The risk of non-melanoma skin cancer in New Zealand in inflammatory bowel disease patients treated with thiopurines.

BACKGROUND AND AIM: New Zealand (NZ) has one of the highest rates of non-melanoma skin cancers (NMSCs) in the world. Thiopurine use in inflammatory bowel disease (IBD) patients has been shown to increase NMSC risk. This study aimed to investigate the possible increase of NMSC risk in thiopurine-treated IBD patients in NZ despite the high background rate. METHODS: Inflammatory bowel disease patients treated with thiopurines and healthy controls were recruited across two different latitude centers in NZ. Consented participants completed a questionnaire to identify additional risk factors and were examined for suspicious skin lesions. These were photographed, and the pictures were evaluated by a dermatologist. Data were compared between centers and between groups with NMSC incidence and thiopurine-associated relative risks estimated. RESULTS: One hundred seventy-one thiopurine-exposed IBD patients and 201 controls were recruited. Twenty seven of 390 photographs (26 participants) showed suspicious lesions (17 exposed, 9 controls) as determined by the dermatologist. Estimated NMSC incidence was 24.7-34.3/1000 patient-years (thiopurine-exposed, depending on classification of unconfirmed suspicious lesions) and 7-14/1000 patient-years (control). The relative risk of NMSC among thiopurine exposed was 2.38-2.97 (P ≤ 0.014), which remained significant after individually adjusting for potential confounders. We estimated the NMSC risk to increase 5.4-6.6% per 6 months of thiopurine use (P < 0.001). Low compliance in avoiding NMSC risk factors in the exposed group was observed. CONCLUSIONS: We found a twofold to threefold increase in NMSC incidence in IBD patients treated with thiopurines in NZ, despite the high background incidence rate.

Delayed post-treatment with bone marrow-derived mesenchymal stem cells is neurorestorative of striatal medium-spiny projection neurons and improves motor function after neonatal rat hypoxia-ischemia.

Perinatal hypoxia-ischemia is a major cause of striatal injury and may lead to cerebral palsy. This study investigated whether delayed administration of bone marrow-derived mesenchymal stem cells (MSCs), at one week after neonatal rat hypoxia-ischemia, was neurorestorative of striatal medium-spiny projection neurons and improved motor function. The effect of a subcutaneous injection of a high-dose, or a low-dose, of MSCs was investigated in stereological studies. Postnatal day (PN) 7 pups were subjected to hypoxia-ischemia. At PN14, pups received treatment with either MSCs or diluent. A subset of high-dose pups, and their diluent control pups, were also injected intraperitoneally with bromodeoxyuridine (BrdU), every 24h, on PN15, PN16 and PN17. This permitted tracking of the migration and survival of neuroblasts originating from the subventricular zone into the adjacent injured striatum. Pups were euthanized on PN21 and the absolute number of striatal medium-spiny projection neurons was measured after immunostaining for DARPP-32 (dopamine- and cAMP-regulated phosphoprotein-32), double immunostaining for BrdU and DARPP-32, and after cresyl violet staining alone. The absolute number of striatal immunostained calretinin interneurons was also measured. There was a statistically significant increase in the absolute number of DARPP-32-positive, BrdU/DARPP-32-positive, and cresyl violet-stained striatal medium-spiny projection neurons, and fewer striatal calretinin interneurons, in the high-dose mesenchymal stem cell (MSC) group compared to their diluent counterparts. A high-dose of MSCs restored the absolute number of these neurons to normal uninjured levels, when compared with previous stereological data on the absolute number of cresyl violet-stained striatal medium-spiny projection neurons in the normal uninjured brain. For the low-dose experiment, in which cresyl violet-stained striatal medium-spiny neurons alone were measured, there was a lower statistically significant increase in their absolute number in the MSC group compared to their diluent controls. Investigation of behavior in another cohort of animals showed that delayed administration of a high-dose of bone marrow-derived MSCs, at one week after neonatal rat hypoxia-ischemia, improved motor function on the cylinder test. Thus, delayed therapy with a high- or low-dose of adult MSCs, at one week after injury, is effective in restoring the loss of striatal medium-spiny projection neurons after neonatal rat hypoxia-ischemia and a high-dose of MSCs improved motor function.

Development of amplitude-integrated electroencephalography and interburst interval in the rat.

Continuous monitoring of electrocortical brain activity with amplitude-integrated electroencephalography (aEEG) is important in neonatology. aEEG is affected by, for example, maturity, encephalopathy, and drugs. Neonatal research uses rat pups of different ages. Postnatal day (P) 7 rats are suggested to be equivalent neurodevelopmentally to near-term infants. We hypothesized that electroencephalography (EEG) and aEEG in P1-P21 rats follow the same developmental pattern with respect to background activity and the longest interburst interval (IBI) as that seen in infants from 23-wk gestational age (GA) to post-term. We examined aEEG and EEG on 49, unsedated rat pups with two clinical monitors. aEEG traces were analyzed for lower and upper margin amplitude, bandwidth and the five longest IBI in each trace were measured from the raw EEG. The median longest IBI decreased linearly with age by 5.24 s/d on average. The lower border of the aEEG trace was <5 microV until P7 and rose exponentially reaching 10 microV by P12. This correlated strongly with the decrease in IBI; both reflect increased continuity of brain activity with postnatal age. Based on aEEG trace analysis, the rat aEEG pattern at P1 corresponds to human aEEG at 23-wk gestation; P7 corresponds to 30-32 wk and P10 to 40-42 wk.

A closed-circuit neonatal xenon delivery system: a technical and practical neuroprotection feasibility study in newborn pigs.

BACKGROUND: Asphyxia accounts for 23% of the 4 million annual global neonatal deaths. In developed countries, the incidence of death or severe disability after hypoxic-ischemic (HI) encephalopathy is 1-2/1000 infants born at term. Hypothermia (HT) benefits newborns post-HI and is rapidly entering clinical use. Xenon (Xe), a scarce and expensive anesthetic, combined with HT markedly increases neuroprotection in small animal HI models. The low-Xe uptake of the patient favors the use of closed-circuit breathing system for efficiency and economy. We developed a system for delivering Xe to mechanically ventilated neonates, then investigated its technical and practical feasibility in a previously described neonatal pig model approximating the clinical scenario of global HI injury, prolonged Xe delivery with and without HT as a potential therapy, subsequent neonatal intensive care unit management, and tracheal extubation. METHODS: Sixteen newborn pigs underwent a global 45 min HI insult (4%-6% inspired oxygen reducing the electroencephalogram amplitude to <7 microV), then received 16 h 50% inspired Xe during normothermia (39.0 degrees C) or HT (33.5 degrees C). A conventional neonatal ventilator provided breaths of oxygen to a lower chamber compressing a hanging bag within. This bag communicated with the upper closed part of the breathing system containing soda lime, unidirectional valves, Xe/oxygen analyzers, and a tracheal tube connection. At each end-inspiration, this bag emptied fully and a bolus of oxygen, the driving gas, crossed from the lower to upper chamber via an additional valve. This mechanically substituted the gas uptake from the circle during the previous breath cycle (oxygen + small volume of Xe) with an equivalent volume of oxygen creating a slow-rising inspired oxygen concentration. This was offset by manual injection of Xe boluses, infrequently at steady state, due to the low-Xe uptake of the patient. RESULTS: Total mean Xe usage was 0.18 (0.16-0.21) L/h with no differences between Xe-HT and Xe-NT groups, which had weights of 1767 (1657-1877) g and 1818 (1662-1974) g, respectively (95% CI). HT reduced heart rate in the cooled animals; 180 (165-195) vs 148 (142-155) bpm (P < 0.0001) with no differences in arterial blood pressure, oxygen saturation, arterial carbon dioxide tension, or weaning times between these groups. CONCLUSION: We describe a closed-circuit Xe delivery system with automatic mechanical oxygen replenishment, which could be developed as a single use device. Gas exchange was maintained while Xe consumption was minimal (<$2/h at $10/L*). We have shown it is both feasible and cost-efficient to use this Xe delivery method in newborn pigs for up to 16 h with or without concurrent cooling after a severe HI insult.

Detailed Multi-Dimensional Assessment of Fatigue in Inflammatory Bowel Disease.

BACKGROUND: Fatigue is a symptom commonly reported by patients with inflammatory bowel disease (IBD). Treating any underlying inflammation in active disease improves the health outcomes and decreases fatigue, but fatigue still persists in remission, negatively affecting patients' quality of life and posing a challenge for the treating physician. The aim of this study was to describe the prevalence of fatigue in patients with IBD and investigate possible contributing factors. METHODS: Recruited IBD patients from the Otago region in southern New Zealand were asked to complete demographic, physical activity (IPAQ) and fatigue questionnaires (Brief Fatigue Inventory, Multidimensional Fatigue Inventory). Disease activity and factors contributing to fatigue were assessed through self-reporting and laboratory biomarkers. RESULTS: One hundred and thirteen of the contacted 469 IBD patients participated in the study. Depending on the questionnaire used, the prevalence of fatigue in IBD was high in remission (39.5-44.2%) but significantly higher (p < 0.001) in active disease (80.0-82.9%). Several factors such as age, disease duration, level of physical activity, gender and diet were found to be associated with increased fatigue and were attributed to either mental or physical fatigue categories. Multifactorial Fatigue Inventory provided insights into different types of fatigue, and revealed a significant mental fatigue component in both active and remission disease patients. Iron deficiency was not associated with fatigue levels. CONCLUSIONS: Fatigue in IBD is multi-faceted and highly prevalent in both active and remission IBD. Further investigations, addressing the complexity of the symptom and its reporting are needed.

Neonatal rat hypoxia-ischemia: long-term rescue of striatal neurons and motor skills by combined antioxidant-hypothermia treatment.

Perinatal hypoxia-ischemia can cause long-term neurological and behavioral disability. Recent multicenter clinical trials suggest that moderate hypothermia, within 6 h of birth, offers significant yet incomplete protection. We investigated the effect of combined treatment with the antioxidant N-tert-butyl-(2-sulfophenyl)-nitrone (S-PBN) and moderate hypothermia on long-term neuronal injury and behavioral disability. S-PBN or its diluent was administered 12-hourly to rats from postnatal day (PN) 7 to 10. On PN8, hypoxia-ischemia was induced. Immediately post-hypoxia, additional S-PBN and 6 h of moderate hypothermia or additional diluent and 6 h of normothermia were administered. At 1 week, and at 11 weeks, after hypoxia-ischemia, the absolute number of surviving medium-spiny neurons was measured in the coded right striatum. In a separate experiment, skilled forepaw ability was investigated in coded 9- to 11-week-old rats. Normal, uninjured animals were also tested for motor skills at 9- to 11-weeks-of-age. The combination of S-PBN and moderate hypothermia provided statistically significant short- and long-term protection of the striatal medium-spiny neurons to normal control levels. This combinatorial treatment also preserved fine motor skills to normal control levels. The impressive histological and functional preservation suggests that S-PBN and moderate hypothermia is a safe and attractive combination therapy for perinatal hypoxia-ischemia.

Neonatal rat hypoxia-ischemia: Effect of the anti-oxidant mitoquinol, and S-PBN.

BACKGROUND: The production of oxygen free radicals after perinatal hypoxia-ischemia is thought to play a critical role in the pathogenesis of the brain injury. Administration of anti-oxidants may thus be neuroprotective. The aim of the present study was to investigate the effect of a mitochondria-targeted anti-oxidant mitoquinol (mitoQ) administered in the form of the prodrug mitoquinone, and an extracellular anti-oxidant N-tert-butyl-(2-sulfophenyl)-nitrone (S-PBN; Aldrich, St Louis, MO, USA), on neuronal survival in the rat striatum after acute perinatal hypoxia-ischemia. METHODS: Mitoquinone at 17 micromol/L (n = 6) or 51 micromol/L (n = 6), or its diluent (n = 12), was continuously infused over 3 days into the right striatum of Sprague-Dawley rats. Infusion was via an Alzet micro-osmotic pump (Alza, Los Angeles, CA, USA), stereotaxically implanted on postnatal day (PN) 7 under anesthesia. In another experiment, S-PBN (100 mg/kg) (n = 8) or its diluent (n = 8) was administered in six s.c. injections every 12 h from the evening of PN7. Hypoxia-ischemia was induced on PN8 by right common carotid artery ligation under anesthesia, followed 2.5 h later by exposure to 8% oxygen for 1.5 h. On PN14 the pups were euthanased and 40 microm serial sections were cut through the entire striatum. The total number of medium-spiny neurons within the right striatum was stereologically determined using the optical disector/Cavalieri method. RESULTS: No significant difference was seen in the total number of striatal medium-spiny neurons between the 17 micromol/L or 51 micromol/L mitoQ-treated pups and their respective diluent-treated controls. No significant difference was seen in the total number of striatal medium-spiny neurons between the S-PBN-treated and diluent-treated pups. CONCLUSION: Solely targeting mitochondrial oxidants with mitoQ, or extracellular oxidants with S-PBN, is not protective for striatal medium-spiny neurons after perinatal hypoxia-ischemia.

Annual Incidence and Phenotypic Presentation of IBD in Southern New Zealand: An 18-Year Epidemiological Analysis.

BACKGROUND: The aim of this study was to describe the incidence of inflammatory bowel disease (IBD) and changes in demographic and phenotypic disease presentation in Otago, New Zealand. METHODS: This study was conducted at Dunedin Hospital and the study period was 1996-2013. Otago residents diagnosed with IBD were identified retrospectively from hospital lists using ICD-10 codes. Diagnosis, and place and date of diagnosis, were confirmed using medical notes and histology reports. Demographic, clinical and diagnostic data were recorded. Age-standardised incidence rates were estimated and trends over time assessed. Multinomial logistic regression was used to assess evidence for any changes in the distribution of disease location for Crohn's disease (CD) cases. RESULTS: The diagnosis of IBD was confirmed in 224 males and 218 females, and most were New Zealand European. Of the total number of confirmed IBD cases, 40.0% were ulcerative colitis (UC), 52.1% were CD and 7.9% were IBD unclassified. The age distribution illustrated bimodal peaks at 20-24 years and 65-69 years. Incidence rates varied from year to year, but there was no statistically significant change over the 18-year study period. The estimated age-standardised IBD incidence varied between 5.8/100,000 in 2006 and 29.8/100,000 in 2012. The incidence rates for UC and CD were 2.8/100,000 and 1.8/100,000, respectively, in 2006 and 6.3/100,000 and 21.8/100,000, respectively, in 2012. There were no significant phenotypic changes in CD patients over the study period. CONCLUSIONS: The IBD incidence in Otago, New Zealand, is high compared to many other countries. Annual age-standardised incidence rates vary, highlighting the limitations of single-year incidence data.

Cooling combined with immediate or delayed xenon inhalation provides equivalent long-term neuroprotection after neonatal hypoxia-ischemia.

Hypothermia (HT) improves outcome after neonatal hypoxia-ischemia. Combination therapy may extend neuroprotection. The noble anesthetic gas xenon (Xe) has an excellent safety profile. We have shown earlier that 3 h of 50% Xe plus HT (32 degrees C) additively gives more protection (72%) than either alone (HT=31.1%, Xe=10.2%). Factors limiting clinical use include high-cost and specialist administration requirements. Thus, combinations of 1 h of 50% Xe were administered concurrently for either the first (1 h(Immediate)Xe) or last (1 h(Delayed)Xe) of 3 h of posthypoxic-ischemic HT as compared with 3 h of 50%Xe/HT to investigate how brief Xe exposure with a delay would affect efficacy. An established neonatal rat hypoxia-ischemia model was used. Serial functional neurologic testing into adulthood was performed, followed by neuropathological examination. Xenon with HT was more effective with longer Xe duration (3 h versus 1 h) (P=0.015). However, 1 h Xe/3 h HT resulted in better neuroprotection than 3 h HT alone (P=0.03), this significant effect was also present with 1 h Xe after a 2-h delay. One (immediate or with a delay) or 3 h Xe also significantly improved motor function (P=0.024). Females had significantly better motor scores than males, but no sex-dependent difference in pathology results. The neuroprotection of short, delayed Xe treatment would allow transport to specialist facilities to receive Xe.

Delayed hypothermia as selective head cooling or whole body cooling does not protect brain or body in newborn pig subjected to hypoxia-ischemia.

The neuroprotective efficacy of hypothermia (HT) after hypoxia-ischemia (HI) falls dramatically the longer the delay in initiating HT. Knowledge is scarce regarding protective or adverse effects of HT in organs beyond the brain. In addition, the relative effectiveness of selective head cooling (SHC) and whole body cooling (WBC) has not been studied. We aimed to examine whether 24 h HT, initiated 3 h after global HI is brain- and/or organ-protective using pathology, neurology, and biochemical markers. Fifty,

Effect of the mitochondrial antioxidant, Mito Vitamin E, on hypoxic-ischemic striatal injury in neonatal rats: a dose-response and stereological study.

A mitochondria-targeted antioxidant, Mito Vitamin E (MitoVit E), has previously been shown to prevent mitochondrial oxidative damage. The aim of this study was to investigate the effect of MitoVit E on neuronal survival in the rat striatum after acute perinatal hypoxia-ischemia. Continuous striatal infusion with 4.35 microM, 43.5 microM, or 148 microM of MitoVit E before, during, and after hypoxia-ischemia was not neuroprotective for striatal medium-spiny neurons. Pre- or posttreatment with 435 microM MitoVit E was neurotoxic. These results suggest that MitoVit E is not significantly neuroprotective for striatal medium-spiny neurons after acute perinatal hypoxic-ischemic brain injury. The results also suggest that mitochondrial oxidative damage does not contribute significantly to the death of striatal medium-spiny neurons after perinatal hypoxia-ischemia.