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Background and ObjectivesThe objective of this study was to discover novel nodal autoantibodies in chronic inflammatory demyelinating polyneuropathy (CIDP).MethodsWe screened for autoantibodies that bind to mouse sciatic nerves and dorsal root ganglia (DRG) using indirect immunofluorescence (IFA) assays with sera from 113 patients with CIDP seronegative for anti-neurofascin 155 and anticontactin-1 antibodies and 127 controls. Western blotting, IFA assays using HEK293T cells transfected with relevant antigen expression plasmids, and cell-based RNA interference assays were used to identify target antigens.Krox20andPeriaxinexpression, both of which independently control peripheral nerve myelination, was assessed by quantitative real-time PCR after application of patient and control sera to Schwann cells.ResultsSera from 4 patients with CIDP, but not control sera, selectively bound to the nodal regions of sciatic nerves and DRG satellite glia (p= 0.048). The main immunoglobulin G (IgG) subtype was IgG4. IgG from these 4 patients stained a 60-kDa band on Western blots of mouse DRG and sciatic nerve lysates. These features indicated leucine-rich repeat LGI family member 4 (LGI4) as a candidate antigen. A commercial anti-LGI4 antibody and IgG from all 4 seropositive patients with CIDP showed the same immunostaining patterns of DRG and cultured rat Schwann cells and bound to the 60-kDa protein in Western blots of LGI4 overexpression lysates. IgG from 3 seropositive patients, but none from controls, bound to cells cotransfected with plasmids containing LGI4 and a disintegrin and metalloprotease domain–containing protein 22 (ADAM22), an LGI4 receptor. In cultured rat Schwann and human melanoma cells constitutively expressing LGI4,LGI4siRNA effectively downregulatedLGI4and reduced patients' IgG binding compared with scrambled siRNA. Application of serum from a positive patient to Schwann cells expressing ADAM22 significantly reduced the expression ofKrox20, but notPeriaxin. Anti-LGI4 antibody-positive patients had a relatively old age at onset (mean age 58 years), motor weakness, deep and superficial sensory impairment with Romberg sign, and extremely high levels of CSF protein. Three patients showed subacute CIDP onset resembling Guillain-Barré syndrome.DiscussionIgG4 anti-LGI4 antibodies are found in some elderly patients with CIDP who present subacute sensory impairment and motor weakness and are worth measuring, particularly in patients with symptoms resembling Guillain-Barré syndrome.

Congenital vitelline duct anomalies other than Meckel's diverticulum are rare in animals. A cyst of approximately 8 mm in diameter was observed on the antimesenteric surface of the ileal serosa in a 10-week-old female Crl:CD(SD) rat. Microscopically, the cyst closely resembled the ileum, but it did not communicate with the ileal lumen. We diagnosed this case as a vitelline cyst derived from the vitelline duct based on the location where it developed and its histological behavior. In rats, only Meckel's diverticulum has been reported with a congenital anomaly of the vitelline duct, and no other spontaneous anomalies including a vitelline cyst have been reported. This case may be the first report concerning a vitelline cyst in the rat ileum.

We reevaluated histological slides of dorsal skin in control animals from past percutaneous dose toxicity studies using dogs, rabbits and rats to provide background data concerning histological changes related to preparation and application procedures and vehicles or embrocations of every variety. Acanthosis, dermal or perifollicular inflammatory cell infiltration in dogs; hyperkeratosis, acanthosis, dermal inflammatory cell infiltration or hemorrhage in rabbits; and acanthosis, dermal inflammatory cell infiltration, crust or foreign body granuloma in rats were present as procedure-related underlying histological changes in the control animals. Four mechanical acts, (1) rubbing with gauze to remove an administered substance for reapplication, (2) use of a taut bandage to avoid slipping from the application site, (3) peeling a patch off as a preparation procedure for reapplication, and (4) clipping or shaving, were considered to cause injury to the skin. The degree of influence of the various application procedures was found to be as follows: sham, lotion < cream < ointment and tape in dogs; untreated control, sham < lotion < tape and poultice in rabbits; and sham, sodium carboxymethylcellulose < olive oil and lotion < ointment and tape in rats. The degree of ointment influence on rabbits is equivocal.

In a study to collect background data using c-Ha-ras transgenic mice (rasH2 mice), epithelial proliferative lesions were observed in the nasal cavities of the animals with or without administration of a single intraperitoneal dose of N-methyl-N-nitrosourea (MNU). These proliferative lesions occurred most frequently in the ventral meatus of the incisive papilla (nasal cavity in the specimen). Most of the proliferative lesions were a polypoid or papillary form consisting mainly of an epithelium resembling a squamous epithelium. In addition, administration of MNU tended to increase the incidence of proliferative lesions. Therefore, in carcinogenicity studies using rasH2 mice, we may come across epithelial proliferative lesions in the nasal cavity.

A tumor was observed in the left mandible of a 3-year-old male Shih-Tzu dog. Histopathology revealed neoplastic alveolar proliferation of round cells, sarcomatoid proliferation of round to spindle-shaped cells and an existing parotid gland tissue around the tumor. A cancellous bone framework was also seen throughout the tumor. The tumor cells in the sarcomatoid area were positive and weakly positive for vimentin and cytokeratin, respectively, demonstrating their myoepithelial character. We diagnosed this tumor as a malignant mixed tumor of the salivary glands, because of the location of the tumor, its invasiveness into the surrounding tissue and the identification of both epithelial and myoepithelial tumor cells.

One of the major dose-limiting toxicities induced by antimicrotubule antitumor agents such as vinca alkaloids and taxanes is peripheral neuropathy. The neurotoxicity of TZT-1027 (a dolastatin 10 derivative antimicrotubule agent) was thus assessed using the animal models for antimicrotubule agent-induced neurotoxicity. Rabbits were intravenously given TZT-1027 or vincristine weekly for 5 weeks. In the mouse study, TZT-1027, vincristine or paclitaxel was intravenously given every 2 days and/or weekly. Despite the neuropathologic evidence such as myelinated axonal and fiber degeneration in the peripheral nerves and in the sensory tracts of the spinal cord following the treatment with vincristine or paclitaxel, no drug-induced alteration was observed in the TZT-1027 groups. Although there are reports that some other dolastatin derivatives with antimicrotubule activity showed no neurotoxic potential in humans, the present study represents the first demonstration in experimental animals that a dolastatin derivative has no, or at least a lower, neurotoxic potential compared to other antimicrotubule agents.