription factors [GC receptor-alpha (GRalpha) and activator protein-1] known to be involved in the exertion of GC effects. METHODS: Twenty-six patients with RA and 17 healthy subjects were studied. IC50 of PSL and MPSL on the blastogenesis of PBMC stimulated with concanavalin A in vitro was estimated. Transcripts for GRalpha, c-fos, c-jun, and GAPDH genes in PBMC were quantitatively determined by real-time RT-PCR procedures. RESULTS: The amount of c-fos transcript in PBMC from RA patients was significantly high compared to the healthy subjects (p = 0.001). However, no difference was found in the amounts of mRNA of other transcription factors between the patients and healthy subjects. When PSL or MPSL IC50 in patients were directly correlated with patients' characteristics in RA, the duration of disease showed a significant positive correlation with PSL IC50 (p = 0.035). However, no significant association of PSL or MPSL IC50 with GRalpha, c-fos, or c-jun mRNA expression determined by RT-PCR was observed. Additionally, there were significant correlations between the amount of GRalpha mRNA and inflammatory indices such as erythrocyte sedimentation rate (p < 0.001) and C-reactive protein (p < 0.05) in the RA patients. CONCLUSION: Chronic exposure to inflammation in RA suggests a decrease in the GC sensitivity of peripheral lymphocytes. Although c-fos and GRalpha transcripts in PBMC have been implicated in the pathology of RA, the amount of expression of these factors may not be critical for the development of GC insensitivity in the PBMC in RA.

Marked hypocomplementemia and tubulointerstitial nephritis in a male patient with Sjögren's syndrome.

We report a case of marked hypocomplementemia and tubulointerstitial nephritis associated with Sjögren's syndrome (SS) in a male patient. Renal biopsy revealed tubulointerstitial nephritis but did not identify specific immune deposits of the tubulo-interstitium. After steroid therapy, the renal failure and hypocomplementemia diminished. Hypocomplementemia without cryoglobulinemia is not commonly observed in SS patients, and hypocomplementemic tubulointerstitial nephritis was strongly suspected. Hypocomplementemic tubulointerstitial nephritis is rare; only one case has been described in the literature. In our case and the previous case, the patients were elderly men, and they had some similar clinical characteristics. Idiopathic hypocomplementemic tubulointerstitial nephritis resembling our case has been reported. These facts suggest that hypocomplementemic tubulointerstitial nephritis may occur in patients with SS, and such cases may not be as rare as once thought because it might be appropriate to include them in the category of idiopathic cases. Such a syndrome should be included in the differential diagnosis of hypocomplementemia.

Thrombotic thrombocytopenic purpura complicating Sjögren's syndrome with crescentic glomerulonephritis and membranous nephritis.

The association of either thrombotic thrombocytopenic purpura (TTP) or crescentic glomerulonephritis with Sjögren's syndrome is rare. We report a case of TTP appearing after the diagnosis of SjOgren's syndrome with crescentic glomerulonephritis and membranous nephropathy. Circulating immune complex was detected, and immune complex deposits were shown along the capillary walls of renal biopsy specimens. Despite steroid pulse therapy and plasma exchange therapy, the patient died. The etiology of TTP is unclear. This case is important when considering the etiology of TTP related to autoimmune disease.