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1.  Trends in 30-day mortality rate and case mix for paediatric cardiac surgery in the UK between 2000 and 2010 
Open Heart  2015;2(1):e000157.
To explore changes over time in the 30-day mortality rate for paediatric cardiac surgery and to understand the role of attendant changes in the case mix.
Methods, setting and participants
Included were: all mandatory submissions to the National Institute of Cardiovascular Outcomes Research (NICOR) relating to UK cardiac surgery in patients aged <16 years. The χ2 test for trend was used to retrospectively analyse the proportion of surgical episodes ending in 30-day mortality and with various case mix indicators, in 10 consecutive time periods, from 2000 to 2010. Comparisons were made between two 5-year eras of: 30-day mortality, period prevalence and mean age for 30 groups of specific operations.
Main outcome measure
30-day mortality for an episode of surgical management.
Our analysis includes 36 641 surgical episodes with an increase from 2283 episodes in 2000 to 3939 in 2009 (p<0.01). The raw national 30-day mortality rate fell over the period of review from 4.3% (95% CI 3.5% to 5.1%) in 2000 to 2.6% (95% CI 2.2% to 3.0%) in 2009/2010 (p<0.01). The case mix became more complex in terms of the percentage of patients <2.5 kg (p=0.05), with functionally univentricular hearts (p<0.01) and higher risk diagnoses (p<0.01). In the later time era, there was significant improvement in 30-day mortality for arterial switch with ventricular septal defect (VSD) repair, patent ductus arteriosus ligation, Fontan-type operation, tetralogy of Fallot and VSD repair, and the mean age of patients fell for a range of operations performed in infancy.
The raw 30-day mortality rate for paediatric cardiac surgery fell over a decade despite a rise in the national case mix complexity, and compares well with international benchmarks. Definitive repair is now more likely at a younger age for selected infants with congenital heart defects.
PMCID: PMC4395835  PMID: 25893099
2.  Haemodynamic consequences of targeted single- and dual-site right ventricular pacing in adults with congenital heart disease undergoing surgical pulmonary valve replacement 
Europace  2014;17(2):274-280.
The purpose of this study was to create an epicardial electroanatomic map of the right ventricle (RV) and then apply post-operative-targeted single- and dual-site RV temporary pacing with measurement of haemodynamic parameters. Cardiac resynchronization therapy is an established treatment for symptomatic left ventricular (LV) dysfunction. In congenital heart disease, RV dysfunction is a common cause of morbidity—little is known regarding the potential benefits of CRT in this setting.
Methods and results
Sixteen adults (age = 32 ± 8 years; 6 M, 10 F) with right bundle branch block (RBBB) and repaired tetralogy of Fallot (n = 8) or corrected congenital pulmonary stenosis (n = 8) undergoing surgical pulmonary valve replacement (PVR) for pulmonary regurgitation underwent epicardial RV mapping and haemodynamic assessment of random pacing configurations including the site of latest RV activation. The pre-operative pulmonary regurgitant fraction was 49 ± 10%; mean LV end-diastolic volume (EDV) 85 ± 19 mL/min/m2 and RVEDV 183 ± 89 mL/min/m2 on cardiac magnetic resonance imaging. The mean pre-operative QRS duration is 136 ± 26 ms. The commonest site of latest activation was the RV free wall and DDD pacing here alone or combined with RV apical pacing resulted in significant increases in cardiac output (CO) vs. AAI pacing (P < 0.01 all measures). DDDRV alternative site pacing significantly improved CO by 16% vs. AAI (P = 0.018), and 8.5% vs. DDDRV apical pacing (P = 0.02).
Single-site RV pacing targeted to the region of latest activation in patients with RBBB undergoing PVR induces acute improvements in haemodynamics and supports the concept of ‘RV CRT’. Targeted pacing in such patients has therapeutic potential both post-operatively and in the long term.
PMCID: PMC4309992  PMID: 25371427
Congenital heart disease; Resynchronization; Right ventricle; Electroanatomic map
3.  Recombinant Protein- and Synthetic Peptide-Based Immunoblot Test for Diagnosis of Neurocysticercosis 
Journal of Clinical Microbiology  2014;52(5):1429-1434.
One of the most well-characterized tests for diagnosing neurocysticercosis (NCC) is the enzyme-linked immunoelectrotransfer blot (EITB) assay developed at the CDC, which uses lentil lectin-bound glycoproteins (LLGP) extracted from Taenia solium cysticerci. Although the test is very reliable, the purification process for the LLGP antigens has been difficult to transfer to other laboratories because of the need for expensive equipment and technical expertise. To develop a simpler assay, we previously purified and cloned the diagnostic glycoproteins in the LLGP fraction. In this study, we evaluated three representative recombinant or synthetic antigens from the LLGP fraction, individually and in different combinations, using an immunoblot assay (recombinant EITB). Using a panel of 249 confirmed NCC-positive and 401 negative blood serum samples, the sensitivity of the recombinant EITB assay was determined to be 99% and the specificity was 99% for diagnosing NCC. We also tested a panel of 239 confirmed NCC-positive serum samples in Lima, Peru, and found similar results. Overall, our data show that the performance characteristics of the recombinant EITB assay are comparable to those of the LLGP-EITB assay. This new recombinant- and synthetic antigen-based assay is sustainable and can be easily transferred to other laboratories in the United States and throughout the world.
PMCID: PMC3993633  PMID: 24554747
4.  Parasite Antigen in Serum Predicts the Presence of Viable Brain Parasites in Patients With Apparently Calcified Cysticercosis Only 
Viable cysticercosis lesions can be missed by computed tomography. Antigen enzyme-linked immunosorbent assay (Ag-ELISA) detected 7 patients with viable cysts among 39 patients with apparently calcified cysticercosis only. Patients with a positive Ag-ELISA were 27 times more likely to have viable cysts.
Background. Computed tomography (CT) remains the standard neuroimaging screening exam for neurocysticercosis, and residual brain calcifications are the commonest finding. Magnetic resonance imaging (MRI) is more sensitive than CT but is rarely available in endemic regions. Enzyme-linked immunoelectrotransfer blot (EITB) assay uses antibody detection for diagnosis confirmation; by contrast, enzyme-linked immunosorbent assay (ELISA) antigen detection (Ag-ELISA) detects circulating parasite antigen. This study evaluated whether these assays predict undetected viable cysts in patients with only calcified lesions on brain CT.
Methods. Serum samples from 39 patients with calcified neurocysticercosis and no viable parasites on CT were processed by Ag-ELISA and EITB. MRI was performed for each patient within 2 months of serologic testing. Conservatively high ELISA and EITB cutoffs were used to predict the finding of viable brain cysts on MRI.
Results. Using receiver operating characteristic–optimized cutoffs, 7 patients were Ag-ELISA positive, and 8 had strong antibody reactions on EITB. MRI showed viable brain cysts in 7 (18.0%) patients. Patients with positive Ag-ELISA were more likely to have viable cysts than Ag-ELISA negatives (6/7 vs 1/32; odds ratio, 186 [95% confidence interval, 1–34 470.0], P < .001; sensitivity 85.7%, specificity 96.9%, positive likelihood ratio of 27 to detect viable cysts). Similar but weaker associations were also found between a strong antibody reaction on EITB and undetected viable brain cysts.
Conclusions. Antigen detection, and in a lesser degree strong antibody reactions, can predict viable neurocysticercosis. Serological diagnostic methods could identify viable lesions missed by CT in patients with apparently only calcified cysticercosis and could be considered for diagnosis workup and further therapy.
PMCID: PMC3765011  PMID: 23788241
neurocysticercosis; antigen detection; calcifications; epilepsy; Peru
5.  Detection of Taenia solium Antigens and Anti–T. solium Antibodies in Paired Serum and Cerebrospinal Fluid Samples from Patients with Intraparenchymal or Extraparenchymal Neurocysticercosis 
The Journal of infectious diseases  2009;199(9):1345-1352.
Neurocysticercosis (NCC) is a frequent cause of epilepsy worldwide. Compared with the more common parenchymal brain cysts, extraparenchymal infections are difficult to manage and have a poor prognosis. Serological assays are used to detect circulating Taenia solium antigens or anti–T. solium antibodies in serum or cerebrospinal fluid (CSF) samples. There are no guidelines on whether to use serum or CSF specimens for a particular assay.
We obtained paired serum and CSF samples from 91 patients with NCC (48 had intraparenchymal NCC, and 43 had extraparenchymal NCC) for detection of antibodies, using an enzyme-linked immunotransfer blot (EITB) assay, and antigens, using a monoclonal antibody–based enzyme-linked immunosorbent assay (ELISA).
For the intraparenchymal NCC group, the EITB assay yielded more true-positive results for serum samples, and the ELISA yielded slightly more true-positive results for CSF samples than for serum samples, but none of these differences were statistically significant. Most patients with calcified NCC were antibody positive but antigen negative. For extraparenchymal disease, all samples were antibody positive, and all but 2 were antigen positive, with most samples containing high antigen levels.
The sensitivity of antibody-detecting EITB assays is not increased through the use of CSF samples rather than serum samples. The antigen-detecting ELISA performed better for CSF samples than for serum samples, but for both specimen types it was less sensitive than the EITB assay. Active and inactive NCC are better differentiated from each other by the antigen-detecting ELISA, for both serum and CSF samples. High antigen levels suggest the presence of subarachnoid NCC.
PMCID: PMC4059603  PMID: 19358669
6.  Neurocysticercosis as a Cause of Epilepsy and Seizures in Two Community-Based Studies in a Cysticercosis-Endemic Region in Peru 
The prevalence of epilepsy added to inadequate treatment results in chronic morbidity and considerable mortality in poor populations. Neurocysticercosis (NCC), a helminthic disease of the central nervous system, is a leading cause of seizures and epilepsy in most of the world.
Taking advantage of a cysticercosis elimination program, we performed two community-based cross-sectional studies between 2006 and 2007 in 58 rural communities (population 20,610) to assess the prevalence and characteristics of epilepsy and epileptic seizures in this endemic region. Serological and computed tomography (CT) data in individuals with epilepsy were compared to previous surveys in general population from the same region.
Principal findings
In two surveys, 17,450 individuals were evaluated. Lifetime prevalence of epilepsy was 17.25/1000, and prevalence of active epilepsy was 10.8/1000 inhabitants. The prevalence of epilepsy increased after age 25 years and dropped after age 45. Only 24% (45/188) of patients with active epilepsy were taking antiepileptic drugs, all at sub-therapeutic doses. Antibodies to cysticercosis were found in approximately 40% of individuals with epilepsy in both studies. In one survey only individuals presenting strong antibody reactions were significantly associated with having epilepsy (OR 5.74; p<0.001). In the second, the seroprevalence as well as the proportion presenting strong antibody reactions were both significantly higher in individuals with epilepsy (OR 2.2 and 4.33, respectively). Brain CT showed NCC-compatible images in 109/282 individuals with epilepsy (39%). All individuals with viable parasites on CT were seropositive.
The prevalence of epilepsy in this cysticercosis endemic region is high and NCC is an important contributor to it.
Author Summary
Epilepsy is a chronic disease affecting more than 50 million people around the world. In many countries neurocysticercosis (NCC), a parasitic disease of the central nervous system, is a frequent cause of seizures and epilepsy. After a human ingests poorly cooked pork with cysts of the tapeworm Taenia solium, the larvae develops in the small intestine as an adult tapeworm. The tapeworm carrier becomes a source of infective eggs which are released with the stools and can infect humans or pigs with the larval stage, causing cysticercosis. There are many forms of clinical manifestations of NCC; epilepsy is one of them and the most frequent. Scarce population based-studies to identify individuals with epilepsy in rural communities exist, including only a few from Latin America. Our community-based study used a validated survey applied by trained non-medical professionals (nurse, nurse technicians, mid-wife, etc.) and found 301 individuals with epilepsy (17.25/1000), 70% of them without antiepileptic medication and 39% of them with images suggestive of NCC. The prevalence of epilepsy is high in this region and cysticercosis is a frequent finding in individuals with epilepsy.
PMCID: PMC3923674  PMID: 24551255
7.  Prevention and control of Taenia solium taeniasis/cysticercosis in Peru 
Pathogens and Global Health  2012;106(5):312-318.
Taenia solium is endemic in most of the world, causing seizures and other neurological symptoms. Transmission is mainly maintained in rural areas by a human to pig cycle. Despite claims on its eradicability, sustainable interruption of transmission has not yet been reported. This manuscript reviews the conceptual basis for control, available diagnostic and control tools, and recent experiences on control in the field performed in Peru along the past decade
PMCID: PMC4005116  PMID: 23265557
Taenia solium; Taeniasis; Cysticercosis; Neurocysticercosis; Epilepsy; Peru
8.  Geographic Correlation between Tapeworm Carriers and Heavily Infected Cysticercotic Pigs 
Neurocysticercosis is a leading cause of preventable epilepsy in the developing world. Sustainable community-based interventions are urgently needed to control transmission of the causative parasite, Taenia solium. We examined the geospatial relationship between live pigs with visible cysticercotic cysts on their tongues and humans with adult intestinal tapeworm infection (taeniasis) in a rural village in northern Peru. The objective was to determine whether tongue-positive pigs could indicate high-risk geographic foci for taeniasis to guide targeted screening efforts. This approach could offer significant benefit compared to mass intervention.
We recorded geographic coordinates of all village houses, collected stool samples from all consenting villagers, and collected blood and examined tongues of all village pigs. Stool samples were processed by enzyme-linked immunosorbent assay (ELISA) for presence of Taenia sp. coproantigens indicative of active taeniasis; serum was processed by enzyme-linked immunoelectrotransfer blot for antibodies against T. solium cysticercosis (EITB LLGP) and T. solium taeniasis (EITB rES33).
Of 548 pigs, 256 (46.7%) were positive for antibodies against cysticercosis on EITB LLGP. Of 402 fecal samples, 6 (1.5%) were positive for the presence of Taenia sp. coproantigens. The proportion of coproantigen-positive individuals differed significantly between residents living within 100-meters of a tongue-positive pig (4/79, 5.1%) and residents living >100 meters from a tongue-positive pig (2/323, 0.6%) (p = 0.02). The prevalence of taeniasis was >8 times higher among residents living within 100 meters of a tongue-positive pig compared to residents living outside this range (adjusted PR 8.1, 95% CI 1.4–47.0).
Tongue-positive pigs in endemic communities can indicate geospatial foci in which the risk for taeniasis is increased. Targeted screening or presumptive treatment for taeniasis within these high-risk foci may be an effective and practical control intervention for rural endemic areas.
Author Summary
Taenia solium, aka the pork tapeworm, is an important cause of epilepsy in developing nations. People with intestinal tapeworms, a condition known as taeniasis, pass infectious eggs in their feces which contaminate the environment. These eggs can cause serious disease in both humans and pigs if they are ingested. Treating taeniasis is one way to potentially control transmission of the parasite in affected communities. However, this is difficult because people with taeniasis usually have no symptoms and therefore don't know they are infected. As a result, control programs may resort to offering treatment to entire communities in order to reach a few tapeworm carriers. Focusing detection and treatment on high-risk subgroups is another approach which might reduce unnecessary treatments. In this study, we found that people with taeniasis are more likely to be found living nearby pigs with visible signs of infection, specifically tapeworm cysts on their tongues. This suggests that routine tongue examination by pig owners and buyers could identify neighborhoods where detection and treatment of taeniasis may be more efficient.
PMCID: PMC3527375  PMID: 23285305
9.  Cardiomyocyte Ca2+ handling and structure is regulated by degree and duration of mechanical load variation 
Cardiac transverse (t)-tubules are altered during disease and may be regulated by stretch-sensitive molecules. The relationship between variations in the degree and duration of load and t-tubule structure remains unknown, as well as its implications for local Ca2+-induced Ca2+ release (CICR). Rat hearts were studied after 4 or 8 weeks of moderate mechanical unloading [using heterotopic abdominal heart–lung transplantation (HAHLT)] and 6 or 10 weeks of pressure overloading using thoracic aortic constriction. CICR, cell and t-tubule structure were assessed using confocal-microscopy, patch-clamping and scanning ion conductance microscopy. Moderate unloading was compared with severe unloading [using heart-only transplantation (HAHT)]. Mechanical unloading reduced cardiomyocyte volume in a time-dependent manner. Ca2+ release synchronicity was reduced at 8 weeks moderate unloading only. Ca2+ sparks increased in frequency and duration at 8 weeks of moderate unloading, which also induced t-tubule disorganization. Overloading increased cardiomyocyte volume and disrupted t-tubule morphology at 10 weeks but not 6 weeks. Moderate mechanical unloading for 4 weeks had milder effects compared with severe mechanical unloading (37% reduction in cell volume at 4 weeks compared to 56% reduction after severe mechanical unloading) and did not cause depression and delay of the Ca2+ transient, increased Ca2+ spark frequency or impaired t-tubule and cell surface structure. These data suggest that variations in chronic mechanical load influence local CICR and t-tubule structure in a time- and degree-dependent manner, and that physiological states of increased and reduced cell size, without pathological changes are possible.
PMCID: PMC4393719  PMID: 22862818
assist device; Ca2+ handling; excitation–contraction coupling
10.  High frequency of spinal involvement in patients with basal subarachnoid neurocysticercosis 
Neurology  2012;78(18):1394-1400.
To determine the frequency of spinal neurocysticercosis (NCC) in patients with basal subarachnoid NCC compared with that in individuals with viable limited intraparenchymal NCC (≤20 live cysts in the brain).
We performed a prospective observational case-control study of patients with NCC involving the basal cisterns or patients with only limited intraparenchymal NCC. All patients underwent MRI examinations of the brain and the entire spinal cord to assess spinal involvement.
Twenty-seven patients with limited intraparenchymal NCC, and 28 patients with basal subarachnoid NCC were included in the study. Spinal involvement was found in 17 patients with basal subarachnoid NCC and in only one patient with limited intraparenchymal NCC (odds ratio 40.18, 95% confidence interval 4.74–340.31; p < 0.0001). All patients had extramedullary (intradural) spinal NCC, and the lumbosacral region was the most frequently involved (89%). Patients with extensive spinal NCC more frequently had ventriculoperitoneal shunt placement (7 of 7 vs 3 of 11; p = 0.004) and tended to have a longer duration of neurologic symptoms than those with regional involvement (72 months vs 24 months; p = 0.062).
The spinal subarachnoid space is commonly involved in patients with basal subarachnoid NCC, compared with those with only intraparenchymal brain cysts. Spinal cord involvement probably explains serious late complications including chronic meningitis and gait disorders that were described before the introduction of antiparasitic therapy. MRI of the spine should be performed in basal subarachnoid disease to document spinal involvement, prevent complications, and monitor for recurrent disease.
PMCID: PMC3345784  PMID: 22517102
11.  Detection of Taenia solium Taeniasis Coproantigen Is an Early Indicator of Treatment Failure for Taeniasis 
Taenia solium causes taeniasis and cysticercosis, a zoonotic complex associated with a significant burden of epilepsy in most countries. Reliable diagnosis and efficacious treatment of taeniasis are needed for disease control. Currently, cure can be confirmed only after a period of at least 1 month, by negative stool microscopy. This study assessed the performance of detection by a coproantigen enzyme-linked immunosorbent assay (CoAg-ELISA) for the early evaluation of the efficacy of antiparasitic treatment of human T. solium taeniasis. We followed 69 tapeworm carriers who received niclosamide as standard treatment. Stool samples were collected on days 1, 3, 7, 15, 30, and 90 after treatment and were processed by microscopy and CoAg-ELISA. The efficacy of niclosamide was 77.9% (53/68). Thirteen patients received a second course of treatment and completed the follow-up. CoAg-ELISA was therefore evaluated for a total of 81 cases (68 treatments, 13 retreatments). In successful treatments (n = 64), the proportion of patients who became negative by CoAg-ELISA was 62.5% after 3 days, 89.1% after 7 days, 96.9% after 15 days, and 100% after 30 days. In treatment failures (n = 17), the CoAg-ELISA result was positive for 70.6% of patients after 3 days, 94.1% after 7 days, and 100% after 15 and 30 days. Only 2 of 17 samples in cases of treatment failure became positive by microscopy by day 30. The presence of one scolex, but not multiple scolices, in posttreatment stools was strongly associated with cure (odds ratio [OR], 52.5; P < 0.001). CoAg-ELISA is useful for the assessment of treatment failure in taeniasis. Early assessment at day 15 would detect treatment failure before patients become infective.
PMCID: PMC3318286  PMID: 22336287
12.  Serologic Diagnosis of Human Taenia solium Cysticercosis by Using Recombinant and Synthetic Antigens in QuickELISA™ 
Diagnosis of Taenia solium cysticercosis is an important component in the control and elimination of cysticercosis and taeniasis. New detection assays using recombinant and synthetic antigens originating from the lentil lectin-purified glycoproteins (LLGPs) of T. solium cysticerci were developed in a QuickELISA™ format. We analyzed a panel of 474 serum samples composed of 108 serum samples from donors with two or more viable cysts, 252 serum samples from persons with other parasitic infections, and 114 serum samples from persons with no documented illnesses. The sensitivities and specificities of T24H QuickELISA™, GP50 QuickELISA™, and Ts18var1 QuickELISA™ were 96.3% and 99.2%, 93.5% and 98.6%, and 89.8% and 96.4%, respectively, for detecting cases with multiple, viable cysts. T24H QuickELISA™ performs best among the three assays, and has sensitivity and specificity values comparable to those of the LLGP enzyme-linked immunosorbent blot. The QuickELISA™ are simple, rapid quantitative methods for detecting antibodies specific for T. solium cysticerci antigens.
PMCID: PMC3062454  PMID: 21460015
13.  Cardiovascular magnetic resonance findings in repaired anomalous left coronary artery to pulmonary artery connection (ALCAPA) 
Anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) is a rare coronary artery anomaly. This study shows the role of cardiovascular magnetic resonance (CMR) in assessing young patients following surgical repair of ALCAPA.
6 patients, aged 9-21 years, with repaired ALCAPA (2 Tackeuchi method, 4 direct re-implantation) underwent CMR because of clinical suspicion of myocardial ischemia. Imaging used short and long axis cine images (assess ventricular function), late-gadolinium enhancement (LGE) (detect segmental myocardial fibrosis), adenosine stress perfusion (detect reversible ischaemia) and 3D whole-heart imaging (visualize proximal coronary arteries).
The left ventricular (LV) global systolic function was preserved in all patients (mean LV ejection fraction = 62.7% ± 4.23%). The LV volumes were within the normal ranges, (mean indexed LVEDV = 75.4 ± 3.5 ml/m2, LVESV = 31.6 ± 9.4 ml/m2). In 1 patient, hypokinesia of the anterior segments was visualized. Five patients showed sub-endocardial LGE involving the basal, antero-lateral wall and the anterior papillary muscle. Three patients had areas of reversible ischemia. In these 3, 3D whole-heart MRA showed that the proximal course of the left coronary artery was occluded (confirmed with cardiac catheterisation).
CMR is a good, non-invasive, radiation-free investigation in the post-surgical evaluation of ALCAPA. In referred patients we show that basal, antero-lateral sub-endocardial myocardial fibrosis is a characteristic finding. Furthermore, stress adenosine CMR perfusion, can identify reversible ischemia in this group, and was indicative of left coronary artery occlusion.
PMCID: PMC3123558  PMID: 21575211
15.  Serologic Evolution of Neurocysticercosis Patients after Antiparasitic Therapy 
The Journal of infectious diseases  1997;175(2):486-489.
Neurocysticercosis is the main cause of acquired epilepsy in developing countries and is an emerging disease in the United States. Introduction of the immunoblot assay provided a new tool for the diagnosis and monitoring of neurocysticercosis. This study analyzed the relationship between clinical characteristics of cerebral infection (number and type of lesions) plus the baseline response on immunoblot and the changes observed after therapy. Reaction to all 7 diagnostic bands was associated with severe infection (more lesions). Seventeen patients (35%) had no active lesions on computed tomography (CT) 3 months after therapy and were considered cured. Although most cured patients remained seropositive after 1 year, 3 became seronegative before 9 months. In these 3 cases, the lesions had resolved on CT at 3 months. Persistent seropositivity does not necessarily indicate active infection. Serologic follow-up will be clinically helpful only in rare cases in which early antibody disappearance occurs.
PMCID: PMC3025428  PMID: 9203680
Taenia solium cysticercosis is an important cause of human disease in many developing countries. Porcine cysticercosis is a vital link in the transmission of this disease and impairs meat production. A treatment for porcine cysticercosis may be an effective way of preventing human disease that would also benefit pig farmers, facilitating control programs in disease-endemic regions. Previous research suggests that reinfection with cysticercosis or immunotherapy with cysticercal antigens may cause degeneration of cysticerci, potentially curing porcine cysticercosis. Therefore, a blinded, randomized, controlled study to assess the efficacy and safety of immunotherapy in 28 naturally parasitized pigs was performed. Four groups of pigs with similar weights were inoculated twice with membrane-enriched cysticercal antigens (MA), saline, aqueous-soluble crude cysticercal antigens (AA) in adjuvant (Freund's complete then incomplete), or adjuvant alone. Immunotherapy was well tolerated but had no consistent effect on the macroscopic appearance of cysticerci or eosinophil count. Histopathologic findings were variable, with both severe and minimal inflammatory reactions seen in adjacent cysticerci in all pigs. Nine (64%) of 14 pigs given immunotherapy developed new antibody bands on electroimmunotransfer blot compared with one (7%) of 14 control pigs (P < 0.01). Treatment with AA in adjuvant caused a significant increase in the proportion of cysticerci that failed to evaginate and were, therefore, not viable for infecting humans (34% for pigs given AA in adjuvant compared with 10% for adjuvant alone; P < 0.04). Although immunotherapy caused a statistically significant decrease in the viability of cysticerci, this immunologic reaction was not great enough to prevent human disease.
PMCID: PMC3025526  PMID: 9063358
17.  Normal passive viscoelasticity but abnormal myofibrillar force generation in human hypertrophic cardiomyopathy 
Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy, increased ventricular stiffness and impaired diastolic filling. We investigated to what extent myocardial functional defects can be explained by alterations in the passive and active properties of human cardiac myofibrils. Skinned ventricular myocytes were prepared from patients with obstructive HCM (two patients with MYBPC3 mutations, one with a MYH7 mutation, and three with no mutation in either gene) and from four donors. Passive stiffness, viscous properties, and titin isoform expression were similar in HCM myocytes and donor myocytes. Maximal Ca2+-activated force was much lower in HCM myocytes (14 ± 1 kN/m2) than in donor myocytes (23 ± 3 kN/m2; P < 0.01), though cross-bridge kinetics (ktr) during maximal Ca2+ activation were 10% faster in HCM myocytes. Myofibrillar Ca2+ sensitivity in HCM myocytes (pCa50 = 6.40 ± 0.05) was higher than for donor myocytes (pCa50 = 6.09 ± 0.02; P < 0.001) and was associated with reduced phosphorylation of troponin-I (ser-23/24) and MyBP-C (ser-282) in HCM myocytes. These characteristics were common to all six HCM patients and may therefore represent a secondary consequence of the known and unknown underlying genetic variants. Some HCM patients did however exhibit an altered relationship between force and cross-bridge kinetics at submaximal Ca2+ concentrations, which may reflect the primary mutation. We conclude that the passive viscoelastic properties of the myocytes are unlikely to account for the increased stiffness of the HCM ventricle. However, the low maximum Ca2+-activated force and high Ca2+ sensitivity of the myofilaments are likely to contribute substantially to any systolic and diastolic dysfunction, respectively, in hearts of HCM patients.
Research Highlights
► The passive stiffness of skinned HCM cardiac myocytes was similar to that of normal (donor) myocytes. ► Maximum Ca-activated force production was reduced by 40% in HCM vs donor myocytes. ► This loss of force could contribute to systolic dysfunction in HCM hearts. ► Myofibrillar Ca sensitivity was higher in HCM than in donor myocytes. ► The enhanced Ca sensitivity could compensate for the smaller maximum force but would tend to cause diastolic dysfunction. ► These characteristics were common to all HCM patients studied, suggesting the changes were secondary consequence of the underlying genetic variants.
PMCID: PMC2954357  PMID: 20615414
Hypertrophic cardiomyopathy; Skinned cardiac myocytes; Viscoelasticity; Ca2+ sensitivity; Cross-bridge kinetics
18.  Development and Evaluation of a Magnetic Immunochromatographic Test To Detect Taenia solium, Which Causes Taeniasis and Neurocysticercosis in Humans▿  
Taeniasis/cysticercosis caused by Taenia solium is a frequent parasitic infection of the human brain in most of the world. Rapid and simple screening tools to identify taeniasis and cysticercosis cases are needed for control programs, mostly to identify tapeworm carriers which are the source of infection and need to be treated, or as tools for point-of-care case detection or confirmation. These screening assays should be affordable, reliable, rapid, and easy to perform. Immunochromatographic tests meet these criteria. To demonstrate proof of principle, we developed and evaluated two magnetic immunochromatographic tests (MICTs) for detection of human Taenia solium taeniasis antibodies (ES33-MICT) and neurocysticercosis antibodies (T24-MICT). These assays detected stage-specific antibodies by using two recombinant proteins, rES33 for detection of taeniasis antibodies and rT24H for detection of cysticercosis antibodies. The sensitivity and specificity of the ES33-MICT to detect taeniasis infections were 94.5% and 96%, respectively, and those of the T24-MICT to detect cases of human cysticercosis with two or more viable brain cysts were 93.9% and 98.9%, respectively. These data provide proof of principle that the ES33- and T24-MICTs provide rapid and suitable methods to identify individuals with taeniasis and cysticercosis.
PMCID: PMC2849338  PMID: 20181766
19.  Quantitative assessment of homograft function 1 year after insertion into the pulmonary position: impact of in situ homograft geometry on valve competence 
European Heart Journal  2009;30(17):2147-2154.
To prospectively evaluate homograft function with cardiac magnetic resonance (CMR) imaging 1 year after insertion into the pulmonary position, and to assess the impact of in situ homograft geometry, surgical factors, and ‘intrinsic’ homograft properties on early valve incompetence.
Methods and results
A total of 60 patients (mean age 21 ± 10 years; 35 females) with congenital heart disease underwent pulmonary valve replacement with homograft insertion and were prospectively enrolled into a study protocol that included serial echocardiography and CMR 1 year after surgery. None of the patients had homograft stenosis but 10 (17%) had significant homograft incompetence (i.e. pulmonary regurgitation fraction >20% on CMR). A higher incidence of ‘eccentric’ pulmonary forward flow pattern (P < 0.001, Fisher's exact test), more acute ‘homograft distortion angle’ (P < 0.001), larger relative ‘annular’ size (P < 0.01), and greater pre-homograft right ventricular outflow tract (RVOT) diameters (P = 0.01) at CMR was seen in those with worse homograft function. In a backward multivariate linear regression model, ‘eccentric’ pulmonary forward flow pattern (rpart = 0.36, P < 0.001), ‘homograft distortion angle’ (rpart = 0.31, P = 0.001), and pre-homograft RVOT diameter (rpart = 0.19, P = 0.03) were independently associated with the degree of pulmonary regurgitation (in %) at 1 year.
Using CMR, in this prospective cohort study, we have shown that significant valve incompetence is present in one-sixth of patients after homograft insertion into the pulmonary position, and that alterations in the in situ homograft geometry were associated with the likelihood of developing valve incompetence. These findings imply that mechanical factors may have an important impact on homograft performance.
PMCID: PMC2735727  PMID: 19502232
Congenital heart disease; Surgical pulmonary valve replacement; Conduit function; Magnetic resonance imaging
20.  Magnitude of the Disease Burden from Neurocysticercosis in a Developing Country 
Cysticercosis contributes to higher epilepsy rates in developing countries than in industrialized ones, yet no estimate exists for the associated burden of disease. We used epidemiological data on neurocysticercosis in Peru to calculate the burden of disease and applied our model to the other countries of Latin America where neurocysticercosis is endemic to determine a regional estimate. Analysis of 12 population-based community studies demonstrated that neurocysticercosis was endemic in highland areas and high jungles, with seroprevalences from 6% to 24%. In one community, the adult seizure disorder rate was 9.1% among seropositive persons versus 4.6% among seronegative persons; we used this difference for estimates. On the basis of average prevalence rates in areas of endemicity of 6%–10%, we estimated that there are 23,512–39,186 symptomatic neurocysticercosis cases in Peru. In Latin America, an estimated 75 million persons live in areas where cysticercosis is endemic, and ~400,000 have symptomatic disease. Cysticercosis contributes substantially to neurological disease in Peru and in all of Latin America.
PMCID: PMC2913118  PMID: 10524964
21.  Multiantigen Print Immunoassay for Comparison of Diagnostic Antigens for Taenia solium Cysticercosis and Taeniasis▿  
One of the best-characterized tests for the diagnosis of neurocysticercosis is the enzyme-linked immunoelectrotransfer blot assay, developed at the CDC, which uses lentil lectin-purified glycoproteins (LLGPs) extracted from Taenia solium cysticerci. The purification of the LLGP antigens has been difficult to standardize, and the polyacrylamide gel system used for the immunoblot assay is not easily transferable to other laboratories. In this study, we developed a multiantigen printing immunoassay (MAPIA) to compare the performance of multiple recombinant Taenia solium proteins with the potential for the detection of cysticercosis and taeniasis. We prepared MAPIA strips using six cysticercosis and two taeniasis diagnostic proteins and compared the performance of the proteins with sera collected from defined cysticercosis and taeniasis cases. Of the six cysticercosis antigens, rT24H performed well in detecting cases with two or more viable cysts in the brain (sensitivity and specificity, 97% and 99.4%, respectively); the use of a combination of cysticercosis antigens did not improve the sensitivity of the test and decreased the specificity. None of the antigens could differentiate the different clinical presentations of cysticercosis. Both of the taeniasis antigens (rES33 and rES38) had the same sensitivity of 99.4% and specificities of 93.9% and 94.5%, respectively. Some cross-reactivity against rES33 and rES38 was found, especially with sera from cases infected with Schistosoma mansoni. We conclude that MAPIA is a simple and effective tool that may be used to compare antibody responses to different cysticercosis and taeniasis antigens and, in this case, may be useful for the rapid detection of T. solium cases.
PMCID: PMC2812080  PMID: 19906893
22.  Epilepsy and Neurocysticercosis: An Incidence Study in a Peruvian Rural Population 
Neuroepidemiology  2009;33(1):25-31.
Epilepsy is a serious neurological disorder and neurocysticercosis (NCC), the central nervous system infection by the larvae of Taenia solium, is the main cause of acquired epilepsy in developing countries. NCC is becoming more frequent in industrialized countries due to immigration from endemic areas. Previously reported epilepsy incidences range from 30 to 50/100,000 people in industrialized countries and 90 to 122/100,000 people in developing countries.
To determine the incidence of epilepsy in a cysticercosis endemic area of Peru.
A screening survey for possible seizure cases was repeated biannually in this cohort for a period of 5 years (1999–2004) using a previously validated questionnaire. All positive respondents throughout the study were examined by a trained neurologist in the field to confirm the seizure. If confirmed, they were offered treatment, serological testing, neuroimaging (CT scans and MRI) and clinical follow-up.
The cohort study comprised 817 individuals. The overall epilepsy incidence rate was 162.3/100,000 person-years, and for epileptic seizures, 216.6/100,000 person-years. Out of the 8 individuals who had epileptic seizures, 4 had markers for NCC (neuroimaging and/or serology).
The incidence of epilepsy in this area endemic for cysticercosis is one of the highest reported worldwide.
PMCID: PMC2826439  PMID: 19325247
Epilepsy; Parasitic infection; Neurocysticercosis; Incidence study
23.  Late magnetic resonance surveillance of repaired coarctation of the aorta☆☆☆ 
Objective: Coarctation of the aorta has often been described as a simple form of congenital heart disease. However, rates of re-coarctation reported in the literature vary from 7% to 60%. Re-coarctation of the aorta may lead to worsening systemic hypertension, coronary artery disease and/or congestive cardiac failure. We aimed to describe the rates of re-coarctation in subjects who had undergone early coarctation repair (<2 years of age) and referred for clinically indicated or routine magnetic resonance (MR) surveillance. Methods: We retrospectively identified 50 consecutive subjects (20.2 ± 6.9 years post-repair) imaged between 2004 and 2008. Patient characteristics, rates of re-coarctation and LV/aortic dimensions were examined. Results: Forty percent of subjects had bicuspid aortic valves (BAV). There were 40 cases of end-to-end repair and 10 cases of subclavian flap repair. Re-intervention with balloon angioplasty or repeat surgery had been performed in 32% of subjects. The MRI referrals were clinically indicated in 34% and routine in 66% of patients. Re-coarctation was considered moderate or severe in 34%, mild in 34% and no re-coarctation was identified in 32% of patients. There was no significant difference in the number of cases of re-coarctation identified in the clinically indicated versus routine referrals for MR imaging (p = 0.20). There were no cases of aortic dissection or aneurysm formation identified amongst the subjects. The mean indexed left ventricular mass and ejection fraction was 72 ± 16 g/m2 and 66 ± 6%, respectively. Amongst those subjects with BAV there were larger aortic sinus (30 ± 1 mm vs 27 ± 1 mm, p = 0.03) and ascending aortic (27 ± 1 mm vs 23 ± 1 mm, p = 0.01) dimensions when compared to subjects with morphologically tricuspid aortic valves. Conclusions: We demonstrate that many years after early repair of coarctation of the aorta, MR surveillance detects significant rates of re-coarctation. These findings were independent of whether or not there was a clinical indication for imaging. Those patients with BAV disease had larger ascending aortic dimensions and may require more frequent non-invasive surveillance.
PMCID: PMC2706949  PMID: 19410477
Coarctation; Aorta; Surgery; Magnetic resonance imaging
24.  Effective transcatheter valve implantation after pulmonary homograft failure: A new perspective on the Ross operation 
The Ross procedure offers good autograft function and low reoperation rates for the neoaortic valve; however, the rate of conduit dysfunction in the right ventricular outflow tract remains a concern. This study assessed percutaneous pulmonary valve implantation in this setting.
We retrospectively analyzed outcomes of 12 patients (mean age 28 ± 5 years) referred for percutaneous pulmonary valve implantation to treat right ventricle–pulmonary artery conduit failure 11.1 ± 3.3 years after Ross procedure.
Percutaneous pulmonary valve implantation was feasible in all 12 patients, with no procedural complications (procedure time 99 ± 16 minutes, fluoroscopy time 21 ± 6 minutes). Right ventricular outflow tract gradient during catheterization and pulmonary regurgitant fraction on magnetic resonance imaging fell after valve implantation (gradient 34 ± 6 to 14 ± 3 mm Hg, P < .01, regurgitant fraction 20% ± 6% to 2% ± 1%, P < .05). After restoration of right ventricular outflow tract function, indexed right ventricular end-diastolic volume decreased (91 ± 13 to 78 ± 12 mL · beat−1 · m−2, P < .01) and maximal cardiopulmonary exercise performance improved (peak oxygen consumption 25.4 ± 2.3 to 30.8 ± 3.0 mL · kg−1 · min−1, P < .01). During follow-up (18.8 ± 4.6 months), there was 1 device explantation (restenosis). The probabilities of freedom from right ventricular outflow tract reoperation were 100% at 1 year and 90% at 3 years.
Percutaneous pulmonary valve implantation provides an effective transcatheter treatment strategy to prolong the lifespan of right ventricle–pulmonary artery conduits after the Ross procedure, reducing the reoperation burden on patients with aortic valve disease.
PMCID: PMC2741608  PMID: 19577061
CPEX, cardiopulmonary exercise; MRI, magnetic resonance imaging; PA, pulmonary artery; PPVI, percutaneous pulmonary valve implantation; RV, right ventricle; RVOT, right ventricular outflow tract
25.  Taenia solium Cysticercosis Hotspots Surrounding Tapeworm Carriers: Clustering on Human Seroprevalence but Not on Seizures 
Neurocysticercosis accounts for 30%–50% of all late-onset epilepsy in endemic countries. We assessed the clustering patterns of Taenia solium human cysticercosis seropositivity and seizures around tapeworm carriers in seven rural communities in Peru.
The presence of T. solium–specific antibodies was defined as one or more positive bands in the enzyme-linked immunoelectrotransfer blot (EITB). Neurocysticercosis-related seizures cases were diagnosed clinically and had positive neuroimaging or EITB.
Principal Findings
Eleven tapeworm carriers were identified by stool microscopy. The seroprevalence of human cysticercosis was 24% (196/803). Seroprevalence was 21% >50 m from a carrier and increased to 32% at 1–50 m (p = 0.047), and from that distance seroprevalence had another significant increase to 64% at the homes of carriers (p = 0.004). Seizure prevalence was 3.0% (25/837) but there were no differences between any pair of distance ranges (p = 0.629, Wald test 2 degrees of freedom).
We observed a significant human cysticercosis seroprevalence gradient surrounding current tapeworm carriers, although cysticercosis-related seizures did not cluster around carriers. Due to differences in the timing of the two outcomes, seroprevalence may reflect recent T. solium exposure more accurately than seizure frequency.
Author Summary
Cysticercosis is a parasitic disease caused by the tapeworm Taenia solium, common in areas with limited sanitation or with migration from these populations. The adult parasite is hosted in the human intestine and releases large numbers of eggs with the feces. Human beings sometimes ingest eggs due to poor hygiene, and then eggs sometimes lodge on the brain and after a few years can cause intense headaches and seizures. During a study in seven rural communities in Peru, individuals exposed to T. solium eggs were often tightly clustered at the homes or immediate surrounding of the carriers of the adult parasite. However, no aggregation of cases of seizures was found near carriers. It appears that seizures do not cluster around carriers because several years pass between exposure to T. solium eggs and the onset of seizures. During these years the adult parasite has probably died or people had moved within or even outside their communities. Therefore, only a partial understanding of the epidemiology of cysticercosis is gained by studying seizures cases.
PMCID: PMC2625436  PMID: 19172178

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