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We present a patient with complication of huge hepatic subcapsular hematoma after extracorporeal shock wave lithotripsy (ESWL) for pancreatic lithotripsy. The hematoma measured 78-110mm. Angiography showed a subcapsular hematoma, rather than a hematoma in the liver. In the arterial phase, the distal end of the small vessel showed spotty opacification similar to microaneurysma, suggesting that it was an injury caused by separation of the liver and its capsule, caused by the shock waves. The portal vein and hepatic vein were normal. After 8 weeks of conservative therapy, the hematoma was gradually absorbed and the patient was discharged. Eight months after the accident, the hematoma had decreased to 40mm in size. After 20 months, it was completely absorbed. The reported rate of renal subcapsular hematoma after ESWL for renal or ureter stones is 0.1%-0.7%. To date, however, only five cases of hepatic subcapsular hematoma after right renal stone disintegration have been reported. This is the first report of hepatic subcapsular hematoma after ESWL for pancreatic stones. [ABSTRACT FROM AUTHOR]

Abstract A nonsense mutation at amino acid residue 184 in the human peptidase D (PEPD) gene caused the production of a truncated polypeptide. Characterizing molecular defects in patients provides clues to elucidate the relationship between the phenotype and the genotype. [ABSTRACT FROM AUTHOR]

Objectives: To compare the involvement of cytotoxic CX3CR1+ T cell subsets between giant cell arteritis (GCA) and Takayasu's arteritis (TAK)., Methods: We examined the proportions of CX3CR1+ CD4+ and CD8+ T cells in whole blood freshly obtained from 30 treatment-naive patients with active large vessel vasculitis (GCA, n=22 and TAK, n=8) and 16 healthy controls (HC). Infiltration of CX3CR1+ T cells into the affected arteries was assessed using immunohistochemical staining. Furthermore, CX3CR1+ CD4+ and CD8+ T cells were followed up after glucocorticoid treatment for longitudinal assessment of both diseases., Results: The proportion of CX3CR1+ CD4+ T cells was significantly higher in GCA than in HC but not in TAK. No differences were observed in the proportions of CX3CR1+ CD8+ T cells among the GCA, TAK, and HC groups. The increased proportion of CX3CR1+ CD4+ T cells in GCA strongly correlated with the severity of systemic inflammation, whereas no significant correlation was found in TAK. Compared to TAK, CX3CR1+ CD4+ T cells from GCA patients showed significantly higher expression of granzyme B and perforin. The inflamed temporal arterial tissues of the GCA were infiltrated by numerous CX3CR1+ T cells, contributing to inflammation, disruption of the elastic lamina, and intimal hyperplasia. In contrast, no infiltration of CX3CR1+ T cells was observed in the aortitis lesions of TAK. Longitudinal analysis of post-glucocorticoid treatment showed a reduction in CX3CR1+ T cells in GCA, whereas no significant change was observed in TAK., Conclusions: Differences in immune mechanisms between GCA and TAK highlight cytotoxic CX3CR1+ T cells as potential drivers for GCA-related inflammation and vessel damage but not for TAK.

The identification and accurate diagnosis of focal liver lesions are important in modern medicine, where diagnostic radiology plays an essential role. This review aimed to examine the hyperechogenicity and histopathological features of focal liver lesions. Hyperechogenic liver lesions can be either benign or malignant. Evidence shows that hyperechogenicity is caused by factors such as fat deposition, sinusoidal dilation, peliotic changes, and pseudoglandular patterns. Fat deposition is a common cause of increased echogenicity in hepatocellular carcinoma (HCC). Meanwhile, sinusoidal dilation and peliotic changes are more frequently observed in larger HCC nodules. Pseudoglandular patterns, characterized by the reflection of ultrasound waves at the walls of numerous acini, are associated with hyperechogenicity in well-to-moderately differentiated HCCs. Moreover, this review comprehensively examined the histological features that may cause hyperechogenic internal echoes in not only HCCs but also localized liver lesions (metastases of adenocarcinoma and neuroendocrine neoplasm, intrahepatic cholangiocarcinoma, cavernous hemangioma, focal nodular hyperplasia, and angiomyolipoma). To make an accurate diagnosis and provide appropriate management, it is important to understand the histopathological basis for hyperechogenicity in focal liver lesions. By maximizing the accuracy of imaging studies and enhancing the radiology-pathology correlation, unnecessary biopsies can be avoided, thereby reducing potential complications and mortality. This review can help facilitate the effective management of patients with focal liver lesions, thereby resulting in timely and appropriate treatment decision-making., (© 2024. The Author(s), under exclusive licence to The Japan Society of Ultrasonics in Medicine.)

Aims/hypothesis: Previous studies have suggested that glucose variability may accelerate atherosclerosis progression in people with type 2 diabetes. Current guidelines recommend assessing glycaemic control using continuous glucose monitoring (CGM), which provides a comprehensive glycaemic profile to supplement HbA 1c measurement. However, the association between CGM-derived metrics and atherosclerosis progression is not entirely clear., Methods: This exploratory study used baseline data and data obtained after 104 weeks from an ongoing prospective, multicentre, observational study. Six hundred study participants with type 2 diabetes and no apparent history of symptomatic cardiovascular disease underwent CGM and ultrasonographic atherosclerosis measurements of the carotid arteries, including the intima-media thickness (IMT) and grey-scale median (GSM), at baseline and 104 weeks. Non-invasive ultrasonic tissue characterisation of the carotid artery wall or plaque using the GSM reflects vascular composition. Multivariate regression models were used to analyse the association between CGM-derived indices, mainly time in range (TIR) and CV, and changes in carotid atherosclerosis index values., Results: Over the 104-week study period, there were modest increases in mean IMT (from 0.759±0.153 to 0.773±0.152 mm, p<0.001) and thickened-lesion GSM (from 43.5±19.5 to 53.9±23.5 units, p<0.001), but no significant changes in common carotid artery maximum-IMT (from 1.109±0.442 to 1.116±0.469 mm, p=0.453) or mean GSM (from 48.7±19.3 to 49.8±20.8 units, p=0.092). In a linear regression model with adjustment for possible atherosclerotic risk factors, including HbA 1c , TIR and CV at baseline were significantly associated with the annual change in mean GSM (regression coefficient per 10% increase in TIR 0.52; 95% CI 0.06, 0.98; Hochberg-adjusted p value 0.038; regression coefficient per 1% increase in CV -0.12; 95% CI -0.22, -0.02; Hochberg-adjusted p value 0.038). TIR and CV at baseline were also significantly associated with the annual change in thickened-lesion GSM (regression coefficient per 10% increase in TIR 0.95; 95% CI 0.12, 1.79; Hochberg-adjusted p value 0.038; regression coefficient per 1% increase in CV -0.19; 95% CI -0.36, -0.01; Hochberg-adjusted p value 0.038). Participants who achieved target CGM-derived metrics at baseline, as proposed by an international consensus, showed significant annual changes in mean GSM compared with those who did not (0.94±6.88 vs -0.21±6.19 units/year, p=0.007)., Conclusions/interpretation: TIR and CV were significantly associated with changes in the tissue characteristics of the carotid artery wall., Trial Registration: University Hospital Medical Information Network Clinical Trials Registry, number UMIN000032325., (© 2023. The Author(s).)

Context: Current guidelines recommend assessing glycemic control using continuous glucose monitoring (CGM) and hemoglobin A1c (HbA1c) measurement., Objective: This study aimed to clarify the characteristics of patients who might benefit from CGM metrics in addition to HbA1c monitoring., Methods: CGM metrics, specifically time in range (TIR), time below range (TBR), and time above range (TAR), were determined in 999 outpatients with type 2 diabetes and compared between HbA1c categories (HbA1c < 53 mmol/mol [7.0%, HbA1c <  53], HbA1c 53-63 mmol/mol [7.0-7.9%, HbA1c 53-63], HbA1c 64-74 mmol/mol [8.0-8.9%, HbA1c 64-74], and HbA1c ≥ 75 mmol/mol [9.0%, HbA1c ≥  75]) and between patients with identical HbA1c categories who were stratified by age, types of antidiabetic agents, and renal function., Results: For HbA1c <  53 category, patients aged ≥ 65 years had a significantly higher nocturnal TBR than those aged < 65 years. For HbA1c <  53 and HbA1c 53-63 categories, patients receiving insulin and/or sulfonylureas had a significantly higher TAR and TBR, and a lower TIR than those not receiving these drugs, and for HbA1c 64-74 category, they had a significantly higher TBR. For HbA1c <  53, HbA1c 53-63, and HbA1c 64-74 categories, patients with an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 had a significantly higher TBR during some periods than those with an eGFR ≥ 60., Conclusion: Higher HbA1c levels do not always protect against hypoglycemic episodes. Our data demonstrate that using CGM metrics to complement HbA1c monitoring is beneficial, especially in older people, users of insulin and/or sulfonylureas, and patients with chronic kidney disease., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Introduction: To determine the relationship between hypoglycemia and glucose variability in outpatients with type 2 diabetes mellitus (T2DM). Materials and Methods: The study participants were 999 outpatients with T2DM who used the FreeStyle Libre Pro for continuous glucose monitoring (FLP-CGM). Hypoglycemia was defined as glucose level of <3.0 mM, and the frequency of episodes and duration of hypoglycemia were evaluated by comparing patients who did or did not achieve time-below-range <3.0 mM (TBR <3.0 ) of <1% of the time. The association of TBR <3.0 and long% coefficient of variation (%CV) with medications used was examined using multivariate analysis with a proportional odds model. Results: The average TBR <3.0 was 0.33% (4.75 min). The TBR <3.0 >1% group comprised 71/999 patients. Patients of the TBR <3.0 >1% group had lower body mass index, longer disease duration, and poorer renal function. For the TBR <3.0 >1% group, the predicted cutoff values were 7.19 mM average glucose (AG), and 30.30% for %CV. When AG <7.19 mM and %CV >30.30% were considered as hypoglycemic risk factors, the frequency and duration of hypoglycemia increased as the risk factor values increased. In multivariate analysis, sulfonylurea (SU) use, insulin use, and low blood glucose index correlated significantly with increased length of TBR <3.0 and %CV, even after adjustment for concomitant diabetes medications. Conclusion: In T2DM, maintaining TBR <3.0 <1% requires to keep AG >7.2 mM and %CV <30%, in addition to comprehensive management of CGM metrics. Since SU and insulin use is associated with prolonged TBR <3.0 and increased %CV, their doses should be adjusted to avoid excessive fall in AG and raising %CV.

Aims: The aim of this study was to define the relationship between time in range (TIR) and hemoglobin A1c (HbA1c) levels in patients with type 2 diabetes mellitus (T2DM)., Methods: The glycemic profile of 999 Japanese patients was analyzed with FreeStyle Libre Pro Continuous Glucose Monitoring (FLP-CGM) while they continued their prescribed glucose-lowering medications. FLP-CGM data recorded over 8 consecutive days were analyzed., Results: The regression model for HbA1c on TIR was HbA1c = 9.4966-0.0309 × TIR. The predicted HbA1c level for TIR of 70% was 7.33% and is higher than reports subjecting mostly T1DM. The TIR corresponding to HbA1c 7.0% was 80.64%. The patients with low TIR tended to have long duration of diabetes, used high dose of daily insulin, high body mass index, high HbA1c, liver dysfunction and high triglyceride. Relatively higher percentages of patients of this group used sulfonylureas, glucagon like peptide-1 receptor agonists and insulin., Conclusions: Our data showed predicted HbA1c corresponding to TIR is largely depends on study population, thus is not uniform. Our results provide new insights on the management of T2DM. However, caution should be exercised in extending the HbA1C-TIR relationship using FLP-CGM to any other sensors since there could be a risk of hypoglycemia in doing so., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Aim: To clarify the relationship between ambulatory glucose profile (AGP) indexes and standardized continuous glucose monitoring (CGM) metrics in patients with type 2 diabetes (T2D)., Methods: This is an exploratory, cross-sectional analysis of baseline data collected from a prospective, multicentre, 5-year follow-up observational study conducted and published previously by our group. The study participants were 999 outpatients with T2D who used CGM at baseline, and had no apparent history of cardiovascular disease. We investigated the relationship between average interquartile range (IQR) and time in range (TIR). We also calculated, for the first time, the cutoff values to achieve the TIR target values., Results: In both the TIR more than 70% and TIR more than 90% achievement groups, the average IQR was notably small compared with the non-achievement groups. Particularly in comparison of the TIR quartiles, the average IQR became significantly smaller as the TIR became larger. The average IQR correlated negatively with TIR, and the cutoff values for TIR of more than 70% achievement and TIR of more than 90% achievement were an average IQR (>70%/>90%) of 2.13/1.85 mmol/L., Conclusion: Our results showed a negative correlation between TIR and the range of blood glucose variations visually represented in AGP. The results also showed that the range of blood glucose variations in AGP is associated with indices of intraday and interday blood glucose variations and also with hypoglycaemia. Our results may provide new perspectives in the assessment and application of AGP in the clinical setting., (© 2021 John Wiley & Sons Ltd.)

Background: The association between glucose variability and the progression of atherosclerosis is not completely understood. We aimed to evaluate the associations of glucose variability with the progression of atherosclerosis in the early stages., Methods: We conducted a cross-sectional analysis to investigate the associations of glucose variability, assessed by continuous glucose monitoring, with intima-media thickness (IMT) and gray-scale median (GSM) of the carotid arteries, which are different indicators for the progression of atherosclerosis. We used baseline data from a hospital-based multicenter prospective observational cohort study among Japanese patients with type 2 diabetes without a history of cardiovascular diseases aged between 30 and 80 years. Continuous glucose monitoring was performed by Freestyle Libre Pro, and glucose levels obtained every 15 min for a maximum of eight days were used to calculate the metrics of glucose variability. IMT and GSM were evaluated by ultrasonography, and the former indicates thickening of intima-media complex in the carotid artery wall, while the latter indicates tissue characteristics., Results: Among 600 study participants (age: 64.9 ± 9.2 (mean ± SD) years; 63.2%: men; HbA1c: 7.0 ± 0.8%), participants with a larger intra- and inter-day glucose variability had a lower GSM and most of these associations were statistically significant. No trend based on glucose variability was shown regarding IMT. Standard deviation of glucose (regression coefficient, β = - 5.822; 95% CI - 8.875 to - 2.768, P < 0.001), glucose coefficient of variation (β = - 0.418; - 0.685 to - 0.151, P = 0.002), mean amplitude of glycemic excursion (β = - 1.689; - 2.567 to - 0.811, P < 0.001), mean of daily differences (β = - 6.500; - 9.758 to - 3.241, P < 0.001), and interquartile range (β = - 4.289; - 6.964 to - 1.614, P = 0.002) had a statistically significant association with mean-GSM after adjustment for conventional cardiovascular risk factors, including HbA1c. No metrics of glucose variability had a statistically significant association with IMT., Conclusions: Continuous glucose monitoring-assessed glucose variability was associated with the tissue characteristics of the carotid artery wall in type 2 diabetes patients without cardiovascular diseases.

Introduction: Preventing the development and progression of diabetic microvascular complications through optimal blood glucose control remains an important challenge. Whether metrics based on continuous glucose monitoring are useful for the management of diabetic microvascular complications is not entirely clear., Research Design and Methods: This is an exploratory analysis of an ongoing prospective, multicenter, 5-year follow-up observational study. Study participants included 999 outpatients with type 2 diabetes who underwent continuous glucose monitoring at baseline. Associations between continuous glucose monitoring-derived metrics and the severity of diabetic retinopathy or albuminuria were investigated using multivariable proportional odds models., Results: The overall prevalence of diabetic retinopathy was 22.2%. Multivariate analysis with proportional odds models demonstrated that continuous glucose monitoring-derived metrics related to intraday and interday glucose variability are significantly associated with the severity of diabetic retinopathy, even after adjusting for various possible risk factors. However, significant relationships were not observed after adjusting for hemoglobin A1c (HbA1c) levels. The prevalence of microalbuminuria and macroalbuminuria was 20.3% and 6.7%, respectively. Similarly, multivariate analysis demonstrated that those metrics are significantly associated with the severity of albuminuria. These relationships remained significant even after further adjusting for HbA1c levels., Conclusions: Continuous glucose monitoring-derived metrics related to intraday and interday glucose variability are significantly associated with the severity of diabetic retinopathy or albuminuria in patients with type 2 diabetes. Thus, evaluating these metrics might possibly be useful for risk assessment of diabetic microvascular complications. Trial registration number UMIN000032325., Competing Interests: Competing interests: TO and HW have received research funds from Abbott Japan. HW is a member of the advisory board of Abbott Japan. All other authors declare no conflicts of interest., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Previous studies have suggested that high mean glucose levels and glycemic abnormalities such as glucose fluctuation and hypoglycemia accelerate the progression of atherosclerosis in patients with type 2 diabetes. Although continuous glucose monitoring (CGM) that could evaluate such glycemic abnormalities has been rapidly adopted, the associations between CGM-derived metrics and arterial stiffness are not entirely clear., Methods: This exploratory cross-sectional study used baseline data from an ongoing prospective, multicenter, observational study with 5 years of follow-up. Study participants included 445 outpatients with type 2 diabetes and no history of apparent cardiovascular disease who underwent CGM and brachial-ankle pulse wave velocity (baPWV) measurement at baseline. Associations between CGM-derived metrics and baPWV were analyzed using multivariate regression models., Results: In a linear regression model, all CGM-derived metrics were significantly associated with baPWV, but HbA1c was not. Some CGM-derived metrics related to intra-day glucose variability, hyperglycemia, and hypoglycemia remained significantly associated with baPWV after adjusting for possible atherosclerotic risk factors, including HbA1c. Based on baPWV ≥ 1800 cm/s as indicative of high arterial stiffness, multivariate logistic regression found that some CGM-derived metrics related to intra-day glucose variability and hyperglycemia are significantly associated with high arterial stiffness even after adjusting for possible atherosclerotic risk factors, including HbA1c., Conclusions: Multiple CGM-derived metrics are significantly associated with baPWV and high arterial stiffness in patients with type 2 diabetes who have no history of apparent cardiovascular disease. These metrics might be useful for identifying patients at high risk of developing cardiovascular disease.

A 54-year-old man with diarrhea and hematochezia for 2 months was referred to our department. A total colonoscopy revealed amoebic colitis caused by Entamoeba histolytica. Concurrently, a submucosal tumor-like yellowish hemispheric polypoid lesion was incidentally detected in the rectum. We speculated that the lesion was a NET, which could be cured by endoscopic treatment. However, histopathological assessment of a biopsy specimen unexpectedly revealed a well- or moderately differentiated adenocarcinoma. After treatment of the amoebic colitis, endoscopic ultrasound revealed a low, hetero-echoic, 6-mm-diameter lesion mainly in the submucosal layer. We performed surgical resection because the invasion was estimated to be to the deeper submucosal layer. Histopathological assessment of the surgically resected specimen revealed a focal lesion of a well-differentiated adenocarcinoma in the granulation tissue of the submucosal layer. In cases accompanied by amoebic colitis, a tumor's initial gross type might change. Diagnostic endoscopic resection could be acceptable in such cases.

Competing Interests: None

Introduction: A recent study demonstrated that large glucose fluctuations were associated with an increased incidence of cardiovascular disease (CVD) in patients with type 2 diabetes mellitus (T2DM) and acute myocardial infarction. However, it is unknown whether glucose fluctuations are related to the incidence of CVD or the progression of atherosclerosis in patients with T2DM with no apparent history of CVD. In this protocol, we will be investigating the relationships of glucose fluctuations evaluated by continuous glucose monitoring (CGM) to the incidence of composite cardiovascular events and the progression of atherosclerosis in patients with T2DM who had no apparent history of CVD., Methods: This is a prospective, multicenter, 5-year follow-up observational study. Between April 2018 and October 2019, 1000 participants are expected to be recruited at 34 medical institutions. CGM using FreeStyle Libre Pro is useful for evaluating glucose fluctuations by continuously monitoring glucose levels in interstitial fluid for up to 14 days. The primary study outcome is the relationship between fluctuations in glucose levels evaluated by CGM and the incidence of composite cardiovascular events. Secondary outcomes include the relationships of fluctuations in glucose levels evaluated by CGM to changes in carotid intima media thickness evaluated by echography or grayscale median (an index of tissue characteristics of the carotid wall), brachial-ankle pulse wave velocity, development or progression of diabetic retinopathy or nephropathy, quality-of-life-related diabetes therapy, quality of sleep, development of dementia, and autonomic nerve function., Planned Outcome: This protocol is designed to investigate the relationship between glucose fluctuations and the incidence of composite cardiovascular events. We completed the registration of 1000 participants in March 2019. Thus, results will be available in 2024. We expect that evaluating glucose fluctuations will aid the identification of patients with a high probability of developing CVD., Trial Registration: ClinicalTrials.gov identifier, UMIN000032325.

The present case involved a 76-year-old man with a cystic mass in the head of his pancreas. The cystic lesion, which measured 17.7 × 9.8 mm, was first detected by ultrasonography (US) at the age of 72 years. Follow-up endoscopic ultrasonography (EUS) performed at 4 years after the lesion had first been detected revealed a mural nodule measuring 14.0 × 8.4 mm in the cyst. Endoscopic retrograde pancreatography (ERP) imaging revealed that the main pancreatic duct was in communication with the cyst and that there was no irregular narrowing of the main pancreatic duct. On the basis of these results, the patient was diagnosed with an intraductal papillary mucinous neoplasm (IPMN), and stomach-preserving pancreaticoduodenectomy was performed. A histopathological examination revealed that the interior of the cystic part of the lesion was lined by a pancreatic ductal epithelium. A pathological examination of the nodular lesion detected storiform fibrosis, severe lymphoplasmacytic infiltration, and hyperplasia in the pancreatic duct epithelium together with a small amount of mucus. On immunohistological staining, the infiltrating lymphoplasmacytes were found to be positive for IgG4. Accordingly, the patient was diagnosed with focal autoimmune pancreatitis (AIP). In conclusion, we reported a case of focal AIP mimicking IPMN. This case showed neither enlargement of the pancreas nor irregular narrowing of the main pancreatic duct.

The methanolic extract from the flower buds of Camellia sinensis cultivated in Fujian Province showed inhibitory effects on body weight gain and the weight of visceral fats in high-fat diet-fed mice and/or Tsumura Suzuki Obese Diabetic (TSOD) mice. A suppressive effect of the extract on food intake was suggested to contribute to the anti-obesity effect. The n-butanol (BuOH)-soluble fraction also reduced food intake in normal diet-fed mice. A principal constituent, chakasaponin II, inhibited gastric emptying (GE) as well as food intake. These inhibitory effects were partly reduced by pretreatment with a high dose of capsaicin. The n-BuOH-soluble fraction and chakasaponin II suppressed mRNA levels of neuropeptide Y (NPY), an important regulator of body weight through its effects on food intake and energy expenditure, in the hypothalamus. Furthermore, chakasaponin II enhanced the release of serotonin (5-HT) from the isolated ilea of mice in vitro. These findings suggested that the active saponins suppressed the appetite signals in the hypothalamus through stimulation of the capsaicin-sensitive sensory nerves, probably vagal afferent nerves, or enhancement of 5-HT release from the ilea, leading to reduced food intake and body weight gain., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Discoid lupus erythematosus (DLE) is a chronic connective tissue disease of unknown etiology, but immunologic factors may play an important role in the pathogenesis. We investigated the features of immunohistochemical characterization of the cellular infiltrate in DLE. Skin samples were obtained from 5 patients using a 6 mm punch biopsy. Samples were stained with monoclonal antibodies against CD1a, CD3, CD4, CD8, CD20, CD25, CD30, and CD57. The number of cells stained with each monoclonal antibody was calculated. The number of cells stained with each monoclonal antibody in the dermis infiltration in DLE was calculated and all were higher than those in the normal control. The numbers of CD3(+), CD4(+), CD8(+), CD20(+), CD25(+), or CD57(+) cells in DLE were statistically higher than those in normal skin (p < 0.05). The numbers of CD1a(+) and CD30(+) cells in DLE were appreciably increased but had no statistical significance compared with normal skin. In conclusion, this study revealed that T lymphocytes, B lymphocytes, and natural killer cells may play some roles in the pathogenesis of DLE.

Distinguishing herpes virus infection from other skin diseases is sometimes difficult. This study aims to detect herpes virus DNA by multiplex real-time PCR without nucleic acid extraction in a short period of time. Specimens of cutaneous vesicles and swabs were obtained from 23 patients suspected of having herpes virus infection. These specimens were stored at -80 degrees C after dissolving them in sterilized water. DNA extraction was not performed. Specific real-time PCR primers for herpes simplex virus (HSV) 1 and 2 and varicella-zoster virus (VZV) were designed. These primers were used to perform realtime PCR with the frozen solution as template. Results clearly revealed a type-specific dissociation curve. Agarose gel electrophoresis was also performed and produced a single band of the expected size. In addition to using multiplex PCR, other steps were used to reduce the time even further. Each experiment took only 2 h to complete; the type of Herpes virus was successfully detected by multiplex real-time PCR without nucleic acid extraction in a short period of time. In conclusion, omission of the nucleic acid extraction step prior to real-time PCR does not negatively affect downstream reactions. Using multiplex PCR may allow more rapid qualitative analysis of HSV1, 2 and VZV.

Background: Localized scleroderma is a connective tissue disorder with hardening of the skin and fibrosis of the affected tissue as the most prominent features. The etiology of localized scleroderma is still unknown, but immunologic factors may play an important role in the pathogenesis. This study was performed to determine the immunohistochemical features of the cellular infiltrate in localized scleroderma., Methods: Skin samples were obtained from six patients by 6-mm punch biopsy. The samples were stained with monoclonal antibodies against CD1a, CD3, CD4, CD8, CD20, CD25, CD30, and CD57. The number of cells stained with each monoclonal antibody was calculated., Results: There were more CD1a+, CD3+, CD4+, CD8+, CD20+, CD25+, and CD57+ cells in the dermal infiltrate in localized scleroderma relative to those in normal controls. The numbers of CD1a+, CD3+, CD4+, CD8+, and CD57+ cells in localized scleroderma were significantly greater than those in normal skin (P < 0.05). The number of CD30+ cells in localized scleroderma was almost the same as that in normal skin., Conclusions: This study reveals that T lymphocytes, Langerhans cells, and natural killer cells may play important roles in the pathogenesis of localized scleroderma.

Scleroderma is a chronic autoimmune connective tissue disorder of unknown etiology that affects the microvasculature and loose connective tissue. Langerhans cells play an important role in the immune system of the skin. By immunohistochemistry we investigated the phenotypical characteristics of epidermal and dermal Langerhans cells and their spatial relationship with infiltrating lymphocytes in systemic scleroderma (SSc) and localized scleroderma. Skin samples were obtained from patients by 6 mm punch biopsy. Samples were stained with antibodies against CD1a and CD86. The number of cells stained with both antibodies in the dermal and epidermal infiltration was calculated. In contrast to normal skin, both types of scleroderma skin showed a marked increase in CD1a+ dermal Langerhans cells, whereas the number of CD1a+ cells in localized scleroderma was much higher than that in SSc (p < 0.05) either in the dermis or in the epidermis. The expression of CD86 was increased in the dermis of localized scleroderma compared with that in SSc or normal skin (p < 0.05). This study revealed that Langerhans cells may play an important role in the pathogenesis of scleroderma, especially in localized scleroderma. CD86 is predominantly expressed on dermal Langerhans cells in the lesional skin of localized scleroderma. Therefore, it might play an important role in the pathogenesis of localized scleroderma.

Anti-epiligrin cicatricial pemphigoid (AECP) is a chronic, mucous membrane-dominated, subepithelial blistering disease characterized by circulating anti-basement membrane zone auto-antibodies to laminin 5. Recent studies have shown that people with AECP have an increased relative risk for malignant tumours. In this report we describe two patients with AECP. In both cases, indirect immunofluorescence demonstrated circulating IgG anti-basement membrane auto-antibodies that bound to the dermal side of 1M NaCl split normal skin. Immunoblotting using laminin 5 purified from keratinocyte extract as a substrate showed that the IgG antibodies of patient 1 reacted with the 140-kDa beta3 subunit of laminin 5 and IgG antibodies of patient 2 reacted with the 165-kDa and 145-kDa alpha3 subunits. Patient 1 had prostate carcinoma and his blistering was resistant to therapy. Patient 2 had no detectable malignancy and treatment with doxycycline was successful.

Activation of the extracellular signal-regulated kinase (ERK) pathway is involved in many human tumors. Little is known about the role of activated ERK1/2 in squamous cell carcinoma (SCC) of the skin. In this study, the expression and distribution of phosphorylated ERK (p-ERK) in normal human skin and SCC with different degrees of differentiation was examined by immunohistochemical analysis using formalin-fixed paraffin embedded sections. PD98059, a specific ERK pathway inhibitor, was used to evaluate the effect a blockade of ERK activation has on the proliferation of a cutaneous SCC cell line (DJM-1) in culture. In this study, p-ERK 1/2 positive staining was observed in all cases of SCC examined but rarely in the control specimens of normal skin. Moreover, the expression of p-ERK1/2 was significantly higher in poorly differentiated SCC in comparison to well-differentiated ones. Expression levels were positively associated with the degree of malignancy and proliferative activity of SCC. In contrast, inhibition of ERK pathway signaling markedly suppressed tumor cell proliferation. These results suggest that ERK1/2 signal pathways play an important role in the proliferation of SCC and that the inhibition of this signal pathway may be effective in the treatment of cutaneous SCC.

Objective: We evaluated the predictive value of bone marrow accumulation of technetium (Tc)-99m tetrofosmin in patients with breast cancer for distant metastases in comparison with conventional prognostic factors such as clinical stage, tumor size, axillary lymph node (Node) status, and estrogen receptor (ER) status., Methods: Bone marrow scans with Tc-99m tetrofosmin were performed on 64 patients with breast cancer who had no clinical evidence of distant metastases. Accumulation in the femoral marrow was classified into four patterns, no detectable, lower, higher, and intensively higher. Higher or intensively higher pattern was interpreted as abnormal. Thirty-six patients with abnormal accumulation (marrow-positive group) and 28 patients without abnormal accumulation (marrow-negative group) were enrolled in the follow-up study. The mean length of observation after scans was approximately 3 years. The predictive value of femoral marrow status and conventional prognostic factors for distant metastases was evaluated by statistical analysis., Results: Univariate analysis showed a significantly higher incidence of subsequent bone metastases (36%>4%; P<0.005), and distant metastases (69%>18%; P<0.001) in the marrow-positive group when compared with the marrow-negative group. Conventional prognostic factors except tumor size were also significantly associated with the development of distant metastases; 77% in clinical stage 3>39% in clinical stages 1, 2, P<0.05; 64% in Node-positive>29% in Node-negative, P<0.01; and 70% in ER negative>27% in ER positive, P<0.005. These conventional factors were not significantly associated with bone metastases. The Cox proportional hazard ratio for bone metastases was markedly higher in femoral marrow status (hazard ratio=11.07). The distant metastases-free survival was significantly reduced in ER negative (P<0.0005), Node-positive (P=0.0215), and clinical stage 3 patients (P=0.0163). On the other hand, a more marked difference was observed in the femoral marrow status (P<0.0001). The hazard ratio for distant metastases was 2.44 in clinical stage, 2.74 in tumor size, 2.74 in Node, and 3.68 in ER, which were each independent prognostic factors associated with distant metastases. However, femoral marrow status was markedly associated with distant metastases (hazard ratio=5.27)., Conclusions: Bone marrow accumulation of Tc-99m tetrofosmin can be a promising prognostic factor independent of conventional prognostic factors for predicting development of not only bone metastases but also distant metastases in breast cancer.

Herein, we describe a rare case of giant malignant peripheral nerve sheath tumor of the head in a 38-year-old Japanese man. The tumor measured 210 mm at its largest diameter and was ulcerated, hemorrhagic, multilocular and non-mobile. It should be noted that the patient stubbornly refused to see a doctor for a long time, resulting in the extreme growth of the tumor. We suspect a psychological basis for this behavior. Dermatohistopathological findings of the biopsy indicated ancient schwannoma and total excision was therefore performed. However, after 4 months, the patient developed multiple metastases and died. Post-mortem skin biopsy revealed features of malignant peripheral nerve sheath tumor. We performed immunohistochemical studies on the primary and recurrent lesions and concluded that there was a difference in the expression of Ki67 and p16. We propose that the expressions of Ki67 and p16 should be checked for all lesions of peripheral nerve sheath tumor for distinguishing benign from malignant forms.

Defective apoptotic program due to the overexpression of the anti-apoptotic Bcl-2 protein of the outer mitochondrial membrane may be a cause of the poor response of malignant pheochromocytoma to 131I-MIBG therapy. We report a case of malignant pheochromocytoma which showed early intense uptake and immediate rapid washout of 99mTc-tetrofosmin characterizing the overexpression of anti-apoptotic Bcl-2 and which was refractory to 131I-MIBG therapy.

Familial amyloidotic polyneuropathy (FAP) is a hereditary disease characterized by the systemic accumulation of amyloid fibrils. A mutant transthyretin (TTR) gene is mainly responsible for the disease. However, the variable age of onset and low penetrance might be due to environmental factors, one of which is the intestinal flora. Three types of intestinal flora were introduced into a transgenic (Tg) mouse FAP model, 6.0-hMet30. The CV1 and CV2 group transgenic mice were transferred with the intestinal flora from two different mouse facilities housed under conventional conditions, and the SPF group transgenic mice were kept under specific pathogen free conditions in our facility. All the mice were maintained under controlled temperature, humidity and bacterial conditions. Over a period of 28 months, amyloid was not deposited in the SPF and CV1 groups. In contrast, amyloid was deposited in the esophagus and small intestine of two of the three CV2 mice at 18 months. Many neutrophils infiltrated the lesions. The numbers of tissue neutrophils were higher in the CV2 group than in the SPF and CV1 groups at 18 months. The CV2 flora included fewer gram-positive anaerobic cocci as well as higher proportions of yeasts, staphylococci and enterobacteriaceae compared with the SPF and CV1 flora. These findings suggest that the intestinal flora plays an important role in amyloid deposition.

The aim of the present study was to determine the extent to which respondents provided the same answers to a health-related lifestyle questionnaire in self- and interviewer-administered forms. A total of 234 subjects completed a 110-item questionnaire in both interviewer and self-administered forms. Modes of administration were separated by a 2-week interval. The order was determined by random allocation. The presence and the extent of the tendency to give socially acceptable responses were evaluated using percentage of bias calculated as the ratio of the difference in proportion of positive responses or the mean between interviews and questionnaires and those in questionnaires. All percentages of bias were in the positive direction, ranging from 1.4% (physical exercise) to 26.1% (general life stress). The average percentage of bias was higher in women than in men and were stronger for younger respondents. The age differences between interviewer and respondent were inversely and most strongly related to percentage of bias. Self- and interviewer-administered questionnaires yield very similar results in discriminating between subjects, but the interviewer-administered questionnaire showed systematically more desirable responses to questions related to lifestyle factors. The differences in characteristics between interviewer and respondent may be important determinants of the socially desirability bias in the interview.

Unlabelled: In this study, we evaluated the potential of (99m)Tc-hexakis-2-methoxyisobutylisonitrile (MIBI) for detecting bone metastases in comparison with a conventional bone tracer., Methods: (99m)Tc-MIBI and (99m)Tc-hydroxymethylene diphosphonate (HMDP) scans were obtained from 99 patients with proven malignant diseases and suspected bone metastases. We compared 373 lesions that showed abnormal uptake on (99m)Tc-MIBI scans or (99m)Tc-HMDP scans (or both)., Results: Bone metastases were confirmed in 334 of 373 lesions. Thirty-nine lesions on (99m)Tc-HMDP scans had false-positive findings, but only 2 of these lesions had false-positive findings on (99m)Tc-MIBI scans. (99m)Tc-MIBI and (99m)Tc-HMDP scans were equivalent in 168 of 334 lesions (50.3%). (99m)Tc-MIBI scans correctly detected more lesions than (99m)Tc-HMDP scans: 284 lesions (85.0%) versus 218 lesions (65.3%) (P < 0.005), respectively. (99m)Tc-MIBI scans showed a markedly higher sensitivity for detecting metastases in the femur and humerus compared with (99m)Tc-HMDP scans: 97 of 98 lesions (99.0%) versus 35 of 98 lesions (35.7%) (P < 0.005) and 21 of 22 lesions (95.5%) versus 11 of 22 lesions (50.0%) (P < 0.005), respectively. (99m)Tc-HMDP scans of 17 patients showed no abnormal images. However, (99m)Tc-MIBI scans correctly detected bone metastases, and subsequent development of multiple lesions was observed on follow-up (99m)Tc-HMDP scans of 15 patients. (99m)Tc-MIBI scans were superior to (99m)Tc-HMDP scans in the detection of metastases attributed to breast cancer, multiple myeloma, and hepatoma. On the contrary, (99m)Tc-MIBI scans were less sensitive than (99m)Tc-HMDP scans for detecting bone metastases attributed to prostate cancer in the other skeletal sites except for femur and humerus., Conclusion: (99m)Tc-MIBI scans have better sensitivity for detecting bone metastases and provide more specific complementary findings than conventional bone scans. (99m)Tc-MIBI accumulation attributed to bone marrow metastases may occur at an early stage, before the bone remodeling process in the surrounding bone can be detected on conventional bone scans.

IL-12 is considered to be one of the most important cytokines in anti-cancer therapy. We have demonstrated that substances derived from Basidiomycetes, such as active hexose-correlated compound (AHCC) and PSK induce the production of IL-12. In this study, the MHC dependency of IL-12 production induced by various mycelial extracts, PSK, AHCC and IL-X, was examined. During tumor-bearing, higher serum IL-12 levels were observed in H-2a and H-2b mice as compared to H-2d mice. Concerning the effect of genetic background of mice on response to mycelial extracts, AHCC administration enhanced the serum IL-12 level in H-2b mice but not in H-2d mice, while PSK administration increased the serum IL-12 level in H-2d mice but not in H-2b mice. IL-X, components derived from the same Basidiomycetes, also enhanced the serum IL-12 level in H-2b mice in the early stage of tumor like AHCC, and maintained serum IL-12 at a level higher than the normal value accompanying tumor growth, whereas AHCC did not restore the lowered serum IL-12 level accompanying tumor growth. These results showed that AHCC or IL-X is effective in a genetically Th1-dominant individual whereas PSK is effective in a genetically Th2-dominant individual or Th2-dominant status in advanced cancer patients. So we propose that the suitable combinations of various mycelial extracts may be effective methods of endogenous IL-12 induction for cancer patients of all stages, which is important as a cancer therapy that is relatively free from adverse reactions and which emphasizes the QOL in individual patients.

To determine the potential of Tc-99m MIBI femoral marrow imaging for detecting minimal residual disease in acute leukemia, MIBI images of 68 patients with acute leukemia and 110 control patients were examined. MIBI accumulation was classified into three patterns: not detectable, mild accumulation, and clearly visualized accumulation. Clearly visualized accumulation was interpreted as abnormal. The mean uptake ratio of the femoral marrow to muscle was calculated. Forty-five patients who were in complete remission (CR) at the time of MIBI imaging had a follow-up study (mean interval, 23 months). Clearly visualized accumulation was demonstrated in 35 patients with acute leukemia: in 7 patients before starting induction chemotherapy, in 12 patients after relapse, and in 16 of the 49 patients in the CR group. Mild accumulation was demonstrated in 14 patients in the CR group and in 13 control group patients. No detectable accumulation was observed in 19 patients in the CR group and in 97 control patients. The marrow and muscle uptake ratio of patients before starting chemotherapy (2.29 +/- 0.26) was greater compared with that in patients after relapse (1.78 +/- 0.44, P < 0.02) and in patients with abnormal accumulation despite complete remission (1.84 +/- 0.36, P < 0.01). The uptake ratio in patients with abnormal accumulation despite CR was higher compared with patients with mild accumulation in CR (1.26 +/- 0.13, P < 0.001) and controls (1.23 +/- 0.10, P < 0.001) who had mild accumulation. Fifteen patients with abnormal accumulation despite CR had a markedly greater relapse rate (66.7% > 10.0%, P < 0.005), a higher mortality rate (46.7% > 6.7%, P < 0.01), and shorter remission time (8.7 +/- 10.2 months < 35.9 +/- 20.1 months, P < 0.001) compared with 30 patients without abnormal accumulation in CR. MIBI femoral marrow imaging may be a useful and simple method for monitoring levels of residual leukemic cells. Clearly visualized MIBI accumulation may be a marker for relapse.

In a 40-year-old man, a mediastinal hemangioma was discovered intially as a compression of the esophagus by upper gastrointestinal endoscopy. Furthermore, perirenal hemangioma and inferior vena cava (IVC) malformation were stimultaneously found. Hemangiomas, which occur in the mediastinal and perirenal area, are extremely uncommon and congenital IVC malformation, like the present case, has not been reported. We review the literature of these vascular abnormalities.

To determine the potential of Tc-99m MIBI for detecting bone marrow malignancy, MIBI imaging of the femur was evaluated. There was no detectable MIBI activity in 125 of 141 (89%) control patients. Clearly demonstrated focal or tubular MIBI activity indicating intramedullary accumulation was demonstrated in 44 of 45 (98%) patients with proven marrow malignancy: 9 patients with multiple myeloma, 10 patients with malignant lymphoma, 11 patients with acute leukemia, 1 patient with chronic leukemia, and 14 patients with skeletal metastases. No abnormal MIBI activity was observed in the femur in 19 of 22 (86%) patients who had no evidence of malignant involvement in the femoral marrow, in 3 patients with solitary plasmacytomas of the spine, sternum or iliac bone, or in 16 patients with malignant lymphoma. In 12 of 24 patients with acute leukemia in complete remission, no abnormal MIBI accumulation was shown in the femur, but in 12 patients, abnormal accumulation indicating residual leukemic activity was demonstrated. MIBI imaging correlated extremely well with MRI studies; 26 of 28 patients with focal or tubular increased MIBI activity in the femur showed decreased signal on T1-weighted images and a high signal on short inversion recovery images, and 11 patients with no abnormal activity showed a high signal on T1 images. MIBI imaging of the femoral bone marrow may be a new modality for detecting marrow malignancy.

We report a case of leiomyosarcoma in a 55-year-old Japanese female. She developed an erythematous nodule, 1.5 cm in diameter, on her right thigh. The totally excised specimen contained tumor cells with variously sized, chromatin-rich nuclei. Gitter staining revealed the so-called encased picture, immunohistopathological staining was positive for smooth muscle actin, and electron microscopy revealed filaments with focal densities. A diagnosis of leiomyosarcoma was made based on these findings, which suggested a muscle cell origin. Normal arrector pili muscles were continuous from the tumor, further suggesting the tumor's origin. The presence of Epstein-Barr virus-encoded RNA (EBER) was examined by in situ hybridization with negative results.

Background: Bart's syndrome is one type of dominant dystrophic epidermolysis bullosa (EB). It is known that, in some familial cases of dominant dystrophic EB, the symptoms differ depending on the individual. We observed the way Bart's syndrome affected four generations in the same family. The proband was a newborn boy who showed congenital localized absence of skin (CLAS) and bullae on the anterior aspects of both legs. Histologically, the bullae were located subepidermally. The CLAS and bullae disappeared within 4 months after birth, leaving scars. His father retained scarring and scaling from the knees down along the anterior aspect of the legs, and the nails of the toes were either lacking or deformed. His paternal grandmother and great-grandmother also presented deformed nails of the toes, although they had not had CLAS or bullae on the legs at birth. The individuals in this family thus showed some heterogeneity depending on the sex: blistering and CLAS were seen on the legs soon after birth in the male family members, but the female members did not share this pattern of symptoms, suggesting that the expression of symptoms may differ depending on the sex of the affected individual.