Magnetic resonance imaging of bone marrow for TAFRO syndrome.

We report two cases of TAFRO syndrome, which is characterized by thrombocytopenia, anasarca, fever, renal insufficiency, and organomegaly. Magnetic resonance imaging (MRI) of the spine showed a dark medullary pattern in the bone marrow on the T1- and T2-weighted images of both patients. One patient showed complete resolution after treatment. Serial MRIs of the improved patient revealed a transition to a normal marrow pattern on both images, which might represent resolution of the disease.

Tubulointerstitial Nephritis with IgM-Positive Plasma Cells.

Infiltration by IgG-positive plasma cells is a common finding in tubulointerstitial nephritis. Indeed, it has been thought that CD138-positive mature plasma cells secrete mainly IgG, and the occurrence of tubulointerstitial nephritis with CD138-positive plasma cells secreting IgM has rarely been reported. Routine immunofluorescence of fresh frozen sections is considered the gold standard for detection of immune deposits. However, the immunoenzyme method with formalin-fixed, paraffin-embedded sections is superior for detecting IgM- or IgG-positive cells within the renal interstitium, thus histologic variants may often go undetected. We recently discovered a case of tubulointerstitial nephritis showing IgM-positive plasma cell accumulation within the interstitium. To further explore the morphologic and clinical features of such cases, we performed a nationwide search for patients with biopsy-proven tubulointerstitial nephritis and high serum IgM levels. We identified 13 patients with tubulointerstitial nephritis and IgM-positive plasma cell infiltration confirmed with the immunoenzyme method. The clinical findings for these patients included a high prevalence of distal renal tubular acidosis (100%), Fanconi syndrome (92%), and anti-mitochondrial antibodies (82%). The pathologic findings were interstitial nephritis with diffusely distributed CD3-positive T lymphocytes and colocalized IgM-positive plasma cells, as well as tubulitis with CD3-positive T lymphocytes in the proximal tubules and collecting ducts. Additionally, levels of H+-ATPase, H+, K+-ATPase, and the HCO3--Cl- anion exchanger were markedly decreased in the collecting ducts. We propose to designate this group of cases, which have a common histologic and clinical form, as IgM-positive plasma cell-tubulointerstitial nephritis.

Effects of different heat-moisture treatments on the physicochemical properties of brown rice flour.

We evaluated the effect of heat-moisture treatment (HMT) on the main chemical components, physical properties, and enzyme activities of two types of brown rice flour: high-amylose Koshinokaori and normal-quality Koshiibuki. Five different HMTs using brown rice (moisture content was 12.0%) were assessed: 0.1 MPa/120 °C for 5 or 10 min, 0.2 MPa/134 °C for 5 or 10 min and 0.3 MPa/144 °C for 10 min. HMT, decreased the α-amylase and lipase activities, and fat acidity, and slightly increased the dietary fiber and resistant starch levels. After 2 months' storage at 35 °C, rice samples that were treated with 0.2 MPa/134 °C or 0.3 MPa/144 °C for 10 min had a lower fat acidity than untreated samples, which would be useful for long-term storage and export of rice flour. And HMT exhibited inhibition of retrogradation in the pasting and physical properties, which is profitable to promote the qualities of the rice products.

The clinical course of patients with IgG4-related kidney disease.

Long-term follow-up for IgG4-related kidney disease, including relapse information, is sparse. To gather data on this we retrospectively examined the clinical course of 43 patients with IgG4-related kidney disease, in which most patients were treated with, and maintained on, corticosteroids. One month after the start of treatment, most of the abnormal serology and radiology parameters had improved. In 34 of the steroid-treated patients whose follow-up period was more than 12 months (median 34 months), excluding one hemodialysis patient, the estimated glomerular filtration rate (eGFR) before treatment was over 60 ml/min in 14 patients (group A) and under 60 ml/min in 20 patients (group B). In group A, there was no difference between the eGFR before therapy and at the last review. In group B, the mean eGFR before treatment (34.1 ml/min) was significantly improved after 1 month (45.0 ml/min), and renal function was maintained at a similar level through last follow-up. Among 24 evaluated patients at the last review, however, renal atrophy had developed in 2 of 9 in group A and in 9 of 15 in group B. Relapse of IgG4-related lesions occurred in 8 of 40 treated patients. Thus, the response of IgG4-related kidney disease to corticosteroids is rapid, not total, and the recovery of renal function persists for a relatively long time under low-dose maintenance. A large-scale prospective study to formulate more useful treatment strategies is necessary.

Effect of heat-moisture treated brown rice crackers on postprandial flow-mediated dilation in adults with mild endothelial dysfunction.

Background: Endothelial dysfunction is an early pathophysiological feature and independent predictor of a poor prognosis in most forms of cardiovascular disease. We evaluated the effect of brown rice crackers (BR-C) on endothelial function. Methods: Effect of heat-moisture treated (HMT) -BR-C on postprandial flow-mediated dilation (FMD) in adults with mild endothelial dysfunction was compared with that of BR-C and white rice crackers (WR-C) in 12 adults with mild endothelial dysfunction (less than 7.0% of FMD) by a randomized, single-blind, three-treatment three-period crossover trial (UMIN 000034898). Since we considered that the FMD increase was associated with the treatment of HMT-BR-C, we examined the effect of three possible factors: postprandial glucose levels, polyphenol content, and polyphenol release from the food matrix. Results: Mean pre-intake baseline FMD values of HMT-BR-C, BR-C, and WR-C were 4.9%, 5.1%, and 4.9%, respectively, and those values 1 h post-intake were 6.3%, 5.1%, and 4.8%, respectively. There was no difference in intergroup comparisons of FMD using Dunnett's multiple comparison test. There was a significant increase in FMD only in HMT-BR-C in intragroup comparisons (P = 0.042 by paired-t test). In comparison with BR-C, no significant difference was noted in the postprandial glucose level nor in the content of total polyphenols and ferulic acid derivatives in HMT-BR-C. However, the 70% ethanol extracted from HMT-BR-C contained a significantly larger amount of free and bound ferulic acids than from BR-C. Conclusion: HMT-BR-C intake increased the postprandial FMD response.

Clinicopathological characteristics of patients with IgG4-related tubulointerstitial nephritis.

IgG4-related disease is a recently recognized multi-organ disorder characterized by high levels of serum IgG4 and dense infiltration of IgG4-positive cells into several organs. Although the pancreas was the first organ recognized to be affected by IgG4-related disorder in the syndrome of autoimmune pancreatitis, we present here clinico-pathological features of 23 patients diagnosed as having renal parenchymal lesions. These injuries were associated with a high level of serum IgG4 and abundant IgG4-positive plasma cell infiltration into the renal interstitium with fibrosis. In all patients, tubulointerstitial nephritis was the major finding. Although 14 of the 23 patients did not have any pancreatic lesions, their clinicopathological features were quite uniform and similar to those shown in autoimmune pancreatitis. These included predominance in middle-aged to elderly men, frequent association with IgG4-related conditions in other organs, high levels of serum IgG and IgG4, a high frequency of hypocomplementemia, a high serum IgE level, a patchy and diffuse lesion distribution, a swirling fibrosis in the renal pathology, and a good response to corticosteroids. Thus, we suggest that renal parenchymal lesions actually develop in association with IgG4-related disease, for which we propose the term 'IgG4-related tubulointerstitial nephritis.'

[Case of IgG4-related tubulointerstitial nephritis showing the progression of renal dysfunction after a cure for autoimmune pancreatitis].

A 78-year-old-man was admitted to our hospital because of renal insufficiency 20 months after the onset of autoimmune pancreatitis. He had cerebral infarction and prostatic hypertrophy as complications. He had been previously diagnosed with autoimmune pancreatitis (AIP). The initial therapy was started with oral prednisolone at the dose of 0.8 mg/kg (40 mg/day). Prednisolone had been tapered off gradually through a one-year period. Four months later from terminating prednisolone, a follow-up CT showed multiple low-density areas in both kidneys without swelling of the pancreas. Furthermore, 4 months later, laboratory findings showed progressive renal insufficiency. On admission, BP was 167/77 mmHg, and the bilateral submaxillary glands were swollen. He did not have pretibial edema. Laboratory findings were as follows. BUN 55.9 mg/dL, Cre 6.17 mg/dL, Amy 65 mg/dL, TP/Alb 9.5/4 g/dL, gamma-gl 43.7%, IgG/IgA/IgM 3,395/112/74 mg/dL, IgG4 1,460 mg/dL, urinary protein 1.38 g/day, and 24 hr-Ccr 11.8 mL/min/1.73 m2. Percutaneous renal needle biopsy was conducted. Light microscopic findings demonstrated tubulointerstitial nephritis (TIN) and membranous change. Immunofluorescent microscopic findings indicated diffuse deposition of IgG2 and IgG4 in the renal interstitium. On the basis of these findings, the condition was diagnosed as IgG4-related tubulointerstitial nephritis. As renal insufficiency was progressing, hemodialysis was started soon after admission and oral prednisolone was also started at the dose of 0.4 mg/kg (20 mg/day). However, improvement of renal function has not been obtained and hemodialysis and prednisolone tapering are still being conducted. This case showed severe tubulointerstitial nephritis requiring hemodialysis after a cure for autoimmune pancreatitis. IgG4-related renal disease rarely needs hemodialysis. This case indicates that the prognosis of IgG4-related systemic disease is not necessarily good and further accumulation of cases is required.

Rho kinase-mediated vasoconstriction is important in severe occlusive pulmonary arterial hypertension in rats.

Vascular remodeling, rather than vasoconstriction, is believed to account for high vascular resistance in severe pulmonary arterial hypertension (PAH). We have found previously that acute Rho kinase inhibition nearly normalizes PAH in chronically hypoxic rats that have no occlusive neointimal lesions. Here we examined whether Rho kinase-mediated vasoconstriction was also important in a rat model of severe occlusive PAH. Adult rats were exposed to chronic hypoxia ( approximately 10% O(2)) after subcutaneous injection of the vascular endothelial growth factor receptor inhibitor SUGEN 5416. Hemodynamic measurements were made in anesthetized rats after 2 weeks of hypoxia (early group) and 3 weeks of hypoxia plus 2 weeks of normoxia (late group). Both groups developed PAH, with greater severity in the late group. In the early group, intravenous fasudil was more effective than intravenous bradykinin, inhaled NO, or intravenous iloprost in reducing right ventricular systolic pressure. Despite more occlusive vascular lesions, fasudil also markedly reduced right ventricular systolic pressure in late-stage rats. Blood-perfused lungs from late-stage rats showed spontaneous vasoconstriction, which was reversed partially by the endothelin A receptor blocker BQ123 and completely by fasudil or Y-27632. Phosphorylation of MYPT1, a downstream target of Rho kinase, was increased in lungs from both groups of rats, and fasudil (intravenous) reversed the increased phosphorylation in the late group. Thus, in addition to structural occlusion, Rho kinase-mediated vasoconstriction is an important component of severe PAH in SUGEN 5416/hypoxia-exposed rats, and PAH can be significantly reduced in the setting of a severely remodeled lung circulation if an unconventional vasodilator is used.

Rho kinase-mediated vasoconstriction in rat models of pulmonary hypertension.

There is current controversy regarding whether vasoconstriction plays a significant role in the elevated pressure of severe, advanced stages of pulmonary hypertension. Results of acute vasodilator testing using conventional vasodilators in such patients suggest there is only a minor contribution of vasoconstriction. However, there is a possibility that these results may underestimate the contribution of vasoconstriction because the most effective vasodilators have not yet been tested. This issue has not been addressed even experimentally, due mainly to a lack of appropriate animal models. A few animal models that mimic the pathology of human severe pulmonary hypertension more closely (i.e., development of occlusive neointimal lesions in small pulmonary arteries/arterioles) have been introduced, including rat models of left lung pneumonectomy plus monocrotaline injection and vascular endothelial growth factor inhibition plus exposure to chronic hypoxia. We have observed that Rho kinase inhibitors, a novel class of potent vasodilators, reduce the high pulmonary artery pressure of these models acutely and markedly, suggesting that vasoconstriction can significantly be involved in pulmonary hypertension with severely remodeled (occluded) pulmonary vessels. This chapter describes methods used for evaluation of the involvement of Rho kinase-mediated vasoconstriction in rat models of pulmonary hypertension.

Dehydroepiandrosterone upregulates soluble guanylate cyclase and inhibits hypoxic pulmonary hypertension.

OBJECTIVE: It has been reported that dehydroepiandrosterone is a pulmonary vasodilator and inhibits chronic hypoxia-induced pulmonary hypertension. Additionally, dehydroepiandrosterone has been shown to improve systemic vascular endothelial function. Thus, we hypothesized that chronic treatment with dehydroepiandrosterone would attenuate hypoxic pulmonary hypertension by enhancing pulmonary artery endothelial function. METHODS AND RESULTS: Rats were randomly assigned to five groups. Three groups received food containing 0, 0.3, or 1% dehydroepiandrosterone during a 3-wk-exposure to simulated high altitude (HA). The other 2 groups were kept at Denver's low altitude (LA) and received food containing 0 or 1% dehydroepiandrosterone. Dehydroepiandrosterone dose-dependently inhibited hypoxic pulmonary hypertension (mean pulmonary artery pressures after treatment with 0, 0.3, and 1% dehydroepiandrosterone=45+/-5, 33+/-2*, and 25+/-1*# mmHg, respectively. *P<0.05 vs. 0% and # vs. 0.3%). Dehydroepiandrosterone (1%, 3 wks) treatment started after rats had been exposed to 3-wk hypoxia also effectively reversed established hypoxic pulmonary hypertension. Pulmonary artery rings isolated from both LA and HA rats treated with 1% dehydroepiandrosterone showed enhanced relaxations to acetylcholine and sodium nitroprusside, but not to 8-bromo-cGMP. In the pulmonary artery tissue from dehydroepiandrosterone-treated LA and HA rats, soluble guanylate cyclase, but not endothelial nitric oxide synthase, protein levels were increased. CONCLUSION: These results indicate that the protective effect of dehydroepiandrosterone against hypoxic pulmonary hypertension may involve upregulation of pulmonary artery soluble guanylate cyclase protein expression and augmented pulmonary artery vasodilator responsiveness to nitric oxide.

Involvement of RhoA/Rho kinase signaling in pulmonary hypertension of the fawn-hooded rat.

The fawn-hooded rat (FHR) develops severe pulmonary hypertension (PH) when raised for the first 3-4 wk of life in the mild hypoxia of Denver's altitude (5,280 ft.). The PH is associated with sustained pulmonary vasoconstriction and pulmonary artery remodeling. Furthermore, lung alveolarization and vascularization are reduced in the Denver FHR. We have recently shown that RhoA/Rho kinase signaling is involved in both vasoconstriction and vascular remodeling in animal models of hypoxic PH. In this study, we investigated the role of RhoA/Rho kinase signaling in the PH of Denver FHR. In alpha-toxin permeabilized pulmonary arteries from Denver FHR, the contractile sensitivity to Ca2+ was increased compared with those from sea-level FHR. RhoA activity and Rho kinase I protein expression in pulmonary arteries of Denver FHR (10-wk-old) were higher than in those of sea-level FHR. Acute inhalation of the Rho kinase inhibitor fasudil selectively reduced the elevated pulmonary arterial pressure in Denver FHR in vivo. Chronic fasudil treatment (30 mg.kg-1.day-1, from birth to 10 wk old) markedly reduced the development of PH and improved lung alveolarization and vascularization in Denver FHR. These results suggest that Rho kinase-mediated sustained vasoconstriction, through increased Ca2+ sensitivity, plays an important role in the established PH and that RhoA/Rho kinase signaling contributes significantly to the development of PH and lung dysplasia in mild hypoxia-exposed FHR.

[Case of Heerfordt's syndrome with prolonged peripheral nerve involvement].

A 28-year-old man complaining of myiodesopsia was given a diagnosis of uveitis. Subsequently he complained facial nerve palsy and enlargement of parotid gland. Heerfordt's syndrome was diagnosed based on the results of several examinations. Facial nerve palsy, enlargement of the parotid gland and uveitis were improved by systemic corticosteroid therapy. At present he is receiving systemic corticosteroid therapy, but numbness in the mouth, thought to be the involvement of the trigeminal nerve, remains. Systemic corticosteroid therapy is usually effective for most cases with Heerford's syndrome. On the other hand, there are some cases with the prolonged peripheral nerve involvement despite systemic corticosteroid therapy, as seen in this case. If peripheral nerve involvement is prolonged, it is necessary to consider small-fibre neuropathy as one possible cause.

The importance of medical interview with CKD patient in diagnoses of a family with Fabry disease.

A 47-year-old Japanese man was admitted to our hospital for evaluation of proteinuria, which was detected when he was 37 years of age. His creatinine clearance levels had fallen to 76.3 mL/min/1.73 m2. A kidney biopsy was conducted, and the patient's low plasma α-galactosidase A levels suggested Fabry disease. After genetic counseling, GLA analysis revealed a novel mutation p.L387P. Interview with the patient revealed that both his younger brother and mother suffered from cardiomyopathy and were undergoing cardiological treatment. They also were positive for proteinuria. About 30 years ago, the patient's cousin (aged 25) was diagnosed with Fabry disease. He underwent hemodialysis for 9 years until his death at 42. At that time, the patient and his brother had not been investigated for Fabry disease so their cousin could not act as a proband for the brothers. Eventually, the patient, his mother, and his brother were put on enzyme replacement therapy with agalsidase beta. As this series of cases shows, medical interviews to collate both medical and family history were essential for the discovery of Fabry disease in these patients. In addition, being a treatable genetic disorder, Fabry disease should be listed in the standard differential diagnoses of systemic and familial diseases, including unknown cause of nephropathy or cardiomyopathy, for early detection of the disorder.

Mizoribine as a safe and effective combined maintenance therapy with prednisolone for anti-neutrophil cytoplasmic antibody-associated vasculitis in a hemodialysis patient.

A 77-year-old man developed severe renal insufficiency due to proteinase 3 anti-neutrophil cytoplasmic antibody (PR3-ANCA)-associated vasculitis, and was started on hemodialysis (HD). Because his renal insufficiency appeared to be irreversible, he was maintained on oral prednisolone (PSL) at 5 mg/day. However, a disease flare-up with alveolar hemorrhage occurred. Serology revealed elevated levels of PR3-ANCA and C-reactive protein (CRP). The patient was given pulse therapy with a quarter dose of methylprednisolone (m-PSL) (250 mg, 3 days), followed by oral PSL at 15 mg/day. As a supplemental treatment, he was given 25 mg of mizoribine (MZR) immediately after each HD session. Subsequently, the levels of PR3-ANCA and CRP decreased, and the alveolar hemorrhage resolved. The dose of MZR to be given was determined by measuring the patient's serum concentrations of MZR at various time points after the HD session. The maintenance dose of MZR was finally set at 50 mg. At present, the oral PSL dosage has been tapered to 10 mg/day, and the patient has achieved a state of remission without any side effects.

Involvement of RhoA/Rho kinase signaling in protection against monocrotaline-induced pulmonary hypertension in pneumonectomized rats by dehydroepiandrosterone.

RhoA/Rho kinase (ROCK) signaling plays a key role in the pathogenesis of experimental pulmonary hypertension (PH). Dehydroepiandrosterone (DHEA), a naturally occurring steroid hormone, effectively inhibits chronic hypoxic PH, but the responsible mechanisms are unclear. This study tested whether DHEA was also effective in treating monocrotaline (MCT)-induced PH in left pneumonectomized rats and whether inhibition of RhoA/ROCK signaling was involved in the protective effect of DHEA. Three weeks after MCT injection, pneumonectomized rats developed PH with severe vascular remodeling, including occlusive neointimal lesions in pulmonary arterioles. In lungs from these animals, we detected cleaved (constitutively active) ROCK I as well as increases in activities of RhoA and ROCK and increases in ROCK II protein expression. Chronic DHEA treatment (1%, by food for 3 wk) markedly inhibited the MCT-induced PH (mean pulmonary artery pressures after treatment with 0% and 1% DHEA were 33+/-5 and 16+/-1 mmHg, respectively) and severe pulmonary vascular remodeling in pneumonectomized rats. The MCT-induced changes in RhoA/ROCK-related protein expression were nearly normalized by DHEA. A 3-wk DHEA treatment (1%) started 3 wk after MCT injection completely inhibited the progression of PH (mean pulmonary artery pressures after treatment with 0% and 1% DHEA were 47+/-3 and 30+/-3 mmHg, respectively), and this treatment also resulted in 100% survival in contrast to 30% in DHEA-untreated rats. These results suggest that inhibition of RhoA/ROCK signaling, including the cleavage and constitutive activation of ROCK I, is an important component of the impressive protection of DHEA against MCT-induced PH in pneumonectomized rats.

Activity of endothelium-derived hyperpolarizing factor is augmented in monocrotaline-induced pulmonary hypertension of rat lungs.

The mechanism of endothelium-dependent vasodilator signaling involves three components such as nitric oxide, prostacyclin, and endothelium-derived hyperpolarizing factor (EDHF). Although EDHF is distinct from nitric oxide and prostacyclin, it requires activation of Ca(2+)-sensitive K(+) channels (K(Ca)) and cytochrome P(450) metabolites. However, the physiological role of EDHF in the pulmonary circulation is unclear. Thus, we tested if EDHF would regulate vascular tone in rat lungs of control and monocrotaline (MCT)-induced pulmonary hypertension. Inhibition of EDHF with a combination of K(Ca) blockers, charybdotoxin (50 nM) plus apamin (50 nM), increased baseline vascular tone in MCT-induced hypertensive lungs. Thapsigargin (TG; 100 nM), an inhibitor of Ca-ATPase, caused greater EDHF-mediated vasodilation in MCT-induced hypertensive lungs. TG-induced vasodilation was abolished with the charybdotoxin-apamin combination. Sulfaphenazole (10 muM), a cytochrome P(450) inhibitor, reduced the TG-induced vasodilation in MCT-induced hypertensive lungs. RT-PCR analysis exhibited an increase in K(Ca) mRNA in MCT-treated lungs. These results indicate the augmentation of tonic EDHF activity, at least in part, through the alteration in cytochrome P(450) metabolites and the upregulation of K(Ca) expression in MCT-induced pulmonary hypertension.

Endothelin-1 and serotonin are involved in activation of RhoA/Rho kinase signaling in the chronically hypoxic hypertensive rat pulmonary circulation.

We have previously reported that vasoconstrictor sensitivity to KCl (a receptor-independent and voltage-gated Ca influx-mediated vasoconstrictor) is augmented in the chronically hypoxic hypertensive rat pulmonary circulation probably through increased Rho kinase-mediated Ca sensitization. However, the upstream mechanism by which the RhoA/Rho kinase signaling pathway is activated is unknown. This study examined if endogenous endothelin-1 (ET-1) and serotonin (5-HT) play roles in the Rho kinase-mediated augmented vasoconstrictor response to KCl and the activation of RhoA in chronically hypoxic hypertensive rat pulmonary arteries. The augmented KCl vasoconstriction in hypertensive lungs was reduced by the ETA receptor antagonist BQ123, while a dual ETA/B antagonist had no further effects. A combination of BQ123 and a 5-HT1B/1D receptor antagonist, GR127935, was more effective than either agent alone. The combined antagonists also reduced augmented contractile sensitivity to KCl in hypertensive intrapulmonary arteries. Membrane-to-cytosol ratio of RhoA expression in hypertensive arteries was greater than that in normotensive arteries and was reduced by BQ123 and GR127935. These results suggest that stimulation of ETA and 5-HT1B/1D receptors by endogenous ET-1 and 5-HT, respectively, is involved in RhoA/Rho kinase-mediated increased Ca sensitization in the chronically hypoxic hypertensive rat pulmonary circulation.