Change in biventricular function after cone reconstruction of Ebstein's anomaly: an echocardiographic study.

Aims: The Cone reconstruction in Ebstein's anomaly (EA) aims to reduce tricuspid valve regurgitation (TR) and reposition the valve to the anatomic annulus, but post-operative progress of ventricular function is poorly understood. This study evaluated biventricular function after Cone reconstruction using echocardiographic techniques. Methods and results: A retrospective study assessing longitudinal change was conducted from 2009 to 2014. All symptomatic patients with EA and severe TR undergoing surgery were included. Transthoracic advanced echocardiography was performed pre- and post-operatively (at short-term (<30 days) and mid-term). Conventional and longitudinal 2D strain parameters were measured for left ventricle (LV) and right ventricle (RV). Paired analyses were compared using Wilcoxon Matched-pairs signed rank test. From the 38 patients operated for EA, the echocardiographic data of 17 patients, aged 15 (1-57 years) at operation could be analysed. Median follow up was 6 months (8 days-54 months). The tricuspid annular plane systolic excursion (26.42 ± 5.79 mm vs. 8.75 ± 3.18 mm, P < 0.001), RV fractional area change (FAC) (45.00 ± 8.13% vs. 35.46 ± 5.76%, P = 0.038) and LV 2D peak systolic strain were significantly reduced post-operatively (-20.49 ± 2.79 vs. -17.73 ± 2.76, P = 0.041), with a trend to later recovery for LV 2D strain. There was no evidence of systolic mechanical dys-synchrony before or after operation. Conclusion: Although clinical outcome of Cone reconstruction for EA remains excellent, acute post-operative changes leads to reduction of myocardial function of both ventricles, with a trend to later recovery for LV. Continuing impairment of RV function is multifactorial but may reflect intrinsic myocardial deficiency.

The value of cardiac MRI versus echocardiography in the pre-operative assessment of patients with Duchenne muscular dystrophy.

BACKGROUND/PURPOSE: Duchenne Mmuscular Ddystrophy (DMD) related cardiomyopathy is associated with significant perioperative mortality. Cardiac MRI (CMR) has not previously been systematically evaluated as pre-operative assessment tool for heart function in DMD. Our aim was to establish whether CMR versus echocardiography contributes to pre-operative DMD assessment. METHODS: Case records were retrospectively reviewed of 35 consecutive DMD boys who underwent evaluation for surgical procedures between 2010 and 2013. RESULTS: Echocardiography revealed a median left ventricular (LV) shortening fraction (SF) of 29/% (range: 7-44). 37% of boys (13/35) had abnormal SF <25%, 66% (23/35) showed hypokinesia and 26% (9/35) had LV dilatation. CMR revealed a median left ventricular ejection fraction (LVEF) of 52% (range: 27-67%). 57% of boys (20/35) had abnormal LVEF <55%, 71% (25/35) had hypokinesia, and 82% late gadolinium enhancement. Extensive versus minimal late gadolinium enhancement was associated with reduced left ventricular ejection fraction (48% vs 58%; p = 0.003) suggesting more severe cardiomyopathy. Although echocardiography shortening fraction correlated with CMR ejection fraction (rs = 0.67; p < 0.001), three-quarter of echocardiography studies had suboptimal scanning windows and in 26% measurements significantly over- or underestimated left-ventricular function compared to CMR. CONCLUSION: Our findings clearly demonstrate the added value of CMR versus echocardiography in assessing DMD-cardiomyopathy. Particularly when echocardiographic scanning windows are suboptimal, CMR should be considered to allow accurate pre-operative cardiac assessment.

Epsilon toxin is essential for the virulence of Clostridium perfringens type D infection in sheep, goats, and mice.

Clostridium perfringens type D causes disease in sheep, goats, and other ruminants. Type D isolates produce, at minimum, alpha and epsilon (ETX) toxins, but some express up to five different toxins, raising questions about which toxins are necessary for the virulence of these bacteria. We evaluated the contribution of ETX to C. perfringens type D pathogenicity in an intraduodenal challenge model in sheep, goats, and mice using a virulent C. perfringens type D wild-type strain (WT), an isogenic ETX null mutant (etx mutant), and a strain where the etx mutation has been reversed (etx complemented). All sheep and goats, and most mice, challenged with the WT isolate developed acute clinical disease followed by death in most cases. Sheep developed various gross and/or histological changes that included edema of brain, lungs, and heart as well as hydropericardium. Goats developed various effects, including necrotizing colitis, pulmonary edema, and hydropericardium. No significant gross or histological abnormalities were observed in any mice infected with the WT strain. All sheep, goats, and mice challenged with the isogenic etx mutant remained clinically healthy for ≥24 h, and no gross or histological abnormalities were observed in those animals. Complementation of etx knockout restored virulence; most goats, sheep, and mice receiving this complemented mutant developed clinical and pathological changes similar to those observed in WT-infected animals. These results indicate that ETX is necessary for type D isolates to induce disease, supporting a key role for this toxin in type D disease pathogenesis.

Assessment of lopinavir pharmacokinetics with respect to developmental changes in infants and the impact on weight band-based dosing.

Improved antiretroviral therapies are needed for the treatment of HIV-infected infants, given the rapid progression of the disease and drug resistance resulting from perinatal exposure to antiretrovirals. We examined longitudinal pharmacokinetics (PK) data from a clinical trial of lopinavir/ritonavir (LPV/r) in HIV-infected infants in whom therapy was initiated at less than 6 months of age. A population PK analysis was performed using NONMEM to characterize changes in lopinavir (LPV) PK relating to maturational changes in infants, and to assess dosing requirements in this population. We also investigated the relationship between LPV PK and viral dynamic response. Age and ritonavir concentrations were the only covariates found to be significant. Population PK of LPV was characterized by high apparent clearance (CL/F) in young infants, which decreased with increasing age. Although younger infants had lower LPV concentrations, the viral dynamics did not correlate with initial LPV exposure. Monte Carlo simulations demonstrated that WHO weight band-based dosing recommendations predicted therapeutic LPV concentrations and provided drug exposure levels comparable to those resulting from US Food and Drug Administration (FDA)-suggested dosing regimens.

Off label use of devices and drugs in interventional radiology.

AIM: To establish how often off-label device and drug use occurs in interventional radiology (IR) in a UK tertiary referral hospital and consider the wider implications for the interventional radiologist. MATERIALS AND METHODS: Prospective data were collected during interventional procedures for 1 working week in a university hospital. Out-of-hours procedures and procedures outside the department were excluded. Operators were asked to record the drugs and devices used, the indication, and method of use. The instructions for use/summary of product characteristics were then studied for each device/drug used to assess if the use was on or off-label. RESULTS: During the study period 52 cases were performed and data were available on 26 cases (50%). In 22 of the 26 cases (84%) there was evidence of off-label use of devices or drugs. Off-label use of drugs included treatment of venous malformations with Fibrovein(©) (sodium tetradecyl sulphate), which is licensed for the treatment of varicose veins in the leg, and intra-arterial injection of heparin, which is licensed for intravenous and subcutaneous use. Off-label device use included placing vascular sheaths in the urinary tract, using angiographic catheters to guide wires in the urinary tract, using sheaths for thrombosuction, reshaping of the tip of most guidewires, and using angioplasty balloons to dislodge the arterial plug at fistula thrombectomy. CONCLUSION: Off-label device and drugs use is common in a UK tertiary hospital IR department and literature suggests this is common in the wider IR community. There are important clinical and legal implications for off-label use for patients and physicians.

Differential insult-dependent recruitment of the intrinsic mitochondrial pathway during neuronal programmed cell death.

Programmed cell death contributes to neurological diseases and may involve mitochondrial dysfunction with redistribution of apoptogenic proteins. We examined neuronal death to elucidate whether the intrinsic mitochondrial pathway and the crosstalk between caspase-dependent/-independent injury was differentially recruited by stressors implicated in neurodegeneration. After exposure of cultured cerebellar granule cells to various insults, the progression of injury was correlated with mitochondrial involvement, including the redistribution of intermembrane space (IMS) proteins, and patterns of protease activation. Injury occurred across a continuum from Bax- and caspase-dependent (trophic- factor withdrawal) to Bax-independent, calpain-dependent (excitotoxicity) injury. Trophic-factor withdrawal produced classical recruitment of the intrinsic pathway with activation of caspase-3 and redistribution of cytochrome c, whereas excitotoxicity induced early redistribution of AIF and HtrA2/Omi, elevation of intracellular calcium and mitochondrial depolarization. Patterns of engagement of neuronal programmed cell death and the redistribution of mitochondrial IMS proteins were canonical, reflecting differential insult-dependencies.

Pancreatic hamartoma.

Pancreatic hamartoma is a rare benign lesion and may be mistaken for a malignancy, as demonstrated by two cases. The first case was a 29-year-old man who presented with a 7-month history of intermittent upper abdominal pain, nausea and vomiting and a 15-kg weight loss. CT and MRI revealed a mass in the head of the pancreas. The second case was a 62-year-old man who presented with a 2-year history of intermittent abdominal pain, vomiting and a 25-kg weight loss. Although positron emission tomography was normal, CT revealed thickening of the duodenal wall and endoluminal ultrasonography revealed a tumour in the head of the pancreas. Both patients recovered from uneventful Kausch-Whipple pancreatoduodenectomy (in the first patient, it was pylorus-preserving), and in each case the histological diagnosis was hamartoma. Pancreatic hamartoma can present with vague, non-specific symptoms which, despite modern diagnostic tools, can be difficult to diagnose. Surgical resection with histopathological examination is required to confirm the diagnosis.

Major resection for chronic pancreatitis in patients with vascular involvement is associated with increased postoperative mortality.

BACKGROUND: The aim was to evaluate the outcome of major resection for chronic pancreatitis in patients with and without vascular involvement. METHODS: Of 250 patients with severe chronic pancreatitis referred between 1996 and 2003, 112 underwent pancreatic resection. The outcome of 17 patients (15.2 per cent) who had major vascular involvement was compared with that of patients without vascular involvement. RESULTS: The 95 patients without vascular involvement had resections comprising Beger's operation (39 patients), Kausch-Whipple pancreatoduodenectomy (28), total pancreatectomy (25) and left pancreatectomy (three). Twenty-five major vessels were involved in the remaining 17 patients. One or more major veins were occluded and/or compressed producing generalized or segmental portal hypertension, and three patients also had major arterial involvement. Surgery in these patients comprised Beger's operation (eight), total pancreatectomy (five), Kausch-Whipple pancreatoduodenectomy (two) and left pancreatectomy (two). Perioperative mortality rates were significantly different between the groups (two of 95 versus three of 17 respectively; P = 0.024). There were similar and significant improvements in long-term outcomes in both groups. CONCLUSION: Resection for severe chronic pancreatitis in patients with vascular complications is hazardous and is associated with an increased mortality rate. Vascular assessment should be included in the routine follow-up of patients with chronic pancreatitis, to enable early identification of those likely to develop vascular involvement and prompt surgical intervention.

Improved early ventricular performance with a right ventricle to pulmonary artery conduit in stage 1 palliation for hypoplastic left heart syndrome: evidence from strain Doppler echocardiography.

OBJECTIVE: To quantify non-invasively right ventricular (RV) performance in infants after stage 1 palliation for hypoplastic left heart syndrome (HLHS). DESIGN: Prospective, observational study with two dimensional and strain Doppler echocardiography. SETTING: Single tertiary paediatric cardiology centre. PATIENTS: Convenience sample of nine consecutive infants with HLHS. Four whose surgery involved a systemic to pulmonary artery (S-PA) shunt were compared with five whose surgery incorporated a right ventricle to pulmonary artery (RV-PA) conduit. METHODS: Basal RV free wall longitudinal strain rate, systolic strain (epsilon), and RV percentage area change were calculated during a single assessment between 27-50 days after surgery. RESULTS: Cardiopulmonary bypass time was longer in patients who underwent RV-PA (226 (30) minutes v 181 (18) minutes, p = 0.03), but cross clamp time, duration of ventilation, and inotrope use did not differ. Two patients in the S-PA group died, on days 29 and 60 after surgery. Peak systolic strain rate (-1.24 (0.19)/s v -0.91 (0.21)/s, p = 0.048), peak epsilon (-17.8 (1.8)% v -13.4 (2.0)%, p = 0.01), and RV percentage area change (56 (6)% v 25 (6)%, p < 0.01) were all greater among RV-PA patients. These indices also tended to be greater in survivors as a group. Ventricular loading conditions (oxygen saturations, diuretic treatment, and blood pressure) were similar in both groups. CONCLUSION: Strain Doppler echocardiography shows improved RV longitudinal systolic contractility in patients during convalescence after the RV-PA modification of stage 1 palliation for HLHS compared with those with an S-PA shunt.

Minimally invasive retroperitoneal pancreatic necrosectomy.

INTRODUCTION: Open surgery for pancreatic necrosis is associated with considerable morbidity and mortality. We report the results of a recently developed minimally invasive technique that we adopted in 1998. METHODS: A descriptive explanation of the approach is given together with the results of a retrospective analysis of patients who underwent a minimally invasive retroperitoneal pancreatic necrosectomy (MIRP) between August 1998 and April 2002. PATIENTS: There were 24 patients with a median (range) age of 61 (29-75) years. The initial median (range) APACHE II score was 8 (2-21). All patients had infected pancreatic necrosis with at least 50% pancreatic necrosis. In three patients it was not possible to complete the first MIRP because of technical reasons. RESULTS: A total of 88 procedures were performed with a median (range) of 4 (0-8) per patient. Twenty-one (88%) patients developed 36 complications during the course of their illness. Five patients required an additional open procedure: 2 for subsequent distant collections, 2 for bleeding and 1 for persisting sepsis and a distant abscess. Six (25%) patients who had MIRP died. The median (range) post-operative hospital stay was 51 (5-200) days. CONCLUSIONS: MIRP is a new technique that has shown promising results, and could be preferable to open pancreatic necrosectomy in selected patients. However, unresolved issues remain to be overcome and the exact role of MIRP in the management of pancreatic necrosis has yet to be defined.

Prospective comparison of costs and short term health outcomes of surgical versus device closure of atrial septal defect in children.

OBJECTIVE: To compare surgical and device closure of isolated secundum atrial septal defect (ASD) in terms of hospital costs, clinical outcome, and impact on the patient and family. DESIGN: Prospective, observational study. SETTING: Paediatric tertiary referral centre. PATIENTS: Consecutive local children with a secundum ASD, admitted between 1 May 1999 and 1 May 2001. METHODS: Parents completed a standardised questionnaire at recruitment (on admission), at discharge, and one month after the procedure. Clinical and hospital generated cost data were collated at discharge. RESULTS: 62 children were included in the analysis: 19 who underwent surgical repair and 43 who underwent device closure with the Amplatzer septal occluder. Median procedure times and hospital stay were significantly longer for surgical patients (170 (147 to 180) v 92 (70 to 115) minutes and 88 (78 to 112) v 29 (28 to 30) hours, respectively; p < 0.01). There was no difference in the complication rate. No device patients required intensive care or blood products. The median values for postoperative pain score, analgesia use, and convalescence time were greater for surgical patients. The median cost of each procedure was similar, but higher nursing and laboratory costs contributed to a slightly greater total cost for surgical repair (Aus$12 969 ($11 569 to $14 215) v Aus$11 845 ($10 669 to $12 555), p = 0.03). CONCLUSIONS: Device closure of ASD involves a shorter hospital stay, causes less discomfort and familial disturbance, and carries less cost than surgical closure. However, there should be guarded acceptance of this technique until long term data are available.

The effects of propofol on the contractility of failing and nonfailing human heart muscles.

We determined the direct effects of propofol on the contractility of human nonfailing atrial and failing atrial and ventricular muscles. Atrial and ventricular trabecular muscles were obtained from the failing human hearts of transplant patients or from nonfailing hearts of patients undergoing coronary artery bypass surgery. Isometric contraction variables were recorded before and after propofol was added to the bath in concentrations between 0.056 and 560 microM. The effects of propofol were compared with its commercial vehicle intralipid. To test beta-adrenergic effects in the presence of propofol, 1 microM isoproterenol was added at the end of each experiment. To determine the cellular mechanisms responsible for the actions of propofol, we examined its effects on actomyosin ATPase activity and sarcoplasmic reticulum (SR) Ca(2+) uptake in nonfailing atrial tissues. Propofol caused a concentration-dependent decrease in maximal developed tension in all muscles, which became significant (P < 0.05) at concentrations exceeding the clinical range (> or =56 microM). Isoproterenol restored contractility to the level achieved before exposure to propofol (P > 0.05 compared with baseline). Failing ventricular muscle exposed to propofol exhibited somewhat diminished ability to recover contractility in response to isoproterenol (P < 0.05 versus failing muscle exposed to intralipid only). Propofol induced a concentration-dependent decrease in the uptake of Ca(2+) into SR vesicles. At the same time, in the presence of 56 microM propofol, the Ca(2+)-activated actomyosin ATPase activity was shifted leftward, demonstrating an increase in myofilament sensitivity to Ca(2+). We conclude that propofol exerts a direct negative inotropic effect in nonfailing and failing human myocardium, but only at concentrations larger than typical clinical concentrations. Negative inotropic effects are reversible with beta-adrenergic stimulation. The negative inotropic effect of propofol is at least partially mediated by decreased Ca(2+) uptake into the SR; however, the net effect of propofol on contractility is insignificant at clinical concentrations because of a simultaneous increase in the sensitivity of the myofilaments to activator Ca(2+).

Evidence for a susceptibility locus on chromosome 6q influencing phonological coding dyslexia.

A linkage study of 96 dyslexia families containing at least two affected siblings (totaling 877 individuals) has found evidence for a dyslexia susceptibility gene on chromosome 6q11.2-q12 (assigned the name DYX4). Using a qualitative phonological coding dyslexia (PCD) phenotype (affected, unaffected, or uncertain diagnoses), two-point parametric analyses found highly suggestive evidence for linkage between PCD and markers D6S254, D6S965, D6S280, and D6S251 (LOD(max) scores = 2.4 to 2.8) across an 11 cM region. Multipoint parametric analysis supported linkage of PCD to this region (peak HLOD = 1.6), as did multipoint nonparametric linkage analysis (P = 0.012). Quantitative trait linkage analyses of four reading measures (phonological awareness, phonological coding, spelling, and rapid automatized naming speed) also provided evidence for a dyslexia susceptibility locus on chromosome 6q. Using a variance-component approach, analysis of phonological coding and spelling measures resulted in peak LOD scores at D6S965 of 2.1 and 3.3, respectively, under 2 degrees of freedom. Furthermore, multipoint nonparametric quantitative trait sibpair analyses suggested linkage between the 6q region and phonological awareness, phonological coding, and spelling (P = 0.018, 0.017, 0.0005, respectively, for unweighted sibpairs < 18 years of age). Although conventional significance thresholds were not reached in the linkage analyses, the chromosome 6q11.2-q12 region clearly warrants investigation in other dyslexia family samples to attempt replication and confirmation of a dyslexia susceptibility gene in this region.

Mechanical unloading restores beta-adrenergic responsiveness and reverses receptor downregulation in the failing human heart.

BACKGROUND: Mechanical unloading of the failing human heart with a left ventricular assist device (LVAD) results in clinically documented reversal of chamber dilation and improvement of cardiac function. We tested the hypothesis that LVAD support normalizes the ability of cardiac muscle to respond to sympathetic nervous system stimulation by reversing the downregulation of beta-adrenergic receptors. METHODS AND RESULTS: Human LV tissue was obtained from nonfailing hearts of unmatched organ donors and failing hearts at the time of transplantation, with or without LVAD. Baseline contractile parameters and inotropic response to a beta-adrenergic agonist were measured in isolated trabecular muscles. beta-Adrenergic receptor density was quantified by radioligand binding. Results showed a significant increase in the response to beta-adrenergic stimulation after LVAD (developed tension increased by 0.76+/-0.09 g/mm(2) in nonfailing, 0.38+/-0.07 in failing, and 0.68+/-0.10 in failing+LVAD; P<0.01), accompanied by an increased density of beta-adrenergic receptors (58.7+/-9.6 fmol/mg protein in nonfailing, 26.2+/-3.8 in failing, and 63.0+/-8.3 in failing+LVAD; P<0.05). These changes were unrelated to the duration of support. CONCLUSIONS: Data demonstrate that mechanically supporting the failing human heart with an LVAD can reverse the downregulation of beta-adrenergic receptors and restore the ability of cardiac muscle to respond to inotropic stimulation by the sympathetic nervous system. This indicates that functional impairment of cardiac muscle in human heart failure is reversible.

Molecular quantification of human beta-glucuronidase levels in a patient with Vohwinkel's syndrome.

The skin must undergo the process of keratinization in order to perform its functions. During the process of differentiation, certain genes are activated while others are repressed, leading to changes in structural proteins and enzymes and in the synthesis of various lipids. An error in any of these steps can ultimately impair the process of keratinization. Vohwinkel's syndrome is the direct result of a defect in keratinization. Patients who have this epidermolytic palmoplantar keratoderma present clinically with hyperkeratosis of the stratum corneum. Hyperkeratosis has been linked to an increase in beta-glucuronidase levels. The authors studied the absolute concentration of human beta-glucuronidase in a patient with Vohwinkel's syndrome as determined through a double-antibody sandwich enzyme-linked immunosorbent assay and a Western blot assay of the blood, urine, and skin of the patient.

Risk factors predictive of positive findings at colonoscopy(1).

PURPOSE:The surgery department at our institution has become the primary provider of colonoscopy. We sought to determine which risk factors, if any, were most predictive of positive findings on colonoscopy.Between March and December 1999, 202 consecutive patients referred for colonoscopy were identified. Each patient was interviewed and a standard questionnaire completed before colonoscopy to establish possible risk factors for the presence of colorectal cancer or polyps. The colonoscopy findings, including pathology reports, were correlated with the questionnaire and subjected to chi-square analysis to determine statistical significance.The risk factors most likely to be associated with a finding of colorectal cancer or polyp were family history of colorectal cancer (65%), bleeding (65%), fecal occult blood positive (64%), abdominal pain (60%), and alteration of bowel habits (53%).No risk factor by history or presenting symptoms reached statistical significance as an independent predictor of a positive colonoscopy finding. However, most frequently associated with positive colonoscopy findings were a family history of colorectal cancer, bleeding, positive fecal occult blood test, presence of abdominal pain, and alteration of bowel habits. A history to include these risk factors can serve to prioritize the need for a colonoscopic examination.

A longitudinal study of electrode impedance, the electrically evoked compound action potential, and behavioral measures in nucleus 24 cochlear implant users.

OBJECTIVE: The primary goal of this study was to examine changes that may occur in electrode impedance, electrically evoked compound action potential (EAP) threshold and slope of the EAP growth function, and behavioral measures of threshold T-level) and maximum comfort (C-level) over time in both adult and child cochlear implant users. Secondary goals were to determine whether changes in these measures are consistent between children and adults, and to determine whether behavioral measures (MAP T- and C-levels) and electrophysiologic measures (EAP thresholds) exhibit the same trends over time. DESIGN: Thirty-five children and 33 adults implanted with the Nucleus CI24M between November 1996 and August 1999 participated in this study. Subjects were included in this study if 1) they had used their implant for at least 1 yr after device connection, and 2) they had participated in the necessary data collection at a minimum number of the time intervals assessed in this study. EAP threshold, slope of the EAP growth function, and common ground electrode impedance measures were collected intraoperatively, at initial stimulation, and at several subsequent visits up to 2 yr post initial stimulation. MAP T- an d C-levels weremeasured at initial stimulation and at the same time intervals as described above. RESULTS: Changes in electrode impedance, EAP thresholds, and slope of the EAP growth function from measures made intraoperatively, at initial stimulation, and at 1 to 2 mo post initial stimulation were similar in both children and adults. Beyond the 1- to 2-mo visit, children exhibited significant increases in electrode impedance, EAP thresholds, slope, and MAP T-levels, whereas these samemeasures in adults remained relatively stable. EAP thresholds in children stabilized by the 3- to 8-mo visit, and electrode impedance stabilized by the 6- to 8-mo visit, while slope of the EAP growth function, MAP T-levels,and MAP C-levels werestable by 1 yr post initial stimulation. C-levels in adults increased up to 1 yr post initial stimulation; however, the amount of increase was much smaller than that seen in children. In both children and adults, longitudinal trends in EAP thresholds mirrored T-level more closely than C-level. CONCLUSIONS: The results of this study suggest that peripheral changes occur in many children that do not generally occur in adults within the first year of cochlear implant use. One implication of these results is that if EAP thresholds are to be used to assist in programming the speech processor for children, it is best to make those measures at the same time interval as device programming rather than using measures made intraoperatively or at the initial programming session to set MAP levels at later visits.