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Background: Peritoneal dialysis (PD) is limited by reduced efficacy over time. We previously showed that a Janus kinase 1/2 inhibitor (JAK1/2i) reduced inflammation, hypervascularity and fibrosis induced by 4.25% dextrose dialysate (4.25%D) intraperitoneally (IP) infused for 10 days in rats with normal kidney function. JAK/STAT signalling mediates inflammatory pathways, including angiotensin signalling. We now tested the effect of long-term JAK1/2i and/or an angiotensin receptor blocker (ARB) on peritoneal membrane (PM) in polycystic kidneys (PCK) rats infused with 4.25%D. Methods: Except for controls, all PCK rats had a tunnelled PD catheter: (1) no infusions; (2) 4.25%D; (3) 4.25%D + JAK1/2i (5 mg/kg); (4) 4.25%D +losartan (5 mg/kg); and (5) 4.25%D + losartan +JAK1/2i (5 mg/kg each) IP BID × 16 weeks ( N = 5/group). PM VEGFR2 staining areas and submesothelial compact zone (SMCZ) width were morphometrically measured. Peritoneal equilibration testing measured peritoneal ultrafiltration (UF) by calculating dialysate glucose at time 0 and 90 min (D/D0 glucose). Results: 4.25%D caused hypervascularity, SMCZ widening, fibrosis and UF functional decline in PCK rats. Angiogenesis was significantly attenuated by JAK1/2i ± ARB but not by ARB monotherapy. Both treatments reduced SMCZ area. UF was preserved consistently by dual therapy ( p < 0.05) but with inconsistent responses by monotherapies. Conclusion: Long-term JAK1/2i ± ARB reduced angiogenesis and fibrosis, and the combination consistently maintained UF. In clinical practice, angiotensin inhibition has been advocated to maintain residual kidney function. Our study suggests that adding JAK1/2i to angiotensin inhibition may preserve PM structure and UF.

AIMS/HYPOTHESIS: We previously reported that renal tubule-specific deletion of Heterogeneous nuclear ribonucleoprotein F (Hnrnpf) results in upregulation of renal angiotensinogen (Agt) and downregulation of sodium-glucose co-transporter 2 (Sglt2) in Hnrnpf(RT) knockout (KO) mice. Non-diabetic Hnrnpf(RT) KO mice develop hypertension, renal interstitial fibrosis and glycosuria with no renoprotective effect from downregulated Sglt2 expression. Here, we investigated the effect of renal tubular Hnrnpf deletion on hyperfiltration and kidney injury in Akita mice, a model of type 1 diabetes. METHODS: Akita Hnrnpf(RT) KO mice were generated through crossbreeding tubule-specific (Pax8)-Cre mice with Akita floxed-Hnrnpf mice on a C57BL/6 background. Male non-diabetic control (Ctrl), Akita, and Akita Hnrnpf(RT) KO mice were studied up to the age of 24 weeks (n=8/group). RESULTS: Akita mice exhibited elevated systolic blood pressure as compared with Ctrl mice, which was significantly higher in Akita Hnrnpf(RT) KO mice than Akita mice. Compared with Akita mice, Akita Hnrnpf(RT) KO mice had lower blood glucose levels with increased urinary glucose excretion. Akita mice developed kidney hypertrophy, glomerular hyperfiltration (increased glomerular filtration rate), glomerulomegaly, mesangial expansion, podocyte foot process effacement, thickened glomerular basement membranes, renal interstitial fibrosis and increased albuminuria. These abnormalities were attenuated in Akita Hnrnpf(RT) KO mice. Treatment of Akita Hnrnpf(RT) KO mice with a selective A1 adenosine receptor inhibitor resulted in an increase in glomerular filtration rate. Renal Agt expression was elevated in Akita mice and further increased in Akita Hnrnpf(RT) KO mice. In contrast, Sglt2 expression was increased in Akita and decreased in Akita Hnrnpf(RT) KO mice. CONCLUSIONS/INTERPRETATION: The renoprotective effect of Sglt2 downregulation overcomes the renal injurious effect of Agt when these opposing factors coexist under diabetic conditions, at least partly via the activation of tubuloglomerular feedback.

Clinical trials indicate that sodium/glucose co-transporter 2 (SGLT2) inhibitors (SGLT2i) improve kidney function, yet, the molecular regulation of SGLT2 expression is incompletely understood. Here, we investigated the role of the intrarenal renin–angiotensin system (RAS) on SGLT2 expression. In adult non-diabetic participants in the Nephrotic Syndrome Study Network (NEPTUNE, n=163), multivariable linear regression analysis showed SGLT2 mRNA was significantly associated with angiotensinogen (AGT), renin, and angiotensin-converting enzyme (ACE) mRNA levels (P

Background: Recent studies show that sodium-glucose cotransporter 2 inhibitors (SGLT2i), originally approved for glycemic control in patients with type 2 diabetes, also exert renoprotective effects independently from effects on dysglycemia. Moreover, recent work indicates that SGLT2i treatment may be effective in patients with nondiabetic chronic kidney disease, including primary and secondary glomerular diseases. Summary: SGLT2i lower blood glucose by blocking glucose resorption in the early renal proximal tubule through the glucose transporter, SGLT2, leading to enhanced urinary glucose excretion. Recent studies indicate that SGLT2i may have pleiotropic effects on cells other than proximal tubular cells. SGLT2i reduce the glomerular workload by decreasing the intraglomerular pressure, thus ameliorating hyperfiltration, if present, and may also decrease systemic blood pressure. SGLT2i may also act directly on endothelial cells, possibly via modulating the effects of adhesion molecules and reducing inflammatory cytokines and reactive oxygen species. SGLT2i may have direct anti-inflammatory and antifibrotic effects on renal tubules. Some reports suggest direct protective effects on podocytes and mesangial cells as well. Here, we provide a review of the potential mechanisms of renoprotection, therapeutic utility, and potential side effects of SGLT2i in patients with nondiabetic glomerular diseases, based on data from studies carried out in cells, experimental animals, and humans. Key Messages: SGLT2i may be a promising addition to the glomerular disease treatment armamentarium. However, it is unclear at what point of the natural history of specific glomerular diseases (whether this is immune or nonimmune mediated) SGLT2i can be beneficial. Additionally, further studies are needed to assess the long-term efficacy and safety of SGLT2i in patients with nondiabetic glomerular diseases.

We investigated the impact of nuclear factor erythroid 2-related factor 2 (Nrf2) overexpression in renal proximal tubular cells (RPTCs) on blood glucose, kidney injury and sodium-glucose co-transporter 2 (Sglt2) expression in diabetic Akita Nrf2-/-/Nrf2RPTC transgenic (Tg) mice. Immortalized human RPTCs (HK2) stably transfected with plasmid containing the SGLT2 promoter, human kidneys from patients with diabetes were also studied. Nrf2 overexpression was associated with increased blood glucose, glomerular filtration rate, urinary albumin-creatinine ratio, tubulointerstitial fibrosis and Sglt2 expression in Akita Nrf2-/-/Nrf2RPTC Tg mice compared to their Akita Nrf2-/- littermates. In vitro, oltipraz or transfection of NRF2 cDNA stimulated SGLT2 expression and SGLT2 promoter activity in HK2, and these effects were inhibited by trigonelline or NRF2 small interfering RNA. The deletion of the NRF2-responsive element (NRF2-RE) in the SGLT2 promoter abolished the stimulatory effect of oltipraz on SGLT2 promoter activity. NRF2 binding to the NRF2-RE of the SGLT2 promoter was confirmed by gel mobility shift assay and chromatin immunoprecipitation assays. Kidneys from patients with diabetes exhibited higher levels of NRF2 and SGLT2 in the RPTCs than kidneys from patients without diabetes. These results suggest a link by which NRF2 mediates hyperglycemia-stimulation of SGLT2 expression and exacerbates blood glucose and kidney injury in diabetes.

Podocyte damage and loss are the early event in the development of focal segmental glomerulosclerosis (FSGS). Podocytes express angiotensin II type-2-receptor (AT2R), which may play a key role in maintaining kidney integrity and function. Here, we examined the effects of AT2R deletion and AT2R agonist compound 21 (C21) on the evolution of FSGS. FSGS was induced by adriamycin (ADR) injection in both male wild-type (WT) and AT2R knockout (KO) mice. C21 was administered to WT-FSGS mice either one day before or 7 days after ADR (Pre-C21 or Post-C21), using two doses of C21 at either 0.3 (low dose, LD) or 1.0 (high dose, HD) mg/kg/day. ADR-induced FSGS was more severe in AT2RKO mice compared with WT-FSGS mice, and included profound podocyte loss, glomerular fibrosis, and albuminuria. Glomerular cathepsin L expression increased more in AT2RKO-FSGS than in WT-FSGS mice. C21 treatment ameliorated podocyte injury, most significantly in the Pre C21-HD group, and inhibited glomerular cathepsin L expression. In vitro, Agtr2 knock-down in mouse podocyte cell line given ADR confirmed the in vivo data. Mechanistically, C21 inhibited cathepsin L expression, which protected synaptopodin from destruction and stabilized actin cytoskeleton. C21 also prevented podocyte apoptosis. In conclusion, AT2R activation by C21 ameliorated ADR-induced podocyte injury in mice by the inhibition of glomerular cathepsin L leading to the maintenance of podocyte integrity and prevention of podocyte apoptosis.

RationaleSodium-glucose co-transporter inhibitors (SGLT2i) are under active clinical investigation in patients with acute inflammatory conditions, based on their clinical cardio-and nephroprotective effects, and a pre-clinical study that demonstrated SGLT2i improve renal outcomes and survival in a lipopolysaccharide (LPS) model. However, a unified mechanism that explains how SGLT2i could prevent hemodynamic consequences of inflammatory conditions has not been described. Apolipoprotein M (ApoM) is inversely associated with mortality in inflammatory conditions and improves cardiac function in endotoxin-treated mice via sphingosine-1-phosphate (S1P) signaling.ObjectiveTest the hypothesis that pre-treatment with SGLT2i dapagliflozin (Dapa) improves hemodynamics in endotoxin-treated mice via the ApoM/S1P pathway.Methods and ResultsMice with diet-induced obesity were gavaged with vehicle or Dapa for 4 days prior to LPS (10 mg/kg, IP). We found that mice receiving Dapa restored circulating ApoM levels, likely by increasing expression of the multi-ligand protein receptor megalin in the proximal tubules. Dapa attenuated LPS-induced reductions in cardiac dysfunction including reductions in ejection fraction, cardiac index, and coronary sinus area as well as vascular permeability as ascertained by intravital microscopy. Using both ApoM transgenic and knockout mice and S1P receptor inhibitors, we show that the ApoM/S1P pathway is important for the beneficial effects of Dapa in the LPS model.ConclusionsIn the setting of acute inflammation, our data suggest that SGLT2i maintains levels of megalin, leading to preservation of ApoM, which in turn promotes endothelial barrier integrity and improves hemodynamics. Our studies suggest a novel mechanism by which SGLT2i can preserve intravascular volume in the acute inflammatory setting.

Glomerular endothelial cell (GEC) dysfunction occurs in diabetic kidney disease (DKD) and generally precedes albuminuria. We recently reported that hedgehog interacting protein (Hhip), highly expressed in GECs, contributes to DKD development in diabetic mice. Here, we hypothesized that urinary Hhip (uHhip) could identify early DKD; we tested uHhip in mice and humans with diabetes (DM). In both type 1 (Akita) and type 2 (db/db) DM mice, uHhip is elevated prior to the development of albuminuria, while non-DM controls excrete minimal amount of uHhip. In 87 type 2 DM patients and 39 healthy controls, the uHhip/creatinine (Cr) ratio provides a significant discrimination between non-DM and DM groups; 0 [0-69.5] in non-DM, 9.9 [1.7-39.5] in normoalbuminuric DM, 167.7 [95.7-558.7] in microalbuminuric DM, and 207.9 [0-957.2] in macroalbuminuric DM (median [IQR] ng/mmol, P < 0.0001). The log-uHhip/Cr is positively correlated with urine albumin/Cr ratio (UACR) (spearman correlation coefficient 0.47, P < 0.0001). The log-uHhip/Cr is also associated with eGFR, pulse pressure, and urinary cytokines (IL-1β, IL-6, IL-8, and TGFβ1) independent of UACR. By immunostaining, Hhip is localized in glomeruli and tubules, and is increased in human DM kidneys compared with non-DM kidneys. TGFβ1 shares the similar staining pattern as Hhip in human DM kidneys. Thus, uHhip appears to be a novel indicator of diabetic GEC injury and is elevated in early DKD before the development of microalbuminuria in mice and humans. Clinical value for detecting early DKD warrants further investigation.

Aims SGLT2 inhibitors have been proposed as an adjunct to insulin therapy for glycemic control in type 1 diabetes (T1D) patients. However, concern has been raised due to an increase in renin–angiotensin-system (RAS) activity reported in a clinical trial in which an SGLT2 inhibitor was added while insulin dose was reduced in T1D patients. We previously reported that insulin inhibits intrarenal angiotensinogen (Agt) gene transcription and RAS activation. We hypothesized that insulin, rather than SGLT2 inhibition might regulate the intrarenal RAS. Methods We compared RAS activity in non-diabetic wild type mice, Akita mice (T1D model) and Akita mice treated with insulin or the SGLT2 inhibitor canagliflozin. Results Treatment of Akita mice with insulin or canagliflozin produced similar reductions in blood glucose, whereas insulin, but not canagliflozin, reduced elevated systolic blood pressure. Akita mice exhibited increased renal Agt mRNA/protein expression, which was attenuated by insulin, but not by canagliflozin. Furthermore, insulin was more effective than canagliflozin in lowering kidney weight and albuminuria. Conclusions Insulin, but not canagliflozin, lowers intrarenal RAS activity in Akita mice. Our findings can be of potential clinical importance, especially for T1D patients who are not on RAS inhibitors at the time of adding SGLT2 inhibitors.

BACKGROUND: Non-adherence to hemodialysis (HD) is associated with increased morbidity and mortality. In this cross-sectional study, we compared correlates and rates of non-adherence between the U.S. and Japan to determine if differences in patient knowledge about HD might account for international variation in adherence. METHODS: We evaluated 100 U.S. and 116 Japanese patients on maintenance HD. Patient knowledge was scored based on the identification of their vascular access, dry weight, cause of kidney disease, and ≥3 phosphorus and potassium rich foods. Patients were considered non-adherent if they missed >3% of HD sessions in 3 months. RESULTS: 23% of the U.S. and none of the Japanese patients were non-adherent. Using logistic regression, we found that in the U.S. non-adherence was more common in black patients [Odds ratio (OR), 3.98; 95% confidence interval (CI), 1.42–11.22)], while high school graduates (OR, 0.20; 95%CI, 0.05–0.81) and those on the transplant waiting list (OR, 0.25; 95% CI, 0.083–0.72) were less likely to miss their treatments. There was no significant association between knowledge and non-adherence in the U.S. However, Japanese patients had significantly higher levels of HD knowledge than U.S. patients after adjusting for age (p

Renal involvement in non-Hodgkin lymphoma, especially mantle cell lymphoma (MCL) is rare. A 77-year-old man presented with acute kidney injury (AKI), which rapidly progressed to dialysis dependence. Kidney biopsy revealed patchy B-cell lymphocytic aggregates in the interstitium, which were positive for cyclin D1, consistent with atypical CD5-negative MCL as confirmed by the detection of translocation t(11;14) by FISH. Crescents were noted in 3 of 26 glomeruli; while PR-3 antineutrophil cytoplasmic antibody (ANCA) positivity and negative immunofluorescence suggested an additional pauci-immune (rapidly progressive) glomerulonephritis pattern of injury. Patient received chemotherapy (cyclophosphamide, vincristine, and prednisone), which improved his renal function and allowed for discontinuation of hemodialysis. However, he died from pulmonary hemorrhage 8 months after initial presentation. This is the first reported case of a patient with coexistence of renal MCL infiltration and ANCA-positive pauci-immune glomerulonephritis.

We reported previously that overexpression of heterogeneous nuclear ribonucleoprotein F (Hnrnpf) in renal proximal tubular cells (RPTCs) suppresses angiotensinogen (Agt) expression, and attenuates systemic hypertension and renal injury in diabetic Hnrnpf-transgenic (Tg) mice. We thus hypothesized that deletion of Hnrnpf in the renal proximal tubules (RPT) of mice would worsen systemic hypertension and kidney injury, perhaps revealing novel mechanism(s). Tubule-specific Hnrnpf knockout (KO) mice were generated by crossbreeding Pax8-Cre mice with floxed Hnrnpf mice on a C57BL/6 background. Both male and female KO mice exhibited elevated systolic blood pressure, increased urinary albumin/creatinine ratio, tubulo-interstitial fibrosis and glycosuria without changes in blood glucose or glomerular filtration rate compared with control littermates. However, glycosuria disappeared in male KO mice at the age of 12 weeks, while female KO mice had persistent glycosuria. Agt expression was elevated, whereas sodium-glucose co-transporter 2 (Sglt2) expression was down-regulated in RPTs of both male and female KO mice as compared to control littermates. In vitro, KO of HNRNPF in human RPTCs (HK-2) by CRISPR gRNA up-regulated AGT and down-regulated SGLT2 expression. The Sglt2 inhibitor canagliflozin treatment had no effect on Agt and Sglt2 expression in HK-2 and in RPTCs of wild-type mice but induced glycosuria. Our results demonstrate that Hnrnpf plays a role in the development of hypertension and glycosuria through modulation of renal Agt and Sglt2 expression in mice, respectively.

Background: Matrix Gla Protein (MGP) is a potent inhibitor of ectopic calcification and modulates bone morphogenesis. Little is known about MGP expression or function in kidney. Methods: We investigated renal MGP expression in Sprague-Dawley rats after 5/6 nephrectomy (5/6 Nx) and in human kidney biopsies in the Nephrotic Syndrome Study Network (NEPTUNE) cohort. We analyzed associations between glomerular (n = 182) and tubulointerstitial (TI) (n = 219) MGP mRNA levels and the disease activity/histologic features in NEPTUNE patients. Additionally, uncarboxylated and carboxylated MGP (ucMGP and cMGP, respectively) were localized by immunohistochemistry and quantitated in kidney tissues of patients at different stages of CKD (n = 18). Results: Renal MGP expression was increased in rats after 5/6 Nx. In NEPTUNE data, baseline estimated glomerular filtration rate (eGFR) negatively correlated with glomerular and TI MGP expression (p < 0.001). TI MGP expression strongly correlated with interstitial fibrosis, tubular atrophy, acute tubular injury, and interstitial inflammation, independent of eGFR. Kaplan-Meier analysis and multivariable Cox regression showed that higher levels of TI MGP expression were associated with an increased risk for the composite of 40% decline in eGFR and end-stage renal disease (ESRD) (HR, 3.31; 95% CI, 1.31 to 6.32; p = 0.02). Glomerular and tubulointerstitial cells demonstrated nuclear and cytoplasmic cMGP and ucMGP staining, and eGFR inversely correlated with quantified glomerular cMGP staining (p < 0.05). Conclusions: Our data demonstrate that renal MGP expression is increased in human and experimental CKD, and is associated with renal outcome. Additional studies are needed to determine its mechanism of action.

Calcific uremic arteriolopathy (CUA) is a rare and potentially fatal disorder of calcification involving subcutaneous small vessels and fat in patients with renal insufficiency. We describe the successful use of intravenous sodium thiosulfate (STS) for the treatment of CUA in two patients. The first case was complicated by the development of a severe anion gap metabolic acidosis, which was accompanied by a seizure. Both patients had complete wound healing within five months. Although STS should be considered in the treatment of CUA, little is known about pharmacokinetics and additional studies are required to determine dosing strategies to minimize severe potential side effects.

A 56-year-old female with Graves' disease who presented with decreased secretion of gonadotropins is described. She was admitted to hospital because of her being in a state of confusion. One month before admission she had been diagnosed as having Graves' disease and was treated with methimazole since then. Plasma LH and FSH levels were undetectable, and their responses to LH-RH were extremely decreased in spite of undetectable levels of plasma estradiol and estriol. One year after treatment, both basal and stimulated values of LH and FSH reverted to normal as did those of TSH. Reversible suppression of gonadotropins as described herein has never been reported in cases of Graves' disease.

We report two cases of Japanese men who presented with proteinuria, eosinophilia, hypocomplementemia, and high serum immunoglobulin G4 (IgG4) concentration and were diagnosed with membranous nephropathy associated with IgG4-related tubulointerstitial nephritis on renal biopsy. The typical renal lesions of IgG4-related disease are tubulointerstitial nephritis, which improves remarkably with steroid therapy, and occasional glomerular changes. In our two cases, renal biopsy revealed IgG4-positive immune complex deposits in glomeruli in a pattern of membranous nephropathy and concurrent tubulointerstitial nephritis with IgG4 plasma cells. In both cases, proteinuria persisted with initial prednisolone treatment and was resolved only after the addition of mizoribine. We report the first two cases in which the combination of prednisolone and mizoribine was effective for treating membranous nephropathy associated with IgG4-related tubulointerstitial nephritis.

All eight possible A-ring diastereomers of 2-methyl-1, 25-dihydroxyvitamin D(3) (2) and 2-methyl-20-epi-1, 25-dihydroxyvitamin D(3) (3) were convergently synthesized. The A-ring enyne synthons 19 were synthesized starting with methyl (S)-(+)- or (R)-(-)-3-hydroxy-2-methylpropionate (8). This was converted to the alcohol 14 as a 1:1 epimeric mixture in several steps. After having been separated by column chromatography, each isomer led to the requisite A-ring enyne synthons 19 again as 1:1 mixtures at C-1. Coupling of the resulting A-ring enynes 20a-h with the CD-ring portions 5a,b in the presence of a Pd catalyst afforded the 2-methyl analogues 2a-h and 3a-h in good yield. In this way, all possible A-ring diastereomers were synthesized. The synthesized analogues were biologically evaluated both in vitro and in vivo. The potency was highly dependent on the stereochemistry of each isomer. In particular, the alpha alpha beta-isomer 2g exhibited 4-fold higher potency than 1 alpha,25-dihydroxyvitamin D(3) (1) both in bovine thymus VDR binding and in elevation of rat serum calcium concentration and was twice as potent as the parent compound in HL-60 cell differentiation. Furthermore, its 20-epimer, that is, 20-epi-alpha alpha beta 3g, exhibited exceptionally high activities: 12-fold higher in VDR binding affinity, 7-fold higher in calcium mobilization, and 590-fold higher in HL-60 cell differentiation, as compared to 1 alpha,25-dihydroxyvitamin D(3) (1). Accordingly, the double modification of 2-methyl substitution and 20-epimerization resulted in unique activity profiles. Conformational analysis of the A-ring by (1)H NMR and an X-ray crystallographic analysis of the alpha alpha beta-isomer 2g are also described.

To investigate the chemical conformations and functions of the -Phe-Phe-Val- or -Phe-Phe- sequences contained in the Alzheimer's disease related beta-amyloid peptide, a series of mini parallel double-stranded peptides conjugated with two peptide residues to one spacer were designed and prepared. The structure of the compounds was elucidated by circular dichroism (CD) spectrum and NMR two dimensional (2D) nuclear Overhauser enhancement and exchange spectroscopy (NOESY) measurments. The structure of 1,2-ethano-bis(L-Phe-L-Phe-L-Leu), 1,12-dodecano-bis(L-Phe-L-Phe-L-Leu), 1,12-dodecano-bis(L-Phe-L-Phe-L-Val), and 1,12-dodecano (D-Phe-D-Phe-D-Leu) conjugated with L-Leu and L-Val residues show a beta-turn-like nucleation. The dihedral angles (theta = +75 degrees, omega = +180 degrees, phi = +90 degrees, phi = -87 degrees, psi = +180 degrees) obtained from experimental coupling constant (J) data, etc. support that 1,12-dodecano-bis(L-Phe-L-Phe) adopts beta-turn mimic nucleation. The 1,12-dodecano- bis(L-Leu-L-Leu-L-Phe), 1,12-dodecano-bis(L-lle-L-Phe-L-Leu), and 1,12-dodecano-bis(L-Phe-L-Val-L-Leu), etc. adopt most probably a random structure by CD studies. It was found by titration spectrum that an inclusion complex of 1:1 ratio (association constant; azobenzene (guest, Ka=1.0 x 10(4)M-1) is formed between 1,12-dodecano-bis(L.-Phe-L-Phe-L-Leu) and [L0]=1.758 x 10(-5)M-1). Moreover, the stability of the complexes was increased in order of 1,12-dodecano-bis(L-Phe-L-Phe-L-Leu) x azobenzene1,12-dodecano-bis(L-Phe-L-Phe-L-Val) x azobenzene1,12-dodecano-bis(L-Phe-L-Val-L-Leu) azobenzene. The data show that X-Phe-L-Phe-L-spacer(S)-L-Phe-L-Phe-X (X=amino acids; S = 1,2-ethano- and 1,12-dodecano-) plays an important role as a binding site of the artificial receptor. The hydrophobic interaction of the four Phes in the two strands is a very interesting issue in the physiological action of proteins as well as the conformation of the backbone of X-L-Phe-L-Phe-spacer(S)-iL-Phe-l.-Phe-X.

We report two cases of elastofibroma dorsi and discuss the CT and MR findings and histopathology of these tumors. Increased awareness of the characteristic MR patterns should lead to reduced misdiagnosis of such lesions as malignant and prevent unnecessary wide excision.

When a spacecraft operates at a high voltage, the spacecraft body potential become highly negative with respect to the surrounding plasma. A laboratory experiment has been carried out to study the interaction between the spacecraft insulator surface and the plasma. Once a discharge occurs through the insulator at one point on the surface, the positive current to the circuit drives the conductor potential, which lies below the insulator, positive. The potential of the un-discharged surface increases as the conductor potential increases and collects electrons by neutralizing all the positive charge stored before the discharge. The current path of RC discharge is formed between the discharge spot and the un-discharged insulator surface, which acts as the capacitance, through the plasma resistance and the spacecraft circuit resistance. An ion acoustic wave was detected by a Langmuir probe, which was launched by the potential jump of the un-discharged surface. There is a possibility that a very large amount of current flows into the spacecraft body circuit because the capacitance of the entire spacecraft surface is very large.

Planar specimens of graphite (Grafoil) and carbon materials (artificial graphite materials derived from petroleum cokes) with different heat-treatment temperatures (HTT) were brought into contact with IBr vapor at 20°C. The resistance of the carbon materials decreased by the contact with IBr vapor. The relative resistance, R/R0, defined as the resistance of IBr-doped material divided by that of the starting carbon material was determined and minimum values were as follows: 0.095 for Grafoil, 0.116 for carbon material with HTT of 2800°C, 0.117 (HTT-2400), 0.167 (HTT-2200), 0.269 (HTT-2000), 0.862 (HTT-1750) and 0.838 (HTT-1000). The composition of the saturated compound was estimated to be approximately C16IBr. By the desorption of IBr from the doped specimens, stable residue compounds were obtained. The nominal composition of the residue compounds estimated from weight change was in the range of about C120IBr to C280IBr, depending on the host material. Values of electric resistance of the residue compounds were about half as much as those of the host materials.

The properties of aqueous slips of sialon were studied. Ammonium polyacrylate was used as a deflocculant. It was shown that the apparent viscosity for slips with solid content 40 vol % was low and the slip resulting from this is almost Newtonian. This slip proved sufficiently fluid for casting. However, the apparent viscosity for slips with solid content 45 vol % increased significantly. The slips resulting from this exhibited dilatant flow and were difficult to cast. The viscosity, fluidity, and pH of the slips were studied and tiles were cast and fired in nitrogen at 1740 °C for 3 h to a bulk density of 3.20 g cm−3.

[60] Fullerene solubilized with polyvinylpyrrolidone (PVP) promoted the mouse embryonic limb bud cell differentiation specifically. The cell lysis caused by C60 was diminished by the addition of superoxide dismutase and catalase.

The physical properties of molybdenum oxide films for use in electrochromic display devices were investigated. This paper mainly concerns the dependence of the properties on the preparation conditions. The oxide films were prepared by thermal evaporation of MoO3 powder. The physical properties of the films depend heavily on the substrate temperature during deposition. The resistivity decreases with increasing substrate temperature, in the range 5×104–1×1010 Ω cm. The optical bandgap and the refractive index of these films are 2.75–2.95 eV and 1.9–2.0, respectively. The structure of the films was examined by X-ray diffraction. The films prepared in the range 50–200°C were amorphous, and the films formed in the range 320–400°C were polycrystalline. The electrochemichromic properties of the films were also studied using asymmetric cells, and it was found that a good electrochromic performance was obtained for the films with ~ 1×1010 Ω cm.

AIMS--This study aimed to characterise the status of viral infection in patients with HTLV-1 uveitis (HU) by quantifying the circulating HTLV-1 infected cells in the peripheral blood. METHODS--Genomic DNA samples of peripheral blood mononuclear cells (PBMC) were obtained from 25 patients with HU, 14 patients with tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM), and 21 asymptomatic carriers of HTLV-1. Quantitative polymerase chain reaction (PCR) of the gag region of HTLV-1 provirus DNA was performed on these DNA samples. To confirm the PCR, genomic Southern blot hybridisation was performed to identify integrated HTLV-1 provirus. This procedure detected a few percent of HTLV-1 infected cells in the PBMC. RESULTS--Most of the HU patients had a significantly increased number of circulating HTLV-1 infected cells (mean (SD) 3.84% (4.45%) of the PBMC), whereas the percentage of infected cells in most asymptomatic carriers was less than 1% (0.54% (1.11%)). Most of the TSP/HAM patients also had a relatively high percentage (11.63% (7.67%)). The differences among these three groups were highly significant by the Mann-Whitney U test. CONCLUSION--The results suggested that the increase in the number of HTLV-1 infected cells is one base for the development of inflammatory HU lesions, as it is for TSP/HAM.

A distinct clinical entity of uveitis associated with human T lymphotropic virus type 1 (HTLV-I) has been reported previously. During the period between January 1989 and April 1992, 93 patients were observed with HTLV-I uveitis and a significant correlation was found between Graves' disease and HTLV-I uveitis. Sixteen of the 93 patients with HTLV-I uveitis (17.2%) had a previous history of Graves' disease. Fifteen patients were female (15/60, 25.0%) and one was male (1/33, 3.0%). Interestingly, uveitis occurred after the onset of Graves' disease in all cases. On the other hand, none of 222 patients with idiopathic uveitis who were seronegative to HTLV-I had a history of Graves' disease. Although the mechanisms by which HTLV-I causes the correlation between uveitis and Graves' disease are unknown, the present data suggest that immune mediated or autoimmune mechanisms are involved in HTLV-I uveitis.

Seroepidemiologic, clinical, and virologic studies were performed to determine whether human T-cell lymphotropic virus type I was closely associated with uveitis in two hospitals. One hospital was in an endemic area of the virus (Miyakonojo, Miyazaki) and the other hospital was in a less endemic area (Kurume). In the endemic area, the seroprevalence of the virus in patients with uveitis without defined causes (35.4%, 62 of 175 patients) was significantly higher than that in patients with nonuveitic ocular diseases (16.1%, 42 of 261 patients), or in patients with uveitis with defined causes (10.3%, eight of 78 patients). The seroprevalence in younger patients (20 to 49 years of age) with uveitis without defined causes in the area was 44.8% (30 of 67 patients), whereas it was only 9.3% (ten of 107 patients) in the other two groups. A similar observation was recorded even in the less endemic area (Kurume). Because the seroprevalence of the virus in the general population is known to be low in younger patients and to increase with age, these findings were interpreted to indicate that the association of human T-cell lymphotropic virus type I with uveitis was significant. Most patients, particularly those aged 20 through 49 years, had an intermediate uveitis characterized by a moderate inflammation in the vitreous body accompanied by an iritis and retinal vasculitis. The ocular symptoms in the patients differed from those of other types of uveitis common in Japan (Behcet's disease, Vogt-Koyanagi-Harada's disease, and toxoplasmosis, for example). Although the symptoms of uveitis are somewhat similar to those in sarcoidosis, none of the patients had any systemic evidence of sarcoidosis. Moreover, the proviral DNA of human T-cell lymphotropic virus type I was detected by polymerase chain reaction by using pol region primers from the inflammatory cells in the anterior chamber in seven of nine seropositive patients with the uveitis, but not in all tested patients with other types of uveitis. These data thus indicate that the uveitis is highly associated with human T-cell lymphotropic virus type I and is a distinct clinical entity.