A Surgical Complexity Factor for Clefts of Primary and Secondary Palates.

The surgical treatment of patients with cleft lip and palate depends on the characteristics of the affected anatomical structures (palate, lip and nose). The objective of this work was to develop a quantified classification for these clefts, to represent their surgical complexity. This work was developed with the team of surgeons of the SUMA Cleft Leadership Center (CLC) Smile Train Mexico. The method of Multiple-Criteria Decision Analysis was applied using the Analytic Hierarchy Approach. A surgical complexity factor associated with each cleft was defined and it was validated in a sample of fifty patients treated at the SUMA-CLC.Clinical Relevance- A quantitative classification that represents the surgical complexity of clefts provides an objective unified criteria for planning the surgical treatment of patients, as well as having standardized procedures for the surgical treatment of patients.

Differential effect with septal and apical RV pacing on ventricular activation in patients with left bundle branch block assessed by non-invasive electrical imaging and in silico modelling.

PURPOSE: It is uncertain whether right ventricular (RV) lead position in cardiac resynchronization therapy impacts response. There has been little detailed analysis of the activation patterns in RV septal pacing (RVSP), especially in the CRT population. We compare left bundle branch block (LBBB) activation patterns with RV pacing (RVP) within the same patients with further comparison between RV apical pacing (RVAP) and RVSP. METHODS: Body surface mapping was undertaken in 14 LBBB patients after CRT implantation. Nine patients had RVAP, 5 patients had RVSP. Activation parameters included left ventricular total activation time (LVtat), biventricular total activation time (VVtat), interventricular electrical synchronicity (VVsync), and dispersion of left ventricular activation times (LVdisp). The direction of activation wave front was also compared in each patient (wave front angle (WFA)). In silico computer modelling was applied to assess the effect of RVAP and RVSP in order to validate the clinical results. RESULTS: Patients were aged 64.6 ± 12.2 years, 12 were male, 8 were ischemic. Baseline QRS durations were 157 ± 18 ms. There was no difference in VVtat between RVP and LBBB but a longer LVtat in RVP (102.8 ± 19.6 vs. 87.4 ± 21.1 ms, p = 0.046). VVsync was significantly greater in LBBB (45.1 ± 20.2 vs. 35.9 ± 17.1 ms, p = 0.01) but LVdisp was greater in RVP (33.4 ± 5.9 vs. 27.6 ± 6.9 ms, p = 0.025). WFA did rotate clockwise with RVP vs. LBBB (82.5 ± 25.2 vs. 62.1 ± 31.7 op = 0.026). None of the measurements were different to LBBB with RVSP; however, the differences were preserved with RVAP for VVsync, LVdisp, and WFA. In silico modelling corroborated these results. CONCLUSIONS: RVAP activation differs from LBBB where RVSP appears similar. TRIAL REGISTRATION: (ClinicalTrials.gov identifier: NCT01831518).

A rule-based method for predicting the electrical activation of the heart with cardiac resynchronization therapy from non-invasive clinical data.

BACKGROUND: Cardiac Resynchronization Therapy (CRT) is one of the few effective treatments for heart failure patients with ventricular dyssynchrony. The pacing location of the left ventricle is indicated as a determinant of CRT outcome. OBJECTIVE: Patient specific computational models allow the activation pattern following CRT implant to be predicted and this may be used to optimize CRT lead placement. METHODS: In this study, the effects of heterogeneous cardiac substrate (scar, fast endocardial conduction, slow septal conduction, functional block) on accurately predicting the electrical activation of the LV epicardium were tested to determine the minimal detail required to create a rule based model of cardiac electrophysiology. Non-invasive clinical data (CT or CMR images and 12 lead ECG) from eighteen patients from two centers were used to investigate the models. RESULTS: Validation with invasive electro-anatomical mapping data identified that computer models with fast endocardial conduction were able to predict the electrical activation with a mean distance errors of 9.2 ±â€¯0.5 mm (CMR data) or (CT data) 7.5 ±â€¯0.7 mm. CONCLUSION: This study identified a simple rule-based fast endocardial conduction model, built using non-invasive clinical data that can be used to rapidly and robustly predict the electrical activation of the heart. Pre-procedural prediction of the latest electrically activating region to identify the optimal LV pacing site could potentially be a useful clinical planning tool for CRT procedures.

A review of signals used in sleep analysis.

This article presents a review of signals used for measuring physiology and activity during sleep and techniques for extracting information from these signals. We examine both clinical needs and biomedical signal processing approaches across a range of sensor types. Issues with recording and analysing the signals are discussed, together with their applicability to various clinical disorders. Both univariate and data fusion (exploiting the diverse characteristics of the primary recorded signals) approaches are discussed, together with a comparison of automated methods for analysing sleep.

Roles of cholesterol and bile salts in the pathogenesis of gallbladder hypomotility and inflammation: cholecystitis is not caused by cystic duct obstruction.

BACKGROUND AND PURPOSE: A large number of human and animal studies have challenged the hypothesis that cystic duct obstruction by gallstones causes cholecystitis. These studies suggest that lithogenic bile that can deliver high cholesterol concentrations to the gallbladder wall causes hypomotility and creates a permissive environment that allows normal concentrations of hydrophobic bile salts to inflame the mucosa and impair muscle function inhibiting gallbladder emptying. High concentrations of cholesterol increase its diffusion rates through the gallbladder wall where they are incorporated into the sarcolemmae of muscle cells by caveolin proteins. High caveolar cholesterol levels inhibit tyrosine-induced phosphorylation of caveolin proteins required to transfer receptor-G protein complexes into recycling endosomes. The sequestration of these receptor-G protein complexes in the caveolae results in fewer receptors recycling to the sarcolemmae to be available for agonist binding. Lower internalization and recycling of CCK-1 and other receptors involved in muscle contraction explain gallbladder hypomotility. PGE2 receptors involved in cytoprotection are similarly affected. Cells with a defective cytoprotection failed to inactivate free radicals induced by normal concentrations of hydrophobic bile salts resulting in chronic inflammation that may lead to acute inflammation. Ursodeoxycholic acid salts (URSO) block these bile salts effects thereby preventing the generation of free radicals in muscle cells in vitro and development of cholecystitis in the ligated common bile duct in guinea pigs in vivo. Treatment with URSO improves muscle contraction and reduces the oxidative stress in patients with symptomatic cholesterol gallstones by lowering cholesterol concentrations and blocking the effects of hydrophobic bile salts on gallbladder tissues.

Signal quality indices and data fusion for determining clinical acceptability of electrocardiograms.

A completely automated algorithm to detect poor-quality electrocardiograms (ECGs) is described. The algorithm is based on both novel and previously published signal quality metrics, originally designed for intensive care monitoring. The algorithms have been adapted for use on short (5-10 s) single- and multi-lead ECGs. The metrics quantify spectral energy distribution, higher order moments and inter-channel and inter-algorithm agreement. Seven metrics were calculated for each channel (84 features in all) and presented to either a multi-layer perceptron artificial neural network or a support vector machine (SVM) for training on a multiple-annotator labelled and adjudicated training dataset. A single-lead version of the algorithm was also developed in a similar manner. Data were drawn from the PhysioNet Challenge 2011 dataset where binary labels were available, on 1500 12-lead ECGs indicating whether the entire recording was acceptable or unacceptable for clinical interpretation. We re-annotated all the leads in both the training set (1000 labelled ECGs) and test dataset (500 12-lead ECGs where labels were not publicly available) using two independent annotators, and a third for adjudication of differences. We found that low-quality data accounted for only 16% of the ECG leads. To balance the classes (between high and low quality), we created extra noisy data samples by adding noise from PhysioNet's noise stress test database to some of the clean 12-lead ECGs. No data were shared between training and test sets. A classification accuracy of 98% on the training data and 97% on the test data were achieved. Upon inspection, incorrectly classified data were found to be borderline cases which could be classified either way. If these cases were more consistently labelled, we expect our approach to achieve an accuracy closer to 100%.

Effect of progesterone on colonic motility and fecal output in mice with diarrhea.

BACKGROUND: Patients with diarrhea and slow transit constipation (STC) have high 5-HT levels. In STC, the high 5-HT levels have been difficult to explain, as 5-HT stimulates peristalsis. Over expression of progesterone (P4) receptors in epithelial and muscle cells of the colon may reconcile this contradiction because P4 decreases SERT and increases 5-HT levels, but their effects are rendered ineffective because of the impaired muscle contraction. AIMS: We examined whether P4 treatment could reduce the stool output in two mouse diarrheal models because of higher 5-HT levels, the SERT knock-out (KO), and the fluoxetine-treated mice. METHODS: Contractility of colon circular muscle strips from wild mice was studied. Fecal water and dry fecal output were measured daily over a 4-day period in wild and SERT-KO mice and in fluoxetine-treated mice treated with IM saline or P4. 5-HT levels were measured using ELISA. KEY RESULTS: Progesterone blocked the spontaneous and stimulated phasic contractions. Fecal water output measured in two consecutive 4-day periods was not different in wild and SERT-KO mice. The fecal output in the SERT-KO mice was higher than in wild mice. P4 treatment reduced the 4-day fecal output in both groups compared with saline treatment. Oral fluoxetine treatment increased 5-HT levels in wild mice and increased the 4-day fecal output compared with oral saline. P4 treatment caused a decrease in the fecal output in both groups. CONCLUSIONS & INFERENCES: Progesterone decreased the contractility of circular muscle strips, and reduced the fecal output in two diarrheal models, the SERT-KO and fluoxetine-treated mice.

Progesterone receptors and serotonin levels in colon epithelial cells from females with slow transit constipation.

BACKGROUND: Females with slow transit constipation (STC) exhibit progesterone receptor (P4R) overexpression in colon muscle that impair their contractility. These studies examined whether these patients have an overexpression of P4R in epithelial cells and whether P4 affects the SERT-5-HT pathway. METHODS: Tissues were obtained from surgical specimens of seven females with STC and six controls. Feasibility studies were performed in biopsies from six patients with STC and three controls. P4R, SERT and TPH-1 mRNA and protein expression and 5-HT by ELISA were determined. Contraction was studied in normal muscle cells pretreated with P4 or buffer. Progesterone effects on SERT and 5-HT levels were studied in normal human mucosa in vitro and in wild and SERT knockout mice in vivo. KEY RESULTS: P4R was overexpressed in epithelial cells in STC compared with controls. The levels of SERT were lower and 5-HT higher in STC. In epithelial cells P4 treatment decreased SERT and increased mucosal 5-HT without affecting TPH-1. Progesterone impaired the contraction of normal muscle cells induced by Ach and 5-HT. Progesterone decreased SERT and increased 5-HT levels in the colon of wild mice in vivo but had no effect on the high basal levels of 5-HT in SERT knockout mice. CONCLUSIONS & INFERENCES: P4R are present in colon epithelial cells and are overexpressed in females with STC. These cells have reduced SERT and high 5-HT levels and normal TPH-1. These 5-HT signaling abnormalities are related to overexpression of P4R since they are reproduced in human epithelial cells in vitro and in mice in vivo.

Effects of cholesterol on CCK-1 receptors and caveolin-3 proteins recycling in human gallbladder muscle.

The contraction of gallbladders (GBs) with cholesterol stones is impaired due to high cholesterol concentrations in caveolae compared with GBs with pigment stones. The reduced contraction is caused by a lower cholecystokinin (CCK)-8 binding to CCK-1 receptors (CCK-1R) due to caveolar sequestration of receptors. We aimed to examine the mechanism of cholesterol-induced sequestration of receptors. Muscle cells from human and guinea pig GBs were studied. Antibodies were used to examine CCK-1R, antigens of early and recycling endosomes, and total (CAV-3) and phosphorylated caveolar-3 protein (pCAV-3) by Western blots. Contraction was measured in muscle cells transfected with CAV3 mRNA or clathrin heavy-chain small-interfering RNA (siRNA). CCK-1R returned back to the bulk plasma membrane (PM) 30 min after CCK-8 recycled by endosomes, peaking at 5 min in early endosomes and at 20 min in recycling endosomes. Pretreatment with cholesterol-rich liposomes inhibited the transfer of CCK-1R and of CAV-3 in the endosomes by blocking CAV-3 phosphorylation. 4-Amino-5-(4-chloro-phenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (inhibitor of tyrosine kinase) reproduced these effects by blocking pCAV-3 formation, increasing CAV-3 and CCK-1R sequestration in the caveolae and impairing CCK-8-induced contraction. CAV-3 siRNA reduced CAV-3 protein expression, decreased CCK-8-induced contraction, and accumulated CCK-1R in the caveolae. Abnormal concentrations of caveolar cholesterol had no effect on met-enkephalin that stimulates a delta-opioid receptor that internalizes through clathrin. We found that impaired muscle contraction in GBs with cholesterol stones is due to high caveolar levels of cholesterol that inhibits pCAV-3 generation. Caveolar cholesterol increases the caveolar sequestration of CAV-3 and CCK-1R caused by their reduced recycling to the PM.

Increased TRPV1 gene expression in esophageal mucosa of patients with non-erosive and erosive reflux disease.

BACKGROUND: Transient receptor potential channel vanilloid subfamily member-1 (TRPV1) may play a role in esophageal perception. TRPV1 mRNA and protein expression were examined in the esophageal mucosa of non-erosive reflux disease (NERD) and erosive esophagitis (EE) patients and correlated to esophageal acid exposure. METHODS: Seventeen NERD patients, eight EE patients and 10 healthy subjects underwent endoscopy after a 3-week washout from proton pump inhibitors or H2 antagonists. Biopsies, obtained from the distal esophagus, were used for conventional histology, for Western blot analysis and/or quantitative real-time polymerase chain reaction (qPCR). Overall 13 NERD patients, four EE patients and five controls underwent ambulatory pH-testing. KEY RESULTS: TRPV1 expression was increased in all NERD and EE patients, as measured by Western blot analysis (0.65 +/- 0.07 and 0.8 +/- 0.05 VS 0.34 +/- 0.04 in controls; P < 0.01) and by qPCR (1.98 +/- 0.21 and 2.52 +/- 0.46 VS 1.00 +/- 0.06; P < 0.01). Neutrophilic infiltration, in the mucosa, was detected only in EE patients. CONCLUSIONS & INFERENCES: Non-erosive reflux disease and EE patients presented increased TRPV1 receptors mRNA and protein, although no correlation with acid exposure was demonstrated. Increased TRPV1 in the esophageal mucosa may contribute to symptoms both in NERD and EE patients and possibly account for peripheral mechanisms responsible for esophageal hypersensitivity in NERD patients.

Hepatic fascioliasis at a London hospital--the importance of recognising typical radiological features to avoid a delay in diagnosis.

Hepatic fascioliasis is a zoonosis caused by the trematode Fasciola hepatica, which can cause hepatobiliary disease in humans via the ingestion of contaminated water or aquatic vegetables. Reported cases of human infection with F. hepatica arise in regions where cattle are raised, with particular abundance in South America and the Middle East. The typical radiological appearances associated with fascioliasis are well reported and are likely to be more easily recognisable by radiologists in these areas of high prevalence. However, in Western countries where the disease is seldom found, there may be a delay in diagnosis and treatment owing to unfamiliarity with the radiological appearances, in addition to the non-specific clinical features on presentation. Here we describe a case of a 22-year-old Bangladeshi woman whose only clinical feature was right upper quadrant pain. Abnormal imaging of her abdomen on admission began a process of investigations to seek the correct diagnosis.

Radial artery aneurysm resulting from repetitive occupational injury: Tailor's thumb.

INTRODUCTION: True radial artery aneurysms are very rare and a cause is rarely identified. CASE REPORT: An unusual case of a true radial artery aneurysm in a tailor of fifty years; presenting with a growing, tender lump at the base of his thumb. DISCUSSION: Radial artery aneurysms are classically pseudoaneurysms from iatrogenic traumatic injury - arterial cannulation. This is the first case in the literature to demonstrate a true aneurysm secondary to repetitive occupational injury.

Hypoxia inhibits the growth, differentiation and bone-forming capacity of rat osteoblasts.

We investigated the effect of hypoxia on rat osteoblast function in long-term primary cultures. Reduction of pO2 from 20% to 5% and 2% decreased formation of mineralized bone nodules 1.7-fold and 11-fold, respectively. When pO2 was reduced further to 0.2%, bone nodule formation was almost abolished. The inhibitory effect of hypoxia on bone formation was partly due to decreased osteoblast proliferation, as measured by 3H-thymidine incorporation. Hypoxia also sharply reduced osteoblast alkaline phosphatase (ALP) activity and expression of mRNAs for ALP and osteocalcin, suggesting inhibition of differentiation to the osteogenic phenotype. Hypoxia did not increase the apoptosis of osteoblasts but induced a reversible state of quiescence. Transmission electron microscopy revealed that collagen fibrils deposited by osteoblasts cultured in 2% O2 were less organized and much less abundant than in 20% O2 cultures. Furthermore, collagen produced by hypoxic osteoblasts contained a lower percentage of hydroxylysine residues and exhibited an increased sensitivity to pepsin degradation. These data demonstrate the absolute oxygen requirement of osteoblasts for successful bone formation and emphasize the importance of the vasculature in maintaining bone health. We recently showed that hypoxia also acts in a reciprocal manner as a powerful stimulator of osteoclast formation. Considered together, our results help to explain the bone loss that occurs at the sites of fracture, tumors, inflammation and infection, and in individuals with vascular disease or anemia.

A new approach to classify cleft lip and palate.

OBJECTIVE: To propose a new method, which allows for a complete description of primary and secondary cleft palates, incorporating elements that are related to the palate, lip, and nose that will also reflect the complexity of this problem. METHOD: To describe the type of cleft, two embryonic structures were considered: (1) the primary palate, formed by the prolabium, premaxilla, and columella and (2) the secondary palate, which begins at the incisive foramen and is formed by a horizontal portion of the maxilla, the horizontal portion of the palatine bones, and the soft palate. Anatomical characteristics to be considered were defined, and a new method is proposed to more fully describe any cleft. RESULTS: A description of five cases was made using the method proposed in this work and compared with other published methods for the classification and description of clefts. CONCLUSIONS: A mathematical expression was developed to characterize clefts of the primary palate, including the magnitude of palatal segment separation and the added complexity of bilateral clefts, yielding a numerical score that reflects overall complexity of the cleft. Clefts of the secondary palate are also considered in a separate score. Using this method, it is possible to incorporate elements that are not considered in other approaches and to describe all possible clefts that may exist.

The National Human Activity Pattern Survey (NHAPS): a resource for assessing exposure to environmental pollutants.

Because human activities impact the timing, location, and degree of pollutant exposure, they play a key role in explaining exposure variation. This fact has motivated the collection of activity pattern data for their specific use in exposure assessments. The largest of these recent efforts is the National Human Activity Pattern Survey (NHAPS), a 2-year probability-based telephone survey (n=9386) of exposure-related human activities in the United States (U.S.) sponsored by the U.S. Environmental Protection Agency (EPA). The primary purpose of NHAPS was to provide comprehensive and current exposure information over broad geographical and temporal scales, particularly for use in probabilistic population exposure models. NHAPS was conducted on a virtually daily basis from late September 1992 through September 1994 by the University of Maryland's Survey Research Center using a computer-assisted telephone interview instrument (CATI) to collect 24-h retrospective diaries and answers to a number of personal and exposure-related questions from each respondent. The resulting diary records contain beginning and ending times for each distinct combination of location and activity occurring on the diary day (i.e., each microenvironment). Between 340 and 1713 respondents of all ages were interviewed in each of the 10 EPA regions across the 48 contiguous states. Interviews were completed in 63% of the households contacted. NHAPS respondents reported spending an average of 87% of their time in enclosed buildings and about 6% of their time in enclosed vehicles. These proportions are fairly constant across the various regions of the U.S. and Canada and for the California population between the late 1980s, when the California Air Resources Board (CARB) sponsored a state-wide activity pattern study, and the mid-1990s, when NHAPS was conducted. However, the number of people exposed to environmental tobacco smoke (ETS) in California seems to have decreased over the same time period, where exposure is determined by the reported time spent with a smoker. In both California and the entire nation, the most time spent exposed to ETS was reported to take place in residential locations.

Myosin light chain kinase- and PKC-dependent contraction of LES and esophageal smooth muscle.

In smooth muscle cells enzymatically isolated from circular muscle of the esophagus (ESO) and lower esophageal sphincter (LES), ACh-induced contraction and myosin light chain (MLC) phosphorylation were similar. Contraction and phosphorylation induced by purified MLC kinase (MLCK) were significantly greater in LES than ESO. ACh-induced contraction and MLC phosphorylation were inhibited by calmodulin and MLCK inhibitors in LES and by protein kinase C (PKC) inhibitors in ESO. Contraction of LES and ESO induced by the PKC agonist 1,2-dioctanoylglycerol (DG) was unaffected by MLCK inhibitors. Caldesmon and calponin concentration-dependently inhibited ACh-induced contraction of ESO and not LES. In ESO, caldesmon antagonist GS17C reversed caldesmon- but not calponin-induced ACh inhibition. GS17C caused contraction of permeabilized ESO but had much less effect on LES. GS17C-induced contraction was not affected by MLCK inhibitors, suggesting that MLCK may not regulate caldesmon-mediated contraction. DG-induced contraction of ESO and LES was inhibited by caldesmon and calponinin, suggesting that these proteins may regulate PKC-dependent contraction. We conclude that calmodulin and MLCK play a role in ACh-induced LES contraction, whereas the classical MLCK may not be the major kinase responsible for contraction and phosphorylation of MLC in ESO. ESO contraction is PKC dependent. Caldesmon and/or calponin may play a role in PKC-dependent contraction.

Abnormalities of gallbladder muscle associated with acute inflammation in guinea pigs.

Muscle strips from experimental acute cholecystitis (AC) exhibit a defective contraction. The mechanisms responsible for this impaired contraction are not known. The present studies investigated the nature of these abnormalities. AC was induced by ligating the common bile duct of guinea pigs for 3 days. Contraction was studied in enzymatic dissociated muscle cells. Cholecystokinin (CCK) and prostaglandin E2 (PGE2) receptor binding studies were performed by radioreceptor assay. The levels of lipid peroxidation, cholesterol, phospholipid, and H2O2 as well as the catalase and superoxide dismutase (SOD) activities were determined. PGE2 content was measured by radioimmunoassay. Muscle contraction induced by CCK, ACh, or KCl was significantly reduced in AC, but PGE2-induced contraction remained normal. GTPgammaS, diacyglycerol (DAG), and 1,4,5-trisphosphate (IP3), which bypass the plasma membrane, caused a normal contraction in AC. The number of functional receptors for CCK was significantly decreased, whereas those for PGE2 remained unchanged in AC. There was a reduction in the phospholipid content and increase in the level of lipid peroxidation as well as H2O2 content in the plasma membrane in AC. The PGE2 content and the activities of catalase and SOD were also elevated. These data suggest that AC cause damage to the constituents of the plasma membrane of muscle cells. The preservation of the PGE2 receptors may be the result of muscle cytoprotection.