Iron deficiency anaemia over the last decades - Osler's disease diagnosed by Doppler and contrast-enhanced ultrasound.

CASE REPORT: A 72-year-old woman with a 30-year history of iron deficiency anaemia was admitted for fatigue and increasing weakness. On physical examination, the patient appeared dyspneic and pallor. The tongue showed angiodysplasias. Laboratory analysis showed a microcytary anaemia with an iron deficiency. Firstly a routine ultrasound examination (iU22, Philips Medical Systems) was performed. A left accessory artery, a dilated common hepatic artery and ectatic tortuous intrahepatic liver arteries were found. A contrast-enhanced ultrasound (CEUS) detected two intrahepatic arteriosystemic shunts in the left liver lobe. Endoscopy revealed multiple angiodysplasias of the stomach and the duodenum, 4 isolated angiodysplasias in the colon and telangiectasias in the oropharyngeal region. The angiodysplasias were treated with argon plasma coagulation. Osler's disease was diagnosed based on the Curacao criteria. CONCLUSION: Transabdominal B-mode sonography in combination with colour Doppler, pulsed wave Doppler and contrast-enhanced ultrasound is a very important tool to detect hepatic vascular malformations. It is an excellent procedure for the screening of patients with an iron deficiency anaemia. For the first time, we have demonstrated CEUS as an additional approach in the diagnosis of liver involvement in patients with Osler's disease.

[Ultrasonographic diagnosis of a biliary-digestive fistula with gallstone ileus]. / Sonographische Diagnose einer biliodigestiven Fistel mit Gallensteinileus.

HISTORY AND CLINICAL FINDINGS: A 72-year-old woman was admitted to the hospital with upper abdominal pain, nausea, vomiting, and obstipation. INVESTIGATIONS: Percutaneous ultrasound found aerobilia, a biliary-digestive fistula, and an ileus with gallstones within the small bowel. The findings were confirmed at computed tomography. TREATMENT AND COURSE: A gallstone ileus on the basis of a biliary-digestive fistula was diagnosed. The patient was treated by surgery and with antibiotics. CONCLUSION: This case report demonstrates that percutaneous ultrasonography should be used as the first imaging procedure in the diagnosis of acute abdominal pain. This procedure makes it possible to detect a gallstone ileus. It is important also to define various intestinal structures accurately.

The serpins alpha-1-antitrypsin and alpha-1-antichymotrypsin specifically interact with immunophilins.

In a yeast two-hybrid screen FKBP13, a member of the FK506 Binding Protein (FKBP) family, was detected to interact with the serpin alpha-1-antichymotrypsin (ACT). The specificity of the interaction was confirmed in vitro and by the lack of interaction of ACT with FKBP25 and FKBP52. Mutational analysis of ACT revealed that the entire protein is necessary to interact with FKBP13. ACT but also different unrelated small regions of the ACT protein were able to interact with the smaller FKBP12, demonstrating a rather nonspecific interaction with this immunophilin. Naturally occuring mutants of ACT were able to interact as well. Antitrypsin (AT) closely related to ACT did only interfere with FKBP12 a protein that does presumably not reside in the same cellular compartment with AT and ACT. Both serpins interacted with the unrelated immunophilin cyclophilin A. In conclusion the serpin alpha-1-antichymotrypsin physiologically interacts with the ER-immunophilin FKBP13 and the secreted immunophilin cyclophilin A in vivo whereas alpha-1-antitrypsin might only react with cyclophilin A; both serpins may be controlled thereby in their genuine function.

High-resolution ultrasound in combination with colour-Doppler sonography for preoperative localization of parathyroid adenomas in patients with primary hyperparathyroidism.

BACKGROUND AND AIMS: Experienced surgeons have the highest sensitivity in the localization of parathyroid adenomas in patients with primary hyperparathyroidism. Correct preoperative localization, however, allows unilateral neck exploration with subsequently reduced operative time and complication rate. In this prospective study, we investigated the accuracy of preoperative high-resolution ultrasound in combination with colour-Doppler sonography for the detection of parathyroid lesions. SUBJECTS/METHODS: Ninety-eight patients (mean age 59.1 years, range 15-86) who referred to our department with symptomatic primary hyperparathyroidism were included in the study from January 1998 to June 2002. Sonography was performed by experienced examiners. The exact diagnosis was based on surgical findings and histology in all patients. RESULTS: The overall sensitivity for the sonographical localization of the adenomas on the correct side of the neck was 86 %. Twenty-three percent of the adenomas located on the cranial margin of the thyroid gland were diagnosed correctly, as were 92 % of the lesions located caudally (p = 0.0001). The detection of feeding vessels was possible by colour-Doppler sonography in 60 % of the cases. The diagnosis was correct for 93 % of these suspected adenomas. No vessels were detected in the remaining lesions, and only 39 % of these tumours were diagnosed correctly (p = 0.0001). CONCLUSIONS: High-resolution ultrasonography by experienced examiners is a highly sensitive procedure for the preoperative diagnosis of parathyroid adenomas in patients with primary hyperparathyroidism. With this method, a unilateral neck exploration is sufficient in about 90 % of the patients. Additionally, detection of feeding vessels by colour-Doppler sonography is an important indication of a parathyroid lesion. Nonetheless, the experienced surgeon remains the standard of reference.

Differentiation of neuroendocrine tumors from other pancreatic lesions by echo-enhanced power Doppler sonography and somatostatin receptor scintigraphy.

BACKGROUND AND AIMS: Echo-enhanced power Doppler sonography is a noninvasive procedure that has been increasingly used for the differential diagnosis of pancreatic tumors. However, to our knowledge, the diagnostic accuracy of this procedure in comparison with somatostatin receptor scintigraphy for the differentiation of neuroendocrine lesions from other pancreatic tumors has never been investigated in a prospective, controlled study. SUBJECTS AND METHODS: One hundred thirty-seven patients were included in the study; the patients were selected from 190 consecutive patients (mean age, 59.8 years; range, 16-85 years) who presented to our department from January 1998 through June 2001 with suspicion of a pancreatic tumor. An experienced examiner who was unaware of the patients' clinical diagnoses performed sonography. Twenty-nine patients with sonographically and/or clinically suspected neuroendocrine tumors were investigated additionally by somatostatin receptor scintigraphy. The exact diagnosis was based upon histologic evidence from biopsy examination (surgical and transabdominal fine-needle biopsy) or a follow-up of at least 18 months. RESULTS: The sensitivity of echo-enhanced power Doppler sonography for diagnosing a neuroendocrine pancreatic tumor was 94%, and its specificity was 96%. The corresponding values for somatostatin receptor scintigraphy were 54% and 81%, respectively. CONCLUSIONS: Echo-enhanced power Doppler sonography has high sensitivity and high specificity for the differentiation of neuroendocrine lesions from other pancreatic tumors. However, histologic evidence is the standard of reference for the differential diagnosis of pancreatic tumors.

Differentiation of pancreatic tumours by conventional ultrasound, unenhanced and echo-enhanced power Doppler sonography.

BACKGROUND: Echo-enhanced power Doppler sonography (power Doppler sonography after injection of a contrast agent) is a non-invasive and increasingly used procedure for differentiating between pancreatic tumours. However, the diagnostic accuracy of this method compared to conventional ultrasound or unenhanced power Doppler sonography has never been investigated in a large prospective controlled study. METHODS: 137 patients were included in the study, selected from 190 consecutive patients with a mean age of 60 years (range 16-85) who presented at our department in the period January 1998 through June 2001 with clinical suspicion of a pancreatic tumour. Sonography was performed by an experienced examiner blind to the patients' clinical diagnoses. The exact diagnosis was based on histological evidence from biopsy examination (surgical and fine needle biopsy) or on a follow-up of at least 18 months. RESULTS: Of the 137 patients, 47 had pancreatic cancer; 41 had masses associated with pancreatitis; 17 had neuroendocrine tumours; 12 had cystic lesions of the pancreas; and 10 had other pancreatic diseases. A normal pancreas was found in 10 patients. The sensitivity of echo-enhanced power Doppler sonography with respect to diagnosing pancreatic carcinoma was 87% and its specificity 94%. The corresponding values for chronic pancreatitis were 85% and 99%, respectively. CONCLUSIONS: Echo-enhanced power Doppler sonography has a high sensitivity and specificity in the differential diagnosis of pancreatic tumours. However, histology is the standard of reference.

Effect of purinergic agonists and antagonists on insulin secretion from INS-1 cells (insulinoma cell line) and rat pancreatic islets.

The effects of purinergic agonists on insulin release are controversial in the literature. In our studies (mainly using INS-1 cells, but also using rat pancreatic islets), ATP had a dual effect on insulin release depending on the ATP concentration: increasing insulin release (EC50 approximately/= 0.0032 microM) and inhibiting insulin release (EC50 approximately/= 0.32 microM) at both 5.6 and 8.3 mM glucose. This is compatible with the view that either two different receptors are involved, or the cells desensitize and (or) the effect of an inhibitory degradation product such as adenosine (ectonucleotidase effect) emerges. The same dual effects of ATP on insulin release were obtained using rat pancreatic islets instead of INS-1 cells. ADPbetaS, which is less degradable than ATP and rather specific for P2Y1 receptors, had a dual effect on insulin release at 8.3 mM glucose: stimulatory (EC50 approximately/= 0.02 microM) and inhibitory (EC50 approximately/= 0.32 microM). The effectiveness of this compound indicates the possible involvement of a P2Y1 receptor. 2-Methylthio-ATP exhibited an insulinotropic effect at very high concentrations (EC50 approximately/= 15 microM at 8.3 mM glucose). This indicated that distinct P2X or the P2Y1 receptor may be involved in these insulin-secreting cells. UTP increased insulin release (EC50 approximately/= 2 microM) very weakly, indicating that a P2U receptor (P2X3 or possibly a P2Y2 or P2Y4) are not likely to be involved. Suramin (50 microM) antagonized the insulinotropic effect of ATP (0.01 microM) and UTP (0.32 microM). Since suramin is not selective, the data indicated that various P2X and P2Y receptors may be involved. PPADS (100 microM), a P2X and P2Y1,4,6 receptor antagonist, was ineffective using either low or high concentrations of ATP and ADPbetaS, which combined with the suramin data hints at a P2Y receptor effect of the compounds. Adenosine inhibited insulin release in a concentration-dependent manner. DPCPX (100 microM), an adenosine (A1) receptor antagonist, inhibited the inhibitory effects of both adenosine and of high concentrations of ATP. Adenosine deaminase (1 U/mL) abolished the inhibitory effect of high ATP concentrations, indicating the involvement of the degradation product adenosine. Repetitive addition of ATP did not desensitize the stimulatory effect of ATP. U-73122 (2 microM), a PLC inhibitor, abolished the ATP effect at low concentrations. The data indicate that ATP at low concentrations is effective via P2Y receptors and the PLC-system and not via P2X receptors; it inhibits insulin release at high concentrations by being metabolized to adenosine.

[Differential diagnosis of frequent pancreatic tumours with echo-enhanced power-Doppler sonography - presentation of case reports]. / Fallbeispiele zur Erläuterung der Differenzialdiagnostik von häufigen Pankreastumoren mit der echosignalverstärkten Power-Doppler-Sonographie.

UNLABELLED: The echo-enhanced Power-Doppler sonography is useful for the differential diagnosis of pancreatic tumours. Tumour criteria for the differentiation of pancreatic tumours with this procedure are explained using selected cases in the present publication. Ductal carcinomas are often hypovascularised compared with the surrounding tissue. On the other hand, neuroendocrine tumours are hypervascularised lesions. Tumours associated with pancreatitis have a different vascularisation pattern depending on inflammation and necrosis. Cystadenomas frequently show many vessels along the fibrotic strands. CONCLUSIONS: Pancreatic tumours have different vascularisation patterns in the echo-enhanced Power-Doppler sonography. These characteristics can be used for the differential diagnosis.

[Pancreatic metastases of renal cell carcinomas - evaluation of the contrast behavior at echo-enhanced power-Doppler sonography in comparison to primary pancreatic tumors]. / Nierenzellkarzinom-Metastasen des Pankreas - Evaluierung ihres Kontrastverhaltens in der echosignalverstärkten Power-Doppler-Sonographie im Vergleich mit primären Pankreastumoren.

BACKGROUND: Renal cell carcinomas are the most common primary tumors leading to pancreatic metastases. The differentiation of metastases from primary pancreatic tumors is important for the prognosis. Echo-enhanced power-Doppler sonography may be used for the differential diagnosis of tumors. In this study, the contrast behavior of metastases of renal cell carcinomas was evaluated in comparison to primary pancreatic tumors. PATIENTS AND METHODS: Each 5 patients with pancreatic metastases of a renal cell carcinoma, a ductal carcinoma, a neuroendocrine tumor and a pancreatitis-associated mass were investigated by B-mode sonography, fundamental and echo-enhanced power-Doppler sonography. RESULTS: Similar to neuroendocrine tumors, metastases of renal cell carcinomas were found to be hypervascularized. In contrast, ductal carcinomas are hypovascularized compared to the surrounding tissue. Tumors associated with pancreatitis show different vascularization pattern depending on inflammation and necrosis. CONCLUSIONS: Metastases of renal cell carcinomas and ductal carcinomas show different vascularization pattern at echo-enhanced power-Doppler sonography. Renal cell metastases and neuroendocrine tumors have similar contrast behaviors, therefore, clinical symptoms should be referred for their differentiation. However, histology is the standard of reference for the differential diagnosis of pancreatic tumors.

Effects of retinoids and thiazolidinediones on proliferation, insulin release, insulin mRNA, GLUT 2 transporter protein and mRNA of INS-1 cells.

Both 9-cis-retinoic acid (9cRA) and all-trans-retinoic acid (ATRA) are active metabolites of vitamin A (retinol). There exists an interaction between retinoid receptors and peroxisome proliferator-activated receptors (PPARgamma). To define their functions in an insulin secreting system the effects of ATRA, 9cRA and the PPARgamma agonist rosiglitazone on cell proliferation, insulin release and glucose transporter (GLUT) 2 of INS-1 cells were tested. Retinoic acid receptor (RAR-alpha and -gamma) and retinoid X receptor (RXR-alpha and -beta) proteins are present (immunoblots). Both 9cRA and ATRA inhibit INS-1 cell proliferation ([3H]-thymidine assay) in a concentration dependent manner. Both 9cRA and ATRA increased insulin release, but only ATRA ralsed the GLUT 2 mRNA in a bell-shaped concentration response curve after 48 h. The insulinotropic effect of one compound is not significantly superimposed by the other indicating that the same binding sites are used by 9cRA and ATRA. The acute and chronic effects of the PPARgamma agonist rosiglitazone on insulin release were additionally determined since glitazones act as transcription factors together with RXR agonists. At high concentrations (100 microM) rosiglitazone inhibited glucose (8.3 mM) stimulated insulin secretion (acute experiment over 60 min). Insulin secretion, however, was increased during a 24 h treatment at a concentration of 10 microM and again inhibited at 100 microM. Changes in preproinsulin mRNA expression were not observed. Rosiglitazone (100 microM) increased GLUT 2 mRNA paralleled by an increase of GLUT 2 protein, but only after 24 h of treatment. This data indicate that RAR and RXR mediate insulin release. The changes in GLUT 2 have no direct impact on insulin release; the inhibition seen at high concentrations of either compound is possibly the result of the observed inhibition of cell proliferation. Effects of rosiglitazone on preproinsulin mRNA and GLUT 2 (mRNA and protein) do not play a role in modulating insulin secretion. With the presence of an RXR receptor agonist the effect of rosiglitazone on insulin release becomes stimulatory. Thus the effects of RAR-, RXR agonists and rosiglitazone depend on their concentrations, the duration of their presence and are due to specific interactions.

[Bile peritonitis in an alcoholic man after traumatic gallbladder perforation--differential ascitic decompensated liver cirrhosis diagnosis]. / Gallige Peritonitis bei einem alkoholkranken Mann nach traumatischer Gallenblasenperforation--Differenzialdiagnostik zur aszitisch dekompensierten Leberzirrhose.

Traumatic rupture of the gallbladder is a very rare event associated with high mortality. Since clinical symptoms are nonspecific, diagnosis is difficult. We present an alcoholic with biliary ascites after traumatic perforation of the gallbladder. Initially, he was misdiagnosed to have ascites caused by liver cirrhosis. This case demonstrates, that the combination of patients history, clinical investigation and ultrasound allows the diagnosis of traumatic rupture of the gallbladder.

Mutation of FKBP associated protein 48 (FAP48) at proline 219 disrupts the interaction with FKBP12 and FKBP52.

Immunophilins are known as intracellular receptors for the immunosuppressant drugs, cyclosporin A, FK506, and rapamycin. They can be divided into two groups, cyclophilins that bind cyclosporin A and FK506 binding proteins (FKBPs) that bind FK506 and rapamycin. Many efforts were made to elucidate the physiological role of the immunophilins. Many of them are involved in intracellular signalling as they bind to calcium channels or to steroid receptor complexes. A yeast two-hybrid screen was used to identify further target proteins that interact with known proteins. Recently, a 48-kDa FKBP associated protein (FAP48) was isolated that binds to FKBP12 and FKBP52. Binding of FAP48 to FKBPs is inhibited by the macrolide FK506 indicating that the binding sites on the immunophilins coincide with the binding site for FK506. A peptidyl-prolyl motif on FAP48 should be responsible for the binding of the protein to FKBPs. We sequentially point mutated proline sites on FAP48 and checked the mutant proteins for interaction with FKBP12 and FKBP52. Mutation of proline 219 to alanine leads to a loss of interaction indicating that a cysteinyl prolyl site might be responsible for the binding of FAP48 to FKBPs. Thus we identified proline 219 being essential for the interaction.

Improved accuracy in the diagnosis of intrahepatic bile duct ectasia in Caroli's disease by combination of ultrasound and endoscopic retrograde cholangiography.

Caroli's disease is characterized by dilatation of the intrahepatic bile ducts. Cholangitis, liver cirrhosis and development of a cholangiocarcinoma are possible complications. For optimal therapy, a correct diagnosis of the extent of the disease is mandatory. The present report demonstrates that the combination of endoscopic retrograde cholangiography and ultrasound may lead to a more reliable diagnosis of the extent of Caroli's disease. It is therefore essential to perform ultrasound in all these patients.

[Biliary-digestive fistula with gallstone ileus--a sonographic diagnosis]. / Biliodigestive Fistel mit Gallensteinileus--eine sonographische Diagnose.

We demonstrate a patient with a fistula between the gallbladder and the small intestine combined with a gallstone ileus of the small bowel, diagnosed by ultrasound. Plain abdominal X-ray only revealed small bowel obstruction. All the typical diagnostic criteria of a biliodigestive fistula could be detected by ultrasound. The patient was operated and discharged a few days later. We demonstrate that biliodigestive fistulas can be diagnosed by ultrasound.

[Evaluation of doppler ultrasonography criteria for the differential diagnosis of pancreatic tumors]. / Evaluierung dopplersono-graphischer Kriterien zur Differentialdiagnostik von Pankreastumoren.

AIM: In order to improve the differential diagnosis of pancreatic lesions, dopplersonographic criteria for the tumours were evaluated. METHODS: 35 patients diagnosed by conventional ultrasound as having a tumour of pancreas were further investigated by B-mode sonography, fundamental and echo-enhanced power-Doppler sonography focusing on specific properties of the tumours. The results were correlated to the histological findings. RESULTS: Ductal carcinomas and cystadenocarcinomas are often hypovascularized in comparison to the surrounding tissue. In contrast to this, neuroendocrine tumours and cystadenomas are mostly hypervascularized. Tumours associated with pancreatitis show different vascularization patterns depending on inflammation and the extent of necrosis. CONCLUSIONS: Pancreatic tumours display different vascularization patterns in the echo-enhanced power-Doppler sonography. These characteristics can be useful for the differential diagnosis of pancreatic tumours.

Modulation of gastrin-releasing peptide (GRP) receptors in insulin secreting cells.

Gastrin-releasing peptide (GRP) receptors are present in pancreatic islets, though their regulation is unknown except for homologous desensitization. The modulation of binding of GRP to mouse pancreatic islets and INS-1 cells was studied. At 60 min (steady-state), total binding of [(125)I-Tyr(15)] GRP was 1.62 per cent of total radioactivity per 50 islets; non-specific binding (presence of 1 mM unlabelled GRP(1-27)) was 0.05 to 0.61 per cent of total radioactivity. A preincubation with 1000 nM cholecystokinin (CCK(8)) or with 1000 nM glucose-dependent insulinotropic peptide (GIP) augmented the number of GRP binding sites but not their affinity. [(125)I-Tyr(15)]GRP binding to INS-1 cells was saturable (90 min) and specific with respect to compounds that are not chemically related to GRP (e.g. calcitonin gene-regulated peptide-CGRP and atrial natriuretic peptide-ANP). Displacement studies showed one binding site with a K(d) of 0.39 nM and a B(max) of 13.2 fmoles mg(-1) protein. When the cells were pretreated for 24 h with 10 nM GIP or CCK(8), only GIP but not CCK(8) increased the B(max) of the GRP binding site. The affinity (K(d)) was not changed by either compound. This effect of GIP pretreatment was not affected by downregulating PKC by TPA (phorbol ester; long-term pretreatment). These data indicate that: (1) specific binding sites for GRP are present in mouse pancreatic islets and INS-1 cells; (2) the GRP binding is upregulated by GIP in both islets and INS-1 cells and additionally by CCK(8 ), albeit only in islets; and (3) PKC does not seem to be involved in the up-regulation process. Thus a positive interplay between both the incretins GIP and CCK(8) and the neurotransmitter GRP is obvious.

Galpha(i2)-mRNA and -protein regulation as a mechanism for heterologous sensitization and desensitization of insulin secretion.

Prolonged exposure of cells to an agonist of a G-protein-coupled receptor usually results in an attenuation of the cellular response. To elucidate the cellular mechanisms of sensitization or desensitization in an insulin secretory cell system (INS-1 cells), we investigated a regulatory link between G-protein alpha(s)- and alpha(i2)-subunits mRNA, their protein levels and insulin secretion as the biological effect using various compounds. Incubation with epinephrine (50 microM) for 8 h decreased alpha(s)- and alpha(i2)-mRNA levels to 58% and 72%, respectively, which is reversed after a longer incubation. From results using isoprenaline and the alpha2-agonist UK 14,304 epinephrine is shown to mediate its actions via alpha2- but not beta-adrenoceptors. The insulin inhibitory neuropeptide galanin (50 nM) caused a decrease of alpha(s)- and alpha(i2)-mRNA levels, whereas insulinotropic compounds (incretin hormones) such as GIP or GLP-1 (both 10 nM) led to an increase of alpha(s)- and alpha(i2)-mRNA levels. By using the Ca2+ channel blocker verapamil (50 microM) alpha(i2)-mRNA changes clearly depend on Ca2+ influx. The effects on alpha(i2)-mRNA were accompanied by a parallel, albeit weaker effect on the protein level (only GIP and UK 14,304 were investigated). The changes in alpha(i2)-mRNA levels by either compound were paralleled by inverse changes in insulin secretion: preincubation with UK 14,304 for 8 h led to an increased insulin secretion when challenged by either GLP-1, GIP or glucose (8.3 mM). This was similar for galanin, another potent inhibitor of insulin release. On the other hand, exposure to the incretins GIP or GLP-1 for 8 h induced a smaller insulin release when challenged afterwards by either UK 14,304, galanin, GIP, GLP-1, or glucose. Thus the influence on insulin secretion of various compounds is reciprocal to the regulation of alpha(i2)-mRNA levels but not alpha(s)-mRNA levels. There is, therefore, evidence from all the manoeuvres used that alpha(i2)-mRNA regulation may play a role in heterologous sensitization and desensitization of insulin secretion.