Twenty years with diabetes and amputations: a retrospective population-based cohort study.

AIM: To investigate the trends in non-traumatic lower limb amputation in people with and without diabetes. METHODS: From the Danish National Patient Register, all people with either type 1 or type 2 diabetes (n = 462 743) as well as a group of people without diabetes from the general population (n = 1 388 886) were identified and separated into three groups based on diabetes type. Among these, 17 265 amputations were identified between 1997 and 2017 and stratified into trans-femoral amputations, trans-tibial amputations and amputations below the ankle using surgical codes. Annual changes were described using least-squares linear regression. RESULTS: The yearly mean decrease in incidence rate of amputation per 1000 person-years was -0.032 [95% CI: -0.062, -0.001], -0.022 [-0.032, -0.012] and -0.006 [-0.009, -0.003] for trans-femoral amputation, -0.072 [-0.093, -0.052], -0.090 [-0.102, -0.078] and -0.015 [-0.016, -0.013] for trans-tibial amputation, and -0.055 [-0.080, -0.020], -0.075 [-0.090, -0.060] and -0.011 [-0.014, -0.007] for amputation below the ankle in people with type 1 diabetes, people with type 2 diabetes and people without diabetes, respectively. CONCLUSIONS: Over recent decades, the incidence of amputation has decreased significantly in people with diabetes and in the general population without diabetes.

Pathophysiology of shunt dysfunction in shunt treated hydrocephalus.

BACKGROUND: We hypothesized that shunt dysfunction in the ventricular catheter and the shunt valve is caused by different cellular responses. We also hypothesized that the cellular responses depend on different pathophysiological mechanisms. METHODS: Removed shunt material was collected. Macroscopic tissue in the catheters was paraffin-embedded and HE-stained. Valves were incubated with trypsin-EDTA in order to detach macroscopically invisible biomaterial, which was then cytospinned and HE-stained. Associated aetiological and surgical data were collected by reviewing patient files, and ventricular catheter position was examined using preoperative radiology (CT scans). RESULTS: We examined eleven ventricular catheters and ten shunt valves. Catheters: 6/11 catheters contained intraluminal tissue consisting of vascularised glial tissue and inflammatory cells (macrophages/giant cells and a few eosinophils). Catheter adherence correlated with the presence of intraluminal tissue, and all tissue containing catheters had some degree of ventricle wall contact. All obstructed catheters contained intraluminal tissue, except one catheter that was dysfunctional because of lost ventricular contact. Valves: Regardless of intraoperative confirmation of valve obstruction, all ten valves contained an almost uniform cellular response of glial cells (most likely ependymal cells), macrophages/giant cells, and lymphomonocytic cells. Some degree of ventricle wall catheter contact was present in all examined valves with available radiology (9/10). CONCLUSIONS: The same cellular responses (i.e., glial cells and inflammatory cells) cause both catheter obstruction and valve obstruction. We propose two synergistic pathophysiological mechanisms. (1) Ventricle wall/parenchymal contact by the catheter causes mechanical irritation of the parenchyma including ependymal exfoliation. (2) The shunt material provokes an inflammatory reaction, either nonspecific or specific. In combination, these mechanisms cause obstructive tissue ingrowth (glial and inflammatory) in the catheter and clogging of the valve by exfoliated glial cells and reactive inflammatory cells.

Differences in distribution and regulation of astrocytic aquaporin-4 in human and rat hydrocephalic brain.

AIMS: Aquaporin-4 (AQP4) is the most abundant cellular water channel in brain and could be a molecular basis for a cerebrospinal fluid absorption route additional to the arachnoid villi. In the search for 'alternative' cerebrospinal fluid absorption pathways it is important to compare experimental findings with human pathophysiology. This study compares expression of AQP4 in hydrocephalic human brain with human controls and hydrocephalic rat brain. METHODS: Cortical biopsies from patients with chronic hydrocephalus (n = 29) were sampled secondary to planned surgical intervention. AQP4 in human hydrocephalic cortex relative to controls was quantified by Western blotting (n = 28). A second biopsy (n = 13) was processed for immunohistochemistry [glial fibrillary acidic protein (GFAP), CD68, CD34 and AQP4] and double immunofluorescence (AQP4 + GFAP and AQP4 + CD34). Brain tissue from human controls and kaolin-induced hydrocephalic rats was processed in parallel. Immunohistochemistry and immunofluorescence were assessed qualitatively. RESULTS: Western blotting showed that AQP4 abundance was significantly increased (P < 0.05) in hydrocephalic human brain compared with controls. AQP4 immunoreactivity was present in both white and grey matter. In human brain (hydrocephalic and controls) AQP4 immunoreactivity was found on the entire astrocyte membrane, unlike hydrocephalic rat brain where pronounced endfeet polarization was present. Endothelial AQP4 immunoreactivity was not observed. CONCLUSIONS: This study shows a significant increase in astrocytic AQP4 in human hydrocephalic cortex compared with control. Cell type specific expression in astrocytes is conserved between rat and human, although differences of expression in specific membrane domains are seen. This study addresses direct translational aspects from rat to human, hereby emphasizing the relevance and use of models in hydrocephalus research.

Description and analysis of 12 years of surveillance for Creutzfeldt-Jakob disease in Denmark, 1997 to 2008.

Prospective surveillance of Creutzfeldt­Jakob disease (CJD) was initiated in Denmark in 1997, following the observation of variant CJD in the United Kingdom. Demographic, clinical and diagnostic information was collected for each patient with clinical suspicion of CJD. Here we describe the methods for surveillance and the observed outcomes between 1 January 1997 and 31 December 2008. A total of 83 patients were classified as sporadic CJD, 47 were definite diagnoses, 34 probable and two possible. This resulted in a mean incidence of 1.26 patients with probable and definite sporadic CJD per million inhabitants. Two sporadic CJD patients were found to have a genetic variant of unknown significance: Thr201Ser and Glu200Asp. One patient was diagnosed with Gerstmann-Sträussler-Scheinker syndrome. No patients were classified as having variant, iatrogenic or familial CJD. The Danish surveillance system, like those in other countries, has a multidisciplinary approach, which is labour-intensive and time-consuming but ensures the most complete set of information possible. With this approach we think that patients with variant CJD would have been detected had they occurred in Denmark. Certain aspects of CJD surveillance need further discussion at European level and beyond, in order to find a balance between efficiency of the systems and accuracy of surveillance data.

The cocaine- and amphetamine-regulated transcript mediates ligand-independent activation of ERα, and is an independent prognostic factor in node-negative breast cancer.

Personalized medicine requires the identification of unambiguous prognostic and predictive biomarkers to inform therapeutic decisions. Within this context, the management of lymph node-negative breast cancer is the subject of much debate with particular emphasis on the requirement for adjuvant chemotherapy. The identification of prognostic and predictive biomarkers in this group of patients is crucial. Here, we demonstrate by tissue microarray and automated image analysis that the cocaine- and amphetamine-regulated transcript (CART) is expressed in primary and metastatic breast cancer and is an independent poor prognostic factor in estrogen receptor (ER)-positive, lymph node-negative tumors in two separate breast cancer cohorts (n=690; P=0.002, 0.013). We also show that CART increases the transcriptional activity of ERα in a ligand-independent manner via the mitogen-activated protein kinase pathway and that CART stimulates an autocrine/paracrine loop within tumor cells to amplify the CART signal. Additionally, we demonstrate that CART expression in ER-positive breast cancer cell lines protects against tamoxifen-mediated cell death and that high CART expression predicts disease outcome in tamoxifen-treated patients in vivo in three independent breast cancer cohorts. We believe that CART profiling will help facilitate stratification of lymph node-negative breast cancer patients into high- and low-risk categories and allow for the personalization of therapy.

Replication stress and oxidative damage contribute to aberrant constitutive activation of DNA damage signalling in human gliomas.

Malignant gliomas, the deadliest of brain neoplasms, show rampant genetic instability and resistance to genotoxic therapies, implicating potentially aberrant DNA damage response (DDR) in glioma pathogenesis and treatment failure. Here, we report on gross, aberrant constitutive activation of DNA damage signalling in low- and high-grade human gliomas, and analyze the sources of such endogenous genotoxic stress. Based on analyses of human glioblastoma multiforme (GBM) cell lines, normal astrocytes and clinical specimens from grade II astrocytomas (n=41) and grade IV GBM (n=60), we conclude that the DDR machinery is constitutively activated in gliomas, as documented by phosphorylated histone H2AX (gammaH2AX), activation of the ATM-Chk2-p53 pathway, 53BP1 foci and other markers. Oxidative DNA damage (8-oxoguanine) was high in some GBM cell lines and many GBM tumors, while it was low in normal brain and grade II astrocytomas, despite the degree of DDR activation was higher in grade II tumors. Markers indicative of ongoing DNA replication stress (Chk1 activation, Rad17 phosphorylation, replication protein A foci and single-stranded DNA) were present in GBM cells under high- or low-oxygen culture conditions and in clinical specimens of both low- and high-grade tumors. The observed global checkpoint signaling, in contrast to only focal areas of overabundant p53 (indicative of p53 mutation) in grade II astrocytomas, are consistent with DDR activation being an early event in gliomagenesis, initially limiting cell proliferation (low Ki-67 index) and selecting for mutations of p53 and likely other genes that allow escape (higher Ki-67 index) from the checkpoint and facilitate tumor progression. Overall, these results support the potential role of the DDR machinery as a barrier to gliomagenesis and indicate that replication stress, rather than oxidative stress, fuels the DNA damage signalling in early stages of astrocytoma development.

Localization of disease-related PrP in Danish patients with different subtypes of prion disease.

OBJECTIVE: The transmissible spongiform encephalopathies are characterized by vacuolization, neuronal loss, gliosis and deposition of a misfolded and Proteinase K resistant isoform of the prion protein (PrP(Sc)) in the central nervous system. METHODS MATERIALS AND PATIENTS: Paraffin-embedded tissue blot (PET-blot), immunohistochemistry (IHC) and Western blotting (WB) were combined to study the morphology and localization of disease related PrP in Danish patients with different subtypes of sporadic Creutzfeldt-Jakob disease, familiar Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker disease. RESULTS AND CONCLUSION: There was a good morphological and anatomical concordance between what was found with PET-blot and IHC in all patients. In some specific cases, the PET-blot was superior to IHC in sensitivity. To our knowledge, this is the first report where PET-blot analysis is applied to hereditary forms of human transmissible spongiform encephalopathies and compared with sporadic cases of Creutzfeldt-Jakob disease.

A novel presenilin 2 mutation (V393M) in early-onset dementia with profound language impairment.

BACKGROUND: Mutations in the Presenilin 2 gene (PSEN2) are rare causes of Alzheimer's disease (AD). Pathogenic mutations in the genes associated with autosomal dominant inherited AD have been shown to alter processing of the amyloid precursor protein (APP) resulting in a relative increase of the amount of Abeta42 peptide. METHODS AND RESULTS: We present a patient with neuropathologically confirmed early-onset AD characterized by profound language impairment. The patient was heterozygous for a novel missense mutation in exon 11 of the PSEN2 gene leading to a predicted amino acid substitution from valine to methionine in position 393, a conserved residue. However, in vitro expression of PSEN2 V393M cDNA did not result in detectable increase of the secreted Abeta42/40 peptide ratio. The mutation was not found in 384 control individuals tested. CONCLUSIONS: The possible pathogenic nature of the mutation is not clarified. We discuss the limitations of functional PSEN2 studies and the challenges associated with genetic counselling of family members at risk.

Fatal neurogenic pulmonary edema in a patient with progressive multiple sclerosis.

We report a case of fatal neurogenic pulmonary edema in progressive multiple sclerosis (MS). The patient had one isolated relapse-like episode. Six years later progressive disease began, lasting 5 years until unexpected death during sleep. Medico-legal autopsy revealed pulmonary edema and neuropathological examination showed infiltrations with lymphocytes and microglia in the respiratory centers of the medulla. More classical demyelinated lesions were found in the white matter of spinal cord and in the gray matter of the brain along with disseminated perivascular lymphocytic infiltrates. Medullary inflammation in progressive MS may result in sudden fatal respiratory failure.

Detecting chromosomal alterations at 1p and 19q by FISH and DNA fragment analysis--a comparative study in human gliomas.

Histological classification of gliomas is important for treatment and as a prognostic predictor, but classification by histology alone can be a challenge. Molecular genetic investigations, in particular the combined loss of the short arm of chromosome 1 and the long arm of chromosome 19 (LOH1p/19q), has become a significant predictor of outcome in oligodendrogliomas. 1p/19q alterations can be investigated by fluorescence in situ hybridization (FISH), but controversies persist in the interpretation ofresults. Another technique is polymerase chain reaction (PCR) analysis using microsatellites as primers and capillary electrophoresis or southern blot as detection method. The objective of the present study was to compare the accuracy, reliability and feasibility of detecting chromosomal changes at 1p/19q with PCR microsatellite analysis and FISH in glial tumors in the clinical laboratory, where often only small formalin-fixed paraffin-embedded samples are available. Commercial DNA and normal cortex were used for comparison. The material comprised 41 glial tumors including 10 oligodendrogliomas (WHO Grades II and III, 5 each), 10 mixed oligoastrocytomas (WHO Grades II and III, 5 each), 10 astrocytomas (WHO Grades II and III, 5 each), and 11 glioblastomas (WHO Grade IV). Our data confirmed a correlation between FISH and LOH fragment analysis in classical oligodendrogliomas and in mixed oligoastrocytomas. Disparity was found among the glioblastomas, where fragment analysis showed 1p/19q loss in three cases, with no changes detected by FISH. The fragment analysis seems reliable and implementable for LOH 1p/19q investigation without patient-related control material.

Classification of surgical procedures for epidemiologic assessment of sporadic Creutzfeldt-Jakob disease transmission by surgery.

BACKGROUND: In this preparatory phase of a case-control study, we propose and evaluate a new tool for classifying surgical procedures (SPs) in categories useful for epidemiologic research on surgical transmission of sporadic Creutzfeldt-Jakob disease (sCJD). METHODS: All SPs reported to the Swedish National Hospital Discharge Registry in the period 1974-2002, and undergone by 212 Swedish patients with registered diagnosis of CJD at death, hospital discharge or notification, in the period 1987-2002, 1060 age-, sex- and residence-matched controls and 1340 randomly chosen population controls, were reclassified into one of six categories of hypothetical transmission risk level. For that purpose the following two attributes were used: non-disposable instruments involved; and highest assigned ad-hoc risk level for four tissues or anatomical structures contacting such instruments. RESULTS: A total of 1170 different SP codes were reclassified as follows: 3.1% in the high-risk, 59.1% in the lower-risk, 24.4% in the lowest-risk, and 2.1% in the no-risk groups, with 11.3% procedures negatively defined by rubric as "other than..." being assigned to two spurious diluted-high and diluted-lower risk categories. The high-risk group mainly comprised neurosurgical (53%) and ophthalmic (39%) procedures. Sensitivity of neurosurgery and of ophthalmic surgery excluding neurosurgery, for the high- and diluted-high risk vs. other categories was 46% and 84%, while specificity was 98% and 95%, respectively. Sensitivity analysis based on these indices revealed that non-significant odds ratio effects of 1.4 and 1.3 for neurosurgery and ophthalmic surgery corresponded to statistically significant values of 5.1 after reclassification. CONCLUSIONS: This classification might contribute to quantify effects masked by use of body-system SP-categories in case-control studies on sCJD transmission by surgery.

Cavernous hemangioma of the spinal cord - conservative or operative management?

Once believed to be extremely uncommon, due to magnetic resonance imaging cavernous hemangiomas of the spinal cord are detected with increasing frequency. Management of both symptomatic and asymptomatic intramedullary cavernous hamangiomas is therefore of growing importance. However, experience with treatment and follow-up is very limited. In particular, patients with multiple central nervous system cavernous hemangiomas represent a therapeutical dilemma. We present a patient with a ruptured intramedullary and multiple cerebral cavernous hemangiomas and a survey of current knowledge of epidemiology, pathophysiology and treatment options. We conclude that the benefit of operative treatment possibly decreases with the number of clinically silent vascular malformations.

Total number of cells in the human newborn telencephalic wall.

The total cell numbers were estimated in the neocortical part of the human telencephalon in 10 normal brains of newborn babies within four major developmental zones: the cortical plate/marginal zone, the subplate, the intermediate zone and the ventricular/subventricular zone. Furthermore, the total number of neuron and glial cells was estimated in the cortical plate. The gestational ages ranged from 38 + 0-42 + 5 weeks + days of gestation. The mean total cell number was 32.6 x 10(9) (coefficient of error = 0.04) and the total number of neurons in the cortical plate 19.8 x 10(9) (coefficient of error = 0.06). This indicates that the total number of neocortical neurons equals the total number in the adults, which, however, is not the case for the glial cells.

Short-term study of the uptake of PrP(Sc) by the Peyer's patches in hamsters after oral exposure to scrapie.

The disease-associated prion protein (PrP(Sc)) has been detected in the ileal Peyer's patches of lambs as early as one week after oral exposure to scrapie. In hamsters, the earliest reported time of PrP(Sc) detection in the Peyer's patches after oral exposure to scrapie is 69 days post-infection. To evaluate the acute uptake of inoculum and to investigate whether the Peyer's patches constitute the primary site of entry for scrapie after oral exposure, hamsters were each exposed orally to 1 ml of a 10% brain homogenate from hamsters in the terminal stage of infection with the 263 K strain of the scrapie agent. PrP(Sc) was demonstrated in the Peyer's patches only a few days after exposure, i.e., much earlier than previously reported. This study supports the view that the Peyer's patches constitute at least one of the primary entry sites of PrP(Sc) after oral exposure to scrapie.

New evidence for the origin of intracranial germ cell tumours from primordial germ cells: expression of pluripotency and cell differentiation markers.

Primary intracranial germ cell tumours are rare neoplasms that occur in children and adolescents. This study examined both the biology and the origin of these tumours, as it has been hypothesized that they originate from a totipotent primordial germ cell. We applied recent knowledge from gonadal germ cell tumours and analysed expression of a wide panel of stem cell-related proteins (C-KIT, OCT-3/4 (POU5F1), AP-2gamma (TFAP2C), and NANOG) and developmentally regulated germ cell-specific proteins (including MAGE-A4, NY-ESO-1, and TSPY). Expression at the protein level was analysed in 21 children and young adults with intracranial germinomas and non-germinomas, contributing to a careful description of these unusual tumours and adding to the understanding of pathogenesis. Stem cell related proteins were highly expressed in intracranial germ cell tumours, and many similarities were detected with their gonadal equivalents, including a close similarity with primordial germ cells. A notable difference was the sex-specific expression of TSPY, a gene previously implicated in the origin of gonadoblastoma. TSPY was only detected in germ cell tumours in the central nervous system (CNS) from males, suggesting that it is not required for the initiation of malignant germ cell transformation. The expression of genes associated with embryonic stem cell pluripotency in CNS germ cell tumours strongly suggests that these tumours are derived from cells that retain, at least partially, an embryonic stem cell-like phenotype, which is a hallmark of primordial germ cells.

Vascular endothelial growth factor (VEGF) receptor neuropilin-1's distribution in astrocytic tumors.

Neuropilin-1 is a VEGF165- and semaphorin receptor expressed by endothelial cells and tumor cells. The specific function of neuropilin-1 is not fully known, but in the developing nervous system neuropilin, as a semaphorin receptor, has been shown to influence neuronal guidance. The expression of neuropilin-1 was studied in low-grade and high-grade astrocytic tumors, the latter characterized by extensive angiogenesis. We examined 20 low-grade astrocytomas (WHO grade II) and 46 glioblastomas (WHO grade IV) immunohistochemically for neuropilin-1, p53 and EGFR. The glioblastomas were according to the p53 and EGFR expression classified as 35 primary--de novo--glioblastomas, 9 secondary glioblastomas, and 2 uncertain cases. Furthermore, the presence of mast cells was evaluated to search for any potential function in angiogenesis. The glioblastomas expressed neuropilin-1 in the endothelial cells of the proliferating vessels and the majority of the glioblastomas had immunoreactive neoplastic astrocytes, with no difference between the glioblastoma subgroups. Six out of twenty of the low-grade astrocytomas were negative in the endothelial cells and 8 out of 20 in the tumor cells for neuropilin-1. Mast cells were observed in the collagen matrix around larger vessels in the leptomeninges, but not adjacent to malignant tumor vessels or as part of the tumor process itself. Increased expression of neuropilin-1 is shown in endothelial cells and in neoplastic astrocytes of glioblastomas. Less neuropilin-1 expression is found in about half of the low-grade astrocytomas in both neoplastic astrocytes and endothelial cells. The results suggest a correlation between neuropilin-1 and vascularity in human astrocytic tumors and a possible role for neuropilin-1 as a receptor for VEGF-induced angiogenesis.

Papillary glioneuronal tumor--a new tumor entity.

Glioneuronal neoplasms of the CNS comprises a heterogeneous group of generally low-grade tumors expressing glial and neuronal cells of varying differentiation. Recently, a new variant of the glioneuronal tumors has been identified. We present a case of a glioneuronal tumor located in the left frontal lobe of a 16-year-old boy who developed seizures 6 months after brain concussion. MR scan demonstrated an irregular, but well circumscribed, mixed cystic and solid tumor with contrast enhancement in the solid part. Histology showed a papillary glioneuronal tumor. The tumor is indolent with no sign of recurrence after gross total resection.

Transvaginal sonography combined with saline contrast sonohysterography in evaluating the uterine cavity in premenopausal patients with abnormal uterine bleeding.

OBJECTIVES: To evaluate whether saline contrast sonohysterography (SCSH) adds additional information to that obtained by transvaginal sonography (TVS) for predicting endometrial abnormality in premenopausal patients with abnormal uterine bleeding. PATIENTS AND METHODS: This was a two-center prospective study at a university clinic and a central hospital in Denmark. The uterine cavity was evaluated with TVS and SCSH in 470 premenopausal patients with abnormal uterine bleeding. One hundred and eighty-nine of the patients had operative hysteroscopy or hysterectomy within 4 months which provided a detailed description of the uterine cavity and was used as the true value for exclusion of polyps and submucous myomas. RESULTS: Based on normal endometrial morphology alone, the results for detection of an abnormal uterine cavity were as follows: sensitivities of TVS 0.92, SCSH 0.99; specificities of TVS 0.62, SCSH 0.72; positive predictive values of TVS 0.80, SCSH 0.85; negative predictive values of TVS 0.82, SCSH 0.98. Transvaginal sonography combined with SCSH was superior to TVS for detection of intracavitary abnormalities (McNemar test, P = 0.008). The post-test probability of there being an abnormal cavity after normal findings on TVS alone was 0.18 (0.10-0.32) and after TVS and SCSH it was 0.02 (0.01-0.11). When normal endometrial morphology was combined with an endometrial thickness of < 12 mm for evaluation of all abnormalities including hyperplasia, the diagnostic potential of TVS or SCSH was almost unchanged except for specificities, which were markedly lower (TVS 0.54; SCSH 0.57). In all the patients referred, TVS had a negative predictive value of 0.94 for identification of polyps and myomas when findings at subsequent SCSH were accepted as the true value. Transvaginal sonography reduced the pretest probability of polyps or submucous myomas from 0.35 to a post-test probability of 0.06, but missed 21% of the polyps. CONCLUSIONS: Sonohysterography was a sensitive tool and was superior to TVS used alone for evaluation of the uterine cavity in patients who underwent operative surgery for abnormal uterine bleeding. All abnormalities except one were found at SCSH, while TVS alone missed polyps and had almost one in four equivocal findings. The use of TVS, without saline contrast, left one in five of the polyps undiagnosed in referred patients with abnormal bleeding.

Can the endometrial thickness as measured by trans-vaginal sonography be used to exclude polyps or hyperplasia in pre-menopausal patients with abnormal uterine bleeding?

BACKGROUND: To combine findings of normal mid-line echoes from TVS (trans-vaginal sonography) with cut-off levels for endometrial thickness, in order to examine the associated risk of abnormalities in the uterine cavity. DESIGN AND SETTING: Two center prospective study at a university clinic and a central hospital in Denmark. PARTICIPANTS: Three hundred and fifty-five pre-menopausal patients with abnormal uterine bleeding, and indications for endometrial sampling or surgery. INTERVENTIONS: The thickness of the endometrium was measured, and the mid-line echoes were evaluated using TVS. The findings from the endometrial sampling, combined with the evaluation of the uterine cavity using operative hysteroscopy (115), hysterectomy (74) or HSE (hysterosonographic examination) (166), were used as the true values. RESULTS: The mean (+/-s.d.) endometrial thickness was significantly different in patients with hyperplasia 11.5 mm (+/-5.0), polyps 11.8 mm (+/-5.1), sub-mucous myomas 7.1 mm (+/-3.4) and in patients without these abnormalities 8.37 (+/-3.9) (p<0.001). Hyperplasia and/or polyps were present in 20% of all patients, and in 8% of 143 patients with an endometrial thickness of < or =7 mm. This proportion did not decrease with lower cut-off levels for endometrial thickness. Receiver operating characteristic (ROC) curves were not optimal for excluding hyperplasia or polyps by endometrial thickness. In 173 cases with a distinct, regular midline echo without echo-dense foci in TVS the proportion of patients with abnormalities was 16% (11-23). This proportion did not decrease with cut-off levels for endometrial thickness. CONCLUSIONS: Using TVS, low levels of endometrial thickness reduced the possibility of abnormalities such as polyps and hyperplasia, but did not exclude them. Low cut-off levels for endometrial thickness did not increase the diagnostic performance in cases with normal sonograms.