Pneumovesical Ureteric Reimplantation in Pediatric Patients: An Intermediate Term Result.

INTRODUCTION: Pneumovesical ureteric reimplantation has gained increasing popularity for the treatment of vesicoureteric reflux (VUR) and vesicoureteric junction obstruction (VUJO) in pediatric patients. In this study we reviewed our experience at an intermediate term basis. METHODS: A retrospective review of all patients with pneumovesical ureteric reimplantation performed in a tertiary referral center between 2005 and 2015 was carried out. Patients' demographics, operative measures, and postoperative outcomes were recorded. RESULTS: Thirty-one patients were identified during the study period. Twenty-three patients had VUR and 8 patients had VUJO. A total of 42 ureteric reimplantation procedures were carried out. The mean age at operation was 6.1 years old. The mean operative time was 221 minutes. On average the length of hospital stay was 7.4 days. Four patients required conversion to open approach. Four patients had low-grade residual VUR after the operation and all of them were treated conservatively. There was no major complication or mortality. CONCLUSION: Pneumovesical ureteric reimplantation is safe and effective for pediatric patients. Intermediate term result confirmed its reliability and low recurrence rate. It has good potential to become the preferred approach of choice in the future.

Use of robotic-assisted laparoscopic Mitrofanoff appendicovesicostomy in a paediatric patient: problem encountered.

This report is of robotic-assisted laparoscopic Mitrofanoff appendicovesicostomy in a 12-year-old patient with detrusor underactivity and hereditary sensory neuropathy. The whole operation was performed in 555 minutes with no open conversion. The patient experienced one episode of stomal stenosis, which required dilatation. At 3-year follow-up, the patient had both stomal and urinary continence. This is a safe and effective procedure to create a means of urinary catheterisation with avoidance of a large unsightly scar and comparable clinical outcome to an open procedure.

Childhood intussusception: 17-year experience at a tertiary referral centre in Hong Kong.

OBJECTIVES: To review all paediatric patients with intussusception over the last 17 years. DESIGN: Retrospective case series. SETTING: A tertiary centre in Hong Kong. PATIENTS: Children who presented with intussusception from January 1997 to December 2014 were reviewed. MAIN OUTCOME MEASURES: The duration of symptoms, successful treatment modalities, complication rate, and length of hospital stay were studied. RESULTS: A total of 173 children (108 male, 65 female) presented to our hospital with intussusception during the study period. Their median age at presentation was 12.5 months (range, 2 months to 16 years) and the mean duration of symptoms was 2.3 (standard deviation, 1.8) days. Vomiting was the most common symptom (76.3%) followed by abdominal pain (46.2%), per rectal bleeding or red currant jelly stool (40.5%), and a palpable abdominal mass (39.3%). Overall, 160 patients proceeded to pneumatic or hydrostatic reduction, among whom 127 (79.4%) were successful. Three (1.9%) patients had bowel perforation during the procedure. Early recurrence of intussusception occurred in four (3.1%) patients with non-operative reduction. No recurrence was reported in the operative group. The presence of a palpable abdominal mass was a risk factor for operative treatment (relative risk=2.0; 95% confidence interval, 1.8-2.2). Analysis of our results suggested that duration of symptoms did not affect the success rate of non-operative reduction. CONCLUSIONS: Non-operative reduction has a high success rate and low complication rate, but the presence of a palpable abdominal mass is a risk factor for failure. Operative intervention should not be delayed in those patients who encounter difficult or doubtful non-operative reduction.

Canonical and non-canonical NF-κB signaling promotes breast cancer tumor-initiating cells.

Tumor-initiating cells (TICs) are a sub-population of cells that exhibit a robust ability to self-renew and contribute to the formation of primary tumors, the relapse of previously treated tumors and the development of metastases. TICs have been identified in various tumors including those of the breast, and are particularly enriched in the basal-like and claudin-low subtypes of breast cancer. The signaling pathways that contribute to the function and maintenance of TICs are under intense study. We explored the potential involvement of the nuclear factor-κB (NF-κB) family of transcription factors in TICs in cell lines that are representative of basal-like and claudin-low breast cancer. NF-κB was found to be activated in breast cancer cells that form tumorspheres efficiently. Moreover, both canonical and non-canonical NF-κB signaling is required for these cells to self-renew in vitro and to form xenograft tumors efficiently in vivo using limiting dilutions of cells. Consistent with this fact, canonical and non-canonical NF-κB signaling is activated in TICs isolated from breast cancer cell lines. Experimental results indicate that NF-κB promotes the function of TICs by stimulating epithelial-to-mesenchymal transition and by upregulating the expression of the inflammatory cytokines interleukin-1ß and interleukin-6. The results suggest the use of NF-κB inhibitors for clinical therapy of certain breast cancers.

Peanut aspiration: an avoidable life-threatening condition.

Foreign body aspiration is a potentially fatal condition. Yet, an accurate diagnosis may not be easy. Management is also challenging and requires a high level of expertise with proper instruments. In this article, we report our experience in the management of peanut aspiration in two young children by means of a ventilating bronchoscope.

Thoracoscopic bullectomy for primary spontaneous pneumothorax in pediatric patients.

INTRODUCTION: Primary spontaneous pneumothorax is a condition that carries significant morbidities and mortalities if not managed properly. Thoracotomy with bullectomy has been the treatment of choice for persistent air leak or recurrence after initial chest drain insertion. With the advancement in minimal invasive surgery, the thoracoscopic approach can dramatically reduce the complications of open thoracotomy. We review our experience in managing spontaneous pneumothorax in children using thoracoscopy. MATERIALS AND METHODS: The medical records of all patients who were discharged with the diagnosis of spontaneous pneumothorax from 1997 to 2007 were reviewed. The demographic data and management were noted. For those patients who underwent thoracoscopic surgery, the intra-operative findings, post-operative outcomes and complications were compared. RESULTS: A total of 15 patients with spontaneous pneumothorax were identified. They all received chest drain insertion as the primary treatment modality. Nine patients, with mean age 16.1 +/- 0.9 years, failed the initial management and subsequently received thoracoscopic surgery with a mean interval of 7.6 +/- 2.5 days after initial chest drain insertion. Among these patients, bullae were found in seven patients (two patients had more than one bulla). The bullae were excised with mean operative time being 63.9 +/- 25.2 min. No conversion to thoracotomy was reported. All patients received paracetamol as pain control and there was no associated complication. No recurrence was found at follow-up till now. CONCLUSION: This study confirms that the presence of bulla is commonly seen in patients with spontaneous pneumothorax who fail initial management. Thoracoscopic bullectomy, a safe and effective operation, should be offered to this group of patients.

Abdominal compartment syndrome after open biopsy in a child with bilateral Wilms' tumour.

Although Wilms' tumour is one of the most common solid malignancies in children, bilateral disease is rare. We report a child with bilateral Wilms' tumour who developed abdominal compartment syndrome after an open biopsy.

Impact of prenatal diagnosis on choledochal cysts and the benefits of early excision.

AIM: To evaluate the clinical outcomes of patients with prenatally diagnosed choledochal cysts compared with those diagnosed after birth and the optimal timing of definitive treatment. METHODS: Retrospective review of all patients who underwent primary choledochal cyst excision and Roux-en-Y hepaticojejunostomy from 1996 to 2006 at a single institution. RESULTS: A total of 45 patients were included. Ten (22.2%) of the patients had prior prenatal diagnosis. The mean age at operation for this group was 4.4 months and mean follow up was 55.9 months. There was no operative complication or late morbidity. For the post-natal diagnosis group, the mean age at operation was 5.7 years (P < 0.000) and mean follow up period was 69 months. The most common presentation in this group was abdominal pain (31.4%), followed by pancreatitis (28.6%) and symptoms of cholestasis (25.7%). Early post-operative morbidities occurred in two (5.7%) patients. On long-term follow up, two (5.7%) further patients in the post-natal group developed complications. CONCLUSION: Prenatal diagnosis of choledochal cysts results in earlier definitive surgery. More adverse complications were seen in those who had surgery at an older age. We therefore recommend early excision of choledochal cysts.

In vitro models of proarrhythmia.

Proarrhythmia models use electrophysiological markers to predict the risk of torsade de pointes (TdP) in patients. The set of variables used by each model to predict the torsadogenic propensity of a drug has been reported to correlate with clinical outcome; however, these reports should be interpreted cautiously as no model has been independently assessed. Each model is discussed along with its merits and shortcomings; none, as yet, having shown a predictive value that makes it clearly superior to the others. As predictive as these models may become, extrapolation of results directly to the clinic must be exercised with caution. The use of in silico models, from subcellular to whole system, is rapidly beginning to form the first line of screening activity in many drug discovery programmes, indicating that biological experimentation may become secondary to analysis by simulation. In vitro proarrhythmia models challenge current perceptions of appropriate surrogates for TdP in man and question existing non-clinical strategies for assessing proarrhythmic risk. The rapid emergence of such models, compounded by the lack of a clear understanding of the key proarrhythmic mechanisms has resulted in a regulatory reluctance to embrace such models. The wider acceptance of proarrhythmia models is likely to occur when there is a clear understanding and agreement on the key proarrhythmia mechanisms. With greater acceptance and ongoing improvements, these models have the potential to unravel the complex mechanisms underlying TdP.

Optimisation and validation of a medium-throughput electrophysiology-based hNav1.5 assay using IonWorks.

INTRODUCTION: The safety implications of blocking the human cardiac Na(+) channel (hNav1.5) make it prudent to test for this activity early in the drug discovery process and design-out any potential liability. This needs a method with adequate throughput and a demonstrable predictive value to effects in native cardiac tissues. Here we describe the validation of a method that combines the ability to screen tens of compounds a day, with direct assessment of channel function. METHODS: The electrophysiological and pharmacological properties of hNav1.5 were compared using two methods: conventional, low-throughput electrophysiology and planar-array-based, medium-throughput electrophysiology (IonWorks HT). A pharmacological comparison was also made between IonWorks HT and canine cardiac Purkinje Fibre action potential upstroke data. RESULTS: Activation curve parameters for hNav1.5 in IonWorks HT were not statistically different (p>0.05) from those generated using conventional electrophysiology. IonWorks HT V(1/2)=-22+/-0.8 mV, slope=6.9+/-0.2 (n=11); conventional electrophysiology V(1/2)=-20+/-1.6 mV, slope=6.4+/-0.3 (n=11). Potency values for a range of hNav1.5 blockers determined using IonWorks HT correlated closely with those obtained using conventional electrophysiology (R=0.967, p<0.001). The assay was able to distinguish between highly use-dependent blockers (e.g. tetracaine) and blockers that do not display strong use-dependence (e.g. quinidine). Comparison of the degree of hNav1.5 inhibition and decrease in canine Purkinje fibre action potential upstroke velocity (V(max)) showed that the IonWorks HT assay would have predicted the outcome in Purkinje fibres in the majority of cases, with false negative and positive rates estimated at 8 and 7%, respectively. Finally, hNav1.5 pharmacology was similar when determined using either IonWorks HT or IonWorks Quattro, although the latter yielded more consistent data. DISCUSSION: The assay described combines a functional assessment of hNav1.5 with medium-throughput. Furthermore the assay was able to reveal information on the use-dependency of compound block, as well as predicting Na(+) channel effects in more integrated systems such as the cardiac Purkinje fibre action potential. This makes it possible to determine quantitative potency data, and mechanistic information about use-dependence, in a timeframe short enough to influence medicinal chemistry.

Acupuncture Treatment for Labyrinthine Tinnitus Based on Intergrated Traditional Chinese Medicine & Western Medicine / 全日本鍼灸学会雑誌

Based on the differentiation of deficiency (hyporeactivity) and excess (hyperreactivity) syndromes according to the Traditional Chinese Medicine (TCM) logic, 65 labyrinthine tinnitus cases of the example was classified into three groups, the excess constitutional type (18 cases), the deficiency constitutional type (37 cases) and the intermediate type (10 cases). Acupuncture treatment was carried out under the guidance of the basic principles of "seeking the fundamental of a disease in treatment"based on TCM. <BR>The effect was evaluated using two parameters of subjective tinnitus assessment score in a special questionnaire (STS) and objective tinnitus loudness level in dB SL (OTL). Based on the changes in STS and OTL before and after the end of all therapeutic courses, the gross effective rate (GER) of 65 cases containing effective STS or OTL was 72.3%, while the strict effective rate where both STS and OTL showed effective (BER) was 47.7%. Among the three TCM syndromes differentiation groups, the excess constitutional type had the best therapeutic effect (66.7%of BER), fellows the deficiency constitutional type (48.7%of BER), and the intermediate type was the worst (only 10%of BER). Statistically, there was a significant difference among each syndrome differentiation group (p<0.05).<BR>Meanwhile, the entire GER and BER went down to 55.4%and 38.5%respectively 2 months after the end of treatment to show a decreasing tendency of therapeutic effectiveness compared with those treatment rates immediately after the end of treatment. Especially, GER of the deficiency constitutional type showed a significant decrease (P<0.05).<BR>We concluded that the TCM differentiation of deficiency and excess syndromes is a prerequisite for the determination of a correct acupuncture treatment for labyrinthine tinnitus. Through a thorough analysis and treatment on 65 clinical cases, the tinnitus of the excess constitutional type showed a higher reactivity for the treatment comparing to the other two types, the deficiency and the intermediate.

A rabbit Langendorff heart proarrhythmia model: predictive value for clinical identification of Torsades de Pointes.

BACKGROUND AND PURPOSE: The rabbit isolated Langendorff heart model (SCREENIT) was used to investigate the proarrhythmic potential of a range of marketed drugs or drugs intended for market. These data were used to validate the SCREENIT model against clinical outcomes. EXPERIMENTAL APPROACH: Fifty-five drugs, 3 replicates and 2 controls were tested in a blinded manner. Proarrhythmia variables included a 10% change in MAPD(60), triangulation, instability and reverse frequency-dependence of the MAP. Early after-depolarisations, ventricular tachycardia, TdP and ventricular fibrillation were noted. Data are reported at nominal concentrations relative to EFTPC(max). Proarrhythmic scores were assigned to each drug and each drug category. KEY RESULTS: Category 1 and 2 drugs have the highest number of proarrhythmia variables and overt proarrhythmia while Category 5 drugs have the lowest, at every margin. At 30-fold the EFTPC(max), the mean proarrhythmic scores are: Category 1, 101+/-24; Category 2, 101+/-14; Category 3, 72+/-20; Category 4, 59+/-16 and Category 5, 22+/-9 points. Only drugs in Category 5 have mean proarrhythmic scores, below 30-fold, that remain within the Safety Zone. CONCLUSIONS AND IMPLICATIONS: A 30-fold margin between effects and EFTPC(max) is sufficiently stringent to provide confidence to proceed with a new chemical entity, without incurring the risk of eliminating potentially beneficial drugs. The model is particularly useful where compounds have small margins between the hERG IC(50) and predicted EFTPC(max). These data suggest this is a robust and reliable assay that can add value to an integrated QT/TdP risk assessment.

Analysis of shape, fluctuations, and dynamics in intermembrane junctions.

A dynamic-elastic model for weakly adhered intermembrane junctions is presented. Helfrich membrane energetics coupled to hydrodynamic modes of the surrounding solvent reproduce the average shape, fluctuations, and dynamics of these junctions as measured experimentally. Comparison between numerical results and experimental data provides the first direct measure of surface tension in these systems (0.01-0.06 dyn/cm). The measurements suggest bilayer-bilayer adhesion energetics as the dominant source of surface tension in the experimental systems.

Can optical recordings of membrane potential be used to screen for drug-induced action potential prolongation in single cardiac myocytes?

INTRODUCTION: Potential-sensitive dyes have primarily been used to optically record action potentials (APs) in whole heart tissue. Using these dyes to record drug-induced changes in AP morphology of isolated cardiac myocytes could provide an opportunity to develop medium throughout assays for the pharmaceutical industry. Ideally, this requires that the dye has a consistent and rapid response to membrane potential, is insensitive to movement, and does not itself affect AP morphology. MATERIALS AND METHODS: We recorded the AP from isolated adult guinea-pig ventricular myocytes optically using di-8-ANEPPS in a single-excitation dual-emission ratiometric system, either separately in electrically field stimulated myocytes, or simultaneously with an electrical AP recorded with a patch electrode in the whole-cell bridge mode. The ratio of di-8-ANEPPS fluorescence signal was calibrated against membrane potential using a switch-clamp to voltage clamp the myocyte. RESULTS: Our data show that the ratio of the optical signals emitted at 560/620 nm is linearly related to voltage over the voltage range of an AP, producing a change in ratio of 7.5% per 100 mV, is unaffected by cell movement and is identical to the AP recorded simultaneously with a patch electrode. However, the APD90 recorded optically in myocytes loaded with di-8-ANEPPS was significantly longer than in unloaded myocytes recorded with a patch electrode (355.6+/-13.5 vs. 296.2+/-16.2 ms; p<0.01). Despite this effect, the apparent IC50 for cisapride, which prolongs the AP by blocking IKr, was not significantly different whether determined optically or with a patch electrode (91+/-46 vs. 81+/-20 nM). DISCUSSION: These data show that the optical AP recorded ratiometrically using di-8-ANEPPS from a single ventricular myocyte accurately follows the action potential morphology. This technique can be used to estimate the AP prolonging effects of a compound, although di-8-ANEPPS itself prolongs APD90. Optical dyes require less technical skills and are less invasive than conventional electrophysiological techniques and, when coupled to ventricular myocytes, decreases animal usage and facilitates higher throughput assays.

Endoscopic plication of massively bleeding peptic ulcer by using the Eagle Claw VII device: a feasibility study in a porcine model.

BACKGROUND AND OBJECTIVE: We examined the efficacy of endoscopic plication when using Eagle Claw VII in a porcine bleeding ulcer model. ANIMAL MODEL PREPARATION: The right gastroepiploic artery (diameter 1.5-2 mm) was isolated and was tunneled to small gastrotomies at either the lesser or greater curvature of the stomach. INTERVENTIONS: We applied the Eagle Claw VII to achieve hemostasis. MAIN OUTCOME MEASUREMENTS: The survival of the pigs after endoscopic plication for hemostasis, time to achieve hemostasis with Eagle Claw VII, recurrent bleeding, number of successful plication, and number of suture remained. RESULTS: Endoscopic plication was performed on bleeding gastric ulcers in 6 pigs. The time to achieve hemostasis was 6 minutes 56 seconds +/- 3 minutes 50 seconds. There was no complication. A total of 14 plications were performed. All animals survived for 1 week without recurrent bleeding. At the postmortem, 10 of the plication sutures remained. LIMITATION: Our model cannot simulate the chronicity of peptic ulcer. CONCLUSIONS: In this porcine model, the Eagle Claw VII effectively stopped bleeding from arteries 2 mm in size.

Nonequilibrium membrane fluctuations driven by active proteins.

We extend a model for nonthermal membrane undulations driven by active (adenosine triphosphate-dependent or light-harvesting) membrane proteins [N. Gov, Phys. Rev. Lett. 93, 268104 (2004)]. The present model accounts for the fact that proteins can diffuse laterally across the membrane surface and that individual proteins are expected to exert forces preferentially in one normal direction over the other (due to their orientation within the bilayer). The addition of these effects alters the scaling of fluctuation amplitudes with system size. Additionally, theoretical arguments and dynamic simulations both suggest that, in certain regimes, the probability distribution of fluctuation amplitudes is expected to be non-Gaussian (in contrast to thermal systems).

Implicit solvent simulation models for biomembranes.

Fully atomic simulation strategies are infeasible for the study of many processes of interest to membrane biology, biophysics and biochemistry. We review various coarse-grained simulation methodologies with special emphasis on methods and models that do not require the explicit simulation of water. Examples from our own research demonstrate that such models have potential for simulating a variety of biologically relevant phenomena at the membrane surface.

Simulating Membrane Dynamics in Nonhomogeneous Hydrodynamic Environments.

Two previously introduced simulation algorithms for the dynamics of elastic membrane sheets embedded in a fluid medium are extended to account for inhomogeneous hydrodynamic environments. We calculate the height autocorrelation function for a lipid bilayer randomly pinned to a flat substrate and the influence of fluid confinement by the spectrin cytoskeleton on short wavelength membrane undulations of the human red blood cell. Altering the hydrodynamic environment of the membrane leads to significant changes in dynamics, and we discuss these effects in the context of recent experiments.

Trends in the prevalence of Helicobacter pylori in symptomatic children in the era of eradication.

PURPOSE: Helicobacter pylori infection is common in Asia and is associated with dyspepsia, peptic ulcer, and gastric cancer. Eradication of the organism remains an important goal. Here, we looked at the trends in the prevalence of H pylori in symptomatic children over an 8-year period to assess the impact of an aggressive eradication program. METHOD: A retrospective review was carried out between 1997 and 2004. All children with a history of dyspepsia or acute gastrointestinal bleeding were included and underwent gastroscopy. Three antral biopsies were taken during endoscopy and sent for histological analysis. Positivity of H pylori was treated aggressively with quadruple therapy under protocol. The demographic data, the histological findings, and the H pylori status were recorded. RESULTS: There were a total of 159 patients (71 males, 88 females) who underwent gastroscopy in this period. One hundred nineteen patients showed histological evidence of gastritis, and the positive rate of H pylori was 25.6%. The overall prevalence has not decreased (33.3% in 1997, 27.7% in 2004). Increasing age, however, was associated significantly with the higher risk of H pylori infection. CONCLUSION: H pylori has a high prevalence in Chinese children with increasing age. Eradication efforts seem to be unsuccessful in the reduction of prevalence. We hypothesize that this may be owing to cross-infection at meal times from sharing chopsticks.

Dynamic simulations of membranes with cytoskeletal interactions.

We describe a simulation algorithm for the dynamics of elastic membrane sheets over long length and time scales. Our model includes implicit hydrodynamic coupling between membrane and surrounding solvent and allows for arbitrary external forces acting on the membrane surface. In particular, the methodology is well suited to studying membranes in interaction with cytoskeletal filaments. We present results for the thermal undulations of a lipid bilayer attached to a regular network of spectrin filaments as a model for the red blood cell membrane. The dynamic fluctuations of the bilayer over the spectrin network are quantified and used to predict the macroscopic diffusion constant of band 3 on the surface of the red blood cell. We find that thermal undulations likely play a role in the mobility of band 3 in the plane of the erythrocyte membrane.