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Recently, integrated geophysical‐geological surveys in the Nankai subduction zone in Japan have revealed that slow earthquakes repeatedly occur beneath the outer wedge of the forearc. During December 2020 to February 2021, clustered slow earthquakes propagated around the frontal thrust of the accretionary wedge. The frontal thrust ramps up from the basal décollement and slips over trench‐filling sediment along the landward edge of the Nankai trough floor. Here, the Paleo‐Zenisu ridge has been subducted beneath the inner‐outer slope border. In addition, ocean floor topography and geologic structure revealed by seismic reflection surveys completed before 2022 document that the basement of the Philippine Sea Plate beneath the frontal thrust has a seamount and a horst‐like basement high. The northern edge of the basement high is located at the ramp‐up position of the frontal thrust. The 2020–2021 clustered slow earthquakes started at the Paleo‐Zenisu ridge and propagated to the topographic highs beneath the deformation front. Considering that the relative plate convergence between the upper Amurian Plate of the Nankai forearc and the subducting Philippine Sea Plate is ∼6.0 cm/year, the basement high at the deformation front has uplifted the frontal crest of the wedge at an average rate of 2.7–5.7 mm/year for several tens to hundred thousand years. These rates are among some of the highest rock uplift rates measured in the world. The slow earthquakes in the off‐Kumano Nankai Trough in 2020–2021 are a snapshot of a "living" Nankai frontal thrust during the megathrust interseismic period. Plain Language Summary: Slow earthquakes family: slow slips, very low frequency earthquakes, and tremors are significant events for understanding the interseismic dynamics between large earthquakes along the convergent plate boundary in the ocean. Slow earthquakes took place during December 2020 to February 2021 in the Nankai Trough in Japan and propagated along the frontal edge of the upper plate. Seismic reflection surveys revealed that seamount‐like and horst‐like basement highs exist beneath the front, collide with the upper plate, and uplift trench filling sediments by a ramp thrust. Even the incipient plate boundary of the décollement is initiated within the sediments beneath the Nankai Trough. Such a deformation feature around the front is a source candidate for the slow earthquakes. The uplift rate of the frontal crest of the upper plate presents the same order of a few to several mm/year as that of the foreland of the Himalayan Mountain belt. The slow earthquakes in the off‐Kumano Nankai Trough in 2020–2021 appear the first snapshot of a "living" Nankai frontal thrust during inter‐large seismic period. Key Points: Between 2020 and 2021, slow earthquakes propagated around the frontal thrust of the accretionary wedge in the Nankai Trough off KumanoSeamount and horst‐like basement highs beneath the frontal thrust cause uplift and are associated with the slow earthquake eventsThe average uplift rate of the frontal crest is 2.7–5.7 mm/year, approximately the same order as that of the Himalayan foreland [ABSTRACT FROM AUTHOR]

The causes for forearc basin and megathrust rupture zone segmentation are controversial. The Nankai forearc, Japan, is separated into five domains based on topography: Enshu, Kumano, Muroto, Tosa, and Hyuga. The boundaries of these domains correspond to the rupture limits of large earthquakes. We examined the geologic structure of the boundary region between the Kumano and Muroto domains off the Kii Peninsula using multichannel seismic reflection data to evaluate the role of upper plate composition in controlling segmentation. The results suggest that thick cover sediments and underlying accretionary prism are obliquely thrust landward over the igneous basement complex rock in the region of offshore of Cape Shionomisaki and separate the forearc basin. The igneous basement complex rocks directly overlying the plate interface in the hypocentral regions of 1944 Tonankai and 1946 Nankai earthquakes. The 1944 earthquake originated at the base of the complex, and the rupture extent slipped past its basement boundary, whereas the 1946 event nucleated at the updip boundary of the basement complex. The dense igneous rocks might have worked as a heavily loaded barrier on the seismogenic megathrust and separated the rupture area of both the earthquakes. Upper plate geology may be an important factor in controlling seismogenesis in the Nankai Trough and may serve as an example for understanding the controls on megathrust slip in other subduction zones. Plain Language Summary: The Nankai Trough, Japan is the place where quakes nucleate in the margin and tsunamis repeatedly devastated circum‐Pacific societies. When, where, why, and how the quakes were started in the trench is a central scientific question but unsolved. The historical records of earthquakes suggest that the rupture started around Cape Shionomisaki of the Kii Peninsula, where there is also a topographic segment boundary of the ∼2,000 m deep basin in the middle continental slope. Our research of the geologic structure beneath the earthquake epicenters indicates a dense and hard rock mass situated upon the hypocenters of 1944, and 1946 megaquakes off Cape Shionomisaki. The rock mass might have worked as a heavy load and barrier on the low angle dipping plate boundary fault when the fault slipped the large rupture was propagated in the Nankai Trough. Key Points: The Nankai forearc basin is separated off the Kii Peninsula owing to the existence of middle Miocene igneous basement in the upper plateThe rupture areas of the 1944 Tonankai, 1946 Nankai, and 2016 off‐Mie earthquakes appear to be controlled by the igneous basementThe shallow distribution of very low‐frequency earthquakes and tremors are related to the geological heterogeneity of the upper plate [ABSTRACT FROM AUTHOR]

To investigate structural characteristics associated with variations in slip behavior on the plate boundary in the Nankai subduction zone, we conducted seismic reflection surveys in the central‐western Nankai Trough. Data were processed by pre‐stack depth migration. The resulting depth map of the top of the subducting Philippine Sea plate shows detailed topographic features of the plate boundary, including subducting seamounts and large‐scale undulations of the plate surface. We report the presence of a structurally anomalous region, potentially with low velocity, in the overriding plate at the boundary between the zone of large coseismic slip during the 1946 Nankai earthquake and the area producing slow earthquakes. This anomaly appears to be related to depth‐dependent variations in plate boundary slip style and plate coupling in the central‐western Nankai Trough. Plain Language Summary: The central‐western Nankai Trough off southwestern Japan is one of the best locations to study variations in slip style on the plate boundary fault in subduction zones because the fault slip distribution during the latest great earthquake, the distribution of slow earthquakes, and interplate coupling are known from previous studies. We conducted seismic surveys along densely distributed survey lines to image detailed subsurface structures in the central‐western Nankai Trough. A three‐dimensional map of the plate boundary fault geometry was created from seismic profiles used in this study. We found a structural anomaly, interpreted as a low‐velocity zone in the overriding plate, at the boundary between the slip zone of great earthquakes and the zone of slow earthquakes. This anomaly might be related to the variation of the plate boundary fault slip styles. Key Points: The topography of the subducting plate is mapped with densely spaced seismic profiles in the central‐western Nankai TroughAn arcuate structural anomaly in the overriding plate ∼100 km long with potentially low velocity coincides with the Tosabae TroughThe arcuate anomaly is located at the boundary between regions of strong and weak plate coupling [ABSTRACT FROM AUTHOR]

Drilling during IODP NanTroSEIZE Expedition 316 led to the recovery of cores from the basal décollement in the frontal part of the Nankai accretionary prism and from a splay fault branching from the décollement at 25‐km landward of the prism toe. The core from the splay fault shows a main shear zone and two secondary shear zones. The main shear zone can be divided into two subzones. The upper subzone consists of a 1.2‐mm thick foliated gouge zone truncated downward by a through‐going fault encompassing a 0.4‐mm thick weakly foliated gouge interval. A nearby 200‐μm thick granular injection vein is interpreted as derived from the fault. The lower subzone consists of a foliated clayey gouge. A 70‐μm thick granular injection vein is also observed along this subzone. In the basal décollement core, microstructures consist of foliated gouge along a flat‐lying shear zone and seven flat‐lying or gently dipping secondary or incipient shear zones above. A redox front lies beneath the main shear zone. The shear zone and the redox front are truncated by a fault surface outlined by microbreccia developed at the expense of the overlying foliated gouge. Foliated gouge from the shear zones is tentatively interpreted as resulting from slow slip or aseismic creep. The weakly foliated gouge, the microbreccia, and the granular injection veins are interpreted as resulting from coseismic slip. The presence of the redox front beneath the main shear zone of the décollement fault core is interpreted as a consequence of oxidizing fluid flow along the microbreccia‐bearing fault. Plain Language Summary: To understand why some large subduction zone earthquakes are followed by destructive tsunamis and others are not is a key issue in seismic hazard assessment. Tsunami genesis is suspected to depend mainly on the capacity of faults in shallow parts of subduction zones to either transfer seismic slip from hypocentral depth upward or to dampen it before it reaches the surface. Expedition 316 of the IODP NanTroSEIZE program drilled across and retrieved cores from two major fault zones in the frontal part of the Nankai accretionary prism off Kii Peninsula. The rocks constituting the cored fault zones show microstructures which testify to both slow slip (plate tectonic steady‐state creep velocity or slow slip transient event velocity) and rapid slip (conventional earthquake slip velocity). It follows that in the Nankai Trough off Kii Peninsula, earthquake rupture can propagate along either of the major faults known there. Key Points: IODP Expedition 316 drilling across two fault zones in the Nankai accretionary prism allowed the recovery of intact cores of fault rocksFault rocks consist of microbreccia and weakly foliated gouge along sharp planar fault surfaces and foliated clayey gouge in millimeter‐thick shear zonesMicrobreccia and weakly foliated gouge suggest propagation of seismic slip along fault surfaces, while foliated gouge suggests aseismic or slow slip along shear zones [ABSTRACT FROM AUTHOR]

Hashimoto Y, Kondo Y, Kimura G, Matsuzawa I, Sato S, Ishizaki M, Imura N, Akimoto M & Hara S (2004) Histopathology 44, 353–359 Cyclooxygenase-2 expression and relationship to tumour progression in human renal cell carcinoma Cyclooxygenase (COX), which catalyses the synthesis of prostaglandins from arachidonic acid, has two isoforms; COX-1 and COX-2. There is ample evidence to suggest an important role for COX-2 in cancer. The aim of this study was to evaluate the clinical significance of COX-2 expression and its localization in the development and progression of human renal cell carcinoma (RCC). The expression and localization of COX-2 were evaluated in human RCC tissues from 75 patients by immunohistochemistry. Immunoreactive COX-2 protein was observed in all cases of RCC, and the levels of COX-2 expression were correlated with tumour grade and pathological stage. Expression of COX-2 was higher in the granular cell subtype than in the clear cell subtype of RCC. Immunoelectron microscopy revealed that COX-2 was expressed in the nuclear membrane, rough endoplasmic reticulum, Golgi complex and mitochondrial membrane of RCC cells. COX-2 overexpression within these intracellular organelles in RCC may be associated with renal cell carcinogenesis and COX-2 may be a useful biomarker in RCC. [ABSTRACT FROM AUTHOR]

Pressure and temperature (P–T) conditions of mélange formation are estimated from fluid inclusions within “syn-mélange” veins developed in the necks of boudins of sandstone blocks in the mélange of the Shimanto accretionary complex, south-west Japan. The mélange records décollement-zone processes. P–T conditions are in the range of 81 (+15) to 235 (±18) MPa and 150 (±25) to 220 (±31)°C. Assuming a constant fluid-pressure to lithostatic-pressure ratio for each data set, we estimate a P–T gradient of between 10.0°C/km (+0.2/−1.5) (lithostatic pressure) and 4.2°C/km (+0.1/−0.9) (hydrostatic pressure) from these results. The estimated lithostatic P–T gradient is much lower than that calculated from the age of the subducting oceanic plate. The estimated P–T conditions suggest that the mélange was formed within the seismogenic zone (hypothesized from thermal modeling), although the deformation mechanism of mélange (i.e. dominant diffusive mass transfer mainly in shale matrix with minor brittle breakage mainly in sandstone blocks) does not show evidence of seismic deformation. In addition, at the time of syn-mélange vein formation, a shale matrix of mélange has injected into the vein, which indicates a ductile deformation of shale. A possible explanation for this discrepancy is that the mélange was formed during the interseismic period. [ABSTRACT FROM AUTHOR]

Map to microscopic-scale structural analysis of the Hanazono Assemblage of the Shimanto Belt in SW Japan, an excellent example of a deeply buried accretionary complex, indicates a detailed process from underthrusting to underplating. The earliest underthursting process is recorded in fabric of melange, which has deformed by shear along the decollement, characterized by thinning strain due to extensional breakage of blocks of sandstone and exotic materials, such as basalt and pelagic sediments of oceanic affinities. The deformation mechanism for melange formation for domain I is plastic flow, concordant with metamorphic grade, which is higher than that of domain II. The deformation mechanism for domain II is predominantly pressure solution partly with grain-scale brittle breakage for the less metamorphosed part of the Hanazono Assemblage. The posterior underplating process recorded is contraction and thickening due to thrust stacking and folding. Locations of the folds developed beneath thrusts are emphasized because they are a line of evidence of thickening. The main deformation mechanism of the second stage is plastic flow for domain I and cataclasis for domain II. The cataclasis in domain II may be a result of change in strain rate and seems to be related to seismicity at the time of underplating. Kinematics deduced from fabric analysis of the earliest deformed melange indicates a good consistency with a relative plate motion between the Eurasian and oceanic plates that is estimated from a hot spot reference plate circuit model by Engebretson et al. [1985], while that of the subsequent thrusting is not. This fact suggests that strain partitioning in association with oblique subduction of oceanic plate was minimum during subduction. Another possibility for strain partitioning is the requirement of coupling between plates that are recorded by the deformation mechanisms. [ABSTRACT FROM AUTHOR]

SummaryIn this study, we have investigated that after the intraperitoneal infection with murine cytomegalovirus (MCMV), the CD3+ CD4– CD8–(double negative; DN) T-cell receptor (TCR)αβ+ T cells increased in peritoneal cavity, liver and spleen in both resistant C57BL/6 and susceptible BALB/c mice. The total cellular population of these cells showed peak levels around day 5 after infection in all the three investigated organs and the following phenotypical and functional characteristics emerged. The peritoneal DN TCRαβ+ T cells expressed highly skewed TCRVβ8 on day 5 after infection compared with the uninfected mice, but those in spleen and liver showed moderate and low skewed TCRVβ8, respectively. The percentages of NK1.1+ DN TCRαβ+ T cells gradually decreased as did modulation of some of their activation markers consistent with an activated cell phenotype. The peritoneal DN TCRαβ+ T cells on day 5 after infection expressed the genes of interferon-γ (IFN-γ), tumour necrosis factor-α, Eta-1 (early T-cell activation-1) and MCP-1 (monocyte chemoattractant protein 1) but lacked expression of interleukin-4 (IL-4). After in vitro stimulation with phorbol 12-myristate 13-acetate and calcium ionophore in the presence of Brefeldin A, higher frequencies of intracellular IFN-γ+ DN TCRαβ+ T cells were detected in all three investigated organs of infected mice compared with those of uninfected mice. Stimulation of peritoneal DN TCRαβ+ T cells with plate-bound anti-TCRβ monoclonal antibodies showed proliferation and also produced IFN-γ but not IL-4. These results suggest that DN TCRαβ+ T cells were activated and may have an antiviral effect through producing IFN-γ and some macrophage-activating factors during an early... [ABSTRACT FROM AUTHOR]

Summary Cytomegalovirus (CMV) causes severe opportunistic infection in immunocompromised hosts. The importance of conventional αβ T cells in protection against CMV infection has been well documented. However, the role of the second T‐cell population (which express the γδ T‐cell receptor) in CMV infection is not known. In the present study, we analysed the function and protective role of γδ T cells in a murine cytomegalovirus (MCMV) infection model. After intraperitoneal infection with MCMV, the number of γδ T cells increased in the liver and peritoneal cavity from day 3, and reached a peak on day 5. The γδ T cells showed an activated T‐cell phenotype and predominantly expressed Vγ1, which is known to be expressed by heat‐shock protein 65 (hsp 65)‐specific γδ T cells. Analysis of cytokine expression demonstrated that the MCMV‐induced γδ T cells expressed interferon‐γ (IFN‐γ) and tumour necrosis factor‐α (TNF‐α) but not interleukin‐4 (IL‐4), implying their participation in the cell‐mediated immune response against MCMV. Depletion of γδ T cells by anti‐T‐cell receptor (TCR) γδ monoclonal antibody (mAb) treatment resulted in significant increase of virus titre and decrease of IFN‐γ in the liver on day 3 after MCMV infection, which further supports the importance of γδ T cells in early protection against infection. Finally, the MCMV‐induced γδ T cells produced IFN‐γ in vitro in response to hsp 65. Our results suggest that γδ T cells participate in early protection against MCMV infection through recognition of hsp 65 and production of IFN‐γ. [ABSTRACT FROM AUTHOR]

Provides information on a study regarding the origin of melange and its role in accretion during underplating. Accretionary complexes at Shimanto Belt in Kii Peninsula in Japan; Duplex structure; Occurrence of melange and melange fabric.

For providing costimulatory signals, we utilized anti-CD28 monoclonal antibody (mAb) for the in vitro culture of turnout-draining lymph node (LN) cells. The proliferation of B16 melanoma-draining LN cells in the culture with anti-CD3 mAb was remarkably enhanced by the addition of anti-CD28 mAb. In culture with both anti-CD3 and anti-CD28 mAb, the B16-draining LN cells produced a higher level of interferon-γ, but not interleukin-4, than with anti-CD3 mAb alone. The B16-draining LN cells efficiently expanded in the culture with both anti-CD3 and anti-CD28 mAb and subsequently with a low dose of IL-2 (anti-CD3 plus anti-CD28/IL-2). The expanded cells consisted predominantly of CD8+ T cells and showed a specific cytolytic activity, in a major histocompatibility complex (MHC) class I-restricted manner, even without in vitro restimulation. In addition, the adoptive transfer of the B16-draining LN cells, expanded in the culture protocol of anti-CD3 plus anti-CD28/IL-2, showed a significant anti-tumour effect against metastatic B16 melanoma in combination with IL-2. The cured mice thus acquired a specific protective immunity. Moreover, this protocol was also moderately effective against poorly immunogenic 3LL carcinoma. Overall, our results suggest the potential for another immunotherapeutic strategy based on ‘the costimulatory theory’ other than vaccination with B7-transfected tumour cells. [ABSTRACT FROM AUTHOR]

Background: Although there is a close relationship between dietary sodium and hypertension, the concept that persons with relatively high dietary sodium are at increased risk of developing hypertension compared with those with relatively low dietary sodium has not been studied intensively in a cohort., Methods and Results: We conducted an observational study to investigate whether dietary sodium intake predicts future blood pressure and the onset of hypertension in the general population. Individual sodium intake was estimated by calculating 24-hour urinary sodium excretion from spot urine in 4523 normotensive participants who visited our hospital for a health checkup. After a baseline examination, they were followed for a median of 1143 days, with the end point being development of hypertension. During the follow-up period, hypertension developed in 1027 participants (22.7%). The risk of developing hypertension was higher in those with higher rather than lower sodium intake (hazard ratio 1.25, 95% CI 1.04 to 1.50). In multivariate Cox proportional hazards regression analysis, baseline sodium intake and the yearly change in sodium intake during the follow-up period (as continuous variables) correlated with the incidence of hypertension. Furthermore, both the yearly increase in sodium intake and baseline sodium intake showed significant correlations with the yearly increase in systolic blood pressure in multivariate regression analysis after adjustment for possible risk factors., Conclusions: Both relatively high levels of dietary sodium intake and gradual increases in dietary sodium are associated with future increases in blood pressure and the incidence of hypertension in the Japanese general population., (© 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

It has been recognized that macrophages play an important role in controlling virus infection in experimental animal models. To evaluate the role of macrophages in acute murine cytomegalovirus infection, macrophages in the spleen and the liver were eliminated by an intravenous injection of liposomes containing a cytolytic agent, dichloromethylene diphosphonate. The depletion of macrophages led to a significant increase of virus titer in the spleen and lungs in both susceptible BALB/c and resistant C57BL/6 mice during the first three days after intravenous infection. In the spleen, the increase of virus titer in macrophage-depleted BALB/c mice was much greater than that in NK cell-depleted mice. These results suggest that macrophages contribute to protection mainly by the mechanisms which are independent of NK cells during the first three days after infection. The increase of virus titer in macrophage-depleted C57BL/6 mice was as great as that in NK cell-depleted mice because of the high contribution of NK cells to protection in C57BL/6 mice. In the liver in both strains of mice, the effects of macrophage depletion on virus titer were not as much as those in the spleen and lungs. Furthermore, the local depletion of peritoneal macrophages resulted in a great increase of virus titer in the spleen at three days after intraperitoneal infection. We conclude that macrophages greatly contribute to decreasing the virus load in some organs possibly through either or both intrinsic and extrinsic mechanisms in the early phase of primary infection with murine cytomegalovirus.

The role of lck gene in T cell proliferation and differentiation was investigated with transgenic mice carrying human lck cDNA whose expression was regulated by the promoter of mouse H-2Kb and the enhancer element of mouse IgH. RNase protection assay revealed that the lck transgene was expressed in the thymus and spleen, whereas immunoblot analysis demonstrated that amounts of p56lck in freshly isolated lymphoid organs were almost equal between transgenic mice and negative littermates. Cell-surface marker analyses of the thymocytes and peripheral lymphocytes revealed no remarkable difference between both groups. Notable finding is that the thymocytes from transgenic mice showed a significant proliferative response to the stimulation with IL-2, but not the thymocytes from negative littermates. Further analysis revealed that CD4+8- single positive thymocytes proliferated in response to IL-2. While surface expression levels of IL-2R alpha and IL-2R beta of these CD4+8- thymocytes from transgenic and control mice were almost equal before stimulation with IL-2, the expression of IL-2R beta was induced only in transgenic thymocytes after stimulation with IL-2. Immunoblot analysis demonstrated that the expression of p56lck of transgenic thymocytes was not down-regulated at 4 hr after stimulation with IL-2, whereas p56lck of control ones were not detectable any more at 4 hr after stimulation with IL-2. Moreover, in vitro kinase assay substantiated such unchanged expression of p56lck in the thymocytes from transgenic mice: the kinase activities of p56lck did not decrease in thymocytes from transgenic mice after stimulation with IL-2, while kinase activities of control ones were significantly down-regulated by stimulation of IL-2. These results suggested that a significant proliferative response found in the thymocytes from lck-transgenic mice after the stimulation with IL-2 was caused by a constitutive expression of p56lck in these thymocytes even after the stimulation. Our findings, therefore, support a possibility that p56lck may play a role in the IL-2R-mediated signaling system in CD4+8- thymocytes.

1. The effects of dietary sodium on blood pressure and levels of sodium, other electrolytes and noradrenaline (NA) in the cerebrospinal fluid (CSF) and blood of 15 patients with essential hypertension were studied. The CSF and blood sampling was carried out after 7 days of a high salt intake (16-18 g/day) and after 7 days of a low salt intake (1-3 g/day). 2. Blood pressure and sodium concentrations in CSF and serum were significantly higher in the high salt period than the low salt period (CSF Na+ concentration: 147.7 +/- 0.4 mmol/L vs 145.3 +/- 0.5 mmol/L; P less than 0.001). Levels of CSF pressure and potassium or calcium concentrations were not different between the two periods. Plasma NA and plasma renin activity (PRA) were lower and CSF NA levels tended to be lower in the high salt period. 3. The levels and the changes in sodium and NA in CSF were not significantly different between the salt-sensitive (n = 8) and the non-salt-sensitive (n = 7) subjects, but the changes in plasma NA and PRA were smaller in the salt-sensitive subjects. 4. These results indicate that the sympathetic nervous system is less suppressed in salt-sensitive subjects during high salt intake. This may be due to altered neural responsiveness to sodium loading rather than being greater increases in sodium concentration in the central nervous system.

We established a cell line (TS) from adenoma sebaceum of a patient with tuberous sclerosis. Through our previous studies, the abnormal cell division and dysfunction of TS cells were indicated. Glial fibrillary acidic protein (GFAP) and 55 kd protein had been to be major cytoskeletal proteins in these cells. This time we have examined the structure and distribution of cytoskeletons in TS cells with immunoelectron microscopy. TS cells were found to coexpress GFAP and vimentin-like substance; both structures seem to be closely related. The coexistence of a few kinds of proteins integrated in the cytoskeletons might lead to the abnormal behavior of the nucleus during the process of cell division.

Using urea and inulin as markers, we have developed a simple method to calculate intracellular and extracellular fluid volume in patients before and after hemofiltration therapy. During conventional hemofiltration using substitution fluid with a Na+ concentration of 140 mEq/L, a decrease in extracellular fluid volume was noted whereas the intracellular fluid volume was unaltered. Furthermore, we have developed a computerized mathematical model to analyze transcellular fluid shifts during hemofiltration. This model also indicates a decrease in extracellular fluid volume only, the intracellular fluid volume remaining unchanged. High-Na+ hemofiltration using substitution fluid with an Na+ concentration of 160 mEq/L has enabled us to remove fluid from both intracellular and extracellular compartments. Thus, high-Na+ hemofiltration is expected to normalize the intracellular hydration in uremic patients, and to reduce the decrease in extracellular fluid volume during hemofiltration therapy. Our data therefore suggest that high-Na+ hemofiltration could prevent hypotension due to large decreases in extracellular fluid volume by inducing a transcellular fluid shift out of body cells. Our computerized model can be a useful tool in the prescription of the optimal Na+ concentration in substitution fluid for individualized hemofiltration therapy.

Tuberous sclerosis is a dominant hereditary disease characterized by the appearance of angiofibromas on the face, epileptic attacks, and mental retardation. Attention has been paid to the atypical cells observed histologically in the stroma of the angiofibroma as they may play an important role in forming lesions. We have established a cell line from an angiofibroma to clarify the nature of these cells at the cellular and biochemical levels. The cultured cells have been stably maintained for four years and show an abnormal morphology resembling that of neuronal cells. In culture, these cells divide into daughter cells, which consist of both normal cells and abnormal ones whose nuclei disintegrate and cannot divide further. The cells resemble normal fibroblasts in their pattern of staining with antibodies against tubulin, actin, vimentin, and fibronectin. However, they also stain with an antibody against the glia-specific acidic protein, which is thought to be a specific marker protein for glial cells. The gel profile of cyclic-AMP binding proteins was not fibroblastic, but rather of the neuron cell type. These results indicate the gene expression of these cells is also abnormal. They are a useful tool for understanding this specific genetic disease.

Small DNA-containing tumor viruses (simian virus 40, mouse polyoma-virus, and adenoviruses) malignantly transform fibroblasts of the susceptible rodents. Fibroblasts can exist, in vitro and in vivo, in either of the two states: the proliferating state or the quiescent state. In the present study, we examined whether the state of fibroblasts at the time of exposure to these DNA viruses affects the frequency of transformation. Dense-focus formation in monolayer culture of rat 3Y1 fibroblasts was used to quantitate transformation. Results show that the frequency of transformation by simian virus 40 and mouse polyomavirus was reduced when cells were in the proliferating state at the time of virus inoculation as compared to cells in the quiescent state, whereas that by adenovirus type 12 was similar in the two cellular states. The reduction of the frequency of transformation in proliferating cells infected with simian virus 40 was also observed in BALB/c 3T3 mouse cells. Mechanisms underlying the difference between the two cellular states and the difference between the papovavirus and adenovirus in this aspect of transformation remain to be investigated.

Eleven temperature-sensitive mutants of adenovirus type 12, capable of forming plaques in human cells at 33 C but not at 39.5 C, were isolated from a stock of a wild-type strain after treatment with either nitrous acid or hydroxylamine. Complementation tests in doubly infected human cells permitted a tentative assignment of eight of these mutants to six complementation groups. Temperature-shift experiments revealed that one mutant is affected early and most of the other mutants are affected late. Only the early mutant, H12ts505, was temperature sensitive in viral DNA replication. Infectious virions of all the mutants except H12ts505 and two of the late mutants produced at 33 C, appeared to be more heat labile than those of the wild type. Only H12ts505 was temperature sensitive for the establishment of transformation of rat 3Y1 cells. One of the late mutants (H12ts504) had an increased transforming ability at the permissive temperature. Results of temperature-shift transformation experiments suggest that a viral function affected in H12ts505 is required for "initiation" of transformation. Some of the growth properties of H12ts505-transformed cells were also temperature dependent, suggesting that a functional expression of a gene mutation in H12ts505 is required to maintain at least some aspects of the transformed state.

The postdialysis levels of serum sodium concentration, urea concentration, and osmolality, as well as the magnitude of both transcellular fluid shifts and sodium removal, were predicted based on computer modeling without measuring body fluid volumes. A 4-h hemodialysis was performed in five patients at a constant ultrafiltration rate of 0.5 L/h using dialysate with normal (141 mEq/L) or high (150 mEq/L) Na+ concentration. The serum sodium concentration, urea concentration, and osmolality, as well as intracellular and extracellular fluid volumes, were determined before and after hemodialysis. The model predictions without measurement of body fluid volumes were in excellent agreement with measured values, suggesting clinical validity. The model may be useful in clinical practice to control the postdialysis levels of sodium and water content by computerized hemodialysis.