First-in-man-proof of concept study with molidustat: a novel selective oral HIF-prolyl hydroxylase inhibitor for the treatment of renal anaemia.

AIMS: Insufficient erythropoietin (EPO) synthesis is a relevant cause of renal anaemia in patients with chronic kidney disease. Molidustat, a selective hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, increases endogenous EPO levels dose dependently in preclinical models. We examined the pharmacokinetics, safety, tolerability and effect on EPO levels of single oral doses of molidustat in healthy male volunteers. METHODS: This was a single-centre, randomized, single-blind, placebo-controlled, group-comparison, dose-escalation study. Molidustat was administered at doses of 5, 12.5, 25, 37.5 or 50 mg as a polyethylene glycol-based solution. RESULTS: In total, 45 volunteers received molidustat and 14 received placebo. Molidustat was absorbed rapidly, and the mean maximum plasma concentration and area under the concentration-time curve increased dose dependently. The mean terminal half-life was 4.64-10.40 h. A significant increase in endogenous EPO was observed following single oral doses of molidustat of 12.5 mg and above. Geometric mean peak EPO levels were 14.8 IU l-1 (90% confidence interval 13.0, 16.9) for volunteers who received placebo and 39.8 IU l-1 (90% confidence interval: 29.4, 53.8) for those who received molidustat 50 mg. The time course of EPO levels resembled the normal diurnal variation in EPO. Maximum EPO levels were observed approximately 12 h postdose and returned to baseline after approximately 24-48 h. All doses of molidustat were well tolerated and there were no significant changes in vital signs or laboratory safety parameters. CONCLUSIONS: Oral administration of molidustat to healthy volunteers elicited a dose-dependent increase in endogenous EPO. These results support the ongoing development of molidustat as a potential new treatment for patients with renal anaemia.

Aneurysmatic disease in patients with Takayasu disease: a case review.

Takayasu disease is a non-specific inflammatory disease of the arterial system. Although various etiopathogenetic hypotheses have been formulated, its etiology remains unknown. The aorta and its main branches are predominantly involved in the disease, which is a form of panarteritis, starting with inflammation of the adventitia followed by involvement of the media and intima. It has been more frequently described in young oriental female patients. However, a worldwide distribution is being recognized. Arterial stenosis represents the most frequently diagnosed manifestation. Progression of the flogistic process may lead to stenosis of the aorta and supraaortic vessels, compromising arterial circulation to the brain and upper limbs. Aneurysm presentation may also rarely occur. Based on a recently treated case, the authors report on the clinical presentation, concomitant inflammatory diseases, current diagnostic methods, and management of this disease.

Recognition of persistent left superior vena cava in non-congenital patients undergoing cardiac surgery.

Persistent left superior vena cava (PLSVC) represents the most frequent congenital malformation of the thoracic venous drainage system. In adults referred to surgery for an acquired cardiac disease, abnormal venous drainage may be missed if not carefully researched. Discovering a previously undiagnosed PLSVC during cardiopulmonary bypass (CPB) may present some inconvenience for both the perfusionist and the surgeon, especially during a minimally invasive approach. The authors believe PLSVC probably may represent an under-reported condition. A careful screening of patients undergoing cardiac surgery may prove helpful. In particular, a complete echocardiographic study may help to better diagnose this condition before surgery. Different signs may raise the suspicion of PLSVC and should be carefully researched during preoperative patient work-up.

[Lung cancer with bronchial stenosis due to foreign body and Entoameba gingivalis infection]. / Carcinoma con stenosi bronchiale da corpo estraneo e infezione da Entoameba gingivalis. Case report.

Oral cavity infection by protozoarian agents may lead to pathologies such as stomatitis and gengivitis. An higher incidence has been reported in immunocompromised patients and in patients with dental disorders. Entoameba gingivalis localizes into oral cavity and in particular into interstitial and interdental spaces. Infection propagation to bronchial or lung parenchyma represents a complication. In this report the Authors, starting from a recently treated case, discuss on the incidence, complications and surgical management of lung infection by Entoameba gingivalis.

Endovascular repair of aortic rupture due to Brucella aortitis.

Brucellosis is a zoonosis, caused by bacteria belonging to the genus Brucella. Aortic involvement is a rare complication, often following embolization from infective endocarditis. However, contiguous propagation from vertebral involvement may occur. We report the case of an 81 year old patient abruptly presenting with aortic rupture due to Brucella melitensis infection. The diagnosis of aortic rupture was made by CT. The patient underwent urgent endovascular treatment using endoprosthesis deployment in the abdominal aorta and iliac arteries. Long term antibiotic treatment was given. Resolution of the acute event was obtained without further surgical treatment. 18 months after endovascular treatment, the patient remains in good health.

Calcified disease of the mitral annulus: a spectrum of an evolving disease.

Mitral annulus calcification may appear under different forms depending from its evolution stage: mitral annulus calcification; homogeneous calcified mass of the mitral valve; liquefaction necrosis of the mass; reduction or stability of the mass dimension. We report a large calcified mass located in between the posterior mitral valve leaflet and adjacent left ventricular myocardium suggesting the homogeneous calcified phase of the disease.

Atrial lipomatous hypertrophy causing reduction in systemic venous return.

Lipomatous hypertrophy of the interatrial septum (LHIAS) is a benign condition characterized by an abnormal deposition of adipose tissue in the interatrial septum which appears as a pseudomass with a bilobed shape. We present the case of a 68-year-old obese female patient. LHIAS is an infrequent finding, but with recent improvements in imaging it is increasingly recognized. Cardiac MRI may prove useful in its diagnosis in terms of tissue characterization, as well as for the evaluation of disease extension and haemodynamic compromise.

Regarding neurogenic malignant tumors in the mediastinum.

This letter reports on the rare presentation of a malignant neurogenic tumor in the phrenic nerve.

Quadricuspid morphology of the aortic valve.

Quadricuspid aortic valve is a rare congenital heart defect. It may be isolated or associated to other cardiac anomalies. It may cause aortic valve dysfunction, commonly aortic regurgitation. Management of patients with quadricuspid aortic valve is represented by strict follow-up, because they may require aortic valve replacement in later life. We report the case of a 37-year old male patient, occasionally diagnosed to have quadricuspid aortic valve. Diagnosis and management are discussed.

Cardiac allograft vasculopathy : complications and imaging studies.

Cardiac allograft vasculopathy (CAV) is an accelerated form of coronary artery disease affecting both intramyocardial and epicardial coronary arteries and is observed in patients during long-term survival after cardiac transplantation. We report a case of CAV complicated with silent transmural myocardial infarction and massive left ventricular thrombus formation associated with silent pericarditis and with ischemic and non-ischemic scar tissue, as detected by cardiac magnetic resonance imaging (CMRI). The authors suggest CMRI as an additional technique along with echocardiography during follow-up of heart transplant recipients. CMRI may contribute to the early identification of areas of myocardial wall abnormalities suggestive of CAV, thus guiding diagnosis and prompt percutaneous treatment.

[Near Infrared Spectroscopy for cerebral monitoring during cardiovascular surgery]. / La "Near Infrared Spectroscopy" (NIRS) per il monitoraggio cerebrale in chirurgia cardiovascolare.

Near-infrared spectroscopy (NIRS) is an optical imaging technique for medical applications, able to monitor the variation of hemoglobin saturation into the tissues. The NIR photon passes through the biological tissue following a path similar to a more or less complex split. The NIR absorption of photons is proportional to the concentration of chromophores (pigments that absorb the light in the spectral region of interest). NIRS probes are used as the light source on the same side of the source receiver, being this last able to capture the photons after their journey into the tissues. The NIRS methodology may be applied as an imaging technique for various organs. In this review the authors describe the use of NIRS for the continuous monitoring of regional cerebral oxygen saturation in the course of cardiovascular surgical procedures. Thanks to the NIRS technique, changes in cerebral oximetry can be monitored continuously during cardiovascular surgery. A desaturation greater than 20% of baseline or an rSO2 absolute value less than 50%, are associated with a reduction of the cortical somatosensory evoked potentials and an increase of neurological damage and / or cognitive impairment. During carotid surgery, reduction and / or asymmetries of rSO2 value are encountered in the course of intraoperative clamping causing cerebral hypoperfusion. Instead, rSO2 increase may predict hyperperfusion syndrome after carotid stenting or endarterectomy. Cerebral hyperperfusion syndrome is rare, but often fatal once it has established. The NIRS may represent an added value in those patients. The NIRS is also applied during surgery performed with cardiopulmonary bypass, including aortic arch surgery with cardiocirculatory arrest. Continuous monitoring of any changes in cerebral rSO2 allows a rapid treatment in the aim to improve the psycho-neurological outcome of patients undergoing this type of surgery.

Cross-femoral venous by-pass (Palma's procedure) to relieve venous hypertension due to retroperitoneal leiomyosarcoma: a case report.

Retroperitoneal leiomyosarcoma arising in, or involving, the inferior vena cava or the iliac vein are infrequent tumours. They are usually treated by "en-block" surgery. Venous reconstruction is usually not needed, since collateral circulation can adequately offset the main vessel flow. However, in rare cases, collateral circulation may be insufficient. The authors report a case of leiomyosarcoma infiltrating the left iliac vein. One week after radical resection surgery, the patient developed left leg compartmental syndrome due to venous hypertension. The patient was successfully treated by thrombectomy of the left femoral vein and cross-femoral venous bypass (Palma's Procedure) by means of an 8 mm diameter polytetrafluoroethylene (PTFE) prosthesis. To improve the flow inside the graft, an arterio-venous fistula (AVF) was performed. The choice of a prosthetic conduit, its diameter, and the AVF are discussed.

Use of FloSeal in the endovascular treatment of voluminous aneurysm of a lower gluteus artery.

We suggest an alternative endovascular treatment for gluteal artery aneurysm using Floseal a matrix of bovine gel and thrombin component. A 70-year-old woman, presented with claudicatio of the lower left limb after 150 m walking and pain at the sciatic nerve irradiation. A pulsating and painful mass was present in the lower gluteal region. No history for previous trauma, nor for orthopedic surgery. The suspect of aneurysm of the left gluteal artery was confirmed by Color Doppler Ultrasound and by computed tomography (CT) showing a fusiform aneurysm in the lower gluteus artery. In order to rule out infective cause, blood coltures were taken. Compression of the sciatic nerve was confirmed by electromyography study. Patient was treated by endovascular treatment. We performed angiography, with a selective study of the lower left gluteus artery, and embolization of the aneurysm by an injection of FloSeal (hemostatic) and fibered platinum coil. At the discharge, we observed absence of pulsation in gluteus region and the complete resolution of clinical symptom. The Color Doppler Ultrasound scan showed a complete occlusion of the aneurysm. This case appears quite peculiar, for the absence of any pelvic trauma, orthopedic operations or previous penetrating lesions, responsible of vascular lesions as reported in literature. The large aneurysm dimensions made the embolization procedure quite difficult, and brought us to use FloSeal. The treatment we proposed may be useful in the treatment of peripheral aneurysms of great dimension, and may be an alternative to the more traditional ones.

Bypass surgery for the treatment of upper limb chronic ischaemia.

OBJECTIVES: This study aims to evaluate the results and complications of surgical arterial revascularisation of the upper limb for treatment of chronic ischaemia using infrabrachial bypass. Results of limb salvage and follow-up with graft patency are analysed. DESIGN: This study is a retrospective analysis of 23 patients affected by chronic upper limb ischaemia and treated by surgical bypass. MATERIALS AND METHODS: We retrospectively analysed 23 patients with upper limb ischaemia treated between January 1998 and January 2008, by means of bypass graft revascularisation. After surgical revascularisation, eight patients (35%) with digital gangrene underwent minor amputations during the same surgical session, or within the following few days. Postoperatively, patients were followed up at regular intervals of 1, 3 and 6 months, and every 6 months thereafter, both clinically and with a duplex ultrasound scan. RESULTS: The mean 34 months' follow-up was 96% complete. Life table analysis revealed a primary patency of 82.6% and secondary patency of 91.3%. Limb salvage was 100%. During the follow-up period, four patients sustained graft occlusion and, of these, two underwent re-do revascularisation with success. CONCLUSIONS: We believe upper limb bypass surgery represents a valid treatment in this clinical setting, both for limb salvage and for relief of symptoms.

Resection and end-to-end anastomosis for ascending aortic aneurysm: surgical technique.

Treatment of ascending aortic aneurysm, without involvement of aortic sinuses of Valsalva, is usually treated by tube graft interposition. Nowadays, many alternative techniques were described. The technique of resection and end-to-end anastomosis has been already described both by our group and by other authors as well. This report will focus on some surgical details of this technique based on a ten-year-experience. The preoperative study of candidates amenable to undergo this technique has to be completed by a computed tomography-scan of thoracic aorta. The ideal candidate has an elongated aorta in the antero-lateral wall. As a consequence, the heart is usually displaced inferiorly and toward a more horizontal plane. The aortotomy is done circumferentially one and half cm above the aortic commissures. A wide wedge resection of the aortic wall is performed. The resected aortic wall is wider in the anterior part than in the posterior. A very accurate hemostasis of the fat tissue close to the pulmonary artery is achieved by diathermy. The amount of wedge resection is mainly dictated by the elongation of the aortic wall. In authors' experience it usually ranges between 4 and 6 cm anteriorly and 1 cm posteriorly. The suture of the two stumps is performed by a running suture. The technique described has extensively been used; up today 136 patients undergo. According to authors' opinion this technique can be a useful alternative to the tube graft interposition in selected patients.

Localised dissection in the convexity of the aortic arch.

We present images of a chest CT scan of an 89-year-old man, showing an area of localised dissection in the convexity of the aortic arch. The ascending and descending aorta were not involved in the disease. The patient suffered a stroke, with severe neurological impairment. Differential diagnosis was undertaken.

Chronic transverse sternal fracture. Role of CT scan and repair by an alternative use of the Synthes-Titanium Sternal Fixation System.

Chest wall fractures, including injuries of the sternum, usually heal spontaneously without specific treatment. However sometimes, they need surgical treatment. To treat these patients the selection criteria often are subjective in spite of many surgical devices for sternal osteosynthesis are available nowadays. One of the most recent device is the Synthes-Titanium Sternal Fixing System, usually used to treat post-sternotomy dehiscence. We describe the case of a 67-year-old man with previous history of chest trauma presenting to our institution with chronic transverse sternal fracture. We describe the pre-operative study, stressing the particular role of the CT scan and a surgical approach by an alternative use of the Synthes.