PD-1/PD-L1 expression in human T-cell leukemia virus type 1 carriers and adult T-cell leukemia/lymphoma patients.

Adult T-cell leukemia/lymphoma (ATLL) develops after infection with human T-cell leukemia virus-1 (HTLV-1) after a long latency period. The negative regulatory programmed death-1/programmed death-1 ligand 1 (PD-1/PD-L1) pathway has been implicated in the induction of cytotoxic T-lymphocyte (CTL) exhaustion during chronic viral infection along with tumor escape from host immunity. To determine whether the PD-1/PD-L1 pathway could be involved in the establishment of persistent HTLV-1 infections and immune evasion of ATLL cells in patients, we examined PD-1/PD-L1 expression on cells from 27 asymptomatic HTLV-1 carriers (ACs) and 27 ATLL patients in comparison with cells from 18 healthy donors. PD-1 expression on HTLV-1-specific CTLs from ACs and ATLL patients was dramatically elevated. In addition, PD-1 expression was significantly higher on CD8+ T cells along with cytomegalovirus (CMV)- and Epstein-Barr virus (EBV)-specific CTLs in ATLL patients compared with ACs and control individuals. Primary ATLL cells in 21.7% of ATLL patients expressed PD-L1, whereas elevated expression was not observed in cells from ACs. Finally, in functional studies, we observed that an anti-PD-L1 antagonistic antibody upregulated HTLV-1-specific CD8+T-cell response. These observations suggest that the PD-1/PD-L1 pathway plays a role in fostering persistent HTLV-1 infections, which may further ATLL development and facilitate immune evasion by ATLL cells.

Association of single nucleotide polymorphisms in endothelin family genes with the progression of atherosclerosis in patients with essential hypertension.

Endothelin-1 (ET-1) is a potent vasoconstrictive peptide and its activity is mediated by the receptors ET type A (EDNRA) and ET type B (EDNRB). Although ET-1 is thought to play an important role in the development of atherosclerosis, it remains unclear whether polymorphisms of ET-1 family genes, including the ET-1 gene (EDN1), EDNRA, EDNRB and the genes for endothelin converting enzymes 1 and 2 (ECE1 and ECE2), are associated with the progression of atherosclerosis. We investigated the relationship between 11 single nucleotide polymorphisms (SNPs) of ET-1 family genes (including three in EDN1, one in EDNRA, two in EDNRB, four in ECE1 and one in ECE2) and atherosclerotic changes assessed using pulse wave velocity (PWV) and carotid ultrasonography in 630 patients with essential hypertension (EHT). In male subjects, we found significant differences in brachial-ankle PWV (baPWV) in additive and recessive models in EDNRB-rs5351 after Bonferroni correction. Also in male subjects, there were significant differences in mean intima-media thickness (IMT) in additive and recessive models in EDNRA-rs5333 after Bonferroni correction. We found no significant correlation between any SNPs in the ET family genes and baPWV, IMT and Plaque score (PS) in female subjects. Furthermore, after multiple logistic regression analysis, only EDNRB-rs5351 indicated as an independent risk of atherosclerosis in male hypertensive subjects. Of the endothelin-related genes, EDNRB-rs5351 was the most susceptible SNP associated with atherosclerosis in male hypertensives, and the genetic background may be involved in the progression of atherosclerosis in EHT patients.

Time-course of Toll-like receptor 2 expression, as a predictor of recurrence in patients with bacterial infectious diseases.

The clinical course of bacterial infectious diseases is often variable, especially in elderly patients. Thus, new biological markers have been sought to predict the disease outcome. Recent studies have revealed that Toll-like receptor (TLR) 2 and/or TLR4 on circulating monocytes are significantly up-regulated in bacterial infections. However, the lack of reliable quantification methods hampers extensive study on the modulation of these molecules in response to the patient's clinical condition. In this study, we developed a new quantitative flow cytometric analysis system for TLR2. We then carried out a longitudinal study on TLR2 expression levels on monocytes from patients suffering from bacterial infectious diseases during and after antibiotic treatment. The clinical outcome divided 37 patients into 'cure' (n = 24) and 'recurrence' (n = 13) groups. A significant difference between the two groups was recognized in the TLR2 levels just after antibiotic treatment (antibody-binding sites/cell, 4395 +/- 784 versus 5794 +/- 1484, P < 0.001). The risk of recurrence was associated significantly with TLR2 (P < 0.001), but not C-reactive protein (P = 0.351) levels assayed during the first remission. Furthermore, antibiotic effectiveness was associated inversely with TLR2 levels during antibiotic administration (P < 0.001). Taken together, TLR2 expression levels on monocytes provide critical information for planning treatment against bacterial infectious diseases.

Preoperative diagnosis of fallopian tube cancer by imaging.

Primary cancer of the fallopian tube (FTC) is among the most unusual gynecologic malignancies and rarely is diagnosed correctly before surgery. The imaging results of eight patients with FTC and four with benign tubal disease were analyzed. FTCs were small cystic or solid masses that typically were shaped like a sausage, a snail, or a gourd, regardless of clinical stage.

Prevalence of Anderson-Fabry disease in male patients with late onset hypertrophic cardiomyopathy.

BACKGROUND: Although studies have suggested that "late-onset" hypertrophic cardiomyopathy (HCM) may be caused by sarcomeric protein gene mutations, the cause of HCM in the majority of patients is unknown. This study determined the prevalence of a potentially treatable cause of hypertrophy, Anderson-Fabry disease, in a HCM referral population. METHODS AND RESULTS: Plasma alpha-galactosidase A (alpha-Gal) was measured in 79 men with HCM who were diagnosed at > or =40 years of age (52.9+/-7.7 years; range, 40-71 years) and in 74 men who were diagnosed at <40 years (25.9+/-9.2 years; range, 8-39 years). Five patients (6.3%) with late-onset disease and 1 patient (1.4%) diagnosed at <40 years had low alpha-Gal activity. Of these 6 patients, 3 had angina, 4 were in New York Heart Association class 2, 5 had palpitations, and 2 had a history of syncope. Hypertrophy was concentric in 5 patients and asymmetric in 1 patient. One patient had left ventricular outflow tract obstruction. All patients with low alpha-Gal activity had alpha-Gal gene mutations. CONCLUSION: Anderson-Fabry disease should be considered in all cases of unexplained hypertrophy. Its recognition is important given the advent of specific replacement enzyme therapy.

Tumor imprint cytology of ovarian ependymoma. A case report.

BACKGROUND: Ependymoma is a tumor that usually develops in the central nervous system and is extremely rare in the ovary. The first case of ovarian ependymoma was reported by Kleinman et al. (Kleinman GM, Young RH, Scully RE. Ependymoma of the ovary: report of three cases. Hum Pathol 1984;15:632-8.) in 1984, and only eight cases have been reported since then. Criteria for the histopathologic diagnosis of ependymoma are already established, but there has been no investigation of the cytologic diagnosis of ovarian ependymoma. METHODS: An imprint cytologic specimen was obtained from a recurrent ovarian ependymoma. The imprint cytologic features were compared with the findings of histologic examination, immunostaining, and electron microscopy. RESULTS: Imprint cytology revealed clusters of small cells with tapering cytoplasmic processes and a round nucleus. On the basis of these features, a neurogenic tumor could be included in the differential diagnosis. Furthermore, many rosette-like collections of cells that were suggestive of ependymal rosettes or perivascular pseudorosettes, characteristic of ependymoma, were found. The presence of ependymal rosettes and perivascular pseudorosettes also were confirmed by the histopathologic examination. Together with positive immunostaining for glial fibrillary acidic protein, this led to the diagnosis of ependymoma, which also was supported by the electron microscopic findings. CONCLUSIONS: Careful observation of the imprint cytologic specimen of an ovarian ependymoma should reveal numerous rosette-like collections of cells that were suggestive of ependymal rosettes or perivascular pseudorosettes. In addition, if we remember that ependymoma can develop in the ovary and find cells with tapering processes that suggest a neurogenic tumor, it may be possible to detect histologic features characteristic of ependymoma by the imprint cytology. To our knowledge, this is the first report on the imprint cytologic diagnosis of ependymoma originating in the ovary.

Comparison of transthoracic Doppler echocardiography and natriuretic peptides in predicting mean pulmonary capillary wedge pressure in patients with chronic atrial fibrillation.

The purpose of this study was to assess whether transthoracic Doppler echocardiography and serum natriuretic peptide levels could predict mean pulmonary capillary wedge pressure (PCWP) in patients with chronic atrial fibrillation. We examined mitral flow velocity and pulmonary venous flow (PVF) velocity patterns in 32 patients with chronic atrial fibrillation. Plasma A-type and B-type natriuretic peptide (ANP, BNP, respectively) levels in the peripheral vein were measured. Significant correlations were observed between mean PCWP and the following: peak velocity (r = 0.51) and deceleration time (r = -0.65) of the mitral flow; peak velocity (r = 0.64) and deceleration time (r = -0.80) of the PVF; BNP (r = 0.60); and ANP (r = 0.36). Stepwise multiple linear regression analysis selected PVF deceleration time and mitral flow deceleration time as independent predictors of PCWP. A cutoff value of PVF deceleration time of < or =150 ms and a mitral flow deceleration time of < or =100 ms predicted a mean PCWP of > or =18 mm Hg, with a sensitivity of 100% and 80% and a specificity of 96% and 85%, respectively. In conclusion, PVF deceleration time and mitral flow deceleration time obtained from transthoracic Doppler echocardiography are more accurate predictors of mean PCWP than values obtained with natriuretic peptides in patients with chronic atrial fibrillation.

Primary ependymoma of the ovary, in which long-term oral etoposide (VP-16) was effective in prolonging disease-free survival.

BACKGROUND: Ovarian ependymoma is an extremely unusual teratoma of the ovary with only eight cases previously reported in the literature worldwide. CASE: A 26-year-old woman presented in 1992 with a sensation of abdominal fullness. The laparotomy revealed ovarian cancer (stage III), which proved to be an ependymoma pathologically. Three courses of the PVP regimen (cisplatin, vinblastine, peplomycin) and pelvic irradiation were administered postoperatively. Oral administration of etoposide (VP-16) was initiated after the residual tumor began to proliferate, and the tumor decreased in size and never regrew during etoposide administration for a total of 5 years and 8 months. The recurrent tumor was observed soon after the drug was discontinued. CONCLUSION: Oral administration of etoposide was effective in prolonging disease-free survival.

Analysis of systolic and diastolic time intervals during dobutamine-atropine stress echocardiography: diagnostic potential of the Doppler myocardial performance index.

Systolic and especially diastolic Doppler time intervals may be early markers of myocardial ischemia inducible by dobutamine-atropine stress echocardiography (DASE). We postulated that the Doppler myocardial performance index (MPI) may help differentiate ischemic from nonischemic responses. Hemodynamic and Doppler echocardiography variables were measured prospectively at every stress level of DASE in 32 patients (mean age 67 +/- 13 years). Adequate recordings were obtained in 27 patients; 13 had an ischemic response (group I) and 14 a nonischemic response (group II). Heart rate differed between groups at baseline. At equivalent peak stress, left ventricular wall motion score index was significantly greater and ejection fraction lower in group I patients. Of the Doppler variables, only the MPI consistently differed between groups, irrespective of the number of stress levels compared. The Doppler MPI may be a useful adjunct to wall motion analysis in the detection of myocardial ischemia during DASE.

Repeated thermal therapy improves impaired vascular endothelial function in patients with coronary risk factors.

OBJECTIVES: We sought to determine whether sauna therapy, a thermal vasodilation therapy, improves endothelial function in patients with coronary risk factors such as hypercholesterolemia, hypertension, diabetes mellitus and smoking. BACKGROUND: Exposure to heat is widely used as a traditional therapy in many different cultures. We have recently found that repeated sauna therapy improves endothelial and cardiac function in patients with chronic heart failure. METHODS: Twenty-five men with at least one coronary risk factor (risk group: 38 +/- 7 years) and 10 healthy men without coronary risk factors (control group: 35 +/- 8 years) were enrolled. Patients in the risk group were treated with a 60 degrees C far infrared-ray dry sauna bath for 15 min and then kept in a bed covered with blankets for 30 min once a day for two weeks. To assess endothelial function, brachial artery diameter was measured at rest, during reactive hyperemia (flow-mediated endothelium-dependent dilation [%FMD]), again at rest and after sublingual nitroglycerin administration (endothelium-independent vasodilation [%NTG]) using high-resolution ultrasound. RESULTS: The %FMD was significantly impaired in the risk group compared with the control group (4.0 +/- 1.7% vs. 8.2 +/- 2.7%, p < 0.0001), while %NTG was similar (18.7 +/- 4.2% vs. 20.4 +/- 5.1%). Two weeks of sauna therapy significantly improved %FMD in the risk group (4.0 +/- 1.7% to 5.8 +/- 1.3%, p < 0.001). In contrast, %NTG did not change after two weeks of sauna therapy (18.7 +/- 4.2% to 18.1 +/- 4.1%). CONCLUSIONS: Repeated sauna treatment improves impaired vascular endothelial function in the setting of coronary risk factors, suggesting a therapeutic role for sauna treatment in patients with risk factors for atherosclerosis.

Case report of serous ovarian tumor of borderline malignancy (Stage Ic) in a pregnant woman.

We encountered a case of Stage Ic ovarian serous borderline malignancy in the first trimester of pregnancy. At laparotomy, spontaneous rupture of the capsule and a small amount of serous ascites was observed. Because of the laparotomy during pregnancy, correct staging of the tumor might not be performed. This case presented a major problem in deciding the treatment strategy, which are reported here together with some discussion of the literature on the preservation of fertility in borderline ovarian malignancy.

Apolipoprotein J/clusterin is induced in vascular smooth muscle cells after vascular injury.

BACKGROUND: Understanding the precise molecular mechanisms underlying the phenomenon of restenosis after PTCA may help us to develop a new strategy for the treatment of restenosis after PTCA. The purpose of this study was to identify the genes involved in vascular restenosis. METHODS AND RESULTS: Applying a differential hybridization method to a model of the balloon-injured rabbit aorta, we identified 6 cDNA clones that were upregulated after injury. Northern blot showed that 5 genes, but not apolipoprotein J (apoJ)/clusterin, were constitutively expressed in noninjured aorta and upregulated after balloon injury. ApoJ mRNA was not detectable in noninjured aorta (control), began to be expressed at 6 hours after injury, showed a peak level at 24 hours (a 48-fold increase), gradually declined, and returned to the control level at 24 weeks. Western blot and immunohistochemistry demonstrated no expression of apoJ protein in noninjured aorta, an expression of apoJ at 2 days after balloon injury, and a peak level (a 55-fold increase) at 2 to 8 weeks. The expression of apoJ protein continued until 24 weeks after injury. In situ hybridization revealed that apoJ mRNA was expressed in smooth muscle cells (SMCs) of media at 2 days after injury and in SMCs of media and neointima at 2 weeks. To analyze the function of apoJ, stably transfected rabbit SMCs were created. The expression of apoJ stimulated proliferation and migration of SMCs. CONCLUSIONS: ApoJ is dramatically induced in media and neointima after vascular injury, suggesting that apoJ contributes to restenosis after angioplasty.

Hyperbaric oxygen for anorexia nervosa.

Hyperbaric oxygen was given to a patient with anorexia nervosa who had developed postoperative ileus, resulting in not only improvement in ileus, but also enhancement of intestinal movement, inducing the feeling of hunger, and thereby increasing food ingestion. Hyperbaric oxygen may be effective as an initial treatment for anorectic patients showing severe bloating and resistance to food ingestion.

Free radical-mediated tolbutamide desensitization of K+ATP channels in rat pancreatic beta-cells.

To study the effects of hydroxyl radicals on the sensitivity of the ATP-sensitive K+ (K+ ATP) channel to tolbutamide, we used patch clamp and microfluorometric techniques in pancreatic beta-cells isolated from rats. cell-attached membrane patches, exposure of the cells to 0.3 mM H2O2 increased the probability of opening of K+ATP channels in the presence of 2.8 mM glucose. Tolbutamide dose-dependently inhibited the K+ATP channel with half-maximal inhibition (IC50) at 0.8 microM before and immediately after exposure to H2O2. After prolonged exposure (>20 min) to H2O2, the IC50 was increased to 15 microM. The presence of both ATP and ADP at concentrations ranging from 0.01 to 0.1 mM in the inside-out bath solution significantly enhanced the inhibition of the channels by 10 microM tolbutamide. Addition of 0.3 mM H2O2 induced a transient minute increase in the cytoplasmic Ca2+ concentration ([Ca2+]i) within 10 min, followed by a sustained pronounced increase in [Ca2]i. After more than 20 min of exposure of cells to 0.3mM H2O2, [Ca2]i was increased to above 2 microM. Treatment of the cytoplasmic face of inside-out membrane patches with 1 microM Ca2+ attenuated the tolbutamide-sensitivity of the K+ATP channel, but not the ATP-sensitivity of the channel. These findings indicate that H2O2 reduces tolbutamide sensitivity by inducing a sustained increase in [Ca2+]i.

Thermal therapy for congestive heart failure: estimation by TEI index.

Systolic dysfunction commonly coexists with diastolic dysfunction in patients with congestive heart failure due to myocardial disease. Also, right ventricular dysfunction is frequently associated with left ventricular dysfunction. The Doppler total ejection isovolume (TEI) index, a combined measurement of systolic and diastolic myocardial performance, is more reflective of overall cardiac function than systolic or diastolic function alone in both ventricles, and provides a conceptually new measure of global cardiac function. Single sauna bathing improves acute hemodynamics and repeated sauna therapy improves cardiac function and clinical symptoms in patients with heart failure. More recently, improvement of vascular endothelial function were observed by repeated sauna therapy in patients with heart failure. The TEI index, combining systolic and diastolic myocardial function, is a promising tool for the quantitative assessment of global cardiac function before and after thermal therapy.

HTLV-I Tax related dysfunction of cell cycle regulators and oncogenesis of adult T cell leukemia.

HTLV-I is causually related to the oncogenesis of adult T cell leukemia (ATL). However, the precise mechanism of HTLV-I oncogenesis is unclear. HTLV-I Tax protein functions as an activator of various cellular genes, including IL-2, IL-2 receptor-alpha, and c-fos through the activation of nuclear transfer factors such as NF-kappaB and SRF, and also potently activates trascription of viral genes through CREB/ATF sites in the viral LTR. However, Tax activation of HTLV-I infected T cells through the above pathways induces polyclonal proliferation of the cells in vitro; Tax however may function only transiently in the immediate post-infection period following infection in vivo. The long latent period of 60 years from infection to onset of disease suggests other mechanisms for ATL oncogenesis. Recent studies suggest that the malignant transformation of ATL is a multi-hit phenomena, suggesting that discrete genetic events are responsible for ATL oncogenesis. These genetic events could be responsible for the different stages of ATL: smoldering, chronic, lymphoma, and acute type, p16 and p53 genes are important negative regulators of the cell cycle and are often found to be mutated in neoplasms. Recent studies including ours demonstrated a high frequency of alteration of these two genes in primary ATL cells. Furthermore, alteration of the two genes is associated with acute but not chronic type ATL. In addition, p16 gene alteration is linked to the growth rate of ATL cells, suggesting that the alteration of these cell cycle regulatory genes may be related to progression from smoldering or chronic to acute or lymphoma type ATL. Tax may be involved in mutagenesis of these genes through suppression of DNA-beta polymerase gene expression during the process from latent period to acute/lymphoma type. Once transformation occurs, activation of the pathway between Tax and the three nuclear transfer factors, NF-kappaB, SRF, and CREB/ATF, contributes to establish the aggressive manifestations of acute/lymphoma type ATL cells.

Monophasic transmitral flow pattern with less increase in heart rate indicates left ventricular dysfunction.

When heart rate (HR) increases, mitral flow can become monophasic. Prolonged isovolumic contraction and relaxation time (ICT and IRT), directly related to left ventricular (LV) function, can potentially influence the HR with monophasic mitral flow. The present study investigated the relation between HR that causes monophasic flow and LV function. During diagnostic catheterization, HR was increased using right atrial pacing by 2 beats/min every 2 min in a stepwise manner until the development of monophasic mitral flow in 17 patients with normal sinus rhythm. ICT, IRT, end-diastolic and end-systolic LV volumes, LV ejection fraction, LV peak + and -dP/dt, peak (+dP/dt)/P, and the relaxation time constant (tau) were measured by Doppler echocardiography or catheterization when monophasic mitral flow developed. The monophasic HR varied from 74 to 106 beats/min. By univariate analysis, ICT (p<0.01, r2=0.73), LV peak +dP/dt (p<0.05, r2=0.37), peak (+dP/dt)/P (p<0.01, r2=0.71), peak -dP/dt (p<0.05, r2=0.25), and tau (p<0.05, r2=0.33) had a significant correlation with monophasic HR. By multivariate analysis, prolonged ICT and reduced LV peak -dP/dt independently contributed to monophasic mitral flow with less increase in HR. Monophasic mitral flow with less increase in HR indicates impaired LV systolic and diastolic function during isovolumic contraction and relaxation.

Adult T-cell leukemia with anti-HTLV-I antibody but no HTLV-I DNA in tumor cells.

Adult T-cell leukemia (ATL) is usually defined as a malignant disease of T cells infected by human T-lymphotropic virus type I (HTLV-I). In the present study, we describe a 49-year-old woman with an acute type ATL, whose leukemic cells do not contain the HTLV-I genome. Laboratory tests revealed an increase in abnormal lymphocytes with convoluted nuclei, elevated serum lactate dehydrogenase levels, increased thymidine kinase activity and soluble interleukin-2 receptor-alpha levels. Serum examination demonstrated positive anti-HTLV-I antibody, but Southern blot analysis using the whole HTLV-I genome as a probe did not detect any integration of the viral genome. In contrast, PCR detected the HTLV-I pX region in the same DNA samples as used for Southern blot analysis. These findings suggest two possibilities. One possibility is that ATL in this patient is generated by other pathogens than HTLV-I virus. She is also an HTLV-I carrier. The other possibility is that her leukemic T cell clone derived its malignant phenotype from HTLV-I infection, and once this malignant phenotype was obtained, partial deletions of viral genome repeated until the whole viral genome was deleted. Although there is no direct evidence, the former possibility is more likely in the present case.