Association between dipeptidyl peptidase‐4 inhibitors and increased risk for bullous pemphigoid within 3 months from first use: A 5‐year population‐based cohort study using the Japanese National Database

Aims/IntroductionWe assessed the association between dipeptidyl peptidase‐4 inhibitors (DPP‐4is) and bullous pemphigoid (BP) and time‐dependent changes in the risk for developing BP after DPP‐4i initiation.Materials and MethodsThe present population‐based, real‐world study was carried out using the Japanese National Database dataset collected between 2013 and 2018. To assess independent correlations between DPP‐4is and the development of BP, the self‐controlled case series method was used.ResultsAmong the cohort followed up for a median of 1,540 days, 53,027 patients were likely to develop BP. The possible incidence rate of BP in all 150,328,339 patients was 10.4/100,000 person‐years. Among the 9,705,814 patients with type 2 diabetes, 15,634 were likely to develop BP. The possible incidence rate of BP in patients with type 2 diabetes was 38.1/100,000 person‐years, whereas that in patients with type 2 diabetes who did and did not use DPP‐4is was 40.7 and 30.0/100,000 person‐years, respectively. Analysis of the 28,705 patients with type 2 diabetes likely to develop BP after initial DPP‐4i use showed a risk ratio of 2.15 (95% confidence interval [CI] 1.75–2.63), 1.70 (95% CI 1.37–2.11), 1.44 (95% CI 1.15–1.82), 1.25 (95% CI 0.98–1.59), 0.84 (95% CI 0.63–1.10), 0.84 (95% CI 0.64–1.11) and 1.05 (95% CI 0.92–1.20), for the risk period of ≤30, 31–60, 61–90, 91–120, 121–150, 151–180 and 181–365 days, respectively.ConclusionsAlthough DPP‐4is were associated with increased risk for BP, the risk was particularly significant within 3 months from first use.     

p16INK4, pRB,p53 and cyclin D1 expression and hypermethylation of CDKN2 gene in thymoma and thymic carcinoma

There have been few reports on genetic alterations in thymomas. To investigate the expression of p16^INK4A, RB, p53 and cyclin D1 in thymomas, we first examined 36 thymomas (non-invasive type, 16 cases; invasive type, 20 cases) and 3 thymic carcinomas, using immunohistochemistry. Abnormal expression of p16^INK4A, RB, p53 and cyclin D1 was observed in 18, 8, 10 and 7 cases, respectively. Only a subgroup of invasive thymomas and thymic carcinomas showed an inverse correlation between p16^INK4A and RB expression. Subsequently, we examined the 36 thymomas and 4 thymic carcinomas for mutations in p53 and CDKN2 genes, using PCR-SSCP and direct-sequencing analyses. No mutation of these genes was detected in the thymomas and thymic carcinomas examined. A polymorphism in the 3′ untranslated region of exon 3 of CDKN2 was detected in 5 cases of thymoma. We searched for hypermethylation in the promoter region of CDKN2, observing it in 4 thymomas and 1 thymic carcinoma. Our data suggest that, unlike other more common cancers, alteration of the p53 gene may not play a significant role in the tumorigenesis of thymoma. However, inactivation of p16^INK4A and RB may play a role in the progression of thymoma and thymic carcinoma. Int. J. Cancer 73:639–644, 1997. © 1997 Wiley-Liss, Inc.     

Absence of CD69 expression on peripheral eosinophils in episodic angioedema and eosinophilia

A 45-year-old woman with episodic angioedema and eosinophilia is presented. CD69, which is one of the surface antigens of activated eosinophils, was not expressed on the peripheral eosinophils in this patient, in contrast to hypereosinophilic syndrome. This suggests that CD69, which is not dependent on eosinophil density, may be another useful activation marker of eosinophils to distinguish episodic angioedema and eosinophilia from hypereosinophilic syndrome. © 1996 Wiley-Liss, Inc.     

A case of primary lung cancer with cervical tuberculous lymphadenitis]

A 66-year-old woman was admitted due to right cervical lymphadenopathy and an abnormal chest radiograph. Acid-fast bacilli smear of fine needle aspiration from a right cervical lymph node was positive. Histopathological examination of the specimen obtained by percutaneous right cervical lymph node biopsy showed necrotizing epithelioid granulomas and no malignant cells. Therefore, right cervical tuberculous lymphadenitis was diagnosed. Partial lung resection of the right S4 was carried out by video-assisted thoracoscopic surgery and primary lung cancer was diagnosed. To our knowledge, there has been no previous report of both primary lung cancer and cervical tuberculous lymphadenitis being present at the time of the first examination. We report this very rare case.     

Association of mitochondrial complex I subunit gene NDUFV2 at 18p11 with bipolar disorder in Japanese and the National Institute of Mental Health pedigrees.

BACKGROUND: Linkage with 18p11 is one of the replicated findings in molecular genetics of bipolar disorder. Because mitochondrial dysfunction has been suggested in bipolar disorder, NDUFV2 at 18p11, encoding a subunit of the complex I, reduced nicotinamide adenine dinucleotide (NADH)ubiquinone oxidoreductase, is a candidate gene for this disorder. We previously reported that a polymorphism in the upstream region of NDUFV2, -602G> A, was associated with bipolar disorder in Japanese subjects; however, functional significance of -602G> A was not known. METHODS: We screened the further upstream region of NDUFV2. We performed a case-control study in Japanese patients with bipolar disorder and control subjects and a transmission disequilibrium test in 104 parent and proband trios of the National Institute of Mental Health (NIMH) Genetics Initiative pedigrees. We also performed the promoter assay to examine functional consequence of the -602G> A polymorphism. RESULTS: The -602G> A polymorphism was found to alter the promoter activity. We found that the other haplotype block surrounding -3542G> A was associated with bipolar disorder. The association of the haplotypes consisting of -602G> A and -3542G> A polymorphisms with bipolar disorder was seen both in Japanese case-control samples and NIMH trios. CONCLUSION: Together these findings indicate that the polymorphisms in the promoter region of NDUFV2 are a genetic risk factor for bipolar disorder by affecting promoter activity.     

Microvenular hemangioma

A case of microvenular hemangioma in a 23-year-old Japanese female Is described. The patient presented with a slowly growing, solitary reddish plague on her back, which measured 15 × 17 mm. Histologlcally, the tumor was an inflltrative growth throughout the dermls. It consisted of thin-walled, small-sized, irregularly branched vascular vessels. The vascular lumina were narrow. The flattened endothelial cells had oval to spindle-shaped nuclei and scant cytoplasm that were immunohistochemically positive for endothelial markers. The tumor cells lacked cellular atypia, pleomorphism, and mitotic figures. The patient was well without disease 8 months after the excision. Pathologists and clinicians should be aware of the existence of this type of hemangioma with an infiltrative growth and avoid overdiagnosis and overtreatment.     

Differentiation between hepatoma and hemangioma by inversion recovery snapshot FLASH MR imaging with variable TIs]

To differentiate hepatoma from hemangioma, MR studies were performed for 18 patients with 21 untreated liver tumors (hepatoma 10, hemangioma 11). We obtained inversion recovery snapshot FLASH images of liver tumors with variable TIs (50, 100, 150, 200, 250, 300, 400, and 500 msec). 8 hemangiomas showed higher intensity than liver parenchyma on the images at 150 msec and less of TI, and lower intensity at 200 msec or more TI. In 7, signal intensity of hepatoma became low at 150 msec or less of TI or remained high with prolonged TI. Inversion recovery snapshot FLASH imaging with variable TIs will be useful for differentiating between hepatoma and hemangioma.     

CEREBRO-HEPATO-RENAL SYNDROME OF ZELLWEGER

An autopsy case of cerebro-hepato-renal syndrome of Zellweger, which occurred in a 14-year-old Japanese girl, is reported. The autopsy revealed widely distributed cystic changes in addition to renal blastema of both kidneys, and the liver was cirrhotic. The case was complicated by anomalies such as high forehead, strabismus, and partial defect of chorioidea. So far there have been only 10 reported cases of cerebro-hepato-renal syndrome of Zellweger in Japan.