Post-marketing surveillance of zinc acetate dihydrate for hypozincemia in Japan.

Zinc is an essential microelement, and its deficit causes various diseases and symptoms. In adults, especially in elderly individuals, zinc shortage can cause symptoms such as taste disorder, dermatitis, and susceptibility to infection. In children, zinc deficiency can lead to growth retardation. In 2017, the indication for zinc acetate dihydrate (NOBELZIN®) was expanded from Wilson's disease to include hypozincemia, leading to wider use of zinc acetate dihydrate. At five years after this broadening of use, we conducted a post-marketing study (PMS) to investigate the utilization, safety, and effectiveness of zinc acetate dihydrate. Over 52 weeks, the overall incidence of adverse drug reactions (ADRs) was 9.4% (87/928). The most common ADR was copper deficiency (2.4%), followed by nausea (1.4%). Among 928 patients, 19 (2%) developed serious ADRs. Of the patients with copper deficiency, 92% were >65 years of age, and all had comorbidities at baseline. Physicians evaluated the effectiveness of zinc acetate dihydrate using three categories: "effective", "not effective", and "indeterminate". The overall efficacy rate was 83.0%. The average serum zinc levels were elevated from 50-60 µg/dL to >90 µg/dL within 12 weeks, and were maintained up to 52 weeks after administration. Among the symptomatic sub-categories, the efficacy rate was highest in pressure ulcer (96.2%; 25/26), followed by in stomatitis (87.5%; 42/48), and taste disorder (87.4%; 181/207). Among pediatric patients with developmental symptoms, an efficacy rate of 66% was achieved. In conclusion, zinc acetate dihydrate has been safely used, and has produced beneficial effects on various diseases and symptoms.

Heparan sulfate deficiency leads to hypertrophic chondrocytes by increasing bone morphogenetic protein signaling.

OBJECTIVE: Exostosin-1 (EXT1) and EXT2 are the major genetic etiologies of multiple hereditary exostoses and are essential for heparan sulfate (HS) biosynthesis. Previous studies investigating HS in several mouse models of multiple hereditary exostoses have reported that aberrant bone morphogenetic protein (BMP) signaling promotes osteochondroma formation in Ext1-deficient mice. This study examined the mechanism underlying the effects of HS deficiency on BMP/Smad signaling in articular cartilage in a cartilage-specific Ext-/- mouse model. METHOD: We generated mice with a conditional Ext1 knockout in cartilage tissue (Ext1-cKO mice) using Prg4-Cre transgenic mice. Structural cartilage alterations were histologically evaluated and phospho-Smad1/5/9 (pSmad1/5/9) expression in mouse chondrocytes was analyzed. The effect of pharmacological intervention of BMP signaling using a specific inhibitor was assessed in the articular cartilage of Ext1-cKO mice. RESULTS: Hypertrophic chondrocytes were significantly more abundant (P = 0.021) and cartilage thickness was greater in Ext1-cKO mice at 3 months postnatal than in control littermates (P = 0.036 for femur; and P < 0.001 for tibia). However, osteoarthritis did not spontaneously occur before the 1-year follow-up. matrix metalloproteinase (MMP)-13 and adamalysin-like metalloproteinases with thrombospondin motifs(ADAMTS)-5 were upregulated in hypertrophic chondrocytes of transgenic mice. Immunostaining and western blotting revealed that pSmad1/5/9-positive chondrocytes were more abundant in the articular cartilage of Ext1-cKO mice than in control littermates. Furthermore, the BMP inhibitor significantly decreased the number of hypertrophic chondrocytes in Ext1-cKO mice (P = 0.007). CONCLUSIONS: HS deficiency in articular chondrocytes causes chondrocyte hypertrophy, wherein upregulated BMP/Smad signaling partially contributes to this phenotype. HS might play an important role in maintaining the cartilaginous matrix by regulating BMP signaling.

Epidemiology and genotypic characterisation of dissemination patterns of uropathogenic Escherichia coli in a community.

To characterise the dissemination patterns of uropathogenic Escherichia coli (UPEC) in a community, we conducted a study utilising molecular and fundamental descriptive epidemiology. The subjects, consisted of women having community-acquired acute urinary tract infection (UTI), were enrolled in the study from 2011 to 2012. UPEC isolates were subjected to antibacterial-susceptibility testing, O serogrouping, phylotyping, multilocus-sequence typing with phylogenetic-tree analysis and pulsed-field-gel electrophoresis (PFGE). From the 209 unique positive urinary samples 166 UPEC were isolated, of which 129 were fully susceptible to the tested antibiotics. Of the 53 sequence types (STs), the four most prevalent STs (ST95, ST131, ST73 and ST357) accounted for 60% of all UPEC strains. Antimicrobial resistance was less frequently observed for ST95 and ST73 than for the others. A majority of rare STs and a few common STs constituted the diversity pattern within the population structure, which was composed of the two phylogenetically distinct clades. Eleven genetically closely related groups were determined by PFGE, which accounted for 42 of the 166 UPEC isolates, without overt geo-temporal clustering. Our results indicate that a few major lineages of UPEC, selected by unidentified factors, are disseminated in this community and contribute to a large fraction of acute UTIs.

The Geriatric Nutritional Risk Index is Independently Associated with Prognosis in Patients with Critical Limb Ischemia Following Endovascular Therapy.

OBJECTIVES: Patients with critical limb ischemia (CLI) have poor overall and limb prognosis. Although nutritional status influences overall prognosis, and the Geriatric Nutritional Risk Index (GNRI) is a widely used, simple and well established nutritional status screening method, the association between the GNRI and the overall and limb prognosis of patients with CLI following endovascular therapy (EVT) has not been explored. METHODS: Clinical outcomes were retrospectively evaluated in 473 consecutive patients (74 ± 10 years; 59% male) with CLI who underwent EVT. The GNRI on admission was calculated as follows: [14.89 × albumin (g/dL)] + [41.7 × (body weight/ideal body weight)]. Cox proportional hazard analysis was performed to explore the independent association between the GNRI and mortality and major amputation. RESULTS: Patients (53% ambulatory, 38% wheelchair bound, and 9% bedridden) were divided into two groups based on the median GNRI: the higher group (GNRI ≥ 91.2, n = 237) and the lower group (GNRI < 91.2, n = 236). Median follow up duration after EVT was 11.3 months. Three years after EVT, the survival rate (74% in the higher GNRI, and 48% in the lower GNRI, respectively), and limb salvage rate (92% in the higher GNRI, and 84% in the lower GNRI) were significantly lower in the lower GNRI group. GNRI (hazard ratio [HR], 1.03; 95% confidence interval [CI], 1.01-1.05), along with being wheelchair bound (HR, 1.87; 95% CI 1.17-2.97; vs. ambulatory status), being bedridden (HR, 3.10; 95% CI, 1.63-2.97; vs. ambulatory status), being on hemodialysis (HR, 2.33; 95% CI, 1.49-3.64), and having chronic heart failure (HR, 2.22; 95% CI, 1.44-3.43) were the independent predictors of mortality. The GNRI (HR, 1.04; 95% CI, 1.01-1.07), being bedridden (HR, 4.15; 95% CI, 1.67-10.3; vs. ambulatory status), isolated below knee disease (HR, 2.49; 95% CI, 1.30-4.77), and hemodialysis (HR, 2.44; 95% CI, 1.23-4.85) were independently associated with major amputation. CONCLUSIONS: The GNRI on admission was independently associated with mortality and major amputation after EVT in patients with CLI.

Effects of Pt dispersion on electronic and oxide ionic conductivity in Pr1.90Ni0.71Cu0.24Ga0.05O4.

The effects of dispersing Pt particles in bulk Pr1.90Ni0.71Cu0.21Ga0.05O(4+δ) (PNCG) on the electrical conductivity and oxygen permeability of the material were studied. The different thermal expansion coefficients of PNCG and Pt generated a mechanical compressive strain in the PNCG. This may cause the electrical conductivity to decrease in samples containing Pt. In contrast, the oxide ion conductivity estimated from the oxygen permeability increased upon dispersion of Pt. These variations appear to be related to the electron hole and interstitial oxygen concentrations. Moreover, the present study suggests that the mechanical strain induces a chemical strain via the introduction of oxygen defects as well as changes in cation valences.

Tumour-suppressive microRNA-144-5p directly targets CCNE1/2 as potential prognostic markers in bladder cancer.

BACKGROUND: Analysis of a microRNA (miRNA) expression signature of bladder cancer (BC) by deep-sequencing revealed that clustered miRNAs microRNA (miR)-451a, miR-144-3p, and miR-144-5p were significantly downregulated in BC tissues. We hypothesised that these miRNAs function as tumour suppressors in BC. The aim of this study was to investigate the functional roles of these miRNAs and their modulation of cancer networks in BC cells. METHODS: The functional studies of BC cells were performed using transfection of mature miRNAs. Genome-wide gene expression analysis, in silico analysis, and dual-luciferase reporter assays were applied to identify miRNA targets. The association between miR-144-5p levels and expression of the target genes was determined, and overall patient survival as a function of target gene expression was estimated by the Kaplan-Meier method. RESULTS: Gain-of-function studies showed that miR-144-5p significantly inhibited cell proliferation by BC cells. Four cell cycle-related genes (CCNE1, CCNE2, CDC25A, and PKMYT1) were identified as direct targets of miR-144-5p. The patients with high CCNE1 or CCNE2 expression had lower overall survival probabilities than those with low expression (P=0.025 and P=0.032). CONCLUSION: miR-144-5p functions as tumour suppressor in BC cells. CCNE1 and CCNE2 were directly regulated by miR-144-5p and might be good prognostic markers for survival of BC patients.

Characterization of ASKP1240, a fully human antibody targeting human CD40 with potent immunosuppressive effects.

Blocking the CD40-CD154 interaction is reported to be effective for transplantation management and autoimmune disease models in rodents and nonhuman primates. However, clinical trials with anti-CD154 mAbs were halted because of high incidence of thromboembolic complications. Thus, we generated and characterized a fully human anti-CD40 mAb ASKP1240, as an alternative to anti-CD154 mAb. In vitro ASKP1240 concentration-dependently inhibited human peripheral blood mononuclear cell proliferation induced by soluble CD154. In addition, ASKP1240 did not destabilize platelet thrombi under physiological high shear conditions while mouse anti-human CD154 mAb (mu5C8) did. And ASKP1240 itself did not activate platelet and endothelial cells. In vivo administration of ASKP1240 (1 or 10 mg/kg, intravenously) to cynomolgus monkeys, weekly for 3 weeks, significantly attenuated both delayed-type hypersensitivity and specific antibody formation evoked by tetanus toxoid. The immunosuppressive effect was well correlated with the CD40 receptor saturation. Thus, these results suggest that ASKP1240 is immunosuppressive but not prothromboembolic, and as such appears to be a promising therapeutic candidate for the management of solid organ transplant rejection and autoimmune diseases therapy.

Role of c-Jun N-terminal kinase isoforms in the cellular activity of melanoma cell lines.

BACKGROUND: The c-Jun N-terminal kinase (JNK) is thought to be involved in inflammation, proliferation and apoptosis. AIM: To examine the role of JNK isoforms in metastasis, proliferation, migration and invasion of the malignant melanoma (MM) cell lines SK-MEL-28, SK-MEL-3 and WM164, using a kinase-specific inhibitor or isoform-specific small interfering (si)RNAs. RESULTS: SK-MEL-3, a cell line established from metastatic MM, showed slightly increased phosphorylation of both JNK1 and JNK2, whereas WM164, a cell line derived from primary MM, showed significant phosphorylation of JNK1. A JNK inhibitor, SP600125, inhibited cell proliferation of SK-MEL-3 but not SK-MEL-28 or WM164. Transfection of JNK1-specific siRNA reduced the migratory activity of WM164 cells, while silencing of either JNK1 or JNK2 strongly suppressed the invasive activity of SK-MEL-3. CONCLUSIONS: Our study suggests that JNK isoforms have different roles in MM. Metastasis of MM may be regulated by JNK2, while invasion is regulated by both JNK1 and JNK2. JNK1 and JNK2 respectively mediate cell migration and cell proliferation. Further understanding of the specific roles of JNK isoforms in the pathogenesis of MM may lead to the development of therapies targeting specific isoforms.

Localization of a gene for Fukuyama type congenital muscular dystrophy to chromosome 9q31-33.

Fukuyama type congenital muscular dystrophy (FCMD) is an autosomal recessive severe muscular dystrophy associated with an anomaly of the brain. Twenty-one FCMD families, 13 of them with consanguineous marriages, were analysed by genetic linkage analyses with polymorphic microsatellite markers to map the FCMD gene. Significant lod scores were obtained with the markers D9S58 (Zmax = 5.81 at theta = 0.06), D9S59 (Zmax = 4.33 at theta = 0.02), and HXB (Zmax = 3.28 at theta = 0.09) on chromosome 9q31-33. Multipoint analysis placed FCMD between D9S58 and D9S59, with a maximum lod score of 16.93. These markers will be useful for presymptomatic, prenatal and carrier diagnosis of family members carrying FCMD, and they represent important resources for the identification of a gene responsible for FCMD.

Pharmacokinetics of the amidine prodrug of a novel oral anticoagulant factor VIIa inhibitor (AS1924269-00) in rats.

AS1924269-00 is a promising orally applicable anticoagulant that inhibits FVIIa but has very low oral absorption. Therefore, in this study, we aimed to develop a prodrug of AS1924269-00, which possesses a carbamate-added amidine functional group, with high membrane permeability. We investigated the pharmacokinetics of the carbamate-type prodrug of AS1924269-00 in rats. The Caco-2 cell monolayer was used as an in vitro model and in parallel an artificial membrane permeability assay (PAMPA) was performed to examine the transport mechanisms of the prodrug. The bioavailability of the active form was determined to be only 0.3% in rats, but the oral absorption of the prodrug was markedly improved, and its bioavailability was 36%. Our in vivo result was consistent with the finding that compared to AS1924269-00, the prodrug showed favorable permeability in Caco-2 cells and PAMPA. We introduced carbamate into the amidine functional group of the FVIIa inhibitor, which possesses the amidine backbone, and converted it to a prodrug using carboxylic acid ethyl ester. This novel prodrug had favorable absorption and membrane permeability in vivo and in vitro. Thus, we suggest a clinical application of the carbamate-added amidine prodrug of the FVIIa inhibitor.

Characterization of in vitro biotransformation of the new oral anticoagulants, the factor VIIa inhibitors AS1927819-00 and AS1932804-00.

We recently developed a prodrug (AS1932804-00, CMP) of the novel FVIIa inhibitor AS1924269-00, which possesses a carbamate amidine backbone. In addition, we developed another type of prodrug (AS1927819-00, OXP) with an oxime amidine backbone. In this study, we investigated the efficiency of conversion of these novel FVIIa prodrugs to their active forms by evaluating the production of the active form in vitro by using microsomes, mitochondria, and cryopreserved hepatocytes, and compared it with the in vivo conversion mechanisms of the prodrugs (oxime amidine vs. carbamate amidine). We observed that OXP and CMP showed improved oral absorption, and the efficiency of conversion of CMP to the active form was higher than that of OXP. The in vivo rate of conversion of OXP to its active form was low in rats, and compared to liver microsomes and mitochondria, cryopreserved hepatocytes supplemented with serum and coenzymes were an appropriate metabolic test tool. On the other hand, the efficiency of conversion of CMP to its active from could be appropriately evaluated using small intestinal microsomes. The development of a prodrug can be optimized when information about the stability of carboxylic acid esters in the presence of serum esterases, membrane permeability of intermediate forms, and differential tissue specificity to metabolic activities for carbamate and oxime backbones of amidine can be obtained.

Induction of immunoglobulin gene expression in mouse fibroblasts by cycloheximide treatment.

A complete set of a rearranged human gamma 1-heavy chain gene, HIG1, was cloned from human plasma cell leukemia line, ARH-77, and transferred into mouse cells. It was strongly expressed in mouse myeloma cells but not in mouse L cells, indicating that immunoglobulin gene expression is not species-specific but cell-specific. However, a remarkable production of human gamma 1 chain was induced in mouse L cells containing HIG1 gene when the cells were treated with cycloheximide for a short period. The role of a labile repressor molecule in the expression of the immunoglobulin gene is proposed.

The presumptive CDR3 regions of both T cell receptor alpha and beta chains determine T cell specificity for myoglobin peptides.

The T cell receptor alpha/beta (TCR-alpha/beta) is encoded by variable (V), diversity (D), joining (J), and constant (C) segments assembled by recombination during thymocyte maturation to produce a heterodimer that imparts antigenic specificity to the T cell. Unlike immunoglobulins (Igs), which bind free antigen, the ligands of TCR-alpha/beta are cell surface complexes of intracellularly degraded antigens (i.e., peptides) bound to and presented by polymorphic products of the major histocompatibility complex (MHC). Therefore, antigen recognition by T cells is defined as MHC restricted. A model has been formulated based upon the similarity between TCR-alpha/beta V region and Ig Fab amino acid sequences, and the crystal structure of the MHC class I and Ig molecules. This model predicts that the complementarity determining regions (CDR) 1 and 2, composed of TCR V alpha and V beta segments, primarily contact residues of the MHC alpha helices, whereas V/J alpha and V/D/J beta junctional regions (the CDR3 equivalent) contact the peptide in the MHC binding groove. Because polymorphism in MHC proteins is limited relative to the enormous diversity of antigenic peptides, the TCR may have evolved to position the highly diverse junctional residues (CDR3), where they have maximal contact with antigen bound in the MHC peptide groove. Here, we demonstrate a definitive association between CDR3 sequences in both TCR alpha and beta chains, and differences in recognition of antigen fine specificity using a panel of I-Ed-restricted, myoglobin-reactive T cell clones. Acquisition of these data relied in part upon a modification of the polymerase chain reaction that uses a degenerate, consensus primer to amplify TCR alpha chains without foreknowledge of the V alpha segments they utilize.

Increased circulating cell signalling phosphoproteins in sera are useful for the detection of pancreatic cancer.

BACKGROUND: Intracellular phosphoprotein activation significantly regulates cancer progression. However, the significance of circulating phosphoproteins in the blood remains unknown. We investigated the serum phosphoprotein profile involved in pancreatic cancer (PaCa) by a novel approach that comprehensively measured serum phosphoproteins levels, and clinically applied this method to the detection of PaCa. METHODS: We analysed the serum phosphoproteins that comprised cancer cellular signal pathways by comparing sera from PaCa patients and benign controls including healthy volunteers (HVs) and pancreatitis patients. RESULTS: Hierarchical clustering analysis between PaCa patients and HVs revealed differential pathway-specific profiles. In particular, the components of the extracellular signal-regulated kinase (ERK) signalling pathway were significantly increased in the sera of PaCa patients compared with HVs. The positive rate of p-ERK1/2 (82%) was found to be superior to that of CA19-9 (53%) for early stage PaCa. For the combination of these serum levels, the area under the receiver-operator characteristics curves was showing significant ability to distinguish between the two populations in independent validation set, and between cancer and non-cancer populations in another validation set. CONCLUSION: The comprehensive measurement of serum cell signal phosphoproteins is useful for the detection of PaCa. Further investigations will lead to the implementation of tailor-made molecular-targeted therapeutics.

The phenotype spectrum of Japanese multiple system atrophy.

OBJECTIVE: This study aimed to determine the spectrum of pathological involvement of the striatonigral (StrN) and olivopontocerebellar (OPC) systems in Japanese patients with multiple system atrophy (MSA). This study also aimed to compare the pathological spectrum of Japanese MSA patients with the previously reported results in British MSA patients. METHODS: A semiquantitative pathological analysis of 50 MSA patients' brains that were referred to the Brain Research Institute, Niigata University, Japan, was performed. The severity of neuronal cell loss was determined as previously described by the study from the Queen Square Brain Bank (QSBB), UK. RESULTS: The mean neuronal cell loss score was significantly higher in the OPC area than in the basal ganglia sites examined, except the dorsolateral putamen. The relative prevalence of pathological phenotypes showed that 40% of cases had OPC-predominant pathology, 18% had StrN-predominant pathology and the remaining (42%) had equivalent StrN and OPC pathology. None of the MSA cases had coexistent Lewy bodies in the dorsal motor nucleus of the vagus and the substantia nigra. CONCLUSIONS: In contrast to the previously reported results involving British patients' brains from the QSBB (OPC-predominant pathology 17%, StrN-predominant pathology 34%, equivalent StrN and OPC pathology 49%), the results of the present study showed more pathological involvement of the OPC system than of the StrN system. The rarity of Lewy bodies may underlie the phenotypic expression of Japanese MSA. The present observations reflect the disequilibrium in the phenotype distribution between the two populations.

Cenozoic motion between East and West Antarctica

The West Antarctic rift system is the result of late Mesozoic and Cenozoic extension between East and West Antarctica, and represents one of the largest active continental rift systems on Earth. But the timing and magnitude of the plate motions leading to the development of this rift system remain poorly known, because of a lack of magnetic anomaly and fracture zone constraints on seafloor spreading. Here we report on magnetic data, gravity data and swath bathymetry collected in several areas of the south Tasman Sea and northern Ross Sea. These results enable us to calculate mid-Cenozoic rotation parameters for East and West Antarctica. These rotations show that there was roughly 180 km of separation in the western Ross Sea embayment in Eocene and Oligocene time. This episode of extension provides a tectonic setting for several significant Cenozoic tectonic events in the Ross Sea embayment including the uplift of the Transantarctic Mountains and the deposition of large thicknesses of Oligocene sediments. Inclusion of this East-West Antarctic motion in the plate circuit linking the Australia, Antarctic and Pacific plates removes a puzzling gap between the Lord Howe rise and Campbell plateau found in previous early Tertiary reconstructions of the New Zealand region. Determination of this East-West Antarctic motion also resolves a long standing controversy regarding the contribution of deformation in this region to the global plate circuit linking the Pacific to the rest of the world.

Extensive multiple piloleiomyoma in the submental region treated successfully by surgery and reconstruction with a submental perforator flap.

Piloleiomyoma is a benign tumour originating in the smooth muscles of the arrector pili muscle in the skin. The lesions are often sensitive to touch, cold and emotional disturbance. We present a patient with multiple piloleiomyoma (MPL) of the submentum who underwent reconstructive surgery using a submental perforator flap. The result was excellent and there were no postoperative complications. MPL of the submental region is relatively rare; to our knowledge, ours is the first report of MPL treated successfully with a submental perforator flap.

Molecular cloning and tissue distribution of a receptor for pituitary adenylate cyclase-activating polypeptide.

Pituitary adenylate cyclase-activating polypeptide (PA-CAP) is a polypeptide hormone related to vasoactive intestinal polypeptide (VIP). Rat PACAP receptor cDNA was isolated from a brain cDNA library by cross-hybridization with rat VIP receptor cDNA. The recombinant PACAP receptor expressed in COS cells bound PACAP with about 1000 times higher affinity than VIP, and PACAP stimulated adenylate cyclase through the cloned PACAP receptor. The rat PACAP receptor consists of 495 amino acids, contains seven transmembrane segments, and has a significant similarity with other Gs-coupled receptors, such as VIP, glucagon, and secretin receptors. PACAP receptor mRNA was abundantly expressed in the brain, but not in the peripheral tissues except for the adrenal gland. In situ hybridization revealed a high level of expression of PACAP receptor mRNA in the hippocampal dentate gyrus, olfactory bulb, and cerebellar cortex.

Functional expression and tissue distribution of a novel receptor for vasoactive intestinal polypeptide.

Vasoactive intestinal polypeptide (VIP), a 28 amino acid peptide hormone, plays many physiological roles in the peripheral and central nerve systems. A functional cDNA clone of the VIP receptor was isolated from a rat lung cDNA library by cross-hybridization with the secretin receptor cDNA. VIP bound the cloned VIP receptor expressed in mouse COP cells and stimulated adenylate cyclase through the cloned receptor. The rat VIP receptor consists of 459 amino acids with a calculated Mr of 52,054 and contains seven transmembrane segments. It is structurally related to the secretin, calcitonin, and parathyroid hormone receptors, suggesting that they constitute a new subfamily of the Gs protein-coupled receptors. VIP receptor mRNA was detected in various rat tissues including liver, lung, intestines, and brain. In situ hybridization revealed that VIP receptor mRNA is widely distributed in neuronal cells of the adult rat brain, with a relatively high expression in the cerebral cortex and hippocampus.

Age-dependent emergence and progression of a tauopathy in transgenic mice overexpressing the shortest human tau isoform.

Filamentous tau aggregates are hallmarks of tauopathies, e.g., frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) and amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC). Since FTDP-17 tau gene mutations alter levels/functions of tau, we overexpressed the smallest human tau isoform in the CNS of transgenic (Tg) mice to model tauopathies. These mice acquired age-dependent CNS pathology similarto FTDP-17 and ALS/PDC, including insoluble, hyperphosphorylated tau and argyrophilic intraneuronal inclusions formed by tau-immunoreactive filaments. Inclusions were present in cortical and brainstem neurons but were most abundant in spinal cord neurons, where they were associated with axon degeneration, diminished microtubules (MTs), and reduced axonal transport in ventral roots, as well as spinal cord gliosis and motor weakness. These Tg mice recapitulate key features of tauopathies and provide models for elucidating mechanisms underlying diverse tauopathies, including Alzheimer's disease (AD).