Increased insulin sensitivity and hypoinsulinemia in APS knockout mice

A tyrosine kinase adaptor protein containing pleckstrin homology and SH2 domains (APS) is rapidly and strongly tyrosine phosphorylated by insulin receptor kinase upon insulin stimulation. The function of APS in insulin signaling has heretofore remained unknown. APS-deficient (APS(-/-)) mice were used to investigate its function in vivo. The blood glucose-lowering effect of insulin, as assessed by the intraperitoneal insulin tolerance test, was increased in APS(-/-) mice. Plasma insulin levels during fasting and in the intraperitoneal glucose tolerance test were lower in APS(-/-) mice. APS(-/-) mice showed an increase in the whole-body glucose infusion rate as assessed by the hyperinsulinemic-euglycemic clamp test. These findings indicated that APS(-/-) mice exhibited increased sensitivity to insulin. However, overexpression of wild-type or dominant-negative APS in 3T3L1 adipocytes did not affect insulin receptor numbers, phosphorylations of insulin receptor, insulin receptor substrate-1, or Akt and mitogen-activated protein kinase. The glucose uptake and GLUT4 translocation were not affected by insulin stimulation in these cells. Nevertheless, the insulin-stimulated glucose transport in isolated adipocytes of APS(-/-) mice was increased over that of APS(+/+) mice. APS(-/-) mice also showed increased serum levels of leptin and adiponectin, which might explain the increased insulin sensitivity of adipocytes.     

Determination of diagnostic threshold in harmonization and comparison of clinical utility for five major antiphospholipid antibody assays used in Japan

BackgroundAnticardiolipin antibodies (aCL) and anti‐β₂‐glycoprotein I antibodies (aβ₂GPI) are essential in diagnosing antiphospholipid syndrome (APS) according to the international APS guideline. Five commercial assays for aCL and aβ₂GPI are available in Japan, but their test results are quite discordant. For harmonization of diagnosing APS, upper reference limit (URL) and diagnostic accuracy of each assay were evaluated and compared by testing common sets of specimens across all assays.MethodsWe evaluated two manual and three automated assays for aCL and aβ₂GPI of IgG‐ and IgM classes. 99%URL (the upper limit of reference interval: as per guideline) together with 97.5%URL were determined by testing sera from 198 to 400 well‐defined healthy subjects. Both URLs were compared with the cutoff values, which were determined based on ROC analysis by testing 50 each of plasma specimens from patients with/without APS. Diagnostic accuracy was evaluated as area under curve (AUC) of the ROC curve.ResultsA variable degree of discrepancy between URLs and the cutoff values was observed, which was partly attributable to between‐year assay variability. 97.5%URLs were set lower and closer to the cutoff values than 99%URLs. For all assays, diagnostic accuracies of both aβ₂GPI‐IgG and aCL‐IgG were generally high (AUC: 0.84−0.93); whereas those for IgM‐class assays were low (AUC: 0.57−0.67), implicating its utility is limited to rare IgG negative APS cases.ConclusionTo ensure harmonized APS diagnosis, the diagnostic thresholds of the five assays were evaluated by common procedures. Contrary to the guideline, 97.5%URL is rather recommended for diagnosing APS, which showed a closer match to the cutoff value.     

Evaluation of extensive lymph node dissection for carcinoma of the stomach

We compared the results of curative resection for carcinoma of the stomach in 254 patients who underwent simple resection (SR) and 454 patients who underwent extensive regional lymph node dissection (ELD). The 5-year survival rates of the 2 procedures were significantly different in carcinoma involving the serosa of the stomach; it was 45% in the ELD group and 18% in the SR group (p<0.001). In patients with regional lymph node metastasis we obtained a 5-year survival rates of 39% and 18% by ELD and SR, respectively (p<0.001). The incidence of metastasis to the secondary lymph nodes, removable only by ELD, was higher in cases with carcinomatous invasion of the deeper layers of the gastric wall, and this may have been the reason why ELD proved to be more effective than SR. ELD is discussed in relation to the site of the primary carcinoma and the extent of lymph node metastasis.     

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.     

Interobserver variation in diagnosis of dementia by brain perfusion SPECT

Brain perfusion SPECT (BP-SPECT) has characteristic patterns of abnormality, enabling the differential diagnosis of dementia. The purpose of this study was to measure interobserver variations in the diagnosis of dementia using BP-SPECT. BP-SPECT images of 57 cases, 19 of Alzheimer's disease (AD), eight of multi-infarct dementia (MID), three of Pick's disease, five of other dementias, and 22 normal controls, were interpreted by ten nuclear medicine physicians with varying levels of experience. Brain MR images of the cases were then interpreted apart from SPECT. The physicians independently rated all of the diagnoses listed beforehand according to a five-point scale, with clinical information provided. Receiver-operating characteristic (ROC) curves and the area under the ROC curve (Az) were calculated. Az varied from 0.48 to 0.87. Mean Az's were significantly larger (p<0.05) in the diagnosis by SPECT than in that by MRI (0.715 and 0.629 for dementia vs. normal, 0.670 and 0.560 for AD or MID vs. normal, 0.610 and 0.416 for AD vs. normal, and 0.672 and 0.412 for AD vs. MID, respectively). Considerable interobserver variation was present in BP-SPECT interpretation. BP-SPECT may be more effective for the evaluation of dementia than MRI when the same nuclear medicine physicians interpret both images.     

Re-evaluation of non-palpable scalene lymph node biopsy for the staging of non-small cell lung cancer.

OBJECTIVES: The purpose of this study was to determine the most suitable candidates for scalene lymph node biopsy to detect non-palpable scalene lymph node metastasis (N(3)-scalene) in non-small cell lung cancer patients. METHODS: Standard cervical mediastioscopies and ipsilateral scalene lymph node biopsies were performed preoperatively by a single surgeon on 121 consecutive patients with non-small cell lung cancer scheduled to have surgical resection between January 1997 and August 2002, who had neither evidence of distant metastasis on imaging diagnosis nor palpable supraclavicular lymph nodes. RESULTS: N(3)-scalene was detected in six patients (5.0%), who all had non-squamous cell carcinoma, including one (1.0%) out of 98 patients with negative standard cervical mediastinoscopy and five (21.7%) out of the remaining 23 patients with positive mediastinal lymph node involvement. There was a significant difference in the incidence of the N(3)-scalene between the two groups (P<0.01). Five patients with N(3)-scalene had metastatic lesions in the multilevel mediastinal lymph node station on the same side as the cancer (multilevel N(2)), and accounted for 31.3% of 16 patients with multilevel N(2) disease. The N(3)-scalene was detected in 5 (45.5%) of 11 patients with lung cancer classified as non-squamous cell carcinoma with multilevel N(2) disease. CONCLUSIONS: The results of the present study suggest that non-palpable scalene lymph node biopsy is indicated for lung cancer patients diagnosed as having non-squamous cell carcinoma with mediastinoscopic multilevel N(2) disease.     

Treatment of spontaneous intracranial hypotension secondary to C-2 meningeal cyst by surgical packing--case report

A 41-year-old man presented with progressive worsening of postural headache. Computed tomography (CT) showed bilateral subdural hematomas without prior history of trauma. The diagnosis was spontaneous intracranial hypotension (SIH). Conservative treatment with oral steroids failed to prevent gradual deterioration of the patient's consciousness. CT myelography revealed massive cerebrospinal fluid (CSF) leakage between the C-1 and C-2 levels. The leak was repaired surgically via a laminectomy. A cyst, thought to be a meningeal cyst, was discovered adjacent to the right C-2 nerve root, and CSF was seen seeping out from around the cyst after a Valsalva maneuver. The presumed dural defect of the cyst was sealed by packing with muscle fragments and fibrin glue. The symptoms disappeared soon after surgery. He was discharged 1 month after surgery without deficits. Most SIH cases are benign and can be managed conservatively, or by the epidural blood patch method. Surgery is more invasive than the epidural blood patch method, but should be performed in patients with a high cervical lesion and massive CSF leakage.     

A case of well controlled renal small cell carcinoma with metastasis treated by intensive therapy

A 18-year-old male visited hospital with macroscopic hematuria. Computed tomography showed slightly enhanced left renal tumor that was uncharacteristic for clear cell carcinoma, and radical nephrectomy was performed. Operative specimen revealed primary small cell carcinoma of the kidney. 18 months after operation, bone metastases were diagnosed. Chemotherapy including cisplatinum, etoposide and bleomycin and external irradiation was performed. This intensive therapy was effective for metastatic lesion. He is still alive for 55 months after diagnosis, and is the best controlled case around the world. To our knowledge, this is the 14th case as primary renal small cell carcinoma in the world literature.