Evaluating the risk of tuberous sclerosis in cases with prenatal diagnosis of cardiac rhabdomyoma

OBJECTIVE: To evaluate the prenatal parameters that increase the risk of tuberous sclerosis in prenatal management of fetal cardiac tumors suspected as rhabdomyoma. METHODS: The study was a retrospective survey of 18 documented cases in which cardiac rhabdomyoma was suspected during pregnancy. The following parameters were evaluated as possible risk factors associated with tuberous sclerosis: tumor size, isolated or multiple, and family history of tuberous sclerosis. RESULTS: Eighteen documented cases in which cardiac rhabdomyoma was found during pregnancy were evaluated. Of these cases, seven (39%) had proven tuberous sclerosis and 11 were found to be non-associated tuberous sclerosis tumors. When combining the present data with previous series, cases with diagnosis of tuberous sclerosis had equal mean tumor size to those with normal outcome. Family history of tuberous sclerosis in the presence of cardiac rhabdomyoma almost invariably ended with tuberous sclerosis (86%). All other cases with diagnosis of tuberous sclerosis and no family history had all multiple cardiac tumors. CONCLUSION: The present data suggest that 39% of in utero suspected cardiac rhabdomyoma would have tuberous sclerosis. Family history and multifocality remain the strongest predictors of tuberous sclerosis, whereas size of the cardiac tumor can not reliably be used to predict tuberous sclerosis in prenatal counseling.     

Expression profiling and interferon-beta regulation of liver metastases in colorectal cancer cells

Liver metastasis is the major cause of death among colorectal cancer patients. Many gene products have been associated with the colon cancer cells' ability to metastasize to the liver, including carcinoembryonic antigen (CEA) and mucins. In this study we examined changes in expression of 384 genes in a model of human colorectal cancer metastasis in nude mice. Using DNA microarrays, we compared expression between MIP-101 cells, a poorly metastatic human colon cancer cell line, with an interferon-beta (IFN-β) resistant subline of MIP-101 (β-MIP) that is metastatic to the liver. Treatment of β-MIP cells with increasing concentrations of IFN-β caused a reversion to the non-metastatic phenotype. The array data showed down-regulation of genes involved in apoptosis in β-MIP cells and their return to the MIP-101 pattern upon IFN-β treatment. Cluster analysis also showed involvement of genes belonging to cell cycle, angiogenesis and invasion pathways. Selected genes were chosen to validate the microarray data by semi-quantitative RT-PCR. Association between gene expression pattern and metastatic phenotype was verified by intra-splenic injection in nude mice. The number of genes examined in this study was small, but carefully selected. Significant changes associated with cell growth and survival were observed, which gave the metastatic cells an advantage to grow in the liver. This information may help identifying new markers for colorectal cancer prognosis as well as aid the development of new therapeutic approaches. This revised version was published online in July 2006 with corrections to the Cover Date.     

Heart function and cytokine expression is similar in mice and rats after myocardial infarction but differences occur in TNFalpha expression

Large myocardial infarction (MI) causes substantial cardiac remodeling and often leads to heart failure. The genetically engineered mouse is believed to provide a powerful tool for investigating the underlying pathophysiological mechanisms and for developing new therapeutic strategies. The present study investigates the functional parameters and expression levels of transforming growth factor (TGF) beta isoforms, interleukin-6 (IL-6) and tumor necrosis factor (TNF) alpha, which may be involved in the remodeling mechanisms, in a mouse model of MI; comparisons with data from rats were also made. Female Sprague-Dawley rats ( n=10-12 at each time point) and female Balb/c mice ( n=6-8 at each time point) were used. In both mice and rats MI induced a time-dependent reduction in heart function with subsequent development of heart failure. The hemodynamic consequences after 4 weeks are characterized by reduced left ventricular (LV) developed pressure and increased right ventricular (RV) developed pressure. The pattern of increased expression of most, but not all, of the analyzed cytokines and growth factors is comparable. This emphasizes the important role of these factors in the remodeling processes. However, TNFalpha was more strongly expressed in both the infarct and the non-infarcted area of mice. Since functional and molecular biological parameters can readily be measured in mice with advanced technologies, this qualifies this species as a powerful experimental model, particularly in view of the various transgenic and knock-out mice that are available.     

Autophagocytosis of the apical membrane in microvillus inclusion disease

BACKGROUNDS: Microvillus inclusion disease (MID) is a disorder with the clinical signs of intractable diarrhoea in the newborn and infancy. The typical pathological features of the disease are well known whereas the pathophysiology is still unclear. AIM: This study was performed to define possible alterations of the cytoskeleton and exocytic as well as endocytic pathways within enterocytes in MID. PATIENTS: Four patients with MID were studied. Three had a congenital onset of diarrhoea and one patient had a late onset form. METHODS: Thin frozen sections of small bowel biopsies of patients were labelled by antibodies against the cytoskeleton and the brush border enzyme sucrase-isomaltase. The binding sites of the primary antibodies were visualised by immunogold particles in the electron microscope. Biopsies were labelled in organ culture to analyse the biosynthetic and endocytic pathways within the enterocytes. RESULTS: Labelling with antibodies against actin and villin did not differ significantly in control and patient biopsies. Biosynthetic labelling revealed normal intracellular processing and transport of the brush border enzyme sucrase-isomaltase. Secretory granules in crypt epithelial cells were positive for sucrase-isomaltase, differing in its labelling density between patients. Patient biopsies showed microvillus inclusion bodies which endocytosed cationised ferritin within five minutes after uptake as well as ovalbumin after incubation for 10 minutes. These microvillus inclusion bodies correspond to early endosomes because they lack lysosome associated membrane proteins. Late endosomes and lysosomes containing sucrase-isomaltase did not reveal microvillus-like structures. CONCLUSION: Microvillus inclusion bodies in MID originate from autophagocytosis of the apical membrane of enterocytes with engulfing of microvilli.     

Primary squamous cell carcinoma of the thyroid gland

A case of primary squamous cell carcinoma of the thyroid is presented. Squamous epithelium is normally not present in the thyroid gland, and this tumor is exceedingly rare. Proper workup is described, including the differentiation from metastatic disease. The case reported is of a 64-year-old woman who presented with an asymptomatic nodule and underwent thyroidectomy. The final pathologic diagnosis, confirmed using immunohistochemistry for cytokeratin and transmission electron microscopy, revealed the unusual tumor. Squamous cell carcinoma of the thyroid is highly aggressive and behaves clinically like anaplastic thyroid carcinoma; the prognosis is poor. The patient described developed local recurrence and expired 7 months after resection from local invasion and airway obstruction. Unfortunately, this is the typical outcome. Chemoradiotherapy is generally not helpful, and complete resection remains the best chance for cure.     

Quantification of blood flow in brain tumors: comparison of arterial spin labeling and dynamic susceptibility-weighted contrast-enhanced MR imaging

PURPOSE: To implement an arterial spin labeling technique that is feasible in routine examinations and to test the method and compare it with dynamic susceptibility-weighted contrast material-enhanced magnetic resonance (MR) imaging for evaluation of tumor blood flow (TBF) in patients with brain tumors. MATERIALS AND METHODS: Thirty-six patients with histologically proven brain tumors were examined at 1.5 T. A second version of quantitative imaging of perfusion by using a single subtraction with addition of thin-section periodic saturation after inversion and a time delay (Q2TIPS) technique of pulsed arterial spin labeling in the multisection mode was implemented. After arterial spin labeling, a combined T2- and T2*-weighted first-pass bolus perfusion study (gadopentetate dimeglumine, 0.2 mmol/kg) was performed by using a double-echo echo-planar imaging sequence. In regions of interest, maps of absolute and relative cerebral blood flow were computed and analyzed with arterial spin labeling and dynamic susceptibility-weighted contrast-enhanced MR imaging, respectively. RESULTS: Both techniques yielded the highest perfusion values in imaging of glioblastomas and the lowest values in imaging of two low-grade gliomas that both showed strong gadopentetate dimeglumine enhancement. There was a close linear correlation between dynamic susceptibility-weighted contrast-enhanced MR imaging and arterial spin labeling in the tumor region of interest (linear regression coefficient, R = 0.83; P <.005). Blood flow is underestimated with arterial spin labeling at low flow rates. High- and low-grade gliomas can be distinguished at the same level of significance with both methods. Absolute TBF is less important for tumor grading than is the ratio of TBF to age-dependent mean brain perfusion. CONCLUSION: Arterial spin labeling is a suitable method for assessment of microvascular perfusion and allows distinction between high- and low-grade gliomas.     

A reduced extracellular serotonin level increases the 5-HT1A PET ligand 18F-MPPF binding in the rat hippocampus.

4,2'-(Methoxyphenyl)-1-[2'-(N-2"-pyridinyl)-p-fluorobenzamido]ethylpiperazine ((18)F-MPPF) is a radiotracer used in clinical PET studies for the visualization of serotonin-1A (5-HT(1A)) receptors. In a previous study, we demonstrated that a rapid enhancement of extracellular serotonin concentrations influences (18)F-MPPF-specific binding. Because endogenous serotonin is significantly decreased in some pathologies, the aim of this study was to determine whether (18)F-MPPF is sensitive to depletion of this neurotransmitter. METHODS: Using the beta-microprobe, an original beta(+)-sensitive intracerebral probe, and microdialysis, the effect of decreased serotonin on the specific binding of (18)F-MPPF to 5-HT(1A) receptors was investigated in the hippocampus of the anesthetized rat. Extracellular serotonin was pharmacologically decreased in the hippocampus after a single injection of p-ethynylphenylalanine ([p-EPA] 5 mg/kg), a new tryptophan hydroxylase inhibitor. RESULTS: Our results showed that the (18)F-MPPF-specific binding was significantly enhanced after the decrease of extracellular serotonin. These results were confirmed by the (18)F-MPPF distribution in cerebral tissues (hippocampus-to-cerebellum ratio) and by the decrease of the extracellular (18)F-MPPF collected in hippocampal dialysates. CONCLUSION: This study further supports the view that (18)F-MPPF binding potential is increased in the hippocampus if the endogenous serotonin is pharmacologically decreased after a p-EPA injection. This phenomenon will be an additional factor in the interpretation of the results from (18)F-MPPF clinical PET studies.     

Orthodontic Space Closure without Contralateral Extraction through Mesial Movement of Lower Molars in Patients with Aplastic Lower Second Premolars

METHOD AND PATIENTS: A method is presented that allows unilateral space closure in patients with aplastic lower second premolars. Based on a straight-wire appliance, space closure was achieved with a combination of "push mechanics" using the second molar as an anchorage unit and Class II "pull mechanics", thus avoiding the application of any distalizing force on the lower incisors. The results from 13 consecutively treated subjects (five boys, eight girls, mean age 12 years and 6 months) were analyzed. RESULTS: Complete bodily space closure was achieved in all 13 cases within a mean treatment time of 2 years and 7 months. The desired Angle Class III molar relationship of one premolar width (+/- 1/4 premolar width) on the aplastic side was successful in eleven patients, an additional 4.7 mm of space being created for the third molar on the aplastic side compared with the contralateral side (p < or = 0.01). However, adverse effects could be kept to a minimum, with no method-dependent side effects being recorded with regard to canine and molar relationships on the contralateral side, or to overbite, overjet, or upper and lower incisor inclination. The mean lower midline shift of 0.8 mm was in accordance with the mean distal canine relationship of 1/3 premolar width on the aplastic side. CONCLUSION: These results confirm that orthodontic space closure in cases of unilateral aplastic lower second premolars can be performed successfully with the presented treatment method without the need for additional premolar extractions, prosthodontic treatment or implants. Furthermore, the prognosis for the lower wisdom tooth on the aplastic side is improved.