Retinal blood flow velocities in infants with retinopathy of prematurity after intravitreal administration of bevacizumab.

BACKGROUND/OBJECTIVES: Progression of retinopathy of prematurity (ROP) is associated with increased retinal blood flow velocities. We investigated changes of central retinal arterial and venous blood flow after intravitreal administration of bevacizumab. SUBJECTS/METHODS: Prospective observational study using serial ultrasound Doppler imaging in preterm infants with bevacizumab-treated ROP. Eyes were examined 1 [0-2] days before injection (median [interquartile range]), and at three time points after injection (1 [1-2] days, 6 [3-8] days, and 17 [9-28] days). Preterm infants with ROP stage 2 displaying spontaneous regression served as controls. RESULTS: In 21 eyes of 12 infants with bevacizumab-treated ROP, peak arterial systolic velocity declined from 13.6 [11.0-16.3] cm/s prior to intravitreal bevacizumab to 11.2 [9.4-13.9] cm/s, 10.6 [9.2-13.3] cm/s and 9.3 [8.2-11.0] cm/s at discharge (p = .002). There was also a decline of the arterial velocity time integral (from 3.1 [2.3-3.9] cm to 2.9 [2.4-3.5], 2.7 [2.3-3.2] cm and 2.2 [2.0-2.7], p = .021) and mean velocity in the central retinal vein (from 4.5 [3.6-5.8] cm/s to 3.7 [2.6-4.1] cm/s, 3.5 [3.0-4.3] cm/s, and 3.2 [2.8-4.6] cm/s, p = .012). Arterial end-diastolic velocity and resistance index remained unchanged. Blood flow velocities in bevacizumab-treated eyes examined before injection were significantly higher than those measured in untreated eyes that ultimately showed spontaneous regression of ROP. Sequential examinations in these controls did not reveal any declines of retinal blood flow velocities. CONCLUSION: Increased retinal arterial and venous blood flow velocities in infants with threshold ROP decline following intravitreal bevacizumab injection.

Impact of the -1T>C single-nucleotide polymorphism of the CD40 gene on the development of endothelial dysfunction in a pro-diabetic microenvironment.

BACKGROUND AND AIMS: Hyperglycemia reinforces pro-inflammatory conditions that enhance CD40 expression in endothelial cells (EC). Thymine to cytosine transition (-1T > C) in the promoter of the CD40 gene (rs1883832) further increases the abundance of CD40 protein on the EC surface. This study examines potential associations of the -1T > C SNP of the CD40 gene with type 1 (T1D) or type 2 (T2D) diabetes. Moreover, it investigates the impact of a pro-inflammatory diabetic microenvironment on gene expression in human cultured umbilical vein EC (HUVEC) derived from CC- vs. TT-genotype donors. METHODS: Tetra-ARMS-PCR was used to compare genotype distribution in 252 patients with diabetes. Soluble CD40 ligand (sCD40L) and soluble CD40 receptor (sCD40) plasma levels were monitored using ELISA. RNA-sequencing was performed with sCD40L-stimulated CC- and TT-genotype HUVEC. Quantitative PCR, Western blot, multiplex-sandwich ELISA array, and immunocytochemistry were used to analyse changes in gene expression in these cells. RESULTS: Homozygosity for the C-allele was associated with a significant 4.3-fold higher odds of developing T2D as compared to individuals homozygous for the T-allele. Inflammation and endothelial-to-mesenchymal transition (EndMT) driving genes were upregulated in CC-genotype but downregulated in TT-genotype HUVEC when exposed to sCD40L. Expression of EndMT markers significantly increased while that of endothelial markers decreased in HUVEC following exposure to hyperglycemia, tumour necrosis factor-α and sCD40L. CONCLUSIONS: The -1T > C SNP of the CD40 gene is a risk factor for T2D. Depending on the genotype, it differentially affects gene expression in human cultured EC. CC-genotype HUVEC adopt a pro-inflammatory and intermediate EndMT-like phenotype in a pro-diabetic microenvironment.

Why has farming in Europe changed? A farmers' perspective on the development since the 1960s.

Farming in Europe has been the scene of several important socio-economic and environmental developments and crises throughout the last century. Therefore, an understanding of the historical driving forces of farm change helps identifying potentials for navigating future pathways of agricultural development. However, long-term driving forces have so far been studied, e.g. in anecdotal local case studies or in systematic literature reviews, which often lack context dependency. In this study, we bridged local and continental scales by conducting 123 oral history interviews (OHIs) with elderly farmers across 13 study sites in 10 European countries. We applied a driving forces framework to systematically analyse the OHIs. We find that the most prevalent driving forces were the introduction of new technologies, developments in agricultural markets that pushed farmers for farm size enlargement and technological optimisation, agricultural policies, but also cultural aspects such as cooperation and intergenerational arrangements. However, we find considerable heterogeneity in the specific influence of individual driving forces across the study sites, implying that generic assumptions about the dynamics and impacts of European agricultural change drivers hold limited explanatory power on the local scale. Our results suggest that site-specific factors and their historical development will need to be considered when addressing the future of agriculture in Europe in a scientific or policy context. Supplementary Information: The online version contains supplementary material available at 10.1007/s10113-023-02150-y.

Effects of Rapamycin on the Expression of Redox Enzymes in Aortic Vascular Smooth Muscle Cells from Marfan Syndrome Mice.

Activation of the mechanistic target of rapamycin (mTOR) pathway has been implicated in an increasing number of diseases, including Marfan syndrome (MFS), an inherited connective tissue disorder. mTOR-dependent reactive oxygen species (ROS) formation has also been suggested to play a role in aortic aneurysm formation in MFS patients. This study aimed to characterize the effects of mTOR inhibition by rapamycin on key redox enzymes and NADPH oxidases (NOX) in cultured vascular smooth muscle cells of a murine MFS model. Therefore, the influence of 5 and 20 nmol/L rapamycin solved in 0.1% (vol/vol) DMSO on glutathione peroxidases 1 (Gpx1) and 4 (Gpx4), superoxide dismutase 2 (Sod2), and catalase (Cat) mRNA and protein expression was investigated in isolated murine aortic smooth muscle cells. Rapamycin inhibited the mRNA expression of all redox enzymes by 30-50%, except Gpx1. In the same cells, the mRNA expression of the transcription factor NFE2-related factor-2 and peroxisome proliferator-activated receptor-γ, key factors against oxidative stress, and controlling redox gene expression were also inhibited to a comparable extent under these conditions. In addition, Nox1 but not Nox4 mRNA expression was significantly inhibited by up to 40%. DMSO alone increased nearly 2-fold the redox enzyme protein expression, which was reduced considerably to basal levels by rapamycin. Proteasomal inhibition by bortezomib could not reverse the observed decrease of GPx protein content. The rapamycin-mediated decrease in GPx protein abundance was reflected in a reduced total GPx enzymatic activity. Higher rapamycin concentrations did not further decrease but led to a renewed increase in enzymatic activity despite low GPx protein concentrations. Baseline ROS formation was slightly inhibited at 13% with 5 nmol/L rapamycin and returned to baseline levels with the higher 20 nmol/L rapamycin concentration. In conclusion, this study further characterized the mechanism of action of rapamycin. It provided an insight into how rapamycin interferes with the regulation of redox homeostasis essential for ROS-dependent signaling that does not incur cellular damage.

Farmer surveys in Europe suggest that specialized, intensive farms were more likely to perceive negative impacts from COVID-19.

It has been shown that the COVID-19 pandemic affected some agricultural systems more than others, and even within geographic regions, not all farms were affected to the same extent. To build resilience of agricultural systems to future shocks, it is key to understand which farms were affected and why. In this study, we examined farmers' perceived robustness to COVID-19, a key resilience capacity. We conducted standardized farmer interviews (n = 257) in 15 case study areas across Europe, covering a large range of socio-ecological contexts and farm types. Interviews targeted perceived livelihood impacts of the COVID-19 pandemic on productivity, sales, price, labor availability, and supply chains in 2020, as well as farm(er) characteristics and farm management. Our study corroborates earlier evidence that most farms were not or only slightly affected by the first wave(s) of the pandemic in 2020, and that impacts varied widely by study region. However, a significant minority of farmers across Europe reported that the pandemic was "the worst crisis in a lifetime" (3%) or "the worst crisis in a decade" (7%). Statistical analysis showed that more specialized and intensive farms were more likely to have perceived negative impacts. From a societal perspective, this suggests that highly specialized, intensive farms face higher vulnerability to shocks that affect regional to global supply chains. Supporting farmers in the diversification of their production systems while decreasing dependence on service suppliers and supply chain actors may increase their robustness to future disruptions. Supplementary Information: The online version contains supplementary material available at 10.1007/s13593-022-00820-5.

An approach for comparing agricultural development to societal visions.

There is broad agreement that agriculture has to become more sustainable in order to provide enough affordable, healthy food at minimal environmental and social costs. But what is "more sustainable"? More often than not, different stakeholders have opposing opinions on what a more sustainable future should look like. This normative dimension is rarely explicitly addressed in sustainability assessments. In this study, we present an approach to assess the sustainability of agricultural development that explicitly accounts for the normative dimension by comparing observed development with various societal visions. We illustrate the approach by analyzing farm- and landscape-scale development as well as sustainability outcomes in a Swiss case study landscape. Observed changes were juxtaposed with desired changes by Avenir Suisse, a liberal think tank representing free-market interests; the Swiss Farmers Association, representing a conservative force; and Landwirtschaft mit Zukunft, an exponent of the Swiss agroecological movement. Overall, the observed developments aligned most closely with desired developments of the liberal think-tank (72%). Farmer interviews revealed that in the case study area farms increased in size (+ 57%) and became more specialized and more productive (+ 223%) over the past 20 years. In addition, interpretation of aerial photographs indicated that farming became more rationalized at the landscape level, with increasing field sizes (+ 34%) and removal of solitary field trees (- 18%). The case study example highlights the varying degrees to which current developments in agriculture align with societal visions. By using societal visions as benchmarks to track the progress of agricultural development, while explicitly addressing their narratives and respective systems of values and norms, this approach offers opportunities to inform also the wider public on the extent to which current developments are consistent with different visions. This could help identify mismatches between desired and actual development and pave the way for designing new policies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13593-021-00739-3.

Hepatotoxicity following administration of onasemnogene abeparvovec (AVXS-101) for the treatment of spinal muscular atrophy.

BACKGROUND & AIMS: Spinal muscular atrophy (SMA) is an autosomal recessive, childhood-onset motor neuron disease. Onasemnogene abeparvovec (OA) is a gene therapy designed to address SMA's root cause. In pivotal mouse toxicology studies, the liver was identified as a major site of OA toxicity. Clinical data reflect elevations in serum aminotransferase concentrations, with some reports of serious acute liver injury. Prophylactic prednisolone mitigates these effects. Herein, we aim to provide pragmatic, supportive guidance for identification, management, and risk mitigation of potential drug-induced liver injury. METHODS: Data from 325 patients with SMA who had received OA through 31 December 2019, in 5 clinical trials, a managed access program (MAP), and a long-term registry (RESTORE), and through commercial use, were analyzed. Liver-related adverse events, laboratory data, concomitant medications, and prednisolone use were analyzed. RESULTS: Based on adverse events and laboratory data, 90 of 100 patients had elevated liver function test results (alanine aminotransferase, and/or aspartate aminotransferase, and/or bilirubin concentrations). Of these, liver-associated adverse events were reported for 34 of 100 (34%) and 10 of 43 (23%) patients in clinical trials and MAP/RESTORE, respectively. Two patients in MAP had serious acute liver injury, which resolved completely. While all events in the overall population resolved, prednisolone treatment duration varied (range: 33-229 days), with a majority receiving prednisolone for 60-120 days. More than 60% had elevations in either alanine aminotransferase, aspartate aminotransferase, or bilirubin concentrations prior to dosing. Greater than 40% received potentially hepatotoxic concomitant medications. CONCLUSIONS: Hepatotoxicity is a known risk associated with OA use. Practitioners should identify contributing factors and mitigate risk through appropriate monitoring and intervention. LAY SUMMARY: Onasemnogene abeparvovec is a type of medicine called a "gene therapy," which is used to treat babies and young children who have a rare, serious inherited condition called "spinal muscular atrophy" (SMA). It works by supplying a fully functioning copy of the survival motor neuron or SMN gene, which then helps the body produce enough SMN protein. However, it can cause an immune response that could lead to an increase in enzymes produced by the liver. This article provides information about the liver injury and how to prevent and recognize if it happens, so that it may be treated properly.

Multifunctional Reactive MALDI Matrix Enabling High-Lateral Resolution Dual Polarity MS Imaging and Lipid C═C Position-Resolved MS2 Imaging.

Local lipid variations in tissues are readily revealed with mass spectrometry imaging (MSI) methods, and the resulting lipid distributions serve as bioanalytical signatures to reveal cell- or tissue-specific lipids. Comprehensive MSI lipid mapping requires measurements in both ion polarities. Additionally, structural lipid characterization is necessary to link the lipid structure to lipid function. Whereas some structural elements of lipids are readily derived from high-resolution mass spectrometry (MS) and tandem-MS (MSn), the localization of C═C double bonds (DBs) requires specialized fragmentation and/or functionalization methods. In this work, we identify a multifunctional matrix-assisted laser desorption/ionization (MALDI) matrix for spatially resolved lipidomics investigations that reacts with lipids in Paternò-Büchi (PB) reactions during laser irradiation facilitating DB-position assignment and allows dual-polarity high-resolution MALDI-MSI and MALDI MS2I studies. By screening 12 compounds for improved ionization efficiency in positive-/negative-ion mode and the functionalization yield compared to the previously introduced reactive MALDI matrix benzophenone, 2-benzoylpyridine (BzPy) is identified as the best candidate. The new matrix enables DB localization of authentic standards belonging to 12 lipid classes and helps to assign 133/58 lipid features in positive-/negative-ion mode from mouse cerebellum tissue. The analytical capabilities of BzPy as a multifunctional MALDI-MSI matrix are demonstrated by imaging endogenous and PB-functionalized lipids in mouse kidney sections with 7 µm lateral resolution in both ion modes. Tracking diagnostic lipid DB-position fragment ions in mouse pancreatic tissue with down to 10 µm pixel size allows us to identify the islets of Langerhans associated with lipid isomer upregulation and depletion.

AAV-Mediated Expression of AP-1-Neutralizing RNA Decoy Oligonucleotides Attenuates Transplant Vasculopathy in Mouse Aortic Allografts.

Transplant vasculopathy (TV), characterized by obstructive lesions in affected vessels, represents one of the long-term complications of cardiac transplantation. Activation of the transcription factor activator protein-1 (AP-1) is implicated in smooth muscle cell (SMC) phenotypic switch from contractile to synthetic function, increasing the migration and proliferation rate of these cells. We hypothesize that adeno-associated virus (AAV)-mediated delivery of an RNA hairpin AP-1 decoy oligonucleotide (dON) might effectively ameliorate TV severity in a mouse aortic allograft model. Aortic allografts from DBA/2 mice ex vivo transduced with modified AAV9-SLR carrying a targeting peptide within the capsid surface were transplanted into the infrarenal aorta of C57BL/6 mice. Cyclosporine A (10 mg/kg BW) was administered daily. AP-1 dONs were intracellularly expressed in the graft tissue as small hairpin RNA proved by fluorescent in situ hybridization. Explantation after 30 days and histomorphometric evaluation revealed that AP-1 dON treatment significantly reduced intima-to-media ratio by 41.5% (p < 0.05) in the grafts. In addition, expression of adhesion molecules, cytokines, as well as numbers of proliferative SMCs, matrix metalloproteinase-9-positive cells, and inflammatory cell infiltration were significantly decreased in treated aortic grafts. Our findings demonstrate the feasibility, efficacy, and specificity of the anti-AP-1 RNA dON approach for the treatment of allograft vasculopathy in an animal model. Moreover, the AAV-based approach in general provides the possibility to achieve a prolonged delivery of nucleic-acids-based therapeutics in to the blood vessel wall.

Endothelial cell modulation of cardiomyocyte gene expression.

The anatomic arrangement of microvascular endothelial cells and cardiomyocytes in vivo enables close interactions among these cells. In our in vitro co-culture system, ANP and BNP expression in the mouse atrial cardiomyocyte cell line HL-1 and subsequent ANP release were significantly upregulated when co-cultured with mouse cardiac microvascular endothelial cells or exposed to endothelial cell-conditioned medium. Endothelin-1 (ET-1) activation of endothelial cells remarkably enhanced their paracrine effect on cardiomyocyte gene expression, suggesting that ET-1 stimulation of endothelial cells affects expression of fetal genes such as ANP and BNP in adult cardiomyocytes through paracrine signalling. Exposure of HL-1 cells and murine induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) to authentic angiopoietin-2 (Ang2) caused a concentration-dependent decrease in ANP expression while ET-1-induced ANP expression was augmented by low but inhibited by high concentrations of Ang2. FK506-mediated inhibition of the calcineurin-NFAT pathway in the HL-1 cells selectively inhibited the stimulatory effect of the conditioned medium derived from ET-1-pre-stimulated endothelial cells on cardiomyocyte fetal gene expression. Combined with previous results indicating a crucial role for ANP and BNP in cardiac homeostasis, our findings provide further evidence that paracrine signalling by cardiac microvascular endothelial cells modulates cardiomyocyte function.

Methylglyoxal evokes acute Ca2+ transients in distinct cell types and increases agonist-evoked Ca2+ entry in endothelial cells via CRAC channels.

Methylglyoxal (MG) is a by-product of glucose metabolism and its accumulation has been linked to the development of diabetic complications such as retinopathy and nephropathy by affecting multiple signalling pathways. However, its influence on the intracellular Ca2+ homeostasis and particularly Ca2+ entry, which has been reported to be mediated via TRPA1 channels in DRG neurons, has not been studied in much detail in other cell types. In this study, we report the consequences of acute and long-term MG application on intracellular Ca2+ levels in endothelial cells. We showed that acute MG application doesn't evoke any instantaneous changes in the intracellular Ca2+ concentration in immortalized mouse cardiac endothelial cells (MCECs) and murine microvascular endothelial cells (muMECs). In contrast, an MG-induced rise in intracellular Ca2+ level was observed in primary mouse mesangial cells within 30 s, indicating that the modulation of Ca2+ homeostasis by MG is strictly cell type specific. The formation of the MG-derived advanced glycation end product (AGE) MG-H1 was found to be time and concentration-dependent in MCECs. Likewise, MG pre-incubation for 6 h increased the angiotensin II-evoked Ca2+ entry in MCECs and muMECs which was abrogated by inhibition of Calcium release activated calcium (CRAC) channels with GSK-7975A, but unaffected by an inhibitor specific to TRPA1 channels. Quantitative PCR analysis revealed that MG pre-treatment did not affect expression of the genes encoding the angiotensin receptors AT1R (Agtr 1a & Agtr 1b), Trpa1 nor Orai1, Orai2, Orai3, Stim1, Stim2 and Saraf which operate as constituents or regulators of CRAC channels and store-operated Ca2+ entry (SOCE) in other cell types. Together, our results show that long-term MG stimulation leads to the formation of glycation end products, which facilitates the agonist-evoked Ca2+ entry in endothelial cells, and this could be a new pathway that might lead to MG-evoked vasoregression observed in diabetic vasculopathies.

Oxytocin reduces a chemosensory-induced stress bias in social perception.

Social transmission of fear is not restricted to visual or auditory cues, but extends to the phylogenetically more ancient olfactory domain. Anxious individuals exhibit heightened sensitivity towards chemosensory stress signals in sweat; however, it is still unknown whether endogenous neuromodulators such as the peptide hormone oxytocin (OXT) influence the chemosensory communication of stress. Here, we investigated whether OXT selectively diminishes behavioral and neural responses to social chemosensory stress cues utilizing a randomized, double-blind, placebo (PLC)-controlled, within-subject functional MRI study design. Axillary sweat was obtained from 30 healthy male donors undergoing the Trier Social Stress Test (stress) and bicycle ergometer training (sport). Subsequently, 58 healthy participants (30 females) completed a forced-choice emotional face recognition task with stimuli of varying intensities (neutral to fearful) while they were exposed to both sweat stimuli and a non-social control odor following intranasal OXT or PLC administration, respectively. OXT diminished stress-induced recognition accuracy and response time biases towards fear. On the neural level, OXT reduced stress-evoked responses in the amygdala in both sexes, the anterior cingulate cortex (ACC) in females, and the hippocampus in males. Furthermore, OXT reinstated the functional connectivity between the ACC and the fusiform face area that was disrupted by stress odors under PLC. Our findings reveal a new role for OXT signaling in the modulation of chemosensory communication of stress in humans. Mechanistically, this effect appears to be rooted in a downregulation of stress-induced limbic activations and concomitant strengthening of top-down control descending from the ACC to the fusiform face area.

Dysfunctional Presynaptic M2 Receptors in the Presence of Chronically High Acetylcholine Levels: Data from the PRiMA Knockout Mouse.

The muscarinic M2 receptor (M2R) acts as a negative feedback regulator in central cholinergic systems. Activation of the M2 receptor limits acetylcholine (ACh) release, especially when ACh levels are increased because acetylcholinesterase (AChE) activity is acutely inhibited. Chronically high ACh levels in the extracellular space, however, were reported to down-regulate M2R to various degrees. In the present study, we used the PRiMA knockout mouse which develops severely reduced AChE activity postnatally to investigate ACh release, and we used microdialysis to investigate whether the function of M2R to reduce ACh release in vivo was impaired in adult PRiMA knockout mice. We first show that striatal and hippocampal ACh levels, while strongly increased, still respond to AChE inhibitors. Infusion or injection of oxotremorine, a muscarinic M2 agonist, reduced ACh levels in wild-type mice but did not significantly affect ACh levels in PRiMA knockout mice or in wild-type mice in which ACh levels were artificially increased by infusion of neostigmine. Scopolamine, a muscarinic antagonist, increased ACh levels in wild-type mice receiving neostigmine, but not in wild-type mice or in PRiMA knockout mice. These results demonstrate that M2R are dysfunctional and do not affect ACh levels in PRiMA knockout mice, likely because of down-regulation and/or loss of receptor-effector coupling. Remarkably, this loss of function does not affect cognitive functions in PRiMA knockout mice. Our results are discussed in the context of AChE inhibitor therapy as used in dementia.

Mice heterozygous for AChE are more sensitive to AChE inhibitors but do not respond to BuChE inhibition.

An impaired central cholinergic system is at least partly involved in Alzheimer's disease (AD) pathogenesis, with cholinergic markers such as acetylcholinesterase (AChE) activity and protein levels decreasing as cognitive decline progresses. AD patients receive AChE inhibitor drugs to enhance cholinergic responses in the brain. The present study characterises the cholinergic system of mice heterozygous for AChE (HZ) as a suitable in vivo model for permanently reduced AChE activity. In comparison to homozygous, wild type (WT) mice, HZ mice show a 40% reduction of AChE activity in the brain, while their hippocampal ACh levels are increased by 56% as measured by microdialysis; choline acetyltransferase levels remain unaltered, and choline uptake increases 2-fold. We demonstrate that HZ mice are significantly more sensitive to local AChE inhibition (BW284c51), but remain insensitive to butyrylcholinesterase (BuChE) inhibition (bambuterol). HZ mice are also more sensitive to the peripheral application of the selective AChE inhibitor donepezil or the mixed inhibitor physostigmine; extracellular ACh levels rise significantly after administration of both drugs; also glucose levels are moderately increased indicating potentially non-cholinergic effects of donepezil. Behavioural tests show comparable cognitive function in both mouse strains. Our results are discussed in relation to the use of AChE/BuChE inhibitors in AD patients.

Near-complete adaptation of the PRiMA knockout to the lack of central acetylcholinesterase.

Acetylcholinesterase (AChE) rapidly hydrolyzes acetylcholine. At the neuromuscular junction, AChE is mainly anchored in the extracellular matrix by the collagen Q, whereas in the brain, AChE is tethered by the proline-rich membrane anchor (PRiMA). The AChE-deficient mice, in which AChE has been deleted from all tissues, have severe handicaps. Surprisingly, PRiMA KO mice in which AChE is mostly eliminated from the brain show very few deficits. We now report that most of the changes observed in the brain of AChE-deficient mice, and in particular the high levels of ambient extracellular acetylcholine and the massive decrease of muscarinic receptors, are also observed in the brain of PRiMA KO. However, the two groups of mutants differ in their responses to AChE inhibitors. Since PRiMA-KO mice and AChE-deficient mice have similar low AChE concentrations in the brain but differ in the AChE content of the peripheral nervous system, these results suggest that peripheral nervous system AChE is a major target of AChE inhibitors, and that its absence in AChE- deficient mice is the main cause of the slow development and vulnerability of these mice. At the level of the brain, the adaptation to the absence of AChE is nearly complete.

Inflammatory bowel disease: perioperative pharmacological considerations.

The perioperative management of patients with inflammatory bowel disease is challenging given the altered immune system that results from a variety of biologic and immunomodulator therapies. Clinicians are often faced with challenges and complicated equations when deciding on the type and dose of medication. To understand the effect of these medications and review the evidence regarding the management of these medications in the perioperative setting, a PubMed-based literature search (January 1, 1960, through April 1, 2011) was conducted using the following search terms: perioperative management, risk, outcome, inflammatory bowel disease, ulcerative colitis, Crohn's disease, aminosalicylates, glucocorticoids, purine analogues, cyclosporine, methotrexate, biologic therapy, infliximab, and thromboembolism. The 414 articles identified were manually sorted to exclude those that did not address perioperative risk, outcomes, and medications in the abstracts, yielding 84 articles for review. Additional references were obtained from the citations within the retrieved articles. This review surveys the findings of the selected articles and presents guidelines and resources for perioperative medication management for patients with inflammatory bowel disease undergoing surgery.

Use and safety of rifaximin in children with inflammatory bowel disease.

BACKGROUND: Rifaximin, Food and Drug Administration approved for traveler's diarrhea, has been used in adult patients with active inflammatory bowel disease (IBD). This retrospective review was undertaken to determine its role in the treatment of pediatric IBD. METHODS: A review of children with IBD, who were treated with rifaximin from 2005 to 2007 at our institution, was performed. Collected data included diagnosis, age, medication history, recent therapy, symptom, and interval to improvement. Response was rated as none, moderate, or optimum relief for each symptom. RESULTS: Twenty-three patients were identified, 12 with Crohn disease and 11 with ulcerative colitis (UC) with a median age of 13 years. The most common complaints were diarrhea in 20 patients (87%), abdominal pain in 17 (74%), and bloody stools in 15 (65%). Rifaximin was given at doses ranging between 10 and 30 mg/kg (Table 1). Of the 20 patients who presented with diarrhea 5 (25%) had relief of diarrhea within 1 week of starting rifaximin and total of 12 patients (60%) experienced relief within 4 weeks. Abdominal pain resolved in 3 of 17 patients (17.6%) within 1 week and in 12 of 17 (70.6%) within 4 weeks. Visible bleeding resolved in 10 of 15 patients (66.7%) within 4 weeks of therapy (Table 2). Analysis of concurrent medications showed 61% experienced relief of symptoms when addition of rifaximin was the only meaningful treatment change. CONCLUSIONS: Rifaximin was well-tolerated and showed favorable results. Larger doses of rifaximin were statistically better for abdominal pain. Further studies are needed to evaluate efficacy and optimal dosing of rifaximin in this population.

Risk of capsule endoscope retention in pediatric patients: a large single-center experience and review of the literature.

OBJECTIVES: Capsule retention is a potential complication of capsule endoscopy (CE). The aims of our study were to determine the incidence of capsule retention in pediatric patients undergoing CE and to identify potential risk factors for capsule retention. MATERIALS AND METHODS: We performed an institutional review board-approved retrospective chart review of pediatric patients undergoing CE studies at a single center. Data collected included patient age, sex, prior diagnosis of inflammatory bowel disease (IBD), CE indication, prior small bowel series results, study result, and complications. RESULTS: Two hundred seven CE procedures were performed in pediatric patients during the study period. Capsule retention occurred in 3 (1.4%) of the 207 studies. All 3 patients had known Crohn disease (CD). The risk of capsule retention in pediatric patients with known IBD was 5.2% (3/58). The risk of capsule retention for patients with suspected IBD and all other indications was 0%. If small bowel disease was identified on upper gastrointestinal series in patients with known CD, then the risk of capsule retention was 37.5% (3/8). Only 7 patients with known IBD had a body mass index (BMI) below the 5th percentile. Of these 7 patients, 3 (43%) had capsule retention. CONCLUSIONS: Red flags for potential CE retention identified in our study include known IBD (5.2% retention risk), previous small bowel follow-through demonstrating small bowel CD (37.5% retention risk), and BMI <5th percentile with known IBD (43% retention risk). Caution is advised in these pediatric patients before capsule ingestion.