Keratinocytes from Gorlin Syndrome-induced pluripotent stem cells are resistant against UV radiation.

Gorlin syndrome (GS) is an autosomal dominant genetic disorder involving Patched 1 (PTCH1) mutations. The PTCH1 is a receptor as well as an inhibitor of hedgehog (Hh) to sequester downstream Hh pathway molecules called Smoothened (SMO). PTCH1 mutations causes a variety of GS conditions including falx calcification, odontogenic keratocytes and basal cell carcinomas (BCC). Because PTCH1 is a major driver gene of sporadic BCC, GS patients are characteristically prone to BCC. In order to elucidate the pathological mechanism of BCC-prone GS patients, we investigated keratinocytes derived from GS patient specific iPS cells (G-OFiPSCs) which were generated and reported previously. We found that keratinocytes derived from G-OFiPSCs (GKCs) have increased expression of Hh target molecules. GKCs were irradiated and those cells showed high resistance to UV induced apoptosis. BCL2, known as anti-apoptotic molecule as well as Hh target, significantly increased in GKCs. Several molecules involved in DNA repair, cell cycle control, senescence, and genotoxic stress such as TP53, BRCA1 and GADD45A increased only in GKCs. GKCs are indicated to be resistant to UV irradiation by upregulating molecules which control DNA repair and genotoxic even under DNA damage caused by UV. The anti-apoptotic properties of GKCs may contribute BCC.

Splenocyte cytokine profile in mouse with oral mucosa-sensitization and oral-tolerization by NiSO(4).

Metals used in the oral cavity have been reported to cause various allergic diseases of the skin and mucosa. Skin manifestations due to dental restorations appear not only in the oral cavity, but also on the hands, feet or the whole body, as in the cases of pustulosis palmoplantaris and lichen planus. These phenomena implicate different pathogeneses from that of conventional skin sensitization and tolerance. Therefore, we compared skin and oral mucosa sensitization with nickel and oral tolerance for nickel in a mouse model. Female C57BL/6J mice were sensitized by injection of NiSO(4) into the skin or oral mucosa. Allergic reactions were evaluated by the mouse ear swelling test and splenocyte proliferation and cytokine profiles. Skin and oral mucosa sensitization succeeded in all mice. Ear swelling was significantly greater in the skin- than in the oral mucosa-sensitized mice at 48 hr after challenge. Ear swelling was also suppressed by single oral administration of NiSO(4) in both the skin- and oral mucosa-sensitized mice to the level of that in nonsensitized mice. Splenocytes from skin-sensitized mice proliferated similarly to those from oral mucosa-sensitized mice. Splenocytes from orally-tolerized mice also showed similar proliferation activity to those from skin and oral mucosa-sensitized mice. In the challenge phase, IL-2, IFN-γ, and IL-10 production was induced in splenocytes from both skin- and oral mucosa-sensitized mice. However, IL-4 was induced only in those from skin-sensitized mice. In addition, IL-4 in splenocytes from oral mucosa-sensitized mice was up-regulated to the level in those from skin-sensitized mice by oral tolerance. These results suggest that sensitization sites in mice influence not only the degree of excitation, but also Th-1 and Th-2 balance in the challenge phase and oral tolerance.

A case of drug-induced hypersensitivity syndrome due to carbamazepine.

The patient was a 51-year-old man who had been prescribed carbamazepine for right third-branch trigeminal neuralgia. He had stopped taking the medication after the neuralgia resolved. When the neuralgia recurred, he resumed medication, and about 1 month later he developed fever, fatigue, cervical lymphadenopathy, generalized skin flushing, facial edema and perioral vesicles, and was admitted to Ichikawa General Hospital, Tokyo Dental College. Oral findings showed reddening and erosion of the buccal mucosa. Routine laboratory examination revealed leukocytosis and hepatic dysfunction. Human herpesvirus 6 antibody titer remarkably increased during development of eruptions. These findings led to a diagnosis of drug-induced hypersensitivity syndrome. Carbamazepine was discontinued, and prednisolone (30 mg/day) was started and tapered based on improvement of symptoms. Because skin symptoms recurred after he was discharged 15 days after admission, the dose of prednisolone was increased and the symptoms finally disappeared. The patient has experienced no further recurrence.

The clinical significance of IgA antimitochondrial antibodies in sera and saliva in primary biliary cirrhosis.

It still remains unclear how antimitochondrial autoantibodies (AMA) are involved with immunopathogenesis of primary biliary cirrhosis (PBC). We have suggested the potential role of IgA-AMA in damage to epithelial cells in PBC. In the current study, we investigated whether IgA-AMA were detectable in sera and saliva of PBC patients, to examine the association between detectable IgA-type autoantibodies in sera or saliva and progression of liver diseases. Fifty-three patients with PBC were enrolled, and IgA-AMA in sera and saliva were sought by immunoblotting using pork heart mitochondria as antigens. The progression of PBC was determined as Scheuer's classification consisting of four histological stages. We found IgA-AMA, IgA-anti-PDC-E2, and IgA-anti-E3BP in 43/53 (81%), 37/53 (70%), and 35/53 (66%) sera of patients with PBC, but none of controls. The progression of PBC was statistically associated with presence of IgA-anti-PDC-E2 (P = 0.0124), but neither with IgA-AMA (P = 0.1296) nor anti-IgA-E3BP (P = 0.5973). In saliva, detectable IgA-AMA, IgA-anti-PDC-E2, and IgA-anti-E3BP were noted in 12/26 (46%), 6/26 (23%), and 11/26 (42%), respectively. Detection of IgA-anti-PDC-E2 was strongly associated with progression of PBC (P = 0.0002), whereas detection of IgA-AMA and IgA-anti-E3BP were not associated (P = 0.2145 and P = 0.5118). The current findings suggest that the presence of IgA-anti-PDC-E2 in sera or saliva might be associated with progression of PBC, although a prospective study with PBC patients with detectable IgA-anti-PDC-E2 at early stages will be required to conclude the contribution of IgA-anti-PDC-E2 to the progression of PBC.

[The medial medullary infarction (Dejerine syndrome) following chiropractic neck manipulation].

A-38-year-old man suddenly developed nausea, vomiting and vertigo during chiropractic neck manipulation. This was followed by right hemiplegia, right deep sensory disturbance and left hypoglossal nerve palsy, consistent with the medial medullary infarction (Dejerine syndrome). The MRI revealed infarction at left medial part of the medulla. The vertebral angiogram and MRA showed marked narrowing of the left vertebral artery. X-rays of the cervical spine showed no spondylosis, dislocation nor osteolysis of the odontoid process. The serological studies, including lupus anticoagulant, protein C, and protein S gave normal results. Although vascular accidents involving the brain stem after chiropractic neck manipulation have been reported since Pratt-Thomas and Berger, previous reports are still rare. In them lateral medullary infarction (Wallenberg syndrome) is probably the most common case. On the other hand, medial medullary syndrome (Dejerine syndrome) is absolutely rare. To our knowledge, the only one report has been made by Watanabe and his colleagues before our present case. The mechanism was suggested that rotation and tilting of the neck stretches and compresses the vertebral artery at the cervical joint causing injury to the vessel, with an intimal tearing, dissection, and pseudoaneurysm formation. Consequently, the present case may be caused by injury to the left vertebral artery with an intimal tearing during neck manipulation sufficient to cause disection and subsequent infarction of the brain stem.