High prevalence of paratuberculosis in rabbits is associated with difficulties in controlling the disease in cattle.

There is increasing evidence that the European wild rabbit (Oryctolagus cuniculus) is a wildlife reservoir for paratuberculosis and infected populations may contribute to the persistence of infection in livestock. The aim of this study was to test the hypothesis that farms with difficulties controlling paratuberculosis in their cattle herds have a higher prevalence of Mycobacterium avium subsp. paratuberculosis (MAP) infection in their rabbit populations. A total of 281 rabbits from 13 beef farms in the East of Scotland were randomly sampled in early spring 2007. Participating farms were in paratuberculosis control programmes under the Premium Cattle Health Scheme (PCHS), and were classified as 'responder' (paratuberculosis under control) or 'low responder' (a persistent number of paratuberculosis-positive cattle despite control measures in place) farms. Of the rabbits sampled, 23.8% tested positive for MAP, with those on 'low responder' farms having a greater probability of being infected (0.4) relative to rabbits on 'responder' farms (0.1). The association suggests that MAP-infected rabbits may contribute to the persistence of paratuberculosis in domestic livestock and undermine control strategies that focus on livestock alone. This study provides the first evidence of an association between the persistence of paratuberculosis in livestock despite the implementation of disease control strategies, and MAP-infected sympatric wild rabbit populations.

Randomised clinical trial: ghrelin agonist TZP-101 relieves gastroparesis associated with severe nausea and vomiting--randomised clinical study subset data.

BACKGROUND: Limited therapeutic options exist for severe gastroparesis, where severe nausea and vomiting can lead to weight loss, dehydration and malnutrition due to inadequate caloric and fluid intake. TZP-101 (ulimorelin) is a ghrelin receptor agonist that accelerates gastric emptying and improves upper gastrointestinal symptoms in diabetic patients with gastroparesis. AIM: To assess effects of TZP-101 in diabetic gastroparesis patients with severe nausea/vomiting and baseline severity scores of ≥3.5 (range: 0-5) on the Gastroparesis Cardinal Symptom Index (GCSI) Nausea/Vomiting subscale. METHODS: Patients were hospitalised and received four single daily 30-min infusions of one of six TZP-101 doses (range 20-600 µg/kg) or placebo. Efficacy was assessed by symptom improvement. RESULTS: At baseline, 23 patients had a mean severity score for GCSI Nausea/Vomiting of 4.45±0.44. Statistically significant improvements over placebo occurred in the 80 µg/kg group for end of treatment changes from baseline in GCSI Nausea/Vomiting subscale (reduction in score of -3.82±0.76, P=0.011) and the GCSI Total score (-3.14±0.78, P=0.016) and were maintained at the 30-day follow-up assessment (-2.02±1.63, P=0.073 and -1.99±1.33, P=0.032 respectively). The proportion of days with vomiting was reduced significantly (P=0.05) in the 80 µg/kg group (mean of 1.2 days of vomiting for four treatment days) compared with placebo (mean of 3.2 days of vomiting across 4 treatment days). CONCLUSIONS: TZP-101 substantially reduced the frequency and severity of nausea and vomiting as well as overall gastroparesis symptoms. The results are consistent with gastrointestinal motility effects of TZP-101, supporting further investigation of TZP-101 in the management of severe gastroparesis.

Safety and efficacy of ghrelin agonist TZP-101 in relieving symptoms in patients with diabetic gastroparesis: a randomized, placebo-controlled study.

BACKGROUND: Gastroparesis, a chronic disorder of abnormal gastric motility, is common in patients with diabetes mellitus. A synthetic, selective ghrelin receptor agonist, TZP-101, is in clinical development for treatment of gastroparesis. This double-blind, randomized, placebo-controlled study evaluated the safety and efficacy of multiple TZP-101 doses in patients with moderate to severe symptomatic diabetic gastroparesis. METHODS: Patients were admitted to the hospital and adaptively randomized to receive a single 30-min intravenous infusion of 20, 40, 80, 160, 320, or 600 µg kg(-1) TZP-101, (n = 57) or placebo, (n = 19) for four consecutive days. Symptoms were evaluated daily with the patient-rated Gastroparesis Cardinal Symptom Index (GCSI) and Gastroparesis Symptom Assessment (GSA). Clinicians rated gastroparesis symptoms on treatment day 4. KEY RESULTS: The 80 µg kg(-1) dose was identified as the most effective dose. On day 4, there was statistically significant improvement compared with placebo in the severity of GCSI Loss of Appetite and Vomiting scores for that dose group (P = 0.034 and P = 0.006). In addition, at the 80 µg kg(-1) dose, the proportion of patients with at least 50% improvement in vomiting score was significantly different (P = 0.019) compared with placebo. Meal-related GSA scores for Postprandial fullness were significantly improved in the 80 µg kg(-1) TZP-101 group compared with placebo (P = 0.012). Clinicians rated the 80 µg kg(-1) group better improved than placebo for overall symptom assessment (P = 0.047). Safety profiles were similar in the placebo and TZP-101 groups and all doses were well-tolerated. CONCLUSIONS & INFERENCES: TZP-101 appears to be safe, well-tolerated, and effective at acutely addressing several gastroparesis symptoms.

Pulmonary vein stenosis: the UK, Ireland and Sweden collaborative study.

OBJECTIVE: To describe clinical features, morphology, management and outcome of pulmonary vein stenosis (PVS) in childhood. DESIGN AND SETTING: Retrospective international collaborative study involving 19 paediatric cardiology centres in the UK, Ireland and Sweden. PATIENTS: Cases of PVS presenting between 1 January 1995 and 31 December 2004 were identified. Cases where pulmonary veins connected to a morphological left atrium were included. Functionally univentricular hearts and total anomalous pulmonary venous connection were excluded. All available data and imaging were reviewed. RESULTS: 58 cases were identified. In 22 cases (38%) there was premature delivery. 46 (79%) had associated cardiac lesions; 16 (28%) had undergone previous cardiac surgery before PVS diagnosis. 16 children (28%) had a syndrome or significant extracardiac abnormality. 36 presented with unilateral disease of which 86% was on the left. Where there was adequate sequential imaging, disease progression was shown with discrete stenosis leading to diffusely small pulmonary veins. Collateral vessels often developed. 13 patients had no intervention. Initial intervention was by catheter in 17 and surgery in 28. Overall 3-year survival was 49% (95% CI 35% to 63%) with patients undergoing initial surgical intervention having greater freedom from death or re-intervention (hazard ratio 0.44, 95% CI 0.2 to 0.99, p = 0.023). CONCLUSIONS: PVS is a complex disease of uncertain cause and frequently associated with prematurity. Early intervention may be indicated to deter irreversible secondary changes.

Ghrelin receptor agonist (TZP-101) accelerates gastric emptying in adults with diabetes and symptomatic gastroparesis.

BACKGROUND: TZP-101 is a synthetic, selective ghrelin agonist in development for gastroparesis. AIM: To assess safety and effects of TZP-101 in diabetes patients with symptomatic gastroparesis. METHODS: Adults with type 1 or type 2 diabetes mellitus received placebo and TZP-101 (80, 160, 320 or 600 microg/kg) infusions in a cross-over manner following a radiolabelled meal. Blood glucose levels were stabilized using a hyperinsulinemic-euglycemic clamp. Primary endpoints were gastric half emptying and latency times. Secondary measures included assessment of gastroparesis symptoms and endocrine responses. RESULTS: Ten patients with type 1 (n = 7) or 2 (n = 3) diabetes, moderate-to-severe gastroparesis symptoms and > or =29% retention 4 h after a radiolabelled solid meal were enrolled. TZP-101 produced significant reductions in solid meal half-emptying (20%, P = 0.043) and latency (34%, P = 0.037) times vs. placebo. Reductions in overall postmeal symptom intensity (24%) and postprandial fullness (37%) following TZP-101 infusion were not statistically significant. Most adverse events were mild and self-limiting and there were no identifiable differences in numbers or types of adverse events between TZP-101 and placebo. CONCLUSIONS: This proof-of-concept study demonstrates that the ghrelin agonist TZP-101 is well-tolerated in diabetes patients with moderate-to-severe chronic gastroparesis and shows statistically significant improvements in gastric emptying.

Time course of changes in cholinergic and neurotrophin-related markers after infusion of colchicine into the basal forebrain.

After bilateral infusions of colchicine or vehicle in the rat nucleus basalis magnocellularis, the time course of changes in several cholinergic and neurotrophin-related markers were assessed. Animals were sacrificed at 3, 7, 14, 28, 35 and 84 days post-lesion, and both the NBM and cortical areas were assessed. Sections were stained immunohistochemically for choline acetyltransferase (ChAT) or p140trk (trk) or histochemically for acetylcholinesterase (AChE). ChAT activity and neurotrophin protein levels were assessed regionally. The number of ChAT immunoreactive NBM neuronal profiles decreased beginning 3 days post-lesion and reach maximal loss by 28 days post-lesion, with no recovery. Examination of trk-IR around the NBM revealed a time-dependent decrease in trk-IR of magnocellular neuron and an increase in trk-IR of astrocytes at 14 and 28 days post-lesion. The density of AChE-stained cortical fibers was maximally decreased 3 days post-lesion followed by an increase in fiber staining across the remaining time points. Cortical ChAT activity showed the largest decrease at 7 days followed by recovery 84 days after colchicine infusion. There was an increase in NGF in the parietal cortex after colchicine infusion but no change in BDNF level. These patterns of changes in the cholinergic and neurotrophin-related markers suggest an association between NGF and lesion-induced compensatory responses in the basal forebrain cholinergic system.

Damage to the NBM leads to a sustained lesion-induced increase in functional NGF in the cortex.

Bilateral infusions of colchicine or vehicle were made in the nucleus basalis magnocellularis of rats. Cortical homogenates were assessed in a choline acetyltransferase (ChAT) activity assay and a PC12 cell neurite outgrowth assay 3, 7, 14, 28, 35 or 84 days post-lesion. Cortical ChAT activity was initially decreased by 30%, followed by recovery to control levels at 84 days post-lesion. Cortical nerve growth factor (NGF) activity was increased 35% above control levels at all time points following colchicine infusion, while addition of a NGF antibody blocking all activity. The data show an increase in functional NGF in the target area of the lesioned neurons preceding and coinciding with regional recovery of a cholinergic marker, suggesting that NGF has a role in the cholinergic recovery.

Neurochemical and behavioral recovery after colchicine lesions of the nucleus basalis magnocellularis in rats.

Experimentally-induced lesions of the basal forebrain have been used to test the hypothesis that the cholinergic system plays a critical role in learning and memory. In the present study, a basal forebrain infusion of colchicine, a microtubule assembly inhibitor, was used to characterize the relationship between a cholinergic marker and behavioral function. Bilateral infusions were made in the nucleus basalis magnocellularis (NBM) of male Long-Evans rats. At 4 weeks post-lesion, behavioral assessments were made on half of the rats in each group. These rats were sacrificed 1 week later and regional choline acetyltransferase (ChAT) activity was measured. The remaining rats were behaviorally tested 11 weeks post-lesion and sacrificed 12 weeks post-lesion. The brains of additional rats were studied for Nissl-staining, ChAT-, GAD- and metEnk immunoreactivity (IR) and AChE histochemistry. At 5 weeks after colchicine infusion, there was a significant decrease in parietal and frontal cortical ChAT activity, impaired acquisition of a water maze spatial navigation task and decreased passive avoidance cross-over latency. At 12 weeks after colchicine infusion, ChAT activity was decreased in frontal but not parietal cortex; acquisition of the water maze task was not significantly different from vehicle-infused rats, and a significant deficit was observed in passive avoidance latency. ChAT-IR in the NBM showed a significant decrease at both time points, while changes in AChE-stained cortical fibers paralleled the ChAT activity. GAD- and metEnk-IR were decreased but were not different between the two time points. These data show task-specific behavioral recovery associated in time with recovery of regional cholinergic markers.

Comparison of intracranial infusions of colchicine and ibotenic acid as models of neurodegeneration in the basal forebrain.

Colchicine and ibotenic acid were compared for their ability to produce neurodegeneration and cognitive deficit after bilateral infusions into the nucleus basalis magnocellularis of male Long-Evans rats. Four weeks post-lesion, there was no difference in locomotor activity following infusion of either neurotoxicant or vehicle. In a passive avoidance task, both treated groups had significantly shorter step-through latencies compared with vehicle. Five weeks post-lesion, rats were killed for neurochemistry or histochemistry. Choline acetyltransferase (ChAT) activity in both the frontal and parietal cortex was significantly decreased (25-35%) in the colchicine- and ibotenic acid-infused rats when compared to control. There was no effect of either neurotoxicant on ChAT activity in the hippocampus or striatum. Both neurotoxicants produced damage in the general area of the ventromedial pallidum, although ibotenic acid infusion consistently produced a larger area of damage as assessed in Nissl-stained sections. Analysis of the number of ChAT-immunoreactive cells in the nucleus basalis magnocellularis (NBM) showed an average 60% cell loss following colchicine infusion and a 75% cell loss after ibotenic acid infusion. Area of glutamic acid decarboxylase (GAD) staining was significantly decreased in several regions surrounding the NBM for ibotenic acid (51% average decrease), and showed non-significant decreases (28%) following colchicine infusion. Colchicine infusion decreased dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum; ibotenic acid had no effect on brain catechol of indoleamine levels. The results indicate that although similar cholinergic hypofunction and behavioral deficits were achieved, several non-cholinergic differences between the neurotoxicants were detected.

Acquisition and retention of multidirectional escape behavior in preweanling rats.

The shock-escape behavior of preweanling rats in a multidirectional escape situation was examined in 3 experiments. In Experiment I, 5-, 7-, 9-, and 11-day-old rats were given shock-escape training on each of 3 days. Rats younger than 7 days of age did not improve escape responding within or over sessions. Animals 7 days of age and older, however, showed both an intrasession improvement and an intersession improvement that could not be attributed solely to maturation. In Experiment II, the escape behavior of 3-, 5-, and 7-day-old was examined in an apparatus modified to take into account the poor locomotor abilities of these animals. They were given escape training on 3 successive days. Again; no within-session improvement was found in rats under 7 days of age. However, an intersession improvement was found in rats whose training began at 5 days of age. This improvement was due to maturation and did not reflect a cumulative effect of training. Experiment III, like Experiment I, demonstrated that the intersession improvement in the older rats was not simply a maturation effect. It also demonstrated that the improvement could not be attributed to the stress of prior handling, shock, or body temperature loss, but was, rather, a retention effect. These results support the contention that the emergence of memory is task specific.