Recent data have linked hypoxia, a classic feature of the tumor microenvironment, to the function of specific microRNAs (miRNAs); however, whether hypoxia affects other types of noncoding transcripts is currently unknown. Starting from a genome-wide expression profiling, we demonstrate for the first time a functional link between oxygen deprivation and the modulation of long noncoding transcripts from ultraconserved regions, termed transcribed-ultraconserved regions (T-UCRs). Interestingly, several hypoxia-upregulated T-UCRs, henceforth named ‘hypoxia-induced noncoding ultraconserved transcripts' (HINCUTs), are also overexpressed in clinical samples from colon cancer patients. We show that these T-UCRs are predominantly nuclear and that the hypoxia-inducible factor (HIF) is at least partly responsible for the induction of several members of this group. One specific HINCUT, uc.475 (or HINCUT-1) is part of a retained intron of the host protein-coding gene, O-linked N-acetylglucosamine transferase, which is overexpressed in epithelial cancer types. Consistent with the hypothesis that T-UCRs have important function in tumor formation, HINCUT-1 supports cell proliferation specifically under hypoxic conditions and may be critical for optimal O-GlcNAcylation of proteins when oxygen tension is limiting. Our data gives a first glimpse of a novel functional hypoxic network comprising protein-coding transcripts and noncoding RNAs (ncRNAs) from the T-UCRs category.
ultraconserved genes; colorectal cancer; glioblastoma; hypoxia; OGT
Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder caused by mutations in the WAS gene. Glomerulonephritis is a frequent complication, however, histopathological data from affected patients is scarce because the thrombocytopenia that affects most patients is a contraindication to renal biopsies. We found that WASp-deficient mice develop proliferative glomerulonephritis reminiscent of human IgA nephropathy (IgAN). We examined whether increased aberrant IgA production is associated with the development of glomerulonephritis in WASp-deficient mice. Serum IgA and IgA production by splenic B cells was increased in WASp-deficient mice compared to wild-type (WT) mice. A lectin-binding study revealed a reduced ratio of sialylated and galactosylated IgA in the sera from old WASp-deficient mice. Circulating IgA-containing immune complexes showed significantly higher titers in WASp-deficient mice compared to WT mice. These results indicate that the increased IgA production and aberrant glycosylation of IgA may be critically involved in the pathogenesis of glomerulonephritis in WAS.
Previous studies have reported prefrontal cortex (PFC) pathophysiology in bipolar disorder.
We examined the hemodynamics of the PFC during resting and cognitive tasks in 29 patients with bipolar disorder and 27 healthy controls, matched for age, verbal abilities and education. The cognitive test battery consisted of letter and category fluency (LF and CF), Sets A and B of the Raven’s Colored Progressive Matrices (RCPM-A and RCPM-B) and the letter cancellation test (LCT). The tissue oxygenation index (TOI), the ratio of oxygenated hemoglobin (HbO2) concentration to total hemoglobin concentration, was measured in the bilateral PFC by spatially resolved near-infrared spectroscopy. Changes in HbO2 concentration were also measured.
The bipolar group showed slight but significant impairment in performance for the non-verbal tasks (RCPM-A, RCPM-B and LCT), with no significant between-group differences for the two verbal tasks (LF and CF). A group × task × hemisphere analysis of variance (ANOVA) on the TOI revealed an abnormal pattern of prefrontal oxygenation across different types of cognitive processing in the bipolar group. Post hoc analyses following a group × task × hemisphere ANOVA on HbO2 concentration revealed that the bipolar group showed a greater increase in HbO2 concentration in the LCT and in RCPM-B, relative to controls.
Both indices of cortical activation (TOI and HbO2 concentration) indicated a discrepancy in the PFC function between verbal versus non-verbal processing, indicating task-specific abnormalities in the hemodynamic control of the PFC in bipolar disorder.
Bipolar disorder; near-infrared spectroscopy; prefrontal cortex; tissue hemoglobin saturation
Objective: To evaluate the relation between QT variables and disproportion of left ventricular wall hypertrophy in patients with hypertrophic cardiomyopathy.
Design: Retrospective analysis of the results of echocardiography and electrocardiography.
Setting: University hospital (tertiary referral centre).
Patients: 70 patients with hypertrophic cardiomyopathy were divided into four groups according to the distribution of left ventricular wall hypertrophy on cross sectional echocardiography: group A—hypertrophy confined to the interventricular septum; group B—hypertrophy confined to the interventricular septum and left ventricular anterior wall; group C—hypertrophy confined to the interventricular septum, left ventricular anterior wall, and lateral free wall; group D—hypertrophy involving all portions of the left ventricle.
Main outcome measures: QT intervals and QT dispersion in precordial six lead ECGs.
Results: There were no significant differences in the maximum left ventricular wall thickness among the four groups, and maximum and minimum QTc intervals also did not differ. QTc dispersion was increased significantly in groups A and B compared with groups C and D. Dispersions of the interval from the J point to the end of the T wave (JTc dispersions) in groups A and B were also increased significantly compared with groups C and D. By linear regression analysis, QTc and JTc dispersions correlated with the ratio of the interventricular septal thickness to left ventricular posterior wall thickness (p = 0.0152 and p = 0.0075, respectively).
Conclusions: QT dispersion may be affected by not only electrical inhomogeneity but also by morphological inhomogeneity of the left ventricle in patients with hypertrophic cardiomyopathy.
hypertrophic cardiomyopathy; left ventricular morphology; QT dispersion
endometriosis; CD10; ovarian endometrial cyst; endometrial polyp
thymidylate synthase; dihydropyrimidine dehydrogenase; S-1; irinotecan; gastric cancer
Images in cardiology
BACKGROUND—Use of the conventional Western and Japanese classification systems of gastrointestinal epithelial neoplasia results in large differences among pathologists in the diagnosis of oesophageal, gastric, and colorectal neoplastic lesions.
AIM—To develop common worldwide terminology for gastrointestinal epithelial neoplasia.
METHODS—Thirty one pathologists from 12 countries reviewed 35 gastric, 20 colorectal, and 21 oesophageal biopsy and resection specimens. The extent of diagnostic agreement between those with Western and Japanese viewpoints was assessed by kappa statistics. The pathologists met in Vienna to discuss the results and to develop a new consensus terminology.
RESULTS—The large differences between the conventional Western and Japanese diagnoses were confirmed (percentage of specimens for which there was agreement and kappa values: 37% and 0.16 for gastric; 45% and 0.27 for colorectal; and 14% and 0.01 for oesophageal lesions). There was much better agreement among pathologists (71% and 0.55 for gastric; 65% and 0.47 for colorectal; and 62% and 0.31 for oesophageal lesions) when the original assessments of the specimens were regrouped into the categories of the proposed Vienna classification of gastrointestinal epithelial neoplasia: (1) negative for neoplasia/dysplasia, (2) indefinite for neoplasia/dysplasia, (3) non-invasive low grade neoplasia (low grade adenoma/dysplasia), (4) non-invasive high grade neoplasia (high grade adenoma/dysplasia, non-invasive carcinoma and suspicion of invasive carcinoma), and (5) invasive neoplasia (intramucosal carcinoma, submucosal carcinoma or beyond).
CONCLUSION—The differences between Western and Japanese pathologists in the diagnostic classification of gastrointestinal epithelial neoplastic lesions can be resolved largely by adopting the proposed terminology, which is based on cytological and architectural severity and invasion status.
Keywords: early carcinoma; adenoma; dysplasia; oesophagus; stomach; colon
AIM: Serrated adenoma is a recently described category of colorectal adenoma. The aim of this study was to determine whether serrated adenomas have clinicopathological findings distinct from "traditional" adenoma. METHODS: Colonoscopy records for 1995-1998 were reviewed, and all traditional adenomas and serrated adenomas identified. Tumour site and endoscopic configuration were compared between the two types of adenoma. In polypectomised lesions, size and grade of dysplasia were compared between the two groups. RESULTS: There were 3305 traditional adenomas and 43 serrated adenomas. Serrated adenomas were more often found in the rectosigmoid colon than the traditional adenomas (67.5% v 41.2%, p = 0.0008). Polypectomy was more often done for serrated adenomas (27 of 43 lesions, 62.8%) than for traditional adenomas (626 of 3305 lesions, 18.9%, p < 0.0001). Size (mean (SD) maximum dimension, 12 (6) mm v 13 (3) mm) and incidence of high grade dysplasia (14.8% v 13.6%) in endoscopically removed specimens were not different between the two types. CONCLUSIONS: The therapeutic judgement applied to the management of traditional adenoma seems to be appropriate for serrated adenoma.
AIMS: To investigate the clinicopathological findings in cases with intraepithelial haemorrhage of the oesophagus (IHO). METHODS: Necropsy records and the histopathology findings in the oesophagus were reviewed for the period 1990 to 1995. Six cases (0.7%) of IHO were found among 919 necropsy cases. Clinical records of these patients and gross and microscopic slides were reviewed in detail. RESULTS: The ages of the IHO cases ranged from 42 to 82 years (average 68 years), with a male to female ratio of 1:2. All cases had underlying haematological disorders with thrombocytopenia, but disseminated intravascular coagulation was not evident in any case. Macroscopically, solitary (two cases) or multiple (four cases) haemorrhagic lesions ranging from 6 to 79 mm in size were identified within the distal oesophagus. Microscopically, there was no inflammatory infiltration, destruction of red blood cells, or submucosal scar formation. CONCLUSIONS: IHO seems to occur shortly before death as a terminal event in haematological disorders. Based on these observations, the term "terminal IHO" can be suggested for this type of oesophageal lesion.
A 58 year old man with a history of cerebral infarction was admitted to hospital with chest discomfort and dyspnoea. He had no history of precordial chest discomfort. Angiography and left ventriculography showed that coronary fistulas connected the coronary sinus with the left circumflex and right coronary arteries. His coronary sinus did not communicate with the right atrium, draining instead into a persistent left superior vena cava. Angiography showed a mass, suspected to be a thrombus, in the coronary sinus. Transoesophageal echocardiography confirmed the presence of a mass in the atrioventricular groove. The mass was removed at surgery and proved to be a cavernous haemangioma.
Keywords: coronary fistulas; persistent left superior vena cava; cavernous haemangioma; coronary sinus
Two cases of beta 2 microglobulin amyloidosis following long term haemodialysis found during necropsy are reported. The patients were 59 and 65 year old Japanese men, respectively. In both cases, systemic distribution of beta 2 microglobulin amyloid deposits was observed. The gastrointestinal tract including the stomach, small intestine, and colon showed the distinctive gross feature of rippled appearance, which was characterised by serosal wrinkles along the muscle layer arrangement. These areas were confirmed to contain deposits of beta 2 microglobulin in the muscularis propria. Although the outline of the muscle layers was preserved, most muscle fibres, encircled by the amyloid deposits, were atrophic or had disappeared microscopically. In neither case could a definite diagnosis of amyloidosis be made while the patient was alive. Interestingly, the oesophagus presented less involvement compared to the remainder of the gastrointestinal tract. In comparison with the AA or AL type of amyloidosis, beta 2 microglobulin haemodialysis related amyloidosis showed a rippled appearance of the serosal rather than mucosal changes, which may explain the difficulty in diagnosing amyloid deposits using biopsies of the gastrointestinal tract.
The microwave tissue coagulator (MTC) is used in hepatectomy because it provides excellent haemostasis during the procedure. A 59 year old man underwent partial hepatic lobectomy with MTC, for metastasis from colon cancer. A tumorous necrotic nodule was discovered in the liver. The nodule measured 2.5 cm at its largest diameter. Microscopically, it showed extensive coagulation necrosis and massive sinusoidal dilatation. To date, such a necrotic mass clinically mimicking neoplasm has not been reported as a complication of hepatectomy using MTC. Although it is unknown how the rounded necrotic nodule was formed in this case, clinicians should be aware of this phenomenon to avoid unnecessary operations. Likewise, pathologists should recognise such histological changes and review the clinical history of the patient when coagulation necrosis with massive sinusoidal dilatation is observed in a biopsy or hepatectomy specimen.
A case of mucinous cystadenoma mimicking ovarian cancer is reported. Serum carcinoembryonic antigen (CEA) concentration was raised, and computed tomography of the abdomen and pelvis demonstrated a long oval shaped cystic mass measuring 9 cm in length on the right anterior side of the uterus. Because of possible right ovarian cancer, laparotomy was performed and the mass was found to be a mucinous cystadenoma of the appendix. This case indicates that mucinous cystadenoma of the appendix may show an unusual presentation including its location as well as the high serum CEA, mimicking ovarian cancer. Therefore, gynaecologists as well as gastroenterologists should consider its possibility as a differential diagnosis of the right adnexal mass in a patient without previous appendectomy.
A 31 year old man was hospitalised with general fatigue and epigastric pain. Abdominal ultrasonography, computed tomography, and magnetic resonance imaging showed a cystic lesion in the left lobe of the liver. Endoscopic retrograde cholangio-pancreatography and percutaneous trans-hepatic cholangiography revealed a localised dilatation of the intrahepatic bile duct without any obstruction. However, a large mass of mucinous material was noted in the saccular intrahepatic duct and the common bile duct. There was no evidence of a choledochal cyst, anomalous pancreaticobiliary ductal union, or congenital cystic change of the kidneys. A possible diagnosis of mucinous cystic neoplasm of the intrahepatic bile duct was made and a left hepatectomy performed. Cholangiography of the resected specimen showed a non-obstructive solitary cystic dilatation of the left hepatic duct. Histologically, the dilated duct was lined with columnar biliary epithelium without any papillary proliferation and/or atypia. Neither malignancy nor hepatic fibrosis was observed; the term "solitary cystic dilatation of the intrahepatic bile duct" perhaps is more descriptive and the concept easier to understand.
AIMS—To identify the patent ductus arteriosus (PDA) shunt flow pattern using Doppler echocardiography; and to assess whether it could be used to predict the development of clinically significant PDA.
METHODS—Premature infants weighing under 1500 g, who required mechanical ventilation, and in whom daily echocardiography could be performed from day 1 until the ductus closed, and on day 7 to confirm closure, were studied. The PDA shunt flow was identified from four Doppler patterns, and the closed pattern of a closed duct was also presented. Clinically significant PDA was diagnosed when there was colour Doppler echocardiographic evidence of left to right ductal shunt associated with at least two of the following clinical signs: heart murmur (systolic or continuous); persistent tachycardia (heart rate>160/min); hyperactive precordial pulsation; bounding pulses; and radiographic evidence of cardiomegaly or pulmonary congestion.
RESULTS—Of 68 infants enrolled into this study, clincally significant PDA developed in 31. The most recordable sequence of transition change of shunt flow pattern for clinically significant PDA was: pulmonary hypertension pattern, to growing pattern, to pulsatile pattern, to closing pattern, to closed pattern. And that for non-clinically significant PDA was: pulmonary hypertension pattern, to closing pattern, to closed pattern. The growing and the pulsatile patterns were mostly documented in infants with clinically significant PDA. The first documented growing pattern to predict clinically significant PDA gave a sensitivity of 64.5% and a specificity of 81.1%; the first documented pulsatile pattern gave a sensitivity of 93.5% and a specificity of 100%.
CONCLUSION—Doppler echocardiographic assessment of PDA shunt flow pattern during the first 4 days of life is useful for predicting the development of clinically significant PDA in premature infants. At that stage, the closing or closed Doppler pattern indicates that infants are not at risk of developing clinically significant PDA; the growing or pulsatile Doppler pattern indicates a continuing risk of developing clinically significant PDA.
Keywords: Echocardiography; patent ductus arteriosus; Doppler flow pattern
AIM—To evaluate the pulmonary artery pressure (PAP) change in very low birthweight (VLBW) infants at risk of chronic lung disease (CLD).
METHODS—The time to peak velocity:right ventricular ejection time (TPV:RVET) ratio calculated from the pulmonary artery Doppler waveform, which is inversely related to PAP, was used. The TPV:RVET ratio was corrected for different heart rate (TPV:RVET(c)). Seventy three VLBW infants studied on days 1, 2, 3, 7, 14, 21 and 28 were enrolled for the analysis.
RESULTS—Twenty two infants developed CLD with a characteristic chest radiograph at day 28. Fifty one did not, of whom 17 were oxygen dependent on account of apnoea rather than respiratory disease, and 34 were non-oxygen dependent. The TPV:RVET(c) ratio rose progressively in all three groups over the first three days of life, suggesting a fall in PAP. In the oxygen and non-oxygen dependent groups, the mean (SD) ratio rose to 0.53 (0.09) and 0.57 (0.09), respectively, on day 7, then remained relatively constant thereafter. The CLD group rose more slowly after day 3 and had a significantly lower mean ratio from day 7 onwards compared with the other two groups (day 7: P<0.001, days 14-28: P<0.0001), and fell significantly from 0.47 (0.11) on day 7 to 0.41 (0.07) on day 28 (P=0.01), suggesting a progressive rise in PAP. The mean (SD) ratios at day 28 of all infants were: CLD group 0.41 (0.07); oxygen dependent group 0.66 (0.15); and the non-oxygen group 0.67 (0.11). The CLD group had a significantly lower ratio than the oxygen dependent group and the non-oxygen group (P<0.0001). Using the TPV:RVET(c) ratio of <0.46, infants at risk of developing CLD could be predicted on day 7 (predictive value 82.8%, sensitivity 54.5%, specificity 94.1%).
CONCLUSION—The non-invasive assessment of PAP using the TPV:RVET(c) ratio may be useful in the longitudinal monitoring of PAP change in VLBW infants, and for prediction of chronic lung disease.
Keywords: Doppler echocardiography; pulmonary artery pressure; chronic lung disease
There is no detailed and practical description of how to identify the adrenal glands at necropsy. A simple technique is described, based on anatomical location. After removing the aorta by the Rokitansky method, the inferior vena cava is opened. The orifice of the right adrenal vein is identified just above the right renal vein, and a probe is inserted into it as a marker. The right adrenal gland is identified at the centre above the line of the probe after separation of the diaphragm, which is attached to the liver. The left adrenal vein arises as the first bifurcation of the left renal vein after its origin from the inferior vena cava. A probe is inserted into it and the vein is opened along the probe. The left adrenal gland is identified at the left side of the left adrenal vein, embedded in fat. This method is also useful in cases with severe adhesion, fibrosis, or metastases.
A case of autoimmune thyroiditis after long term treatment with lithium is described in a 29 year old Japanese woman with manic depression. Positive serum antithyroglobulin and antimicrosomal antibodies, diffuse goitre, and microscopic chronic thyroiditis, as well as the clinical history of long term lithium treatment were suggestive of lithium associated autoimmune thyroiditis. Microscopically, there was a mild degree of interstitial fibrosis and a moderate degree of lymphocytic infiltration. Some areas showed a moderate degree of stromal fibrosis and atrophic thyroid follicles. Lymphoid follicles with germinal centres, disrupted thyroid follicles with lymphocytic infiltration, and Hürthle cells were also observed. The differential diagnosis in patients presenting with these histological features includes painless (silent) thyroiditis, autoimmune thyroiditis and lithium associated autoimmune thyroiditis. A detailed clinical history is essential if the correct diagnosis is to be reached.
A case of endometrial ossification in a 62 year old woman is reported. The patient presented with increased vaginal discharge. On transvaginal ultrasonography, a hyperechoic area within the uterine cavity, suggestive of an intrauterine foreign body, was noted. Histological examination of the endometrial curettage showed mature bone with neutrophilic infiltration. There was no evidence of malignancy. Endometrial ossification in postmenopausal women is very rare; most women presenting with this condition are between 20 and 40 years of age. Therefore, clinicians should consider the possibility of endometrial ossification as a differential diagnosis of intrauterine foreign body on ultrasound, even in older patients. In addition, pathologists should be aware of this rare entity to avoid a misdiagnosis of malignant mixed müllerian tumor in the endometrial curettage specimen, which may result in unnecessary hysterectomy.
AIMS: To evaluate the histological criteria used to diagnose chronic pancreatitis; and to assess interobserver variation among general pathologists. METHODS: Forty five cases of chronic pancreatitis diagnosed in necropsy were reviewed to determine whether the diagnosis was acceptable retrospectively. These cases were diagnosed initially as chronic pancreatitis in the final necropsy report complied by general pathologists. In reviewing these cases, special attention was paid to irregular fibrosis and destruction of the lobular architecture. RESULTS: The 45 cases were re-assigned to seven different diagnostic categories: chronic pancreatitis, 21 (47%) cases; interstitial fibrosis with or without chronic inflammation, 11 (24%) cases; repair stage of acute pancreatitis, four (9%) cases; severe fatty infiltration, three (7%) cases; chronic inflammation without interstitial fibrosis, two (4%) cases; haemochromatosis, one (2%) case; and undetermined, three (7%) cases. CONCLUSIONS: The histological spectrum of chronic pancreatitis was very wide and it was often misdiagnosed. Acinar atrophy, acinar dilation and intralobular fibrosis were diagnostic of chronic pancreatitis. Differential diagnoses include the repair stage of acute pancreatitis, severe fatty infiltration and haemochromatosis. Recognition of these findings may help to reduce overdiagnosis of chronic pancreatitis.
Navelbine (NVB, vinorelbine ditartrate, KW-2307), a new vinca alkaloid analogue, has been shown to be clinically effective against advanced breast cancer. In this report, the combined effect of NVB with medroxyprogesterone acetate (MPA), a synthetic progesterone derivative, was examined in vitro against human breast carcinoma MCF-7 cells. The combined effect was demonstrated to be synergistic using the isobologram and median-effect plot analyses. To elucidate the mechanism of action, we further examined effects of both drugs on cell cycle distribution of the cells in combination and/or alone. NVB at 2 nM induced apparent G1-phase accumulation as well as the induction of cyclin-dependent kinase (CDK) inhibitor p21(WAF1/CIP1) protein and the dephosphorylated form of retinoblastoma protein (pRb). In contrast, MPA at 0.1 microM also induced G1-phase accumulation as well as the reduced expression of cyclin D1 protein. In addition, the combination of both drugs induced augmented G1-phase accumulation, which occurred along with p21(WAF1/CIP1) protein induction, cyclin D1 protein reduction and pRb dephosphorylation. These results demonstrate that the synergistic combined effect of NVB with MPA was mediated through enhancement of G1-phase accumulation that resulted from the different action point(s) of each drug. Furthermore, the synergistic combined effect of NVB with MPA was also observed in other human breast carcinoma cell lines, such as T-47D and ZR-75-1. These results suggest that combination therapy of NVB with MPA in breast cancer might be effective in clinical studies.