Safety of Lumason® (SonoVue®) in special populations and critically ill patients.

Evidence for the safe use of Lumason® (SonoVue®), an ultrasound enhancing agent (UEA), in special patient populations is critical to enable healthcare professionals to make informed decisions concerning its use in such patients. Herein, we provide insight on the safety and tolerability of Lumason® in special patient populations. Findings are presented from clinical pharmacology studies conducted in patients with compromised cardiopulmonary conditions, from a retrospective study performed in critically ill patients, and from post-marketing surveillance data from over 20 years of market use of Lumason® (SonoVue®). No detrimental effects of Lumason® on cardiac electrophysiology were observed in patients with coronary artery disease (CAD), and no significant effects on pulmonary hemodynamics were noted in patients with pulmonary hypertension or congestive heart failure. Similarly, no effects on several assessments of pulmonary function (e.g., FVC) were observed in patients with chronic obstructive pulmonary disease (COPD), and no clinically meaningful changes in O2 saturation or other safety parameters were observed after administration of Lumason® to patients with diffuse interstitial pulmonary fibrosis (DIPF). The retrospective study of critically ill patients revealed no significant difference for in-hospital mortality between patients administered Lumason® for echocardiography versus those who had undergone echocardiography without contrast agent. Post-marketing surveillance revealed very low reporting rates (RR) for non-serious and serious adverse events and that serious hypersensitivity reactions were rare. These findings confirm that Lumason® is a safe and well tolerated UEA for use in special populations and critically ill patients.

PCR-based approach for qualitative molecular analysis of six neurotropic pathogens.

In the last few years, polymerase chain reaction analysis is frequently required to improve the detection of pathogen infections in central nervous system as a potential cause of neurological disorders and neuropsychiatric symptoms. The goal of this paper is to set up a fast, cheap and reliable molecular approach for qualitative detection of six neurotropic pathogens. A method based on PCR has been designed and implemented to guarantee the qualitative DNA detection of herpes simplex virus types 1 and 2 (HSVI/II), Epstein-Barr virus (EBV), cytomegalovirus (CMV), varicella-zoster virus (VZV), rubella virus (RUBV) and Toxoplasma gondii in the cerebrospinal fluid, where otherwise they are barely detectable. Each PCR assay was tested using dilutions of positive controls, which demonstrated a sensitivity allowing to detect up to 102 copies/ml in PCR and 10 copies/ml in real-time PCR for each pathogen. Once been set up, the protocol was applied to evaluate the cerebrospinal fluid from 100 patients with suspected infectious diseases of the central nervous system and 50 patients without any infection. The method allowed to identify 17 positive cerebrospinal fluid with polymerase chain reaction and 22 with real-time PCR (RT-PCR), respectively. Therefore, application of RT PCR allows a fast and sensitive evaluation of neurotropic DNA pathogens in the course of diagnostic routine within neurological units.

KFLC Index utility in multiple sclerosis diagnosis: Further confirmation.

The Multiple Sclerosis (MS) diagnosis is based on dissemination of focal lesions in time and space. The free light chains (FLCs) determination might be a sensitive alternative to oligoclonal bands assay. The study aim was to redefine sensitivity, specificity of the kFLC Index cut-off. We analyzed serum and cerebrospinal fluid of 176 patients, with different neurological disorders. We obtained a cut off of 12,3 for kFLC Index with a sensitivity and specificity of 93% and 100% respectively. Our data confirm that the kFLC Index is a valid tool in the diagnosis of MS.

Radiographic evaluation of mediastinal lines as a diagnostic approach to occult or subtle mediastinal abnormalities.

The mediastinal lines visible at conventional radiography represent the interfaces between the mediastinum and adjacent lung parenchyma. Preservation, obliteration, thickening and distortion of these lines represent the key to detecting and localising mediastinal abnormalities on chest radiographs. The learning objectives of this review are to: illustrate radiographic anatomy of the mediastinum with particular attention to mediastinal lines; describe radiographic signs that allow identification of mediastinal abnormalities that are difficult to detect on conventional chest radiographs; describe findings that help localise abnormalities in the anterior, middle or posterior mediastinum. The anterior junction line obliteration, the hilum overlay sign, the preservation of the posterior mediastinal lines and the silhouette sign with the right cardiac border are radiographic signs that allow identification and localisation of anterior mediastinal lesions. Widening of the right paratracheal stripe, distortion of the azygo-oesophageal recess and the convex border of the aortopulmonary window indicate the presence of a middle mediastinal abnormality. Thickening, distortion or disruption of paraortic and paraspinal lines and posterior junction line obliteration are caused by posterior mediastinal lesions. Knowledge of normal radiographic mediastinal anatomy and mediastinal lines is crucial to identifying subtle mediastinal abnormalities that can be easily missed on conventional radiography. Moreover, this approach allows identification of the involved mediastinal compartment on chest radiographs, thereby directing the most appropriate further diagnostic workup.

Misty mesentery: a pictorial review of multidetector-row CT findings.

The term "misty mesentery" indicates a pathological increase in mesenteric fat attenuation at computed tomography (CT). It is frequently observed on multidetector CT (MDCT) scans performed during daily clinical practice and may be caused by various pathological conditions, including oedema, inflammation, haemorrhage, neoplastic infiltration or sclerosing mesenteritis. In patients suffering from acute abdominal disease, misty mesentery may be considered a feature of the underlying disease. Otherwise, it may represent an incidental finding on MDCT performed for other reasons. This article describes the MDCT features of misty mesentery in different diseases in order to provide a rational approach to the differential diagnosis.

Low-dose multidetector-row CT-angiography of abdominal aortic aneurysm after endovascular repair.

PURPOSE: To investigate the possibility of reducing radiation dose exposure while maintaining image quality using multidetector computed tomography angiography (MDCTA) with high-concentration contrast media in patients undergoing follow-up after endovascular aortic repair (EVAR) to treat abdominal aortic aneurysm. MATERIALS AND METHODS: In this prospective, single center, intra-individual study, patients underwent two consecutive MDCTA scans 6 months apart, one with a standard acquisition protocol (130 mAs/120 kV) and 120 mL of iomeprol 300, and one using a low dose protocol (100 mAs/80 kV) and 90 mL of iomeprol 400. Images acquired during the arterial phase of contrast enhancement were evaluated both qualitatively and quantitatively for image noise and intraluminal contrast enhancement. RESULTS: Thirty adult patients were prospectively enrolled. Statistically significantly higher attenuation values were measured in the low-dose acquisition protocol compared to the standard protocol, from the suprarenal abdominal aorta to the common femoral artery (p<0.0001; all vascular segments). Qualitatively, image quality was judged significantly (p=0.0002) better with the standard protocol than with the low-dose protocol. However, no significant differences were found between the two protocols in terms of contrast-to-noise ratio (CNR) (13.63±6.97 vs. 11.48±8.13; p=0.1058). An overall dose reduction of up to 74% was observed for the low-dose protocol compared with the standard protocol. CONCLUSION: In repeat follow-up examinations of patients undergoing EVAR for abdominal aortic aneurysm, a low-dose radiation exposure acquisition protocol provides substantially reduced radiation exposure while maintaining a constant CNR and good image quality.

Endoleaks after endovascular repair of abdominal aortic aneurysm: value of CEUS.

Endovascular repair (EVAR) is playing an increasingly role in the treatment of abdominal aortic aneurysm. A successful procedure depends on the complete sealing of the aneurysm sac from blood flow to achieve general pressure relief and avoid aneurysm rupture, with a shrinkage of the aneurysm sac. The most common complication of EVAR is endoleak that is the persistence of perigraft flow within the aneurysm sac, which has to be considered the major cause of enlargement and rupture of the aneurysm, and the main indication for surgical late conversion. For this reason, strict surveillance of these patients is mandatory for the early detection of endoleaks and the preferred method of follow-up is represented by CT angiography. However, CTA has limitations. The investigation is repeated several times, making radiation exposure a necessary concern. Therefore, it would be useful to have another reliable diagnostic examination during follow-up. Color duplex ultrasound is non-invasive, does not use radiation or contrast medium, is less expensive, easy to perform and widely available. However, this technique obtained poor results in terms of sensitivity in the detection of endoleaks. In the last years, the introduction of ultrasound contrast agents and contrast-specific imaging has, however, rekindled interest in this modality and its potential for replacing of CTA in routine surveillance. The purpose of this review is to highlight the diagnostic value of CEUS in the post-EVAR endoleaks detection.

Switch in the expression of mGlu1 and mGlu5 metabotropic glutamate receptors in the cerebellum of mice developing experimental autoimmune encephalomyelitis and in autoptic cerebellar samples from patients with multiple sclerosis.

Recent evidence suggests that changes in the expression of membrane receptors/ion channels in cerebellar Purkinje cells contribute to the onset of cerebellar motor symptoms in patients with multiple sclerosis (MS). We examined the expression of group-I metabotropic glutamate receptors (mGlu1 and mGlu5 receptors) in the cerebellum of mice developing experimental autoimmune encephalomyelitis (EAE) and in autoptic cerebellar samples of MS patients. EAE was induced in mice by immunization with the 35-55 fragment of MOG (myelin oligodendrocyte glycoprotein). EAE mice showed a progressive loss of mGlu1a receptors in the cerebellum, associated with an increased expression of mGlu5 receptors. These changes were restricted to Purkinje cells and their dendritic arborization, as shown by immunohistochemistry. A reduced expression of mGlu1a receptors in cerebellar Purkinje cells was also found in 7 of 9 MS patients. In addition, a light/moderate to very strong mGlu5 receptor immunoreactivity was detected in Purkinje cells of 8 MS patients, but was always absent in non-MS control patients. In EAE mice, an acute treatment with the mGlu1 receptor enhancer, 9H-xanthene-9-carboxylic acid (4-trifluoromethyl-oxazol-2-yl)-amide (RO0711401), significantly improved motor coordination, whereas treatment with the mGlu5 receptor antagonists, 2-methyl-6-(phenylethynyl)-pyridine (MPEP) and 6-methyl-2-(phenylazo)-3-pyridinol (SIB-1757), had no effect. We conclude that mGlu1 receptor enhancers improve motor symptoms associated with EAE and might be helpful as symptomatic drugs in patients with MS.

Automated volumetry of pulmonary nodules on multidetector CT: influence of slice thickness, reconstruction algorithm and tube current. Preliminary results.

PURPOSE: To evaluate the influence of slice thickness, reconstruction algorithm and tube current (mA) on the performance of a software package in determining the volume of solid pulmonary nodules on multidetector-row computed tomography (MDCT). MATERIALS AND METHODS: A chest phantom containing artificial solid nodules with known volume was imaged with two MDCT scans at 100 and 40 mAs (200 mA and 80 mA, 0.5-s rotation time), respectively. Data were reconstructed with slice thicknesses of 1.25 and 2.5 mm and five different algorithms. The volumes of three nodules (juxtavascular, intraparenchymal, juxtapleural) were calculated using three-dimensional (3D) volumetric software. Differences between estimated and real volume were reported for each nodule and reconstruction set. RESULTS: The software segmented all nodules on 1.25-mm-thick reconstructions, independently from the mAs. It did not segment the juxtapleural nodule on 2.5-mm-thick reconstructions at 40 mAs. Mean values of the differences, which better approximated the real volume of the nodules, were obtained with high-spatial-resolution algorithms on both 100 and 40 mAs images at 1.25-mm slice thickness. CONCLUSIONS: Slice thickness, reconstruction algorithm and tube current can affect the 3D volume measurement of solid nodules. The best performance of the software, on both 100 and 40 mAs images, was observed with a slice thickness of 1.25 mm and high-spatial-resolution algorithms.

Endovascular abdominal aortic aneurysm repair and renal complications: a comparison between suprarenal and infrarenal fixation of stent grafts.

PURPOSE: This study was performed to compare the rate of morphological (renal infarction and/or ischaemic lesions) and functional renal complications after the suprarenal and infrarenal fixation of aortic stent-grafts for endovascular abdominal aortic aneurysm repair (EVAR). MATERIALS AND METHODS: We retrospectively reviewed all followup computed tomography (CT) angiograms (obtained at 1, 6 and 12 months and yearly thereafter) and laboratory data pertaining to 102 patients who underwent suprarenal (60 patients, group A) or infrarenal (42 patients, group B) placement of aortic stent-grafts. The groups were compared in terms of complications affecting kidney function (creatinine clearance) and morphology (renal artery steno-occlusions, morphological and structural parenchymal changes), and pre- and postprocedural arterial pressure (AP). RESULTS: Analysis of patient demographics revealed no statistically significant difference between the two groups. The proximal neck was shorter in group A (2.14 cm+/-0.84 cm) than in group B (3.41 cm+/-1.21 cm). Creatinine clearance (CrCl) decreased in both groups (group A: from 64.24 ml/min to 60.66 ml/min; group B: from 72.41 ml/min to 68.73 ml/min) without any significant difference in terms of changes in renal function (CrCl variation: -8.75% vs. -6.4%) or morphology (post-EVAR stenosis: 2.6% vs. 0%; progression of existing steno-occlusive lesions: 1% vs. 0%; ischaemic lesions: 3.2% vs. 0%), or in AP. CONCLUSIONS: In our experience, the use of abdominal endografts with suprarenal fixation did not lead to any significant increase in morphological and/or functional renal complications compared with those with infrarenal fixation.

Endovascular abdominal aortic aneurysm repair: how many patients are eligible for endovascular repair?

PURPOSE: The purpose of this study was to determine how many patients with abdominal aortic aneurysm (AAA) are eligible for endovascular abdominal aortic aneurysm repair (EVAR). MATERIALS AND METHODS: We retrospectively reviewed computed tomography (CT) angiograms obtained between January 2002 and June 2003 in 182 patients with suspected AAA. Indication for surgical or endovascular treatment was based on clinical and radiological criteria. The percentage of patients eligible for EVAR was evaluated. RESULTS: Out of a total of 182 patients with suspected AAA studied by CT angiography, after combined radiological-surgical assessment, 130 were considered eligible for surgical or endovascular treatment (71.4%). EVAR was indicated in 51 patients (39.3%, group A) and surgical repair was indicated in 79 patients (60.7%, group B). The reasons for ineligibility for EVAR were the following: unfavourable anatomy of the proximal neck in 41 patients (51.9%), diameter of the aneurysm sac >7 cm in 13 patients (16.4%), markedly tortuous/dilated iliac axis in six patients (7.6%), age <65 years in 17 patients (21.5%) and patient refusal in two cases (2.5%). There were no statistically significant differences in aneurysm diameter (52.7+/-0.8 versus 49.8+/-1.2 mm, p=ns), patients' age (73.2+/-1.2 versus 70.6+/-2.02 years, p=ns) or proximal neck length (2.95+/-1 versus 3.03+/-1.2 cm, p=ns) between groups A and B. CONCLUSIONS: Endovascular repair of abdominal aortic aneurysms through the placement of aortic stent-grafts has now become a viable alternative to open surgery. In recent years, the number of patients treated with EVAR has steadily risen as a result of increased physician experience, availability of new and more versatile devices and improvements in noninvasive imaging techniques. Unfavourable neck anatomy is the primary factor for exclusion from endovascular repair.

Metabotropic receptors as targets for drugs of potential use in the treatment of neuropathic pain.

Glutamate is the major neurotransmitter in the mammalian central nervous system and plays a pivotal role in both acute and chronic pain. The actions of glutamate are mediated by two receptor families: ionotropic glutamate receptors (iGluRs), and metabotropic glutamate receptors (mGluRs). Activation of glutamate receptor can elicit both hyperalgesic and analgesic effects. Eight mGluRs subtypes (mGluR1-mGluR8) have been identified and classified into three groups. Among these, group I mGluRs (mGlu1 and -5) have been implicated in the processes of central sensitization and persistent nociception, whereas activation of group II mGluRs (mGlu2/3) is effective against neuropathic or inflammatory pain. In this review we focus on the role of mGlu2/3 in the modulation of persistent pain, and on their potential use as drug targets in pain management.

An increased expression of the mGlu5 receptor protein following LTP induction at the perforant path-dentate gyrus synapse in freely moving rats.

The involvement of metabotropic glutamate (mGlu) receptors in the induction of long-term potentiation (LTP) in vivo has been consistently documented. We have investigated whether LTP induction in the dentate gyrus of rats leads to changes in expression of mGlu2/3 or -5 receptor subtypes in the hippocampus. LTP was induced at the medial perforant path-dentate gyrus synapses, and mGlu receptor expression was examined by Western blot or in situ hybridization. An up-regulation of mGlu5 receptors was observed in the hippocampus both 24 and 48 h following LTP induction. This effect was restricted to the dentate gyrus and CA1 region, whereas no changes in mGlu5 receptor protein (but an increase in mRNA levels) were observed in the CA3 region. The increased expression of mGlu5 receptors was directly related to the induction of LTP, because it was not observed when tetanic stimulation was carried out in animals treated with the NMDA receptor antagonist, 2-amino-5-phosphonopentanoate (AP5). Western blot analysis also showed a reduced expression of mGlu2/3 receptors in the whole hippocampus 24 h after LTP induction, indicating that the increased expression of mGlu5 receptors was specific. These data suggest that an up-regulation of mGlu5 receptors is a component of the plastic changes that follow the induction of LTP at the perforant path-dentate gyrus synapse.

Imipramine treatment up-regulates the expression and function of mGlu2/3 metabotropic glutamate receptors in the rat hippocampus.

We examined the effect of a chronic imipramine treatment (10 mg/kg, i.p., once daily for 21 days) on the expression and function of metabotropic glutamate (mGlu) receptors in discrete regions of the rat brain. Chronic imipiramine treatment up-regulated the expression of mGlu2/3 receptor proteins in the hippocampus, nucleus accumbens, cerebral cortex and corpus striatum. Expression of mGlu1a receptor protein was increased exclusively in the hippocampus, whereas no changes in the expression of mGlu4 and mGlu5 receptors or Homer-1a protein were detected. Using hippocampal slices, we examined the stimulation of polyphosphoinositide (PI) hydrolysis induced by mGlu receptor agonists in control and imipramine-treated rats. Imipramine treatment amplified the PI response to the non subtype-selective mGlu receptor agonist, 1S,3R-aminocyclopentane-1,3-dicarboxylated (1S,3R-ACPD) in both hippocampal and cortical slices, but failed to affect the response to the selective mGlu1/5 receptor agonist, S-3,5-dihydroxyphenylglycine (DHPG). Amplification was restored when DHPG was combined with the selective mGlu2/3 receptor agonist, LY379268. In addition, 1S,3R-ACPD-stimulated PI hydrolysis was no longer enhanced in imipramine-treated rats when the mGlu2/3 component of the PI response was abrogated by the antagonist, LY341495. In contrast, the ability of LY379268 to inhibit forskolin-stimulated cAMP formation was reduced in hippocampal slices of rats chronically treated with imipramine. Taken together, these results suggest that neuroadaptive changes in the expression and function of mGlu2/3 receptors occur in response to chronic antidepressants.

L-Acetylcarnitine induces analgesia by selectively up-regulating mGlu2 metabotropic glutamate receptors.

L-Acetylcarnitine (LAC, 100 mg/kg, s.c.), a drug commonly used for the treatment of painful neuropathies, substantially reduced mechanical allodynia in rats subjected to monolateral chronic constriction injury (CCI) of the sciatic nerve and also attenuated acute thermal pain in intact rats. In both cases, induction of analgesia required repeated injections of LAC, suggesting that the drug induces plastic changes within the nociceptive pathway. In both CCI- and sham-operated rats, a 24-day treatment with LAC increased the expression of metabotropic glutamate (mGlu) receptors 2 and 3 in the lumbar segment of the spinal cord, without changing the expression of mGlu1a or -5 receptors. A similar up-regulation of mGlu2/3 receptors was detected in the dorsal horns and dorsal root ganglia of intact rats treated with LAC for 5-7 days, a time sufficient for the induction of thermal analgesia. Immunohistochemical analysis showed that LAC treatment enhanced mGlu2/3 immunoreactivity in the inner part of lamina II and in laminae III and IV of the spinal cord. An increased mGlu2/3 receptor expression was also observed in the cerebral cortex but not in the hippocampus or cerebellum of LAC-treated animals. Reverse transcription-polymerase chain reaction combined with Northern blot analysis showed that repeated LAC injections selectively induced mGlu2 mRNA in the dorsal horns and cerebral cortex (but not in the hippocampus). mGlu3 mRNA levels did not change in any brain region of LAC-treated animals. To examine whether the selective up-regulation of mGlu2 receptors had any role in LAC-induced analgesia, we have used the novel compound LY 341495, which is a potent and systemically active mGlu2/3 receptor antagonist. LAC-induced analgesia was largely reduced 45 to 75 min after a single injection of LY 341495 (1 mg/kg, i.p.) in both CCI rats tested for mechanical allodynia and intact rats tested for thermal pain. We conclude that LAC produces analgesia against chronic pain produced not only by peripheral nerve injury but also by acute pain in intact animals and that LAC-induced analgesia is associated with and causally related to a selective up-regulation of mGlu2 receptors. This offers the first example of a selective induction of mGlu2 receptors and discloses a novel mechanism for drug-induced analgesia.

Neuroprotection mediated by glial group-II metabotropic glutamate receptors requires the activation of the MAP kinase and the phosphatidylinositol-3-kinase pathways.

The mGlu2/3 receptor agonists 4-carboxy-3-hydroxyphenylglycine (4C3HPG) and LY379268 attenuated NMDA toxicity in primary cultures containing both neurons and astrocytes. Neuroprotection was abrogated by PD98059 and LY294002, which inhibit the mitogen activated protein kinase (MAPK) and the phosphatidylinositol-3-kinase (PI-3-K) pathways, respectively. Cultured astrocytes lost the ability to produce transforming growth factor-beta1 (TGF-beta1) in response to mGlu2/3 receptor agonists when co-incubated with PD98059 or LY294002. As a result, the glial medium was no longer protective against NMDA toxicity. Activation of the MAPK and PI-3-K pathways in cultured astrocytes treated with 4C3HPG or LY379268 was directly demonstrated by an increase in the phosphorylated forms of ERK-1/2 and Akt. Similarly to that observed in the culture, intracerebral or systemic injections of mGlu2/3 receptor agonists enhanced TGF-beta1 formation in the rat or mouse caudate nucleus, and this effect was reduced by PD98059. PD98059 also reduced the ability of LY379268 to protect striatal neurons against NMDA toxicity. These results suggest that activation of glial mGlu2/3 receptors induces neuroprotection through the activation of the MAPK and PI-3-K pathways leading to the induction of TGF-beta.

Expression of metabotropic glutamate receptors in the rat and human testis.

The G protein-coupled receptor kinase type 4 mediates the homologous desensitisation of type-1 metabotropic glutamate (mGlu1) receptors and is predominantly expressed in the testis. Hence, we searched for the expression of mGlu1 or other mGlu receptor subtypes in rat and human testes. RT-PCR analysis showed the presence of mGlu1, -4 and -5 (but not -2 or -3) receptor mRNA in the rat testis. The presence of mGlu1 and -5 (but not mGlu2/3) receptor proteins was also demonstrated by Western blot analysis. In the rat testis, both mGlu1a and -5 receptors were highly expressed in cells of the germinal line. It is likely that these receptors are functional, because the agonist, (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid, was able to stimulate inositol phospholipid hydrolysis in slices prepared from rat testes. Immunocytochemical analysis of bioptic samples from human testes showed a high expression of mGlu5 receptors inside the seminiferous tubuli, whereas mGlu1a immunoreactivity was restricted to intertubular spaces. mGlu5 receptors were also present in mature spermatozoa, where they were localised in the mid-piece and tail. This localisation coincided with that of beta-arrestin, a protein that is critically involved in the homologous desensitisation and internalisation of G protein-coupled receptors. Taken collectively, these results offer the first evidence for the expression of any glutamate receptor in testes, and suggest that at least mGlu5 receptors are present and functionally active in mature human sperm.