Disease-associated CIAS1 mutations induce monocyte death, revealing low-level mosaicism in mutation-negative cryopyrin-associated periodic syndrome patients

Cryopyrin-associated periodic syndrome (CAPS) is a spectrum of systemic autoinflammatory disorders in which the majority of patients have mutations in the cold-induced autoinflammatory syndrome (CIAS)1 gene. Despite having indistinguishable clinical features, some patients lack CIAS1 mutations by conventional nucleotide sequencing. We recently reported a CAPS patient with mosaicism of mutant CIAS1, and raised the possibility that CIAS1 mutations were overlooked in "mutation-negative" patients, due to a low frequency of mosaicism. To determine whether there were latent mutant cells in "mutation-negative" patients, we sought to identify mutation-associated biologic phenotypes of patients' monocytes. We found that lipopolysaccharide selectively induced necrosis-like cell death in monocytes bearing CIAS1 mutations. Monocyte death correlated with CIAS1 up-regulation, was dependent on cathepsin B, and was independent of caspase-1. Cell death was intrinsic to CIAS1-mutated monocytes, was not mediated by the inflammatory milieu, and was independent of disease severity or anti-IL-1 therapy. By collecting dying monocytes after lipopolysaccharide treatment, we succeeded in enriching CIAS1-mutant monocytes and identifying low-level CIAS1-mosaicism in 3 of 4 "mutation-negative" CAPS patients. Our findings reveal a novel effect of CIAS1 mutations in promoting necrosis-like cell death, and demonstrate that CIAS1 mosaicism plays an important role in mutation-negative CAPS patients.     

The immunomodulatory effect of cryopreservation in rat tracheal allotransplantation.

BACKGROUND: Cryopreservation is one solution to the problem of donor organ deficit. To investigate the effect of cryopreservation on tracheal allografts, we performed 2 experiments in rats. METHODS: In Experiment 1, we assessed second-set graft rejection. Two weeks after primary heterotopic transplantation (Group 1, fresh isografts; Group 2, fresh allografts from Lewis rats; and Group 3, cryopreserved allografts from Lewis rats; n = 5, respectively), each animal underwent secondary heterotopic grafting with isografts and allografts from Lewis and Wistar Furth rats (n = 5, respectively). Four weeks after the secondary transplantation, all grafts were retrieved for histologic analysis. In Experiment 2, we assessed the long-term results of allograft cryopreservation, without immunosuppression therapy. Six months after transplantation of fresh (Group 4) and cryopreserved (Group 5) allografts, the tracheal segments (each group, n = 5) were histologically evaluated. RESULTS: In Experiment 1, only the secondary allografts from Lewis rats in Group 2 did not maintain lumen structure and often showed dislocated or destroyed cartilage. Second-set graft rejection was specifically recognized in Group 2, but not in Group 1 or 3. In Experiment 2, the cryopreserved allografts appeared almost normal and lumen rigidity was preserved 6 months after transplantation. These allografts were superior to the fresh allografts in patency and in cartilage dislocation and mononuclear cell infiltration scores, but not in the viable chondrocyte ratio. CONCLUSIONS: We conclude that cryopreservation may produce successful long-term results because of its immunomodulatory effect on tracheal allografts.     

Beating coronary bypass with right-heart bypass

Two patients with bilateral obstructive carotid artery disease underwent beating heart coronary bypass including revascularization of the circumflex branch using right-heart bypass in a stable hemodynamic state. Without this mechanical support, lifting the left ventricle for the exposure of the posterior wall could impair the hemodynamic state of the patient. Right-heart bypass in addition to aortic no-touch technique can be a safer option for complete coronary revascularization in patients at high risk for neurological complications.     

Mediastinal parathyroid cyst with tracheal constriction.

A 63-year-old man visiting a physician for slight dyspnea, attributed to a lump on his neck, was found in ultrasonography and computed tomography to have a cyst extending from the left lobe of the thyroid gland to the superior mediastinum. Radiography showed right deviation of the trachea. The cyst disappeared after fine-needle aspiration, but cyst fluid subsequently reaccumulated and he was admitted to our hospital. No abnormalities were detected in tests of thyroid and parathyroid function or blood chemical analysis. The cyst was surgically removed and diagnosed as a nonfunctioning parathyroid cyst, based on the high-intact parathyroid hormone in cyst fluid. The patient recovered fully and has shown no recurrence in the 11 months to data since surgery.     

Endovascular aortic repair for spontaneous rupture of a non-aneurysmal infrarenal aorta

We report the case of a patient who underwent an endovascular aortic repair for spontaneous rupture of a non-aneurysmal infrarenal aorta. A 67-year-old male with a diagnosis of infrarenal aortic rupture was referred to our hospital. Preoperative computed tomography showed focal ulcers adjacent to the site of rupture, with no evidence of aneurysm formation, suggesting that this aortic rupture was likely to be associated with perforation of penetrating atheromatous ulceration. Open surgical repair might have carried a high-risk because of the patient's history of laparotomy and respiratory impairment, so endovascular aortic repair was planned. We deployed a Powerlink proximal infrarenal cuff 25-25-75L at the rupture site through the femoral artery, with the additional placement of two extra large Palmaz stents at the proximal and distal sites of the Powerlink stent-graft. Completion angiography showed total exclusion with no endoleaks. The patient was successfully extubated on the third postoperative day and recovered well until he contracted aspiration pneumonia two weeks after surgery. Unfortunately, he eventually died of a non-aortic cause three months after the operation. Endovascular aortic repair may be an alternative to conventional surgical repair for high-risk patients with spontaneous infrarenal aortic rupture.     

Successful treatment of acute promyelocytic leukemia in a patient on hemodialysis

Acute promyelocytic leukemia (APL) has the best prognosis among acute leukemias, but there is little data about APL in patients on hemodialysis. A 64-year-old hemodialysis patient was successfully treated for APL by induction therapy with all-trans retinoic acid (ATRA), three courses of consolidation therapy with Ara-C, mitomycin?C (MIT), daunorubicin (DNR), and idarubicin (IDR), and maintenance therapy with ATRA. Complete remission has been maintained for 42?months in this patient. With dose modification, ATRA and chemotherapy may be safely given to patients on hemodialysis.     

Value of Multidetector-row Computed Tomography in Diagnosis of Portal Vein Invasion by Perihilar Cholangiocarcinoma

BACKGROUND: Although knowledge of cancer invasion of the portal bifurcation is vitally important in planning an operation for perihilar cholangiocarcinoma, the diagnostic capability of multidetector-row computed tomography (MDCT) for this purpose has not been assessed. We evaluated how well MDCT could identify cancer invasion of the portal bifurcation by perihilar cholangiocarcinoma. METHODS: Between April 2003 and June 2005, perihilar cholangiocarcinoma was resected in 87 patients, 83 of whom underwent MDCT within 1 month before the surgery. Three-dimensional volume-rendered (3DVR) and multiplanar reformation (MPR) images were examined for evidence of portal vein invasion. Agreement with intraoperative and pathologic findings was assessed. Portal bifurcation findings by 3DVR and MPR were classified into no portal vein stenosis, unilateral stenosis, or more extensive stenosis, and also into tumor contact with the bifurcation in no, one of two, or two projections. RESULTS: For macroscopic portal vein invasion, sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy were 81.5, 91.1, 81.5, 91.1, and 88.0% in 3D portography and 96.3, 92.6, 86.7, 98.1, and 94.0% in MPR, respectively. Findings by both 3DVR and MPR were significantly correlated with depth of cancer invasion (p < 0.001). CONCLUSION: MDCT is useful in assessing cancer invasion of the portal vein bifurcation by perihilar cholangiocarcinoma.     

p53 antibodies in the serum of patients with prostate cancer

We assessed the potential clinical utility of levels of p53-specific antibodies as a novel serum biomarker of prostate cancer that could be used in conjunction with level of PSA. Material and methods Serum levels of p53-specific antibodies in patients with relapsed, newly diagnosed prostate cancer and in patients with benign prostate hyperplasia were quantified by an enzyme-linked immunoabsorbent assay. Result There was no significant difference (P = 0.96) between the serum levels of p53-specific antibodies in patients with newly diagnosed prostate cancer and with benign prostatic hyperplasia. In the newly diagnosed prostate cancer group, stage T1c (n = 8) showed the lowest p53-specific antibody level. However, the difference between T1c group and benign prostatic hyperplasia group was not significant (P = 0.686). The relapsed cancer group tended to have low levels of the antibodies, and, there was no significant difference between the relapsed prostate cancer group and the benign prostatic hyperplasia group (P = 0.14). The serum levels of p53-specific antibodies in patients with metastatic and with localized prostate cancer showed no significant difference (P = 0.68). Conclusion The use of titers of p53-specific antibodies to make differential diagnosis between prostate cancer and benign prostatic hyperplasia might have no role, and the antibodies should not be used as a marker of prostate cancer by itself. Because our study is based on small number of patients, further studies are necessary before its absolute validity can be determined.     

Prospective analysis of clinical evaluation and self-assessment by patients after decompression surgery for degenerative lumbar canal stenosis.

BACKGROUND CONTEXT: Objective measures including neurological findings, radiographic evaluation, and the Japanese Orthopaedic Association (JOA) score are commonly used for the evaluation of surgical outcomes. Because many surgeries are performed primarily to improve quality of life, a patient's subjective evaluations are also important for accurately assessing surgical outcomes. Currently available instruments for assessing quality of life include the Short-Form 36 (F-36), the Oswestry disability index (ODI), and the visual analog scale (VAS) clinical pain scale. PURPOSE: The aims of this study were to measure surgical outcomes by using both objective measures and subjective measures including patient self-assessments and psychological changes; to assess the adequacy of the JOA alone for measuring outcome; and to determine which measures, the SF-36v2, ODI, VAS, or JOA correlate with the VAS pain scale score in lumbar canal stenosis. STUDY DESIGN: We performed a prospective study to measure surgical outcomes for lumbar canal stenosis using traditional objective measures such as neurological findings and subjective measures such as performance of ADLs, patient self-assessments, and psychological changes. PATIENT SAMPLE: Forty-two surgical patients with a mean age of 66.8+/-10.9 years at the time of surgery were included in the study. All cases were followed for more than 2 years. Surgical indications included no response to conservative treatment and neurological deterioration. Neurological symptoms were classified as nerve root type, cauda equine type, or combined type. We performed surgical decompression at the location of the dural or root indentation by myelography. The concomitant diagnosis causing the spinal stenosis was degenerative spondylolisthesis in 20 cases undergoing posterolateral fusion with pedicle screws. OUTCOME MEASURES: Surgical outcomes were assessed by comparing preoperative and 24-month postoperative JOA scores for low back pain, SF-36v2, ODI-v2, and VAS scores. Statistical analysis was performed by using the analysis of variance. A p value<0.05 was considered statistically significant. METHODS: Objective clinical measures, patient self-assessments, and psychological changes were measured before and at 24 months postoperatively. We also examined which measurements correlated with the VAS scale for pain evaluation, thereby relating patient satisfaction to surgery outcome. RESULTS: All JOA, SF-36v2, ODI-v2, and VAS scores significantly improved postoperatively. The physical component summary (PCS) of the SF-36 v2 showed significant improvement, although all scores remained less than the Japanese norm-based scores (NBSs). The mental component summary (MCS) exhibited such a significant improvement that all postoperative subscales were higher than the Japanese NBS. JOA scores significantly correlated only with postoperative lower-extremity VAS score. All PCS and two MCS scores significantly correlated with the VAS score for low back pain. Parts of the PCS and MCS significantly correlated with the lower-extremity VAS. The ODI significantly correlated with both the preoperative and postoperative VAS scores for low back pain as well as with the postoperative lower-extremity VAS score. CONCLUSIONS: The JOA, SF-36, ODI, and VAS questionnaires are all useful instruments for measuring surgical outcomes. The VAS score is a better assessment of physical rather than mental health. The ODI is more reflective of patients' subjective symptoms. Finally, the SF-36 is particularly informative because it includes questions addressing both psychological and physical status. Therefore, when combined, the SF-36v2, VAS, and ODI scores are a valuable complement to the JOA scores in evaluating outcomes of surgery for lumbar canal stenosis.     

Possibility of "distraction arthrogenesis": first report in rabbit model

We investigated the possibility of articular cartil-age distraction for use in reconstructing joint structure and for increasing the donor site of osteochondral grafts. Intraarticular osteotomy was performed at the femoral condyle in 12 Japanese white rabbits. The bone segment was fixed with a specially designed external fixator. After a 3-week waiting period, distraction was performed intermittently for 3 weeks (0.7 mm × 3 times per week) in the distraction group (n = 7) and, in the remaining animals (gap group; n = 5), a gap of 6.3 mm in length was made at surgery. All rabbits received etidronate injections (20 mg/kg ×2 times per week) for 5 weeks, to slow mineralization. The femoral condyle was harvested 9 weeks postoperatively and decalcified sagittal sections were stained and evaluated, using a histological grading scale. In the distraction group, distraction of 4.2 ± 1.4 mm was achieved, and the distracted cartilage area was filled with regenerated cartilage, without any gap between the regenerated and the adjacent articular cartilage. This regenerated cartilage showed metachromasia with toluidine blue. In the gap group, newly formed cartilage tissue was folded from the edge of the osteotomy site and fibrous tissue was interposed in the gap. The histological grading score was significantly lower in the distraction group (P < 0.02). Our preliminary results demonstrated the possibility of cartilage distraction; however, long-term observation will be necessary to confirm the characteristics of the distracted cartilage. We may call the process "distraction arthrogenesis", because the entire articular entity, which consists of cartilage, subchondral bone, and bone, could be distracted at once. Received: April 5, 2001 / Accepted: July 15, 2001