Fully covered metallic stents in biliary stenosis after orthotopic liver transplantation.

BACKGROUND AND STUDY AIMS: Data from a preliminary study suggested that the placement of a fully covered metal stent may be a valid alternative to surgery in patients who do not respond to standard endoscopic treatment. The aims of the current study were to evaluate the clinical success of self-expandable metallic stents (SEMS) in a large cohort of patients and with a long followup,and the effectiveness of SEMS placement as a first-line procedure. MATERIALS AND METHODS: Between January 2008 and August 2010, 54 consecutive patients with biliary complications following orthotopic liver transplantation were treated with SEMS placement:39 after failure of conventional endoscopic therapy (Group I), and 15 with no previous endoscopic treatment who were undergoing SEMS placement as first-line treatment for complications(Group II). RESULTS: In Group I, resolution after SEMS removal was observed in 71.8% of patients. Mean followup after resolution was 22.1 ±10 months. Recurrence of the complication was observed in 14.3%of patients after a mean of 8.5 months and SEMS migration was observed in 33.3% of patients. In Group II, resolution was observed in 53.3% of patients.Mean follow-up after resolution was 14.4±2.2 months. Recurrence was observed in 25% of patients and SEMS migration was observed in 46.7 %. CONCLUSIONS: For endotherapy of biliary complications after orthotopic liver transplantation, metallic stents should not be used as the primary modality. In patients in whom the standard approach fails, treatment with temporary SEMS placement can solve biliary complications in almost three-quarters of cases; however stent migration(33 %) remains a problem.

Fully covered self-expandable metallic stents in benign biliary strictures: a multicenter study on efficacy and safety.

BACKGROUND AND STUDY AIM: Benign biliary diseases include benign biliary stricture (BBS), lithiasis, and leaks. BBSs are usually treated with plastic stent placement; use of uncovered or partially covered metallic stents has been associated with failure related to mucosal hyperplasia. Some recently published series suggest the efficacy of fully covered self-expandable metal stents (FCSEMSs) in BBS treatment. We aimed to assess the efficacy and safety of FCSEMS in a large series of patients with BBS and a long follow-up.  PATIENTS AND METHODS: Prospective multicenter clinical study at three tertiary referral centers: ISMETT/UPMC Italy, Palermo, San Paolo Hospital, Milan, and the ARNAS Civico Hospital, Palermo, Italy. All consecutive patients with BBS were treated with placement of FCSEMS rather than plastic stents, as first approach (11 patients, 17.7 %), or as a second approach after failure of other treatments (51 patients, 82.2 %). RESULTS: From January 2008 to March 2011, 62 patients (40 male) were included. Mean period of FCSEMS indwelling was 96.7 days (standard deviation [SD] 6.5 days). In 15 patients (24.2 %) the SEMS migrated. Resolution of BBS occurred in 56 patients (90.3 %), while in 6 (9.6 %) the treatment failed. Mean (SD) follow-up after SEMS removal was 15.9 (10) months. FCSEMS placement as first- or second-line approach showed no difference in failure. Recurrence was observed in 4 /56 patients (7.1 %); all were transplant recipients: P = 0.01; odds ratio (OR) 1.2, confidence interval (CI) 1.1 - 1.3. CONCLUSIONS: Despite the noteworthy migration rate, FCSEMSs should be considered effective for refractory benign biliary strictures. Further studies are needed to assess their role as a first approach in the management of BBS.

Upper limb motor evoked potentials as outcome measure in progressive multiple sclerosis.

OBJECTIVE: To assess the usefulness of upper limb (UE) motor evoked potential (MEPs) as a marker of motor impairment in a cohort of people with progressive multiple sclerosis (PwPMS). METHODS: we evaluated UE and lower extremities (LE) MEPs, 6-minutes walk-test (6MWT), 10-meter walk-test (10MWT), EDSS, 9-hole peg-test (9HPT), and measures of strength (MRC) and tone (MAS) to the UE and LE in 50 PwPMS (EDSS 4.0-6.5; P ≥ 3, C ≤ 2). RESULTS: Bilateral absence of LE-MEPs, found in 74% of cases, was associated with worse 10MWT and 6MWT. UE-MEPs were rarely absent (8%) but often delayed (74%). Abnormal UE-MEPs were associated with worse performance at 9HPT (25.8 vs 33.2 s). UE-MEPs latency correlated with 10MWT (rho = 0.597), 6MWT (rho = -0.425) and EDSS (rho = 0.296). CONCLUSION: UE-MEPs may represent a clinically relevant outcome measure to quantify corticospinal tract integrity in PwPMS, at least when LE-MEPs cannot provide a measurable response. SIGNIFICANCE: The strive for novel remyelination strategies in MS points to the need for quantitative conduction measurements in addition to clinical outcomes. The frequent absence of MEPs to the lower limbs in PwPMS may greatly limits their usefulness in monitoring progression or response to therapies. With this respect, the upper extremities may represent a better target.

Acquired haemophilia A as a secondary autoimmune disease after alemtuzumab treatment in multiple sclerosis: A case report.

Alemtuzumab is a highly effective monoclonal antibody for the treatment of multiple sclerosis (MS). During the immune reconstitution following the use of this treatment severe secondary autoimmune diseases (SADs) can develop. We present the case of a patient affected by active MS who failed to achieve disease control with several disease-modifying drugs and was thereafter successfully treated with alemtuzumab, obtaining no evidence of disease activity and a high quality of life. Twenty months after the first infusion of alemtuzumab the patient developed acquired haemophilia A (AHA), a treatable but potentially lifethreatening condition that should be considered a possible SADs associated to this drug. In order to allow an early diagnosis and to prevent possible complications of AHA, routine coagulation tests (prothrombin time and activated partial thromboplastin time) should be included in the laboratory serological monitoring of patients treated with alemtuzumab.

Behavioral consequences of bone marrow transplantation in the treatment of murine mucopolysaccharidosis type VII.

The gusmps/gusmps mouse is a model of the human lysosomal storage disease mucopolysaccharidosis type VII caused by deficient beta-glucuronidase activity. Bone marrow transplantation has been shown to correct some of their biochemical and pathological abnormalities but its efficacy in correcting their neurological functional deficits is unknown. We transplanted the neonatal gusmps/gusmps mice and their normal controls and evaluated their central nervous system function with two behavioral tests: the grooming test, a developmentally regulated and genetically based activity, and a Morris water maze test which assessed spatial learning abilities. The two transplanted groups groomed less than the normals, were unable to remember the location of an invisible platform from day to day, and were severely impaired at developing strategies to locate the platform in unfamiliar locations. The performance of both normal and mutant transplanted groups was clearly inferior to the untreated normals and, in some instances, close to or worse than the untreated mutants, even though the enzyme abnormalities of the mutants have been partially corrected. Hence, the behavioral deficits in the mutant mice were not restored to normal while similarly treated normal mice showed significant functional deterioration, indicating the detrimental consequence of this therapy in the neonatal period.

Unsaturated acyl chains dramatically enhanced cellular uptake by direct translocation of a minimalist oligo-arginine lipopeptide.

The recurring issue with cell penetrating peptides is how to increase direct translocation vs. endocytosis, to avoid premature degradation. Acylation by a cis unsaturated chain (C22:6) of a short cationic peptide provides a new rational design to favour diffuse cytosolic and dense Golgi localisations.

Four glycoproteins are expressed in the cat zona pellucida.

The mammalian oocyte is surrounded by a matrix called the zona pellucida (ZP). This envelope participates in processes such as acrosome reaction induction, sperm binding and may be involved in speciation. In cat (Felis catus), this matrix is composed of at least three glycoproteins called ZP2, ZP3, and ZP4. However, recent studies have pointed to the presence of a fourth protein in several mammals (rat, human, hamster or rabbit), meaning that a reevaluation of cat ZP is needed. For this reason, the objective of this research was to analyze the protein composition of cat ZP by means of proteomic analysis. Using ZP from ovaries and oocytes, several peptides corresponding to four proteins were detected, yielding a coverage of 33.17%, 71.50%, 50.23%, and 49.64% for ZP1, ZP2, ZP3, and ZP4, respectively. Moreover, the expression of four genes was confirmed by molecular analysis. Using total RNA isolated from cat ovaries, the complementary deoxyribonucleic acids encoding cat ZP were partially amplified by reverse-transcribed polymerase chain reaction. Furthermore, ZP1 was totally amplified for the first time in this species. As far as we are aware, this is the first study that confirms the presence of four proteins in cat ZP.

Homotaurine (3 aminopropanesulfonic acid; 3APS) protects from the convulsant and cytotoxic effect of systemically administered kainic acid.

Pretreatment of rats with homotaurine (3 aminopropanesulfonic acid; 3APS), a synthetic gamma-aminobutyric acid (GABA) analog, protected from the convulsant and cytotoxic action of systemically injected kainic acid (KA). Wet dog shaking (WDS) behavior was significantly reduced. Taurine, an inhibitory non-GABA-mimetic amino acid, and muscimol (another direct GABA-agonist) reduced the number of seizures and lesions in the brain but were less effective than homotaurine. Progabide (a GABA-agonist) did not modify kainic acid effects. The neurotoxicity of kainic acid could have been due to repetitive convulsive activity. Activation of GABA-mediated inhibition is an effective, but not the determinant means of preventing KA-induced abnormalities.

Motor functions of the striatum in the rat: critical role of the lateral region in tongue and forelimb reaching.

The findings of this study indicate a critical and selective role of the rat's lateral striatum in performance of tongue and forelimb reaching. To test the hypothesis of regional specificity of motor control in the striatum, the effects of bilateral, ibotenate-induced lesions of either the lateral or the medial regions of the striatum on reaching movements of the tongue and the forelimbs were examined. Lesions of the lateral striatum caused severe and chronic impairments of movement initiation, postural synergisms and amplitude of both tongue and forelimb reaches. In contrast, lesions of the medial striatum produced mild or no chronic alterations of these motor parameters. These findings support the hypothesis of a selective role of the lateral striatum in the initiation and execution of reaching movements.

Dissociable motor roles of the rat's striatum conform to a somatotopic model.

The findings of this study indicate distinctive roles of different regions of the rostral striatum of rat in segmental motor control. In order to test the hypothesis of somatotopically organized motoric functions in the striatum, the effects of bilateral ibotenate-induced lesions of either the dorsomedial or the dorsolateral or the ventrolateral regions of the rostral striatum on reaching movements of the tongue and the forelimbs were examined. Lesions of the dorsolateral region chronically impaired reaching movements of the forelimbs but not of the tongue. Lesions of the ventrolateral region impaired initiation and execution of reaching movements of both the tongue and the forelimbs, with the impairment of forelimb reaching being somewhat less severe than that produced by dorsolateral lesions. Neuronal loss in the medial striatum had no chronic effects on either movements. The impairments of reaching performance reflected failures of motor synergisms between tongue and head and between limb and paw, as well as alterations in the scaling of movement amplitude. These findings support the hypothesis of a motor somatotopy in the lateral region of the rat's rostral striatum and of a critical role of the lateral striatum in initiation, scaling, and coordination of reaching movements.

Intact selective attention in rats with lesions of the dorsal noradrenergic bundle.

Mason's hypothesis (1980) was tested that lesions of the dorsal noradrenergic bundle (DNB), which induce depletion of forebrain noradrenaline, alter performance of discrimination tasks because they retard habituation to naturally attractive, but instrumentally irrelevant, stimuli. In Experiment 1, groups of rats with either vehicle or 6-hydroxydopamine injections into the DNB were assigned to five different discrimination tasks in a cross-maze with black and white goal arms. The tasks were acquisition and reversal of position, visual, or turn discrimination, and acquisition of visual or turn discrimination followed by a shift to the alternative discrimination. In spite of evidence that the rats preferred to attend more to the visual stimuli of the goal arms than to directions of turns, lesions of the DNB did not impair acquisition and reversal of turn discrimination with visual stimuli irrelevant, and did not facilitate performance of turn-to-visual shift. In fact, the lesions did not alter performance of any tasks. In Experiment 2, control and noradrenaline-depleted rats were trained in a task of light-dark discrimination followed by shift to position discrimination in a Y-maze. At the onset of training, the rats of both groups reliably avoided the bright goal arm and responded to the dark goal arm, thus demonstrating predominant attention for the relevant brightness stimuli rather than the irrelevant position stimuli. The DNB lesions impaired acquisition of brightness discrimination only when the positive stimulus was the illuminated goal arm, and they did not alter shift performance. These results do not support the hypothesis at test. On the other hand, they indicate that DNB lesions in the rat can impair habituation of light avoidance.

Experimental influences on catalepsy.

Normal saline-injected rats were tested repeatedly on a standard catalepsy test. With repeated testing the animals showed a progressive increase in their catalepsy scores. It is suggested that this behaviour may be a form of tonic immobility and should be controlled for in catalepsy experiments.

Behavioural abnormalities in a murine model of a human lysosomal storage disease.

The gusmps/gusmps mouse is a model of the human lysosomal storage disease mucopolysaccharidosis type VII due to deficient beta-glucuronidase activity. We now report behavioural abnormalities associated with this single gene defect. In grooming, a developmentally regulated and genetically based activity, the mutant mice spent 1-5% of the normal time for body grooming and about 60% of the normal time in face grooming when stimulated with a light water mist. In the Morris water maze which tests spatial learning, the mutants could learn to locate an invisible platform but were deficient in remembering its location the next day or developing strategies to locate it in new positions. Thus, the gusmps/gusmps mouse demonstrates behavioural, memory and cognitive deficiencies suitable for monitoring functional restorations in therapy.

Motor somatotopy in the striatum of rat: manipulation, biting and gait.

The objective of this study was to examine the hypothesis of somatotopically organized motor functions in the striatum. In Experiment 1, ibotenate-induced lesions of the rostrolateral striatum in rats produced a transient decrease of ad libitum food intake, a more enduring decrease of body weight, and chronic impairments of food biting, holding of hard food pellets and feeding efficiency, with no apparent alterations of gait balance in a beam walking task. Lesions of the medial striatum had minimal or no reliable effects on any of the measured parameters. In Experiment 2, the motoric effects of ibotenate lesions restricted to either the dorsomedial or the dorsolateral or the ventrolateral regions of the rostral striatum were examined. Lesions of the dorsolateral striatum produced the most deleterious effect on holding postures of the forelimbs, whereas lesions of the ventrolateral striatum maximally affected food biting, feeding efficiency, ad libitum food intake, and body weight. No regional lesions affected gait balance. Dorsomedial striatal lesions did not affect any of the measured parameters. The findings support the hypothesis of a somatotopically organized role of the rostrolateral striatum in orofacial and forelimb motor control.

Regionally selective roles of the rat's striatum in modality-specific discrimination learning and forelimb reaching.

Rats with ibotenate lesions of either the medial striatum or the lateral striatum were trained in a forelimb reaching task and in acquisition, retention and reversal of either turn (left-right) discrimination or brightness (black-white) discrimination in a cross-shape maze. Compared with the controls, the rats with lesions of the medial striatum showed a reliable, modality-selective impairment in reversal of turn discrimination, but no significant impairment of reaching. In contrast, the rats with lateral striatal lesions showed a significant impairment of forelimb reaching, but not of reversal of either discriminations. Neither medial nor lateral lesions significantly affected acquisition and retention of both discriminations. The findings indicate a predominant role of the medial striatum in monitoring of directional responses, confirm the regionally specific role of the lateral striatum in reaching, and are interpreted to support the hypothesis of parallel motor and cognitive forebrain circuits comprising distinctive regions of the striatum.

Evidence against a role of the rat's dorsal noradrenergic bundle in selective attention and place memory.

In Experiment 1, 6-hydroxydopamine-induced lesions of the dorsal noradrenergic bundle (DNB) in rats did not impair either acquisition of non-delayed alternation, retention of non-delayed alternation, or performance of alternation with delays in a T-maze, whether or not the goal arms of the maze were visually distinctive. These results were in contrast with those of a previous report indicating that DNB lesions impair learning of spatial alternation. In Experiment 2, the lack of a reliable effect of DNB lesions on learning performance of spatial alternation was confirmed. However, the rats with DNB lesions showed an impairment of spontaneous alternation. The negative results of the present study do not support either the hypothesis that depletion of forebrain noradrenaline impairs selective attention or the hypothesis that such depletion induces an amnesia for past places. On the other hand, the finding of impaired spontaneous alternation is consistent with previous observations suggesting that depletion of forebrain noradrenaline impairs habituation of fear reactions.

Spontaneously recurrent seizures after intracerebral injections of kainic acid in rat: a possible model of human temporal lobe epilepsy.

Intrastriatal injection of kainic acid in rats acutely induced repeated episodes of clonic convulsions. Spontaneously recurrent generalized seizures and a potentiation of the convulsant effects of phentylenetetrazol were then observed in most of the injected rats several weeks after surgery. In addition to marked loss of striatial neurons, limbic pathological alterations similar to those found in human temporal lobe epilepsy were observed in the brains of the kainic-acid treated rats. It is proposed that this preparation might serve as an animal model of human temporal lobe epilepsy.