Accumulation of filamentous tau in the cerebral cortex of human tau R406W transgenic mice

Missense mutations of the tau gene cause autosomal dominant frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), an illness characterized by progressive personality changes, dementia, and parkinsonism. There is prominent frontotemporal lobe atrophy of the brain accompanied by abundant tau accumulation with neurofibrillary tangles and neuronal cell loss. Using a hamster prion protein gene expression vector, we generated several independent lines of transgenic (Tg) mice expressing the longest form of the human four-repeat tau with the R406W mutation associated with FTDP-17. The TgTauR406W 21807 line showed tau accumulation beginning in the hippocampus and amygdala at 6 months of age, which subsequently spread to the cortices and subcortical areas. The accumulated tau was phosphorylated, ubiquitinated, conformationally changed, argyrophilic, and sarcosyl-insoluble. Activation of GSK-3beta and astrocytic induction of mouse tau were observed. Astrogliosis and microgliosis correlated with prominent tau accumulation. Electron microscopic examination revealed the presence of straight filaments. Behavioral tests showed motor disturbances and progressive acquired memory loss between 10 to 12 months of age. These findings suggested that TgTauR406W mice would be a useful model in the study of frontotemporal dementia and other tauopathies such as Alzheimer's disease (AD).     

First cutaneous branch of the internal pudendal artery: an anatomical basis for the so-called gluteal fold flap

We investigated the cutaneous blood supply in the gluteal and perineal regions of 35 donated cadavers to provide an anatomical basis for reliable vulvo-vaginal reconstruction using a skin flap such as the so-called gluteal fold flap. The cutaneous areas along the gluteal cleft and sulcus were likely to be supplied by 3 routes: 1) the internal pudendal artery (IPA), especially its first cutaneous branch; 2) perforators running through the gluteus maximus muscle and arising from the inferior gluteal artery (IGA); and 3) a non-perforator running around and inferior to the ischial tuberosity and originating from the IGA. Route 1 supplied the skin along the gluteal cleft, route 2 the gluteal fold (i.e., a bulky skin fold along the upper edge of the gluteal sulcus), and route 3, just along the gluteal sulcus. In those 3 routes, we noted the consistent morphology of the thick and long, first cutaneous branch of the IPA. The first arterial branch, 1.5 mm in diameter at its origin on average (ranging from 0.7-2.6 mm), usually originated from the IPA under the cover of or at the inferomedial or distal side of the sacrotuberous ligament (almost always less than 20 mm from the inferomedial margin of the ligament). The branch ran superomedially toward the coccyx or ran medially in the ischiorectal fat. It accompanied the vein and nerve at its distal (peripheral) course although the nerve often ran independently at its proxomal course near the ligament. Therefore, the first branch of the IPA seems to provide a reliable pedicle using the skin along the gluteal cleft whether the incision for approach is conducted along the gluteal sulcus or not. However, if the gluteus maximus muscle extended much inferomedially, the pedicle would be very short. In this case, preparation of the pedicle seems to be necessary along the arterial course under the cover of the muscle.     

Reduction of a vascular endothelial growth factor receptor, fetal liver kinase-1, by antisense oligonucleotides induces motor neuron death in rat spinal cord exposed to hypoxia

Vascular endothelial growth factor (VEGF) is reported to play a neuroprotective role through a VEGF receptor, fetal liver kinase-1 (Flk-1) in vitro. We investigated whether reduction of Flk-1 could induce motor neuron loss in rat spinal cord by inhibiting the expression of Flk-1 in rat spinal cord using antisense oligodeoxynucleotides (ODNs) against the Flk-1 receptor. Rat spinal cord was repetitively exposed to 12% hypoxia, and the change of the phosphatidylinositol 3-kinase (PI3-K)/Akt pathway and the mitogen-activated protein kinase kinase (MEK)/extracellular-signal-regulated kinase (ERK) pathway was examined. Intrathecal infusion of Flk-1 antisense ODNs for 7 days suppressed almost completely Flk-1 expression in the lumbar segment of the spinal cord and was followed by a hypoxic challenge with 12% oxygen for 1 h that was repeated for 7 more days. In the lumbar segment, we observed that reduced Flk-1 expression and hypoxic challenge for 7 days resulted in approximately 50% loss of motor neurons, in which the activation of Akt and ERK, that is, increased levels of phosphorylated-Akt and of phosphorylated-ERK by hypoxia, was markedly inhibited. In contrast, the reduction of Flk-1 expression alone did not induce motor neuron loss. These results suggest that VEGF exerts its protective effect on motor neurons against hypoxia-induced toxicity by the Flk-1 receptor through the PI3-K/Akt and the MEK/ERK signaling pathways.     

Keratin in human lung tumors. Patterns of localization of different-molecular-weight keratin proteins.

In this immunohistochemical study, antiserums to different molecular weight keratin proteins (45kd, 46kd, 55kd, and 63kd) were utilized to determine the profiles of keratin proteins present in a variety of pulmonary neoplasms. Different histologic types of lung carcinoma exhibited different patterns of keratin staining. Squamous cell carcinomas stained strongly for 45K, 46K, and 55K keratin, with staining for 63K restricted to areas or individual cells with cytoplasmic keratinization. Adenocarcinomas showed variable, generally weak staining for 45K, 46K, and 55K keratin and were uniformly negative for 63K keratin both in frozen and paraffin sections. Mesotheliomas and reactive mesothelial cells, by contrast, stained positively for 63K keratin in addition to keratins of lower molecular weights. Differences in staining for 63K keratin between mesothelioma and adenocarcinoma may have diagnostic application. Moreover, individual cytokeratins may serve as markers of tumor differentiation and provide information as to the origin of neoplastic cells.     

Effect of increased task procedures on correlation dimensions of the electroencephalogram

Changes in correlation dimensions of the electroencephalogram (EEG) were examined in three different tasks. These three tasks differed from each other with respect to the number of procedures. In the present experiment, left-hand movement and mental arithmetic were controlled, respectively, during an auditory linguistic task. Subjects were 13 healthy right-handed males. EEG signals from eight electrode sites were analyzed and the correlation dimensions were obtained. In addition, the relative power was obtained for the alpha band. An increase in the number of procedures yielded high dimensionality on the occipital EEG. In contrast, left-hand movement had no significant effect on EEG dimensions over the motor area. The relative power of the alpha band was seen to decrease in all channels as the number of procedures increased. The fact that changes in EEG dimensions did not necessarily exhibit a simple correspondence to changes in alpha wave activity was also discussed.     

Neuroimaging of direction-selective mechanisms for second-order motion

Psychophysical findings have revealed a functional segregation of processing for 1st-order motion (movement of luminance modulation) and 2nd-order motion (e.g., movement of contrast modulation). However neural correlates of this psychophysical distinction remain controversial. To test for a corresponding anatomical segregation, we conducted a new functional magnetic resonance imaging (fMRI) study to localize direction-selective cortical mechanisms for 1st- and 2nd-order motion stimuli, by measuring direction-contingent response changes induced by motion adaptation, with deliberate control of attention. The 2nd-order motion stimulus generated direction-selective adaptation in a wide range of visual cortical areas, including areas V1, V2, V3, VP, V3A, V4v, and MT+. Moreover, the pattern of activity was similar to that obtained with 1st-order motion stimuli. Contrary to expectations from psychophysics, these results suggest that in the human visual cortex, the direction of 2nd-order motion is represented as early as V1. In addition, we found no obvious anatomical segregation in the neural substrates for 1st- and 2nd-order motion processing that can be resolved using standard fMRI.     

Clinical heterogeneity of neonatal intrahepatic cholestasis caused by citrin deficiency: case reports from 16 patients

A deficiency of citrin, which is encoded by the SLC25A13 gene, causes both adult-onset type II citrullinemia (CTLN2) and neonatal intrahepatic cholestasis (NICCD). We analyzed 16 patients with NICCD to clarify the clinical features of the disease. Severe intrahepatic cholestasis with fatty liver was the most common symptom, but the accompanying clinical features were variable, namely; suspected cases of neonatal hepatitis or biliary atresia, positive results from newborn screening, tyrosinemia, failure to thrive, hemolytic anemia, bleeding tendencies and ketotic hypoglycemia. Laboratory data showed elevated serum bile acid levels, hypoproteinemia, low levels of vitamin K-dependent coagulation factors, and hypergalactosemia. Hypercitrullinemia was detected in 11 out of 15 patients examined. Most of the patients were given a lactose-free and/or medium chain triglycerides-enriched formula and lipid-soluble vitamins. The prognosis of the 16 patients is going fairy well at present, but we should observe these patients carefully to see if they manifest any symptom of CTLN2 in the future.     

Growth of Bacteroides fragilis in Rabbit Tracheal Organ Culture: Anaerobiosis and Tissue Respiration

Rabbit tracheal explants supporting growth of inoculated Bacteroides fragilis in air were shown to keep low oxygen tension. Treating the explants with sodium azide induced high oxygen tension and arrested reversibly the growth of B. fragilis.     

Histochemical changes of rat skeletal muscles induced by cold acclimation

After cold acclimation of rats the augmentation of succinic dehydrogenase activity in the fast-twitch oxidative glycolytic (FOG) and the slow-twitch oxidative (SO) fibers was observed in entire regions of the soleus, the extensor digitorum longus, the plantaris, the longissimus and the gastrocnemius muscles. Furthermore, a tendency to increased proportion of the FOG and the SO fibers was observed more prominently in superficial regions than in deep regions of a large muscle such as the gastrocnemius muscle.     

Reproduction of menstrual changes in transplanted human endometrial tissue in immunodeficient mice

BACKGROUND: Cultures of human endometrial tissue are useful for analysing the mechanisms underlying the menstrual cycle. However, long-term culture of endometrial tissue is difficult in vitro. Xenotransplantation of normal human endometrial tissue into immunodeficient mice could allow prolonged survival of the transplanted tissues. METHODS: Proliferative-phase endometrial tissue samples from three women were transplanted into the subcutaneous space of ovariectomized, immunodeficient, non-obese diabetic (NOD)/severe combined immunodeficiency (SCID)/gammaC(null) (NOG) mice. The mice were treated with 17beta-estradiol (E2) for the first 14 days after transplantation, followed by E2 plus progesterone for the next 14 days. The transplants were investigated morphologically and immunohistochemically at various times after implantation. RESULTS: The transplanted tissues contained large numbers of small glands, pseudostratification of the nuclei and dense stroma after treatment with E2 alone. After treatment with E2 plus progesterone, subnuclear vacuolation, luminal secretion and decidualization of the stroma were observed. When the hormone treatment ceased, tissue destruction occurred and the transplants returned to the proliferative phase. Lymphocytes were identified immunohistochemically: the numbers of CD56-positive and CD16-negative cells increased significantly in the stroma during the late secretory phase (day 28). CONCLUSIONS: Human endometrial tissue transplanted into NOG mice showed similar histological changes to eutopic endometrial tissue during treatment with sex steroid hormones for 1 month. Moreover, lymphocytes were produced in the transplanted human endometrial tissue. This system represents a new experimental model of the human endometrium in vivo.