Molecular modeling of mechanism of action of anti-myasthenia gravis slow-binding inhibitor of acetylcholinesterase.

BACKGROUND: Myasthenia gravis (MG) is a chronic autoimmune neuromuscular disorder characterized by fluctuating weakness of voluntary skeletal muscles. The cause of autoimmune response is unknown and only symptomatic therapies for MG are currently available. Pharmacological correction of synaptic failure underlying MG, involves partial inhibition acetyl- and butyrylcholinesterase. Effectiveness of cholinesterase inhibitors in the symptomatic treatment of MG is based on their ability to potentiate the effects of acetylcholine by decreasing the rate of its enzymatic hydrolysis at neuromuscular junctions. Several new inhibitors of AChE were tested in animal model of MG and may be considered as valuable candidates for the treatment of pathological muscle weakness syndromes. In this study, we have investigated mechanisms of ChE inhibition by one of the most active 6-methyluracil derivatives (C547), as well as the possible benefits of using this compound for MG treatment compared to traditionally used pyridostigmine bromide.It was experimentally shown that C547 is a «pseudo-irreversible¼ slow-binding inhibitor of human AChE. Human BChE is reversibly inhibited by C547 with an affinity about 4 orders of magnitude lower than that of human AChE. Slow-binding inhibition of AChE leads to a lasting (over 24 hours) effect on the symptoms of muscle weakness in animal model of MG after a single administration of C547. OBJECTIVE: The aim of the present molecular modeling study was to reveal mechanism of AChE inhibition by C547 and elucidate its apparent «pseudo-irreversibility¼. METHODS: Two principle methods used in the present study were molecular docking and molecular dynamics (MD). Molecular docking was performed with Autodock 4.2.6 software, Lamarckian Genetic Algorithm to obtain structure of protein inhibitor complexes and Local Search for MD snapshots to compare relative binding affinity. For MD simulations NAMD 2.10 software with Charrm 36 force field was used, for the ligand C547 Charmm General Force Field was used, and missing parameters were obtained with quantum mechanical calculations. Unconstrained MD, steered MD (SMD) and free energy calculations with adaptive biasing force were performed. RESULTS: During unconstrained MD, C547 very rapidly binded to the peripheral anionic site (PAS) of AChE. To pass the bottleneck, application of the external force was required (SMD). Both SMD modelling and free energy calculation revealed that after crossing the AChE bottleneck, C547 falls into very favorable position. At the same time the rupture of interactions as well as overcoming the bottleneck gates in the course of pulling out procedure requires application of much higher force than during the pulling-in process. This difference between binding and dissociating processes explains apparent «pseudo-irreversibility¼ of the inhibitor. CONCLUSIONS: These findings are in good agreement with kinetics study showing that C-547 is a slow-binding inhibitor of type B, i.e. after rapid initial binding of inhibitor, the enzyme-inhibitor complex undergoes an isomerization step. Position obtained by SMD is in good agreement with X-ray data obtained by F. Nachon, IBS, France.

Transcatheter arterial embolisation in anticoagulant-related haematoma--a current therapeutic option: a report of four patients and review of the literature.

The aim of this study is to present the computed tomography (CT) and angiographic findings of life-threatening extraperitoneal haemorrhage complicating anticoagulant therapy, treated with transcatheter arterial embolisation (TAE). CT and angiographic studies of four consecutive patients with large, extraperitoneal anticoagulant-related haematomas (ACH) treated by TAE were retrospectively reviewed. Attention was directed to the location of the haematoma and to the possible presence of active arterial extravasation on CT. Four women (mean age 70 years) with large extraperitoneal ACH's demonstrated on CT as extended rectus sheath haematoma in three and expanding iliopsoas haematoma in one, were successfully treated by TAE of the inferior epigastric (n=3) and lumbar artery (n=1). Two patients were diagnosed by contrast-enhanced CT as having active arterial bleeding within the haematoma requiring TAE. The other two were referred to angiography because of haemodynamic instability. We also reviewed the imaging findings of 26 patients with extraperitoneal ACH's requiring TAE described in the literature. In the reviewed cases, a female predominance was found, the retroperitoneum was the most frequent site and most patients recovered. To conclude, unenhanced CT has proved an excellent modality for the diagnosis of ACH's. TAE has been shown to be an effective and safe method for managing such haematomas when conservative treatment is insufficient. We suggest that whenever a large extraperitoneal ACH is seen on unenhanced CT, a subsequent contrast-enhanced dynamic scan should be performed, unless contraindicated. Enhanced CT has a supplementary role in detecting active bleeding that provides an indication for angiographic therapy. Awareness of this optional treatment improve patient's outcome.

Granulomatous appendicitis presenting as right lower quadrant pain: CT findings.

BACKGROUND: We present the computed tomographic (CT) findings of granulomatous appendicitis. METHODS: Five of 652 (0.9%) patients who had undergone appendectomy for clinically suspected acute appendicitis over a 19-month period proved to have granulomatous appendicitis. One patient had surgery based on a clinical diagnosis of acute appendicitis. Four patients (three men and one woman; age range = 14-39 years) underwent abdominal CT. The CT findings were retrospectively reviewed with special attention to the appendiceal abnormalities. RESULTS: All four patients presented with subacute clinical presentation. Enlarged appendices of 4.5 and 2 cm in diameter with thickened walls of soft tissue density were found in two patients, and periappendicular inflammatory masses were found in the other two. Enlarged mesenteric lymph nodes and right lower quadrant fat stranding was seen in all four patients. Histopathology showed numerous granulomas within the inflamed appendix. CONCLUSION: Radiologists should be familiar with the rare entity of granulomatous appendicitis in patients examined by CT for suspected acute appendicitis. An insidious clinical presentation with CT findings of an exceptionally large appendix and associated periappendiceal inflammatory changes should raise the possibility of granulomatous appendicitis or carcinoma or lymphoma of the appendix.

Urinomas caused by ureteral injuries: CT appearance.

BACKGROUND: We report the computed tomographic (CT) features of urinomas caused by ureteral injuries which are often not clinically suspected, causing delay in diagnosis. METHODS: CT studies of 12 patients with ureteral injury were reviewed. Ureteral injuries were iatrogenic in 9 patients and traumatic in the remaining three. CT was performed between 2 and 139 days (average = 33 days) after the insult. The most common presenting symptoms were severe abdominal pain and fever. All CT studies were performed before and after intravenous contrast administration. In 11 of 12 cases, delayed scanning was added 15 min to 5 h later. RESULTS: The sites of injury were the proximal ureter in two patients, the middle ureter in three, the distal ureter in two, and the ureteral anastomosis in five. The urinomas appeared as confined water-density fluid collections in seven patients, as free fluid (urinary ascites) in two, and as both in three. Extravasation of contrast from the ureter was observed on early scans in six patients and on delayed scanning only in the other six. The density of the opacified urinoma measured 80-200 HU. Ipsilateral hydronephrosis was observed in seven patients. Ureteral injuries were treated conservatively in eight patients and surgically in four. CONCLUSION: Ureteral injuries after iatrogenic or penetrating trauma often are diagnosed with considerable delay. The presence of ascites or localized fluid collections in symptomatic patients after abdominal surgery or penetrating trauma should raise the possibility of a ureteral injury and prompt delayed scanning.

Iliopsoas abscess: a report of 24 patients diagnosed by CT.

BACKGROUND: We wanted to define the role of computed tomography (CT) in the diagnosis, etiology, and treatment of iliopsoas abscess. METHODS: Twenty-four patients (18 men, six women; age range = 17-86 years) with iliopsoas abscesses diagnosed over 8 years were retrospectively reviewed. All presented with fever and elevated white blood cell counts. Twenty-one had abdominal, flank or pelvic pain and nine had specific psoas signs suggesting the diagnosis. RESULTS: Seventeen of the abscesses were right-sided. Twenty were regarded as secondary to various underlying causes that were clearly demonstrated on CT and related to gastrointestinal (n = 12), skeletal (n = 5), or urinary tract (n = 3) diseases. All patients received appropriate antibiotic treatment. Thirteen also had their abscesses drained and eight had definitive surgical procedures. CONCLUSION: CT is an effective imaging technique for diagnosing iliopsoas abscess, even when classic clinical signs are absent. Treatment by percutaneous drainage under CT guidance is another advantage. When a psoas abscess is a complication of Crohn's disease, resection of the affected bowel segment is recommended in addition to drainage because drainage alone even in conjunction with appropriate medical therapy is usually not effective.

Computerized tomography findings of abdominal tuberculosis: report of 19 cases.

BACKGROUND: Abdominal tuberculosis usually presents with general symptoms and obscure abdominal complaints for which computerized tomography is often the first imaging study. OBJECTIVE: To evaluate the CT findings of abdominal tuberculosis. METHODS: The CT scans of 19 patients (10 men and 9 women aged 20-85 years) with proven abdominal tuberculosis were retrospectively reviewed to define the location and extent of the disease. The patients were referred for the study mainly with general systemic symptoms. Additional abdominal complaints were present in four, including acute abdomen in one. Two had symptoms deriving from the urinary tract. Nine patients had recently arrived from high prevalence countries; five of them and two others were positive for human immunodeficiency virus. Three patients had a family history of tuberculosis; one had previously been treated for tuberculosis and four others had an underlying chronic disease. The diagnosis of tuberculosis was established by standard microbiological and histological techniques. RESULTS: We divided the disease manifestations into intraperitoneal (n = 13) and genitourinary involvement (n = 6). Peritoneal tuberculosis was fairly common, characterized by ascites, omental and mesenteric infiltration, and smooth thickening of the parietal peritoneum. One oncology patient had a false positive Tc-99m CEA isotope scanning, suggesting tumor recurrence. Genitourinary disease manifested mainly as hydronephrosis and calcifications. Three patients had pulmonary tuberculosis as well. CONCLUSION: The CT findings of abdominal tuberculosis may mimic various diseases, mainly diffuse peritoneal malignancy. We emphasize the need to consider tuberculosis in the differential diagnosis in patients with obscure abdominal symptoms, especially with multi-organ involvement. A high degree of clinical suspicion and familiarity with the abdominal CT manifestations allow early diagnosis of this treatable disease.

Renal duplication with associated complications in adults: CT findings in 26 cases.

AIM: To review the computed tomography (CT) findings in 26 adult patients with complicated renal duplication, and to assess whether the complications were anomaly-related or superimposed by acquired disease. MATERIALS AND METHODS: Fifteen women and 11 men, aged 17-83 years took part in the study. All CT studies were reviewed to define the moieties affected. RESULTS: The duplication was unilateral in 18 cases and bilateral in six, one patient had a single left kidney and the remaining one a horseshoe kidney. In 14 patients the pathology was related only to the anomaly. Upper pole abnormalities were seen in 13 patients (seven related to the anomaly) and lower pole abnormalities in five (all related to duplication). Both systems were affected in eight cases, six of them by pathological processes unrelated to duplication. Hydronephrosis of the affected collecting system was the most common imaging finding. CONCLUSION: Computed tomography is often used to evaluate abdominal conditions in adults and may therefore be the first imaging modality to reveal a duplex kidney complicated by a pathological process. Involvement of only one moiety was frequently related to the duplication, with a predilection for the upper moiety, while involvement of both systems was used unrelated to the duplication. Zissin, R. (2001). Clinical Radiology, 56, 58-63.

Acute appendicitis with intestinal non-rotation presenting with partial small bowel obstruction diagnosed on CT.

The findings of acute appendicitis on CT have been extensively described in the literature. This is a report of a case of acute appendicitis in a patient with intestinal non-rotation presenting with partial small bowel obstruction. Analysis of the CT findings allowed a correct diagnosis.

Hepatic periportal tracking associated with severe acute pyelonephritis.

The computed tomographic appearance of hepatic perivascular halos has been described in a variety of disorders. We observed three cases with sepsis due to acute pyelonephritis who presented with anasarca and had identical computed tomographic features of periportal edema associated with ascites, pleural effusion, a thickened gallbladder wall, and a dilated inferior vena cava. None of the three patients had an underlying disease process that was previously described as an etiology for an altered hepatic lymphatic dynamics. Acute severe pyelonephritis should be included in the differential diagnosis of extrahepatic diseases that cause hepatic perivascular lucencies.

Intestinal malrotation as an incidental finding on CT in adults.

BACKGROUND: Intestinal malrotation in adults is usually an incidental finding on computed tomography (CT). We present the CT findings of 18 adult patients with malrotation and discuss the clinical implications. METHODS: Abdominal scans of 18 patients (12 women, six men; age range = 15-79 years) with intestinal malrotation were reviewed. Special attention was directed to the location of the superior mesenteric vessels, the location of the small and large bowels, the size of the uncinate process, the situs definition, and additional anomalies. RESULTS: The malrotation was an incidental finding in all but one patient. The malrotation was type Ia in 17 patients and IIc in the one symptomatic patient. The superior mesenteric vessels were vertically oriented in 10, inverted in two, normally positioned in four, and mirror imaged in two cases with situs ambiguus. All patients had aplasia of the pancreatic uncinate process, five had a short pancreas, and two had a preduodenal portal vein. Fourteen patients had a normal situs and four had heterotaxia. Seven patients had polysplenia, six of which with associated inferior vena cava anomalies. CONCLUSIONS: Intestinal malrotation can be diagnosed on CT by the anatomic location of a right-sided small bowel, left-sided colon, an abnormal relationship of the superior mesenteric vessels, and aplasia of the uncinate process. Awareness of these abnormalities is necessary to diagnose this anomaly. It should be sought in patients with a situs problem, inferior vena cava anomalies, polysplenia, or preduodenal portal vein. Although usually an incidental finding, it is important to diagnose such a malrotation because it may cause abdominal symptoms. Also, knowledge of associated vascular anomalies is important when abdominal surgery is planned.

Imaging of mucocoele of the appendix with emphasis on the CT findings: a report of 10 cases.

AIM: Mucocoele of the appendix denotes an obstructive dilatation of the appendiceal lumen due to abnormal accumulation of mucus. It is sometimes associated with pseudomyxoma peritonei, which predicts a malignant origin. We present the CT findings and additional imaging studies of 10 patients with neoplastic appendiceal mucocoele and discuss the clinical implications. MATERIALS AND METHODS: Abdominal CT findings from 10 patients with appendiceal mucocoele were reviewed. Barium enema, US and MRI were additionally performed in three patients. There were five men and five women aged 45-80 years. Special attention was directed to the shape and nature of the mass, its relation to the caecum and the presence of ascites or peritoneal implants, as well as possible additional ovarian tumours in female patients. RESULTS: The mucocoele was an incidental finding in five patients. They were either spherical or elongated cystic lesions, attached to the wall of the caecum, six of them with mural calcification. Ascites were present in six patients and hypodense large peritoneal implants representing pseudomyxoma peritonei in four. Pathologically the series included five cases of cystadenoma (in one, a malignant pseudomyxoma peritonei subsequently developed), four cases of cystadenocarcinoma and one villous adenoma (this patient later developed pseudomyxoma peritonei). Pseudomyxoma peritonei was found in five cases. Three women had associated ovarian cystic tumour. CONCLUSION: The appearance of an appendiceal mucocoele is quite characteristic and can be diagnosed on CT. CT can also depict additional findings suggesting pseudomyxoma peritonei. In women with an appendiceal mucocoele the ovaries should be examined closely for cystic tumour and vice versa.

Lung metastasis invading the left atrium--CT diagnosis.

A case of metastatic colonic adenocarcinoma invading the left atrium is reported in a patient with clinical signs of cardiac tamponade. The intracavitary extension of the tumour was clearly demonstrated by contrast enhanced CT. As CT plays an important role in the evaluation of patients with intrathoracic masses, intravenous contrast medium is recommended in those cases with associated clinical symptoms of heart disease or pericardial effusion. Its use may establish the diagnosis of cardiac involvement.

[Intravenous digital subtraction ventriculography: technical and methodologic aspects, a comparison with cineventriculography]. / Vnutrivennaia tsifrovaia subtraktsionnaia ventrikulografiia: tekhniko-metodicheskie aspekty, sravnenie s kinoventriculografiei.

Intravenous digital subtraction ventriculography (IDSV) was performed in 294 patients with various pathology. The IDSV method and conditions for obtaining informative ventriculograms were described. Hemodynamic indices and LV segmental contractility were assessed. IDSV and CVG data were compared in 52 cases. The results of both methods showed high correlation, IDSV having advantages over CVG (the absence of a cardiosuppressive effect resulting from direct administration of a contrast medium into the LV chamber and excluding LV quantitative overload). IDSV as a semiinvasive and easy-to-perform method has no contraindications.

[Lesions of the coronary bed in patients with ischemic heart disease and ECG changes at rest]. / Porazhenie koronarnogo rusla u bo'lnykh ishemicheskoi bolez'niu serdtsa s izmeneniiami EKG pokoia.

The data of ECG at rest and of coronary angiography have been analyzed in 184 patients. Correlations between various ECG changes and the coronary bed involvement have been revealed. The authors have calculated the sensitivities and specificities of some ECG symptoms for the prediction of an atherosclerotic involvement of the coronary arteries. A sufficiently high specificity of ECG examination (89.1%) makes it useful for active detection of coronary patients, whereas its low specificity (54.2%) necessitates employment of supplementary methods of investigation.