Diffuse large B-cell lymphoma with composite germinal center and non-germinal center types: A report of two cases.

We report two cases of diffuse large B-cell lymphoma (DLBCL) with composite germinal center B-cell (GCB) and non-GCB types. Case 1 was a 72-year-old woman with inguinal lymph node swelling. Two morphologically different lesions were concurrently observed in needle biopsy specimens. One lesion was DLBCL with centroblastic morphology and a GCB phenotype (CD10+, BCL6+, and MUM1-), according to the Hans algorithm. The other lesion was DLBCL with anaplastic morphology and a non-GCB phenotype (CD10-, BCL6+, and MUM1+). Considering cellular atypia, the GCB-type DLBCL likely progressed to non-GCB-type DLBCL. Case 2 was a 34-year-old man who underwent ileocecal resection, with four lesions observed in the ileum. All four lesions indicated centroblastic morphology. Three lesions showed a GCB phenotype (CD10+, BCL6+, and MUM1+), while the other showed a non-GCB phenotype (CD10-, BCL6+, and MUM1+). These tumors were clonally related. BCL2 expression and MYC rearrangement were not related to changes in the cell of origin (COO) in either case. In conclusion, changes in the COO in DLBCL may not be uncommon. Therefore, investigation of the COO in other sites or at relapse may be needed if new drugs with different indications for each COO are developed.

Effect of prolonged hospitalization on fetal growth in threatened preterm labor.

OBJECTIVE: We aimed to demonstrate the effect of prolonged hospitalization on fetal growth in cases of threatened preterm labor (TPL). METHODS: In this retrospective cohort study, we included women who received prenatal care for TPL but delivered their child after 36 weeks of gestation. These were compared with a control group of healthy pregnant women and fetuses delivered at term. Fetal growth was compared using biparietal diameter, abdominal circumference (AC), femur length, and estimated fetal weight (EFW) assessed using ultrasonography at 18, 26, 30, and 36 weeks of gestation. Neonatal parameters at birth were also compared. RESULTS: In total, we enrolled 228 control women and 114 women with TPL who were treated with hospitalization,including bed rest. The AC at 30 and 36 weeks of gestation and EFW at 36 weeks of gestation were smaller in women treated with bed rest than for normal pregnant women. The mean duration of pregnancy was shorter in the hospitalization group than in the control group. Neonatal weight, length, head circumference, and chest circumference at birth were smaller after prolonged hospitalization for TPL than after normal pregnancy. CONCLUSION: Prolonged hospitalization for threatened preterm labor is associated with impaired fetal growth, particularly AC. J.Med.Invest.66:153-156, February, 2019.

Formulae Based on Biomathematics to Estimate the Standard Value of Fetal Growth of Japanese.

We devised biomathematics-based formulae to estimate the standard values of fetal growth of Japanese after 22 weeks' gestation. The growth rates of bi-parietal diameter (BPD), abdominal circumference (AC), femur length (FL), and estimated fetal body weight (EFBW) at the time of gestation were assumed to be proportional to the product of the value at the time and the rest value of an unknown maximum value, respectively. The EFBW was also assumed to follow a multiple logistic function of BPD, AC and FL to fit the standard values of Japanese fetuses published by the Japan Society of Ultrasonics in Medicine. The Mann-Whitney test was used for statistical analysis. The values as a function of gestational day, t, were as follows: BPD(t)=99.6/(1+exp (2.725-0.01837＊t)) (mm); AC(t)=39.7/(1+exp (2.454-0.01379＊t)) (cm); FL(t)=79.6/(1+exp (2.851-0.01710＊t)) (mm); EFBW(t)=8045.1/(1+exp (6.028-0.06582＊BPD(t)-0.1469＊AC(t)+ 0.07377＊FL(t))) (g). EFBW as a function of BPD, AC and FL was as follows: EFBW=8045.1/(1+exp (4.747+ 0.02584＊BPD+0.1010＊AC-0.1416＊FL)) (g). When the BPD, AC and FL were at -2 standard deviation (SD), -1SD, mean and + 2SD, the EFBW values calculated by the formula were statistically closer to the standard values than conventional formulas with p-values of 4.871×10-7, 4.228×10-7, 9.777×10-7 and 0.028, respectively. The formulae based on biomathematics might be useful to estimate the fetal growth standard values.

Non-uniform Progression of Chronic Tubulointerstitial Nephritis and Widespread Nephrocalcification in a Patient with Anorexia Nervosa.

Although patients with anorexia nervosa (anorexia) are known to show tubulointerstitial nephritis (TIN), the pathophysiology of its progression is not fully understood. We herein report a 31-year-old woman with anorexia who showed acute exacerbation of chronic kidney disease. Renal biopsy showed non-uniform chronic TIN; some areas were obsolete lesions and other areas were active lesions. In addition, many calcium-containing crystals were widely deposited in the distal tubules. The results suggest that chronic TIN in the setting of anorexia does not uniformly progress and that not only TIN but also widespread calcification of distal tubules might aggravate the renal function of anorexia patients.

Hydrogen Gas Ameliorates Hepatic Reperfusion Injury After Prolonged Cold Preservation in Isolated Perfused Rat Liver.

Hydrogen gas reduces ischemia and reperfusion injury (IRI) in the liver and other organs. However, the precise mechanism remains elusive. We investigated whether hydrogen gas ameliorated hepatic I/R injury after cold preservation. Rat liver was subjected to 48-h cold storage in University of Wisconsin solution. The graft was reperfused with oxygenated buffer with or without hydrogen at 37° for 90 min on an isolated perfusion apparatus, comprising the H2 (+) and H2 (-) groups, respectively. In the control group (CT), grafts were reperfused immediately without preservation. Graft function, injury, and circulatory status were assessed throughout the perfusion. Tissue samples at the end of perfusion were collected to determine histopathology, oxidative stress, and apoptosis. In the H2 (-) group, IRI was indicated by a higher aspartate aminotransferase (AST), alanine aminotransferase (ALT) leakage, portal resistance, 8-hydroxy-2-deoxyguanosine-positive cell rate, apoptotic index, and endothelial endothelin-1 expression, together with reduced bile production, oxygen consumption, and GSH/GSSG ratio (vs. CT). In the H2 (+) group, these harmful changes were significantly suppressed [vs. H2 (-)]. Hydrogen gas reduced hepatic reperfusion injury after prolonged cold preservation via the maintenance of portal flow, by protecting mitochondrial function during the early phase of reperfusion, and via the suppression of oxidative stress and inflammatory cascades thereafter.

An adult case of severe steroid-resistant Henoch-Schönlein purpura nephritis treated with intravenous cyclophosphamide and tonsillectomy.

A previously healthy 37-year-old Canadian man living in Japan visited a hospital in Thailand while traveling because of edematous legs, purpura, arthralgia, bloody stool, and fever after an insect bite. Henoch-Schönlein purpura (HSP) was suspected. His creatinine level was 5.2 mg/dL. He was treated with oral prednisolone (PSL) and oral cyclophosphamide (CPA); after treatment, his creatinine level improved to 2.4 mg/dL. Upon returning to Japan, he was admitted to the National Center for Global Health and Medicine Hospital in Tokyo. A kidney biopsy was performed, and HSP nephritis (HSPN) was diagnosed. Renal dysfunction and proteinuria persisted despite 4 administrations of steroid-pulse therapy and 3 sessions of plasma exchange. Finally, he was treated with intravenous cyclophosphamide (IVCY). His creatinine level and proteinuria markedly improved. His microscopic hematuria disappeared after he underwent tonsillectomy. There have been only a few case reports describing patients with adult-onset HSPN necessitating IVCY. We present here a rare case of steroid-resistant HSPN treated with IVCY and tonsillectomy, with reference to some recent findings.

A case of acute interstitial nephritis and granulomatous hepatitis induced by ingesting quinine.

Quinine is used for the treatment of malarial infection, though not in common use. It is especially valuable for the parenteral treatment of severe illness owing to drug-resistant strains of Plasmodium falciparum. Quinine is also known to occasionally cause acute renal failure (ARF). Although quinine is listed in some reviews as a cause of acute interstitial nephritis, most cases of quinine-associated acute renal failure have been attributed to the hemolytic-uremic syndrome (HUS). Only two cases of acute renal failure due to acute interstitial nephritis associated with quinine have been reported [1, 2]. To our knowledge, there have been 6 reported cases of quinine-induced hepatic granuloma [3-8]. We report a case of quinine-induced acute interstitial nephritis (AIN) along with granulomatous hepatitis, both of which were confirmed on biopsy. A 50-year-old Nigerian man was admitted to the hospital with complaints of fever and general fatigue. He had been prescribed quinine as an antimalarial drug in a Nigerian hospital. The patient was febrile and showed nonoliguric ARF and liver dysfunction. In this case, liver injury showed gradual and spontaneous resolution after discontinuing quinine, and ARF resolved after treatment with oral prednisolone.

[Case of serious HIV-associated nephropathy resulting in the introduction of hemodialysis].

A previously healthy 46-year-old black man visited the other hospital because of fever, appetite loss and nausea. Renal dysfunction, liver injury, and a highly markedly elevated LDH level were found. Abdominal CT demonstrated enlarged liver, spleen, kidney and lymph nodes. Human immunodeficiency virus (HIV) was serologically positive. His serum BUN, creatinine and potassium were 74.9 mg/dL, 11.78 mg/dL, and 5.6 mEq/L, respectively. After admission, anuria persisted and the progression of renal failure continued despite various treatment methods, necessitating the introduction of maintenance hemodialysis(HD). A kidney biopsy was performed to confirm classical HIV-associated nephropathy (HIVAN). Antiretroviral therapy (ART) was started. Although urine was transiently excreted, HD could not be discontinued. It has been reported that HIVAN is too difficult to treat and that kidney dysfunction seldom recovers. HIVAN is well-known to occur frequently in black HIV-infected patients. However, in Japan, there have been only a few reports describing patients with serious HIVAN and renal failure necessitating HD. We present here a very rare case with HIVAN, with reference to some recent findings.

Thrombotic microangiopathy associated with tuberculous infection.

A 32-year-old man was diagnosed as having thrombotic microangiopathy (TMA) and treated by plasma exchange (PE). During the course of admission, he was also newly diagnosed with pulmonary tuberculosis, tuberculous peritonitis and pleuritis, which was thought to be the cause of the TMA. There are only a few previous reports on TMA associated with tuberculous infection. Although its pathogenetic mechanism is not well understood, it would be valuable to recognize that this worldwide infectious disease could cause TMA.

Factors associated with recovery of renal function in patients with multiple myeloma who were treated with hemodialysis.

BACKGROUND: The presence of renal failure in patients with multiple myeloma (MM) has been considered an ominous prognostic factor associated with a significantly decreased life expectancy. The prognostic factors have seldom been analyzed to predict discontinuation of hemodialysis (HD) therapy in MM patients with renal failure after HD initiation. It is clinically very important to predict whether HD can be discontinued after introducing HD in such patients. METHODS: All medical and HD records were reviewed in MM patients who underwent HD in the National Center for Global Health and Medicine Hospital between January 1995 and May 2009. Thirty-two patients with MM had undergone HD. The clinical features and the factors that might be associated with recovery of renal function leading to discontinuation of HD in MM patients with severe renal failure were examined. RESULTS: The factors associated with recovery of renal function and discontinuation of HD were: low International Staging System (ISS) score (p = 0.0034); high response to chemotherapy (p = 0.036); low serum Ca (p = 0.006); low Cr (p = 0.019), and low serum ß2-microglobulin (sß2M) (p = 0.002). On multivariate analysis, low serum Ca and sß2M were significantly associated with HD discontinuation. Moreover, discontinuing HD was the significant factor associated with improved overall survival in MM patients who required HD at least once. CONCLUSION: sß2M and Ca were the laboratory parameters that were significant, independent prognostic factors for predicting the probability of recovery from severe renal failure and discontinuation of HD in MM patients who needed HD at least once.

Antiepoetin antibody-related pure red cell aplasia: successful remission with cessation of recombinant erythropoietin alone.

An elderly patient with pure red cell aplasia (PRCA) with antierythropoietin (anti-EPO) antibodies is described. PRCA due to alloimmunization is a rare and severe complication of recombinant human erythropoietin (rHu-EPO) therapy. Most reported patients with PRCA were cured primarily by immunosuppressive drug therapy. The patient in this case, however, did not want to receive any immunosuppressive drugs. Therefore, rHu-EPO injection was simply discontinued, the severe anemia gradually improved, and the hemoglobin approached normal range. This case is very rare and significant in that there have been few such elderly patients with rHu-EPO-induced PRCA in whom PRCA remission was achieved, with decreasing antibody titers, after cessation of rHu-EPO alone. Further cases are needed to assess how PRCA should be treated in patients with anti-EPO antibodies.

Reduced expression of perlecan in the aorta of secondary hyperparathyroidism model rats with medial calcification.

BACKGROUND: Vascular calcification is an important complication that worsens the prognosis for dialysis patients, although its detailed molecular mechanisms are still unknown. METHODS: We produced a rat model for vascular calcification with hyperphosphatasemia and hyperparathyroidism, performing a 5/6 nephrectomy and providing a high-phosphorus, low-calcium diet for eight weeks. We examined mRNA obtained from the calcified aortae using microarray analysis, and searched for alterations in gene expression specifically in the calcified lesions. RESULTS: Medial calcification was demonstrated in the abdominal aorta of 12 out of 42 hyperparathyroidism rats. In the aortae of hyperparathyroid rats with vascular calcification, the genes for heparan sulfate proteoglycans, including perlecan, were found to be down-regulated using microarray analysis and real time PCR. Immunohistochemistry also demonstrated reduced production of perlecan in the aortae of hyperparathyroid rats. DISCUSSION: Perlecan is a major component of the vascular wall basement membrane and may play a role in protecting vascular smooth muscle cells from inflammatory cells and various toxins. It has also been reported that heparan sulfate chains may inhibit osteogenesis. Our findings indicate that perlecan may protect vascular smooth muscle cells from various factors that promote vascular calcification. CONCLUSIONS: It may be that reduced expression of perlecan in the calcified aortae of hyperparathyroid rats is a risk factor for vascular calcification.

Mechanism of phosphate-induced calcification in rat aortic tissue culture: possible involvement of Pit-1 and apoptosis.

BACKGROUND: Hyperphosphataemia is a known contributing factor in the progression of vascular calcification in dialysis patients. The cellular mechanisms underlying phosphate-induced calcification are still unclear despite intense study, so in this study, we investigated the possible involvement of the type III sodium-dependent phosphate cotransporter, Pit-1, in an aortic tissue culture model. METHODS: Aortic segments from 9-week-old male Sprague-Dawley rats were incubated in serum-supplemented medium for 10 days. The phosphate concentration of the medium was elevated to induce calcification, which was assessed by histology and calcium content. Phosphonoformic acid (PFA) was used to inhibit phosphate uptake. The involvement of apoptosis was examined using the terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate (dUTP) nick-end labelling (TUNEL) assay, caspase 3 activation, and inhibition of apoptosis using a general caspase inhibitor. Phenotypic changes in vascular smooth muscle cells (VSMC) were assessed using expression of osteochondrogenic differentiation markers. RESULTS: Medial vascular calcification was induced in aortas cultured in a high phosphate medium. PFA decreased the rates of calcification and apoptosis of VSMC in the media, concomitant with calcification. Caspase inhibitor reduced calcification. No phenotypic transition of VSMC was seen in this model. CONCLUSIONS: These results indicate that phosphate uptake through the type III sodium-dependent phosphate cotransporter, Pit-1, leads to induction of apoptosis and subsequent calcification of VSMC.

The value of QuantiFERON TB-Gold in the diagnosis of tuberculosis among dialysis patients.

BACKGROUND: It is difficult to diagnose tuberculosis (TB) in dialysis patients because of the high rate of extrapulmonary TB in these patients compared with the general population. Recently, a new diagnostic test called QuantiFERON (QFT) has been developed and shown promise as a diagnostic tool for active TB diseases and latent TB infection. METHODS: We examined 162 dialysis patients admitted to a single institute, including 8 patients with active TB, and evaluated the utility of this test in dialysis patients. RESULTS: Among 162 dialysis patients, positive QFT results occurred in 28 (17.3%), negative QFT results occurred in 95 (58.6%) and indeterminate QFT results occurred in 39 (24.1%). All eight active TB patients had positive QFT results, and none of the 95 patients with negative results had active TB. Among 23 patients with a history of active TB, 10 (43.5%) had positive results. Although the indeterminate rate was relatively high, no patient with an indeterminate result had active TB. Factors such as shorter duration of dialysis, lower lymphocyte count and higher white blood cell count were associated with indeterminate results. Among 105 cases after excluding the patients with previous TB or indeterminate results, the sensitivity of the QFT is 100% (8 of 8) and the specificity is 89.7% (87 of 97 cases). CONCLUSIONS: Our data suggest that the QFT test is a useful supplementary tool for the diagnosis of active TB even in dialysis patients. Negative and indeterminate results on this test may be used to exclude the presence of active TB.

Acute toxicity of pierisin-1, a cytotoxic protein from Pieris rapae, in mouse and rat.

To investigate the toxicity of pierisin-1, a cytotoxic protein present in the cabbage butterfly, Pieris rapae, pierisin-1 was administered via intraperitoneally in mice and rats and the effects examined. Common findings in these experiments were hypoactivity with a gradual decrease in body weight due to decreased food intake, relative polycythemia with low serum albumin concentration and atrophy of the thymus, spleen, seminal vesicles and adipose tissue. Characteristic findings were diarrhea, fusion and atrophy of the villi and dilatation of the crypts in the small intestine at 6-100 microg/kg in BALB/c mice as well as elevation of LDH activity and creatinine value, hemolysis and renal and hepatic injuries at 1,000 and 10,000 microg/kg in BALB/c mice. In the case of ICR mice, severer renal injury was observed. On the other hand, in Fischer 344/Du rats, sudden stop of food intake, elevation of both AST and ALT activities, interlobar adhesion of the right hepatic lobe, capsular thickening, septal fibrosis and single cell necroses of subcapsular hepatocytes in the liver and basophilic tubules in the kidneys were observed. Oral administration of pierisin-1 at a dose of 10,000 microg/kg in BALB/c mice did not exert any obvious effects. Thus, existence of species and strain differences in toxicity of pierisin-1 to animals was demonstrated.

[Apoptosis: a possible mechanism of suppressing parathyroid hyperplasia by calcimimetics].

The mechanism through which calcimimetic compounds suppress parathyroid cell growth has not been fully elucidated. We investigated the effect of the calcimimetic compound (NPS R-568:R568) on the parathyroid cell growth in vitro. Whole parathyroid glands of subtotally nephrectomized rats fed high phosphorus diet for 8 weeks were used in this study. Fresh rat parathyroid glands were incubated in a media (phosphorus concentration is 1.0 mM and calcium is 1.25 mM) with R-568 (10-4 M) or calcitriol (10-7 M) or vehicle for 6 hours. Medium PTH level was significantly decreased in both R568-treated group and calcitriol-treated group compared with either vehicle-treated group, or no-treated group. While TUNEL-positive cells were similar in calcitriol-treated group compared with both vehicle-treated and no-treated groups, they were significantly increased in R568-treated group compared with other three groups. These results suggest that calcimimetic compounds, NPS R-568 reduces PTH secretion and induces apoptosis of hyperfunctional parathyroid cell in vitro.