bluuebunny/crossref_metadata_2025 huggingface dataset:
Endocytic Accessory Proteins Are Functionally Distinguished by Their Differential Effects on the Maturation of Clathrin-coated Pits
Authors: Mettlen Marcel , Stoeber Miriam , Loerke Dinah , Antonescu Costin N. , Danuser Gaudenz , Schmid Sandra L.
Published: May 2009

Diverse cargo molecules (i.e., receptors and ligand/receptor complexes) are taken into the cell by clathrin-mediated endocytosis (CME) utilizing a core machinery consisting of cargo-specific adaptors, clathrin and the GTPase dynamin. Numerous endocytic accessory proteins are also required, but their differential roles and functional hierarchy during CME are not yet understood. Here, we used a combination of quantitative live-cell imaging by total internal reflection fluorescence microscopy (TIR-FM), and decomposition of the lifetime distributions of clathrin-coated pits (CCPs) to measure independent aspects of CCP dynamics, including the turnover of abortive and productive CCP species and their relative contributions. Capitalizing on the sensitivity of this assay, we have examined the effects of specific siRNA-mediated depletion of endocytic accessory proteins on CME progression. Of the 12 endocytic accessory proteins examined, we observed seven qualitatively different phenotypes upon protein depletion. From this data we derive a temporal hierarchy of protein function during early steps of CME. Our results support the idea that a subset of accessory proteins, which mediate coat assembly, membrane curvature, and cargo selection, can provide input into an endocytic restriction point/checkpoint mechanism that monitors CCP maturation.
Gap Junction Turnover Is Achieved by the Internalization of Small Endocytic Double-Membrane Vesicles
Authors: Falk Matthias M. , Baker Susan M. , Gumpert Anna M. , Segretain Dominique , Buckheit Robert W.
Published: May 2009

Double-membrane–spanning gap junction (GJ) channels cluster into two-dimensional arrays, termed plaques, to provide direct cell-to-cell communication. GJ plaques often contain circular, channel-free domains (∼0.05–0.5 μm in diameter) identified >30 y ago and termed nonjunctional membrane (NM) domains. We show, by expressing the GJ protein connexin43 (Cx43) tagged with green fluorescent protein, or the novel photoconvertible fluorescent protein Dendra2, that NM domains appear to be remnants generated by the internalization of small GJ channel clusters that bud over time from central plaque areas. Channel clusters internalized within seconds forming endocytic double-membrane GJ vesicles (∼0.18–0.27 μm in diameter) that were degraded by lysosomal pathways. Surprisingly, NM domains were not repopulated by surrounding channels and instead remained mobile, fused with each other, and were expelled at plaque edges. Quantification of internalized, photoconverted Cx43-Dendra2 vesicles indicated a GJ half-life of 2.6 h that falls within the estimated half-life of 1–5 h reported for GJs. Together with previous publications that revealed continuous accrual of newly synthesized channels along plaque edges and simultaneous removal of channels from plaque centers, our data suggest how the known dynamic channel replenishment of functional GJ plaques can be achieved. Our observations may have implications for the process of endocytic vesicle budding in general.
A Meta-analysis of Clinical Screening Tests for Obstructive Sleep Apnea
Authors: Ramachandran Satya Krishna , Josephs Lydia A.
Published: May 2009

The purpose of this meta-analysis is to compare clinical screening tests for obstructive sleep apnea and establish an evidence base for their preoperative use. Diagnostic odds ratios were used as summary measures of accuracy, and false-negative rates were used as measures of missed diagnosis with each screening test in this review. Metaregression revealed that clinical models, logarithmic equations, combined techniques, cephalometry, and morphometry are significant characteristics, whereas body mass index, history of hypertension, and nocturnal choking are significant test elements associated with higher diagnostic accuracy. Test accuracy in repeated validation studies of the same screening test is variable, suggesting an underlying heterogeneity in either the clinical presentation of obstructive sleep apnea or the measured clinical elements of these models. Based on the false-negative rates, it is likely that most of the clinical screening tests will miss a significant proportion of patients with obstructive sleep apnea.
Postoperative Neurocognitive Dysfunction in Elderly Patients after Xenon versus Propofol Anesthesia for Major Noncardiac Surgery
Authors: Höcker Jan , Stapelfeldt Claudia , Leiendecker Jörn , Meybohm Patrick , Hanss Robert , Scholz Jens , Bein Berthold
Published: May 2009

Background

Postoperative cognitive dysfunction (POCD) in elderly patients after noncardiac surgery is a common problem. The noble gas xenon has been demonstrated to exert substantial neuroprotective properties in animal studies. Therefore, this study was designed to assess POCD after xenon anesthesia in comparison to propofol in elderly patients undergoing major noncardiac surgery.

Methods

After approval of the local ethical committee was obtained, 101 patients (American Society of Anesthesiologists physical status I-III; age, 65-83 yr) undergoing elective abdominal or urologic surgery (duration, > 2 h) were enrolled into this randomized, double-blinded controlled pilot study. Patients received anesthesia with sufentanil and either propofol or xenon and were assessed before treatment and 1, 6, and 30 days after treatment using a neuropsychological test battery based on previous studies investigating POCD.

Results

There were no significant differences in terms of age, American Society of Anesthesiologists status, education, duration of surgery, administered analgetics, and preoperative neurocognitive status between study groups. POCD as classified was present in 22 patients (44%) of the xenon group versus 25 patients (50%) of the propofol group 1 day after treatment, in 6 xenon patients (12%) versus 9 propofol patients (18%) 6 days after treatment, and in 3 xenon patients (6%) versus 6 propofol patients (12%) 30 days after treatment. These differences were not statistically significant.

Conclusion

Postoperative impairment of neurocognitive function was observed in a substantial proportion of elderly patients even 30 days after treatment. Xenon-based anesthesia was not associated with decreased incidence of POCD in comparison to propofol.
Opioid Tolerance Blunts the Reduction in the Sevoflurane Minimum Alveolar Concentration Produced by Remifentanil in the Rat
Authors: Gómez de Segura Ignacio A. , de la Vibora Javier Benito , Aguado Delia
Published: May 2009

Background

Acute opioid tolerance is a known entity leading to reduced analgesic efficacy of these drugs in the postoperative period. However, the development of acute opioid tolerance in the very short term, i.e., during the intraoperative period when opioids are being administered, has not been reported. Therefore, the aim of this study was to determine if acute opioid tolerance could develop and limit the opioid-induced reduction in the minimum alveolar concentration (MAC) for inhalant anesthetics.

Methods

Male Wistar rats were randomly allocated to receive two doses of remifentanil (120 and 240 microg . kg(-1) . h(-1)) under sevoflurane anesthesia, and the sevoflurane MAC was determined before and at two time intervals afterwards. In a second experiment, the low dose of remifentanil was increased once an acute opioid tolerance effect was observed. The sevoflurane MAC was determined from alveolar gas samples at the time of tail clamp.

Results

A remifentanil constant rate of infusion dose-dependently reduced the sevoflurane MAC from 2.4 to 1.8 +/- 0.2 vol% and from 2.3 +/- 0.3 vol% to 1.5 +/- 0.3 vol%, at the low and high doses, respectively. However, 90 min later, when the sevoflurane MAC was redetermined, the observed reduction was blunted to nearly 50% of the previous sevoflurane MAC values. When this acute opioid tolerance effect was observed with the low dose, the sevoflurane MAC reduction originally achieved could be reattained by doubling the dose; i.e., giving the high dose.

Conclusions

Remifentanil efficacy in reducing the sevoflurane MAC diminishes within a short term, suggesting that increased opioid doses may be required to maintain intraoperative analgesia during sevoflurane anesthesia.
Volatile Anesthetic Action in a Computational Model of the Thalamic Reticular Nucleus
Authors: Gottschalk Allan , Miotke Sam A.
Published: May 2009

Background

Although volatile anesthetics (VAs) modulate the activity of multiple ion channels, the process whereby one or more of these effects are integrated to produce components of the general anesthetic state remains enigmatic. Computer models offer the opportunity to examine systems level effects of VA action at one or more sites. Motivated by the role of the thalamus in consciousness and sensory processing, a computational model of the thalamic reticular nucleus was used to determine the collective impact on model behavior of VA action at multiple sites.

Methods

A computational model of the thalamic reticular nucleus was modified to permit VA modulation of its ion channels. Isobolographic analysis was used to determine how multiple sites interact.

Results

VA modulation of either T-type Ca(2+) channels or gamma-aminobutyric acid type A receptors led to increased network synchrony. VA modulation of both further increased network synchronization. VA-induced decrements in Ca(2+) current permitted greater impact of inhibitory currents on membrane potential, but at higher VA concentrations the decrease in Ca(2+) current led to a decreased number of spikes in the burst generating the inhibitory signal. MAC-awake (the minimum alveolar concentration at which 50% of subjects will recover consciousness) concentrations of both isoflurane and halothane led to similar levels of network synchrony in the model.

Conclusions

Relatively modest VA effects at both T-type Ca(2+) channels and gamma-aminobutyric acid type A receptors can substantially alter network behavior in a computational model of a thalamic nucleus. The similarity of network behavior at MAC-awake concentrations of different VAs is consistent with a contribution of the thalamus to VA-induced unconsciousness through action at these channels.
Approach Combining the Airway Scope and the Bougie for Minimizing Movement of the Cervical Spine during Endotracheal Intubation
Authors: Takenaka Ichiro , Aoyama Kazuyoshi , Iwagaki Tamao , Ishimura Hiroshi , Takenaka Yukari , Kadoya Tatsuo
Published: May 2009

Background

The Airway Scope (AWS, AWS-S100; Hoya-Pentax, Tokyo, Japan), a recently introduced video laryngoscope, has been reported to reduce movement of the cervical spine during intubation attempts in comparison with conventional laryngoscopes. Use of the bougie as an aid for the AWS may cause further reduction. The authors compared cervical spine movement during intubation with the AWS with and without a bougie.

Methods

Thirty patients without cervical spine abnormality were randomized into two groups: intubation with AWS only and intubation with the AWS and the bougie. The cervical spine motion between the occiput (C0) and the fourth cervical vertebra (C4) was observed fluoroscopically, and change in movement between adjacent vertebrae created by each intubation method was compared. Time to intubation was also measured.

Results

Laryngoscopy with the AWS produced extension of the cervical spine segments assessed (C0-4). Median extension angle of the C0-4 during intubation using the AWS was reduced from 16.0 degrees without the bougie to 6.5 degrees with the bougie (P < 0.01). There was no significant difference in time to intubation between them.

Conclusions

Use of the bougie resulted in significantly reduced extension of the cervical spine during intubation attempt with the AWS in patients with a normal cervical spine.
Morphine-6β-glucuronide Rapidly Increases Pain Sensitivity Independently of Opioid Receptor Activity in Mice and Humans
Authors: van Dorp Eveline L. A. , Kest Benjamin , Kowalczyk William J. , Morariu Aurora M. , Waxman Amanda R. , Arout Caroline A. , Dahan Albert , Sarton Elise Y.
Published: May 2009

Background

Previous data indicate that morphine-6beta-glucuronide (M6G), a morphine metabolite with analgesic properties, can paradoxically increase pain sensitivity in mice and humans. The authors tested mice and humans for M6G hyperalgesia and assessed the contribution of N-methyl-D-aspartate receptor activity in mice.

Methods

Nociception after acute injection (10 mg/kg) and chronic infusion (1.6 mg/kg per 24 h) of M6G or saline was assayed using the tail-withdrawal test in CD-1 mice implanted with pellets containing the opioid antagonist naltrexone or placebo and in knockout mice lacking mu-, kappa-, and delta-opioid receptors and their B6129F(1) controls. In volunteers, responses to heat pain were tested after a M6G (0.4 mg/kg) injection in the presence of a continuous high naloxone (0.04-mg/kg bolus followed by 0.04 mg/kg per hour) or saline background infusion.

Results

Acute M6G injection evoked analgesia in CD-1 mice implanted with placebo pellets and B6129F(1) control mice, whereas it caused hyperalgesia in CD-1 mice treated concurrently with naltrexone and in knockout mice. Continuous M6G infusion produced hyperalgesia within 24 h, lasting for a minimum of 6 days, in both placebo- and naltrexone-pelleted mice. The N-methyl-D-aspartate receptor antagonist MK-801 (0.05 mg/kg) blocked and reversed hyperalgesia after the acute injection and continuous infusion of M6G, respectively. In humans, M6G increased heat pain sensitivity for at least 6 h independently of simultaneous naloxone infusion.

Conclusions

These data indicate that M6G causes hyperalgesia independent of previous or concurrent opioid receptor activity or analgesia. In mice, a causal role for the N-methyl-D-aspartate receptor is also indicated.
Anesthetic-induced Improvement of the Inflammatory Response to One-lung Ventilation
Authors: De Conno Elisena , Steurer Marc P. , Wittlinger Moritz , Zalunardo Marco P. , Weder Walter , Schneiter Didier , Schimmer Ralph C. , Klaghofer Richard , Neff Thomas A. , Schmid Edith R. , Spahn Donat R. , Z’graggen Birgit Roth , Urner Martin , Beck-Schimmer Beatrice
Published: May 2009

Background

Although one-lung ventilation (OLV) has become an established procedure during thoracic surgery, sparse data exist about inflammatory alterations in the deflated, reventilated lung. The aim of this study was to prospectively investigate the effect of OLV on the pulmonary inflammatory response and to assess possible immunomodulatory effects of the anesthetics propofol and sevoflurane.

Methods

Fifty-four adults undergoing thoracic surgery with OLV were randomly assigned to receive either anesthesia with intravenously applied propofol or the volatile anesthetic sevoflurane. A bronchoalveolar lavage was performed before and after OLV on the lung side undergoing surgery. Inflammatory mediators (tumor necrosis factor alpha, interleukin 1beta, interleukin 6, interleukin 8, monocyte chemoattractant protein 1) and cells were analyzed in lavage fluid as the primary endpoint. The clinical outcome determined by postoperative adverse events was assessed as the secondary endpoint.

Results

The increase of inflammatory mediators on OLV was significantly less pronounced in the sevoflurane group. No difference in neutrophil recruitment was found between the groups. A positive correlation between neutrophils and mediators was demonstrated in the propofol group, whereas this correlation was missing in the sevoflurane group. The number of composite adverse events was significantly lower in the sevoflurane group.

Conclusions

This prospective, randomized clinical study suggests an immunomodulatory role for the volatile anesthetic sevoflurane in patients undergoing OLV for thoracic surgery with significant reduction of inflammatory mediators and a significantly better clinical outcome (defined by postoperative adverse events) during sevoflurane anesthesia.
Is the Performance of Acceleromyography Improved with Preload and Normalization?
Authors: Claudius Casper , Skovgaard Lene Theil , Viby-Mogensen Jørgen
Published: May 2009

Background

Many studies have indicated that acceleromyography and mechanomyography cannot be used interchangeably. To improve the agreement between the two methods, it has been suggested to use a preload and to refer all train-of-four (TOF) ratios to the control TOF (normalization) when using acceleromyography. The first purpose of this study was to test whether a preload applied to acceleromyography would increase the precision and the agreement with mechanomyography. The second purpose was to evaluate whether normalization would improve the agreement with mechanomyography.

Methods

Sixty patients were randomized to acceleromyography with or without a preload (Hand Adapter; Organon, Oss, the Netherlands). On the contralateral arm, mechanomyography was used. Anesthesia was induced with propofol and an opioid, and neuromuscular block with 0.6 mg/kg rocuronium. The precision and the bias and limits of agreement (with or without normalization) between the methods were evaluated using TOF stimulation.

Results

Preload improved the precision of acceleromyography by 21%, but it also increased the mean control TOF ratio from 1.07 to 1.13. Normalization of the acceleromyographic TOF ratios diminished the bias to mechanomyography during recovery (e.g., from 0.15 to 0.05 at TOF 0.90); when the mechanomyographic TOF values were normalized as well, the bias was eliminated. However, normalization did not exclude wide individual differences between acceleromyography and mechanomyography (+/- 0.10-0.20 at TOF 0.90).

Conclusion

Preload increases the precision of acceleromyography, and normalization of the TOF ratios decreases bias in relation to mechanomyography. When both acceleromyography and mechanomyography are normalized, there is no significant bias between the two methods.
Extraneural versus Intraneural Stimulation Thresholds during Ultrasound-guided Supraclavicular Block
Authors: Bigeleisen Paul E. , Moayeri Nizar , Groen Gerbrand J.
Published: May 2009

Background

A stimulation current of no more than 0.5 mA is regarded as safe in avoiding nerve injury and delivering adequate stimulus to provoke a motor response. However, there is no consistent level of stimulating threshold that reliably indicates intraneural placement of the needle. The authors determined the minimally required stimulation threshold to elicit a motor response outside and inside the most superficial part of the brachial plexus during high-resolution, ultrasound-guided, supraclavicular block.

Methods

After institutional review board approval, ultrasound-guided, supraclavicular block was performed on 55 patients. Patients with neurologic dysfunction were excluded. Criteria for extraneural and intraneural stimulation were defined and assessed by independent experts. To determine success rate and any residual neurologic deficit, qualitative sensory and motor examinations were performed before and after block placement. At 6 month follow-up, the patients were examined for any neurologic deficit.

Results

Thirty-nine patients met all set stimulation criteria. Median +/- SD (interquartile range) minimum stimulation threshold outside was 0.60 +/- 0.37 mA (0.40, 1.0) and inside 0.30 +/- 0.19 mA (0.20, 0.40). The difference of 0.30 mA was statistically significant (P < 0.0001). Stimulation currents of 0.2 mA or less were not observed outside the trunk in any patient. Significantly higher thresholds were observed in diabetic patients. Success rate was 100% after 20 min. Thirty-four patients had normal sensory and motor examination at 6 months. Five patients were lost to follow-up.

Conclusion

Within the limitations of this study and the use of ultrasound, a stimulation current of 0.2 mA or less is reliable to detect intraneural placement of the needle. Furthermore, stimulation currents of more than 0.2 and no more than 0.5 mA could not rule out intraneural position.
Survival Probabilities of Patients With Childhood Spinal Muscle Atrophy
Authors: Mannaa Mohannad M , Kalra Maninder , Wong Brenda , Cohen Aliza P , Amin Raouf S
Published: May 2009

Objective:

Medical and technological advances over the past 2 decades have resulted in improved patient care for children with spinal muscular atrophy (SMA). The objective of the present study was to describe changes in the life expectancy of pediatric patients with SMA over time and to compare these findings with previously reported survival patterns.

Methods:

Medical records of all patients diagnosed with SMA over a 16-year period (1989-2005) at Cincinnati Children's Hospital Medical Center were reviewed. Data pertaining to date of birth, type of SMA, medical and surgical interventions, pulmonary complications, and date of death were obtained.

Results:

Kaplan-Meier survival analyses showed a significant improvement in survival probabilities in the severest form of SMA.

Conclusions:

We found a positive trend in the survival of patients with severe SMA. Although we cannot attribute this trend to any single factor, it is likely that advances in pulmonary care and aggressive nutritional support have played a significant role.
Unilateral Myokymia of the Tongue After Radiation Therapy for Cervical Nodal Melanoma
Authors: Richardson Randal C , Weiss Michael D
Published: May 2009

Hypoglossal neuropathy with associated myokymia as a delayed effect of radiation is a rare occurrence, presumably due to the relative resistance of cranial nerves to injury from irradiation. The authors describe the first case of myokymia of the unilateral tongue with myokymic discharges on needle electromyography after hypofractionated radiation therapy for an extracranial melanoma of the neck. The earlier onset of myokymia than previous cases may represent more direct radiation exposure due to radiation site or the higher radiation dosage administered for treatment of melanomas.
Simultaneous Presentation of Coarctation of the Thoracic Aorta and Aneurysm of the Superior Mesenteric Artery
Authors: Karmy-Jones Riyad , Bloch Robert , Martin M. Alan
Published: May 2009

A 34-year-old woman presented with both coarctation of the thoracic aorta and aneurysm of the superior mesenteric artery. The former was managed by open surgical repair, the latter by stent-graft. This case illustrates the need for facility with both percutaneous and open approaches to diseases of the aorta and its branches.
13C‐Breath Tests for Sucrose Digestion in Congenital Sucrase Isomaltase–deficient and Sacrosidase‐supplemented Patients
Authors: Robayo‐Torres Claudia C , Opekun Antone R , Quezada‐Calvillo Roberto , Villa Xavier , Smith EO , Navarrete Marilyn , Baker Susan S , Nichols Buford L
Published: May 2009

Background:

Congenital sucrase‐isomaltase deficiency (CSID) is characterized by absence or deficiency of the mucosal sucrase‐isomaltase enzyme. Specific diagnosis requires upper gastrointestinal biopsy with evidence of low to absent sucrase enzyme activity and normal histology. The hydrogen breath test (BT) is useful, but is not specific for confirmation of CSID. We investigated a more specific 13C‐sucrose labeled BT.

Objectives:

Determine whether CSID can be detected with the 13C‐sucrose BT without duodenal biopsy sucrase assay, and if the 13C‐sucrose BT can document restoration of sucrose digestion by CSID patients after oral supplementation with sacrosidase (Sucraid).

Methods:

Ten CSID patients were diagnosed by low biopsy sucrase activity. Ten controls were children who underwent endoscopy and biopsy because of dyspepsia or chronic diarrhea with normal mucosal enzymes activity and histology. Uniformly labeled 13C‐glucose and 13C‐sucrose loads were orally administered. 13CO2 breath enrichments were assayed using an infrared spectrophotometer. In CSID patients, the 13C‐sucrose load was repeated adding Sucraid. Sucrose digestion and oxidation were calculated as a mean percent coefficient of glucose oxidation averaged between 30 and 90 minutes.

Results:

Classification of patients by 13C‐sucrose BT percent coefficient of glucose oxidation agreed with biopsy sucrase activity. The breath test also documented the return to normal of sucrose digestion and oxidation after supplementation of CSID patients with Sucraid.

Conclusions:

13C‐sucrose BT is an accurate and specific noninvasive confirmatory test for CSID and for enzyme replacement management.
Polymorphisms in the IBD5 Locus Are Associated With Crohn Disease in Pediatric Ashkenazi Jewish Patients
Authors: Tomer Gitit , Wetzler Graciela , Keddache Mehdi , Denson Lee A
Published: May 2009

Objectives:

To analyze the IBD5 locus in a homogenous cohort of Ashkenazi Jewish (AJ) children with Crohn disease (CD).

Patients and Methods:

A total of 83 AJ children with CD and 73 AJ healthy controls were studied. Genotyping for single nucleotide polymorphisms (SNPs) including OCTN1 (SLC22A4; 1672C→T), OCTN2 (SLC22A5; 207G→C), IGR2096, IGR2198, and IGR2230 genes was performed using the TaqMan system. NOD2/CARD15 variants also were typed using established methods.

Results:

All IBD5 SNPs tested were in linkage disequilibrium (D′>0.8), and showed significant association with CD in our cohort of AJ children. The IGR2096 SNP, which is not located within the same linkage disequilibrium block as the OCTN1 and 2 SNPs, showed an even stronger association with CD (P = 0.017; odds ratio = 1.7). Patients with CD who had the OCTN1 susceptibility allele were more likely to carry 1 of the 3 NOD2/CARD15 SNPs tested (P = 0.01; odds ratio = 4.8).

Conclusions:

We have demonstrated a significant association between the IBD5 locus and CD in a homogenous cohort of pediatric AJ patients. Due to the tight linkage disequilibrium in the region, it is not possible to identify the causative IBD5 variant. Future functional studies will ultimately reveal the causative gene variant at this locus.
Circulating Adiponectin as a Marker for Glucocorticoid‐related Side Effects in Children and Adolescents With Inflammatory Bowel Disease
Authors: Vihinen Marianne K , Kolho Kaija‐Leena , Jänne Olli A , Andersson Sture , Raivio Taneli
Published: May 2009

Glucocorticoid therapy is widely used in clinical practice. However, treatment with steroids carries the risk of side effects. We investigated changes in serum adiponectin and leptin in response to systemic glucocorticoid treatment in 18 pediatric patients with inflammatory bowel disease and contrasted these findings to circulating glucocorticoid bioactivity measured with a mammalian cell bioassay. Interestingly, serum adiponectin levels at 2 to 4 weeks of therapy were significantly higher in patients who experienced acute glucocorticoid‐related side effects (22.9 ± 2.6 μg/mL, n = 7) than in those who did not (16.0 ± 2.1 μg/mL, n = 11, P < 0.05). Serum leptin was not associated with side effects. Circulating adiponectin may serve as an early and readily available endogenous biomarker for acute glucocorticoid‐related side effects in pediatric patients.
Prenatal Lipopolysaccharide Increases Postnatal Intestinal Injury in a Rat Model of Necrotizing Enterocolitis
Authors: Giannone Peter J , Nankervis Craig A , Richter Juli M , Schanbacher Brandon L , Reber Kristina M
Published: May 2009

Background:

An increased incidence of necrotizing enterocolitis (NEC) has been noted in infants who are born to mothers with chorioamnionitis.

Hypothesis:

Our objective was to test the hypothesis that newborn rat pups born to mothers exposed to prenatal lipopolysaccharide during pregnancy would be more susceptible to intestinal injury in a rat model of NEC and that the increased intestinal injury is mediated by dysregulation of inducible nitric oxide synthase.

Methods:

Time‐dated pregnant Sprague‐Dawley dams were given an intraperitoneal injection of either 2 mg/kg of lipopolysaccharide or vehicle. Rat pups from each group of dams were delivered at term and placed in a rat NEC model. A subset of pups was given either vehicle or aminoguanidine. Intestines were harvested and graded for degree of intestinal injury.

Results:

Maternal prenatal lipopolysaccharide exposure increased the frequency and severity of intestinal injury in the neonatal rat NEC model. Treatment with aminoguanidine significantly decreased plasma nitric oxide levels. Additionally, aminoguanidine significantly decreased intestinal injury.

Conclusions:

Intestinal injury observed may be mediated via nitric oxide synthase dysregulation.
Capsule Endoscopy in the Evaluation of Patients With Unexplained Growth Failure
Authors: Moy Libia , Levine Jeremiah
Published: May 2009

Background:

Poor weight gain and growth can be caused by many medical, nutritional, behavioral, and psychological factors. Crohn disease is one of the more common gastrointestinal etiologies associated with growth failure. The aim of this study is to determine the role of capsule endoscopy (CE) in the evaluation of older children and adolescents who were referred to a pediatric gastroenterology service for a chief complaint of unexplained growth failure.

Patients and Methods:

We retrospectively reviewed the records of children with growth failure undergoing CE between August 2002 and November 2005. Height and weight (expressed as z scores) were recorded at least 6 months before study, at the time of the study, and at least 6 months poststudy. All of the patients had celiac disease and Crohn disease excluded using standard biochemical, radiologic, endoscopic, and histologic assessment.

Results:

Seven children (4 males and 3 females) were included in the study—mean age 11.7 ± 3.6 years. Indications for CE were growth failure associated with abdominal pain (3 patients), diarrhea and apthous ulcers (2 patients), delayed puberty (1 patient), or a family history of Crohn disease (1 patient). The mean z score for weight at the time of the study was −2.10 ± 1.0 and for height was −1.50 ± 0.7 All 7 children had normal small bowel series performed before the CE. All had both endoscopically and histologically normal esophagogastroduodenoscopy and colonoscopy. In 4 of 7 patients, multiple small bowel apthous ulcerations consistent with Crohn disease were identified by CE. All 4 patients who had abnormal CE were treated and started gaining weight. The mean z score for weight after 6 months of treatment was −1.35 ± 1.2 and for height was −0.50 ± 1.7. The mean z score for weight after treatment was significantly improved compared with the mean z score at diagnosis (P < 0.05).

Conclusions:

In our study, 4 of the 7 older children and adolescents with unexplained growth failure and normal small bowel series were found to have Crohn disease involving the small intestine. In addition, we were able to show the improvement on the mean z score for weight after treatment of small bowel Crohn disease was instituted.
Malposition of Feeding Tubes in Neonates: Is It an Issue?
Authors: Quandt Daniel , Schraner Thomas , Ulrich Bucher Hans , Arlettaz Mieth Romaine
Published: May 2009

Objectives:

Accurate tube placement of orogastric and nasogastric feeding tubes in neonates is important to ensure safe and effective enteral feeding. Errors in placement and position of feeding tubes are described in literature, but there is little evidence of the exact prevalence of improperly placed tubes, especially in neonates.

Materials and Methods:

To evaluate the prevalence of improperly placed feeding tubes, we reviewed 381 consecutive radiographs and defined the position of the feeding tubes.

Results:

We found that in 41% of the placements, the optimal position of the feeding tubes was achieved, whereas overall 59% of the feeding tubes had been placed incorrectly.

Conclusions:

There is a need for both better rules to measure the distance between nose (lips) and the body of the stomach and improved methods to confirm correct tube position in neonates.
Pediatric Inflammatory Bowel Diseases and the Risk of Lymphoma: Should We Revise Our Treatment Strategies?
Authors: Cucchiara Salvatore , Escher Johanna C , Hildebrand Hans , Amil‐Dias Jorge , Stronati Laura , Ruemmele Frank M
Published: May 2009

Inflammatory bowel diseases (IBDs) are lifelong inflammatory gastrointestinal diseases starting in about one third of patients during childhood. Treatment strategies aim to control this chronic inflammatory process. Owing to recent advances in the understanding of IBD, immunosuppressive agents (mainly against TNFα directed) as well as biological drugs are more and more often used. This therapeutic approach clearly improved the clinical condition of the majority of patients with IBD. However, with this more aggressive treatment strategy, safety concerns clearly arise. Recently, the description of a series of a particularly severe form of T cell lymphoma in pediatric and young adult patients with IBD under immunomodulator and biological combination therapy raised the question of the risks of treatment‐induced side effects or complications. As reviewed in the present article, there is a slightly increased risk of not only lymphoma development in IBD patients, potentially related to the inflammatory process, but also to the use of immunosuppressive therapies. On the basis of the literature data, we reanalyzed current treatment strategies for children with moderate‐to‐severe IBD, who are candidates to receive immunomodulator and/or biological agents potentially accelerating the risk of lymphoma development. Comparative clinical studies in IBD are still missing; however, it is prudent to think about adapting immunosuppressive therapies to the inflammatory process of the underlying disorder and if possible to reduce them to monotherapy. Alternative treatment strategies for heavy immunosuppression exist (eg, enteral nutrition in Crohn disease or colectomy in patients with ulcerative colitis) and should be considered whenever appropriate. There is a major need for comparative studies before evidence‐based guidelines can be established for safest and best treatment strategies of pediatric patients with IBD.
In Vitro Effects of Sera From Children With Acute Liver Failure on Metabolic and Synthetic Activity of Cryopreserved Human Hepatocytes
Authors: Mitry Ragai R , Bansal Sanjay , Hughes Robin D , Mieli‐Vergani Giorgina , Dhawan Anil
Published: May 2009

Objective:

The aim of the study was to investigate the in vitro effects of sera from children with acute liver failure (ALF) who had received N‐acetylcysteine (NAC) on the metabolic and synthetic activity of cryopreserved human hepatocytes.

Materials and Methods:

Cryopreserved human hepatocytes were plated on collagen‐coated culture plates and incubated in cell culture medium containing pooled sera at 20% (v/v) obtained from children with ALF (ALF) who received treatment with NAC (ALF + NAC), no treatment with NAC and from normal controls (normal sera [NS]). The effects of the sera on cell metabolic functions were assessed using methylthiazolyldiphenyltetrazolium bromide, [14C]‐leucine incorporation, and cytochrome P‐450 (CYP1A1/2) activity assays.

Results:

The overall hepatocyte metabolic activity was lower with ALF sera than with NS and ALF + NAC sera. [14C]‐leucine incorporation was higher with both ALF sera (ALF and ALF + NAC) than with NS sera. There was a slightly higher activity of cytochrome P450 (CYP1A1/2 activity) in cultures treated with ALF and ALF + NAC than with normal sera treated hepatocyte cultures.

Conclusions:

Sera from children with ALF who received NAC did not impair the overall cell metabolic activity of cryopreserved human hepatocyte in vitro, which is encouraging for the use of hepatocytes transplantation in these patients.
Bacterial Mucosa Cross‐talk and Pathophysiology of Inflammation
Authors: Ruemmele Frank M
Published: May 2009

The intestinal mucosa harbors a complexly organized immune system, which accomplishes important, partially contradictory surveillance and protective functions. It has to protect the host from potential external (microbial and nonmicrobial) aggression, whereas at the same time avoiding an inflammatory reaction toward harmless antigenic structures of microbial (commensal microflora) or alimentary origin. Professional sentinels (of the innate immune system) are in close and interactive contact with the intestinal microflora, which plays via this exchange an important role during the postnatal period in the maturation of the intestinal immune system. The innate immune system is a key regulator of local and systemic immune responses, including the adaptive immune system. Distinct signals induce tolerance to specific antigens presented by intestinal dendritic cells, whereas proinflammatory mediators easily switch these tolerogenic responses toward protective or destructive inflammatory reactions. Given the intense exchange between the intestinal microflora and the mucosal immune system, a permanent but actively controlled and downregulated physiological inflammation characterizes the intestinal mucosa. Therefore, it is easily conceivable that perturbation of the intestinal microflora or immune control mechanisms can initiate or contribute to pathological and potentially chronic inflammatory reactions, such as seen in inflammatory bowel diseases.
Intestinal Mucus Barrier in Normal and Inflamed Colon
Authors: Corazziari Enrico Stefano
Published: May 2009

Intestinal bacteria are usually regarded as harmless commensals in healthy intestine but are pathogens, if these invade the tissues. The mucus gel separates the luminal bacteria from the epithelial surface throughout the colon in healthy individuals. This viscoelastic mucus gel is protective against adhesion and invasion by microorganisms, bacterial toxins, and antigens. The mucus viscosity increases progressively toward the distal colon, separating bacteria selectively in the proximal colon and completely in the distal colon. Mucus in normal subjects is usually intact and devoid of bacteria, by contrast mucus barrier is broken and penetrated by bacteria and inflammatory cells in patients with colonic inflammation. The immune inclusion hypothesis postulates that the host mucosa maintains an adherent bacterial biofilm that develops immune tolerance with specific immune mechanisms. The bacterial biofilm, growing in the mucus matrix, would prevent contact of pathogenic bacteria with the intestinal mucosal wall. On the contrary, recent evidence indicates that bacteria are absent in mucus from healthy individuals and present in mucus from patients with inflammatory bowel disease. In inflammatory bowel disease alteration in the types of mucins or, alternatively, the altered mucus layer as a response to inflammation contributes to the underlying pathology by affecting the mucus barrier function.
Colon in Acute Intestinal Infection
Authors: Guarino Alfredo , Buccigrossi Vittoria , Armellino Carla
Published: May 2009

The colon is actively implicated in intestinal infections not only as a target of enteric pathogens and their products but also as a target organ for treatment. In the presence of diarrhea, both of osmotic and secretory nature, the colon reacts with homeostatic mechanisms to increase ion absorption. These mechanisms can be effectively exploited to decrease fluid discharge. A model of intestinal infections using rotavirus (RV) in colonic cells was set up and used to define a dual model of secretory and osmotic diarrhea in sequence. Using this model, antidiarrheal drugs were tested, namely zinc and the enkephalinase inhibitor racecadotril. Zinc was able to decrease the enterotoxic activity responsible for secretory diarrhea. It also inhibited the cytotoxic effect of RV. The mechanism of zinc was related at least in part to the activation of MAPK activity, but also a direct antiviral effect was observed. Racecadotril showed a potent and selective inhibition of active secretion, being particularly effective in the first phase of RV diarrhea. The use of drugs active at the colonic level, therefore, offers effective options to treat intestinal infections in childhood. In addition, the colon is the natural site of colonic microflora, a target of probiotic therapy, which is the first line of approach recommended by the European Society for Paediatric Gastroenterology, Hepatology and Nutrition to treat infectious diarrhea.
Clostridium difficile Infections: Emerging Epidemiology and New Treatments
Authors: Cohen Mitchell B
Published: May 2009

Clostridium difficile infections (CDIs) are increasingly a cause of morbidity and mortality. Although the pathogenicity of C difficile is based on toxin A and B expression, new hypervirulent strains express novel virulence factors. The etiology of recent increases in prevalence and severity of disease is not clearly explained by known mechanisms. New at‐risk groups include children (without prior antibiotic exposure) and patients with inflammatory bowel disease. Vancomycin has an important role in the treatment of CDIs, but does not prevent recurrence. Other therapies for recurrent disease include antibiotics, probiotics, and immunotherapy. Novel therapies are under investigation for recurrent and resistant CDI.
Congenital Anorectal Malformations: Anything New?
Authors: Rintala Risto J
Published: May 2009

Management of anorectal malformations, especially that of proximal and more severe forms have developed significantly in the last 25 years. Echography and magnetic resonance imaging have improved the diagnostic accuracy, especially in terms of associated anomalies that are the main cause of fatalities among patients with anorectal malformations. Animal models, novel molecular biological techniques and knock‐out gene models have widened our knowledge on aetiology and pathogenesis of these anomalies.

From early 1980s, the posterior sagittal anorectoplasty originally designed by deVries and Pena has systematized the surgical management of anorectal anomalies leading to improved functional outcomes. Surgical mini‐invasive techniques are increasingly applied to the management of these anomalies, although their role is as yet not clearly established. Long‐term functional follow data are also available today indicating a reasonable favourable faecal and urinary control in the majority of patients with anorectal malformations. For the patients with less favourable functional outcome there are bowel and bladder management options that provide sufficient social continence.
Food-supplementing parents reduces their sons' song repertoire size
Authors: Zanette Liana , Clinchy Michael , Sung Ha-Cheol
Published: May 2009

Food-supplemented parents typically produce more offspring, as numerous experiments on vertebrate populations have shown. ‘Propagule’ (egg or neonate) size and parental care may also be affected, with implications concerning the adult quality of offspring, although few experiments have addressed whether food-supplementing one generation affects adult quality in the next. We conducted a food supplementation experiment on song sparrows (
Melospiza melodia
) and tested whether song repertoire size, a demonstrated indicator of male quality, differed between the adult sons of fed (food-supplemented) and unfed (non-food-supplemented) parents. Counterintuitively, fed parents produced sons with smaller adult song repertoires, who may thus be expected to contribute fewer offspring, and fewer grand-offspring, to the population. Fed and unfed parents invested equally in the total biomass of their clutches and broods, and average nestling condition was comparable, but because fed parents produced more offspring, average egg and nestling sizes were reduced. Fed and unfed parents apportioned care differently within their broods, and we suggest compensatory growth of offspring emerging from light eggs, or egg size itself, may have affected adult repertoire size. Conceivably, the conservation benefits of food-supplementing populations could attenuate over time if fed parents produce offspring of poorer quality than themselves.
AtBXL1 Encodes a Bifunctional β-d-Xylosidase/α-l-Arabinofuranosidase Required for Pectic Arabinan Modification in Arabidopsis Mucilage Secretory Cells
Authors: Arsovski Andrej A. , Popma Theodore M. , Haughn George W. , Carpita Nicholas C. , McCann Maureen C. , Western Tamara L.
Published: May 2009

Following pollination, the epidermal cells of the Arabidopsis (Arabidopsis thaliana) ovule undergo a complex differentiation process that includes the synthesis and polar secretion of pectinaceous mucilage followed by the production of a secondary cell wall. Wetting of mature seeds leads to the rapid bursting of these mucilage secretory cells to release a hydrophilic gel that surrounds the seed and is believed to aid in seed hydration and germination. A novel mutant is identified where mucilage release is both patchy and slow and whose seeds display delayed germination. While developmental analysis of mutant seeds reveals no change in mucilage secretory cell morphology, changes in monosaccharide quantities are detected, suggesting the mucilage release defect results from altered mucilage composition. Plasmid rescue and cloning of the mutant locus revealed a T-DNA insertion in AtBXL1, which encodes a putative bifunctional β-d-xylosidase/α-l-arabinofuranosidase that has been implicated as a β-d-xylosidase acting during vascular development. Chemical and immunological analyses of mucilage extracted from bxl1 mutant seeds and antibody staining of developing seed coats reveal an increase in (1→5)-linked arabinans, suggesting that BXL1 is acting as an α-l-arabinofuranosidase in the seed coat. This implication is supported by the ability to rescue mucilage release through treatment of bxl1 seeds with exogenous α-l-arabinofuranosidases. Together, these results suggest that trimming of rhamnogalacturonan I arabinan side chains is required for correct mucilage release and reveal a new role for BXL1 as an α-l-arabinofuranosidase acting in seed coat development.
β2 Integrin deficiency yields unconventional double‐negative T cells distinct from mature classical natural killer T cells in mice
Authors: Oreshkova Tsvetelina , Wang Honglin , Seier Anne M. , Sindrilaru Anca , Varga Georg , Grabbe Stephan , Scharffetter‐Kochanek Karin , Peters Thorsten
Published: May 2009

Expressed on leucocytes, β2 integrins (CD11/CD18) are specifically involved in leucocyte function. Using a CD18‐deficient (CD18−/−) mouse model, we here report on their physiological role in lymphocyte differentiation and trafficking. CD18−/− mice present with a defect in the distribution of lymphocytes with highly reduced numbers of naïve B and T lymphocytes in inguinal and axillary lymph nodes. In contrast, cervical lymph nodes were fourfold enlarged harbouring unconventional T‐cell receptor‐αβ (TCR‐αβ) and TCR‐γδ CD3+ CD4− CD8− (double‐negative; DN) T cells that expanded in situ. Using adoptive transfer experiments, we found that these cells did not home to peripheral lymph nodes of CD18wt recipients but, like antigen‐experienced T or natural killer (NK) T cells, recirculated through non‐lymphoid organs. Lacking regulatory functions in vitro, CD18−/− TCR‐αβ DN T cells did not suppress the proliferation of polyclonally activated CD4+ or CD8+ (single‐positive; SP) T cells. Most interestingly, CD18−/− TCR‐αβ DN T cells showed intermediate TCR expression levels, an absent activation through allogeneic major histocompatibility complex and a strong proliferative dependence on interleukin‐2, hence, closely resembling NKT cells. However, our data oppose former reports, clearly showing that, because of an absent reactivity with CD1d‐αGalCer dimers, these cells are not mature classical NKT cells. Our data indicate that CD18−/− TCR‐αβ DN T cells, like NKT and TCR‐γδ T cells, share characteristics of both adaptive and innate immune cells, and may accumulate as a compensatory mechanism to the functional defect of adaptive immunity in CD18−/− mice.