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1.  Placebo controlled trial of enteric coated pancreatin microsphere treatment in patients with unresectable cancer of the pancreatic head region 
Gut  1998;42(1):92-96.
Background—Impeded flow of pancreatic juice due to mechanical obstruction of the pancreatic duct in patients with cancer of the pancreatic head region causes exocrine pancreatic insufficiency with steatorrhoea and creatorrhoea. This may contribute to the profound weight loss that often occurs in these patients. 
Aims—To investigate whether pancreatic enzyme replacement therapy prevents this weight loss. 
Patients—Twenty one patients with unresectable cancer of the pancreatic head region with suspected pancreatic duct obstruction, a biliary endoprosthesis in situ, and a Karnofsky performance status greater than 60. 
Methods—Randomised double blind trial of eight weeks with either placebo or high dose enteric coated pancreatin enzyme supplementation. All patients received dietary counselling. 
Results—The mean difference in the percentage change of body weight was 4.9% (p=0.02, 95% confidence interval for the difference: 0.9 to 8.9). Patients on pancreatic enzymes gained 1.2% (0.7 kg) body weight whereas patients on placebo lost 3.7% (2.2 kg). The fat absorption coefficient in patients on pancreatic enzymes improved by 12% whereas in placebo patients it dropped by 8% (p=0.13, 95% confidence interval for the difference: -6 to 45). The daily total energy intake was 8.42 MJ in patients on pancreatic enzymes and 6.66 MJ in placebo patients (p=0.04, 95% confidence interval for the difference: 0.08 to 3.44). 
Conclusions—Weight loss in patients with unresectable cancer of the pancreatic head region and occlusion of the pancreatic duct can be prevented, at least for the period immediately after insertion of a biliary endoprosthesis, by high dose enteric coated pancreatin enzyme supplementation in combination with dietary counselling. 


Keywords: pancreatic cancer; weight loss; pancreatic enzyme therapy; enteric coated enzyme therapy; palliation; dietary counselling
PMCID: PMC1726970  PMID: 9505892
2.  Canine and Human Visual Cortex Intact and Responsive Despite Early Retinal Blindness from RPE65 Mutation 
PLoS Medicine  2007;4(6):e230.
Background
RPE65 is an essential molecule in the retinoid-visual cycle, and RPE65 gene mutations cause the congenital human blindness known as Leber congenital amaurosis (LCA). Somatic gene therapy delivered to the retina of blind dogs with an RPE65 mutation dramatically restores retinal physiology and has sparked international interest in human treatment trials for this incurable disease. An unanswered question is how the visual cortex responds after prolonged sensory deprivation from retinal dysfunction. We therefore studied the cortex of RPE65-mutant dogs before and after retinal gene therapy. Then, we inquired whether there is visual pathway integrity and responsivity in adult humans with LCA due to RPE65 mutations (RPE65-LCA).
Methods and Findings
RPE65-mutant dogs were studied with fMRI. Prior to therapy, retinal and subcortical responses to light were markedly diminished, and there were minimal cortical responses within the primary visual areas of the lateral gyrus (activation amplitude mean ± standard deviation [SD] = 0.07% ± 0.06% and volume = 1.3 ± 0.6 cm3). Following therapy, retinal and subcortical response restoration was accompanied by increased amplitude (0.18% ± 0.06%) and volume (8.2 ± 0.8 cm3) of activation within the lateral gyrus (p < 0.005 for both). Cortical recovery occurred rapidly (within a month of treatment) and was persistent (as long as 2.5 y after treatment). Recovery was present even when treatment was provided as late as 1–4 y of age. Human RPE65-LCA patients (ages 18–23 y) were studied with structural magnetic resonance imaging. Optic nerve diameter (3.2 ± 0.5 mm) was within the normal range (3.2 ± 0.3 mm), and occipital cortical white matter density as judged by voxel-based morphometry was slightly but significantly altered (1.3 SD below control average, p = 0.005). Functional magnetic resonance imaging in human RPE65-LCA patients revealed cortical responses with a markedly diminished activation volume (8.8 ± 1.2 cm3) compared to controls (29.7 ± 8.3 cm3, p < 0.001) when stimulated with lower intensity light. Unexpectedly, cortical response volume (41.2 ± 11.1 cm3) was comparable to normal (48.8 ± 3.1 cm3, p = 0.2) with higher intensity light stimulation.
Conclusions
Visual cortical responses dramatically improve after retinal gene therapy in the canine model of RPE65-LCA. Human RPE65-LCA patients have preserved visual pathway anatomy and detectable cortical activation despite limited visual experience. Taken together, the results support the potential for human visual benefit from retinal therapies currently being aimed at restoring vision to the congenitally blind with genetic retinal disease.
The study by Samuel Jacobson and colleagues suggests that retinal gene therapy can improve retinal, visual pathway, and visual cortex responses to light stimulation, even after prolonged periods of blindness and in congenitally blind patients.
Editors' Summary
Background.
The eye captures light but the brain is where vision is experienced. Treatments for childhood blindness at the eye level are ready, but it is unknown whether the brain will be receptive to an improved neural message. Normal vision begins as photoreceptor cells in the retina (the light-sensitive tissue lining the inside of the eye) convert visual images into electrical impulses. These impulses are sent along the optic nerve to the visual cortex, the brain region where they are interpreted. The conversion of light into electrical impulses requires the activation of a molecule called retinal, which is subsequently recycled by retinal pigment epithelium (RPE) cells neighboring the retina. One of the key enzymes of the recycling reactions is encoded by a gene called RPE65. Genetic changes (mutations) in RPE65 cause an inherited form of blindness called Leber congenital amaurosis (LCA). In this disease, retinal is not recycled and as a result, the photoreceptor cells cannot work properly and affected individuals have poor or nonexistent vision from birth. Previous studies in dog and mouse models of the human disease have demonstrated that the introduction of a functional copy of RPE65 into the RPE cells using a harmless virus (gene therapy) dramatically restores retinal activity. Very recently, a pioneering gene therapy operation took place in London (UK) where surgeons injected a functional copy of RPE65 into the retina of a man with LCA. Whether this operation results in improved vision is not known at this time.
Why Was This Study Done?
Gene therapy corrects the retinal defects in animal models of LCA but whether the visual pathway from the retina to the visual cortex of the brain can respond normally to the signals sent by the restored retina is not known. Early visual experience is thought to be necessary for the development of a functional visual cortex, so replacing the defective RPE65 gene might not improve the vision of people with LCA. In this study, the researchers have studied the visual cortex of RPE65-deficient dogs before and after gene therapy to see whether the therapy affects the activity of the visual cortex. They have also investigated visual pathway integrity and responsiveness in adults with LCA caused by RPE65 mutations. If the visual pathway is disrupted in these patients, they reasoned, gene therapy might not restore their vision.
What Did the Researchers Do and Find?
The researchers used a technique called functional magnetic resonance imaging (fMRI) to measure light-induced brain activity in RPE65-deficient dogs before and after gene therapy. They also examined the reactions of the dogs' pupils to light (in LCA, the pupils do not contract normally in response to light because there is reduced signal transmission along the visual pathway). Finally, they measured the electrical activity of the dogs' retinas in response to light flashes—the retinas of patients with LCA do not react to light. Gene therapy corrected the defective retinal and visual pathway responses to light in the RPE65-deficient dogs and, whereas before treatment there was no response in the visual cortex to light stimulation in these dogs, after treatment, its activity approached that seen in normal dogs. The recovery of cortical responses was permanent and occurred soon after treatment, even in animals that were 4 years old when treated. Next, using structural MRI, the researchers studied human patients with LCA and found that the optic nerve diameter in young adults was within the normal range and that the structure of the visual cortex was very similar to that of normal individuals. Finally, using fMRI, they found that, although the visual cortex of patients with LCA did not respond to dim light, its reaction to bright light was comparable to that of normal individuals.
What Do These Findings Mean?
The findings from the dog study indicate that retinal gene therapy rapidly improves retinal, visual pathway, and visual cortex responses to light stimulation, even in animals that have been blind for years. In other words, in the dog model of LCA at least, all the components of the visual system remain receptive to visual inputs even after long periods of visual deprivation. The findings from the human study also indicate that the visual pathway remains anatomically intact despite years of disuse and that the visual cortex can be activated in patients with LCA even though these people have very limited visual experience. Taken together, these findings suggest that successful gene therapy of the retina might restore some functional vision to people with LCA but proof will have to await the outcomes of several clinical trials ongoing or being planned in Europe and the USA.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040230.
General information on gene therapy is available from the Oak Ridge National Laboratory
Information is provided by the BBC about gene therapy for Leber congenital amaurosis (includes an audio clip from a doctor about the operation)
The National Institutes of Health/National Eye Institute (US) provides information about an ongoing gene therapy trial of RPE65-Leber congenital amaurosis
ClinicalTrials.gov gives details on treatment trials for Leber congenital amaurosis
The Foundation Fighting Blindness has a fact sheet on Leber congenital amaurosis (site includes Microsoft Webspeak links that read some content aloud)
The Foundation for Retinal Research has a fact sheet on Leber congenital amaurosis
Find more detailed information on Leber congenital amaurosis and the gene mutations that cause it from GeneReviews
WonderBaby, information for parents of babies with Leber congenital amaurosis
doi:10.1371/journal.pmed.0040230
PMCID: PMC1896221  PMID: 17594175
3.  Randomised clinical trial: a 1-week, double-blind, placebo-controlled study of pancreatin 25 000 Ph. Eur. minimicrospheres (Creon 25000 MMS) for pancreatic exocrine insufficiency after pancreatic surgery, with a 1-year open-label extension 
Background
Pancreatic exocrine insufficiency (PEI) often occurs following pancreatic surgery.
Aim
To demonstrate the superior efficacy of pancreatin 25 000 minimicrospheres (Creon 25000 MMS; 9–15 capsules/day) over placebo in treating PEI after pancreatic resection.
Methods
A 1-week, double-blind, randomised, placebo-controlled, parallel-group, multicentre study with a 1-year, open-label extension (OLE). Subjects ≥18 years old with PEI after pancreatic resection, defined as baseline coefficient of fat absorption (CFA) <80%, were randomised to oral pancreatin or placebo (9–15 capsules/day: 3 with main meals, 2 with snacks). In the OLE, all subjects received pancreatin. The primary efficacy measure was least squares mean CFA change from baseline to end of double-blind treatment (ancova).
Results
All 58 subjects randomised (32 pancreatin, 26 placebo) completed double-blind treatment and entered the OLE; 51 completed the OLE. The least squares mean CFA change in the double-blind phase was significantly greater with pancreatin vs. placebo: 21.4% (95% CI: 13.7, 29.2) vs. −4.2% (−12.8, 4.5); difference 25.6% (13.9, 37.3), P < 0.001. The mean ± s.d. CFA increased from 53.6 ± 20.6% at baseline to 78.4 ± 20.7% at OLE end (P < 0.001). Treatment-emergent adverse events occurred in 37.5% subjects on pancreatin and 26.9% on placebo during double-blind treatment, with flatulence being the most common (pancreatin 12.5%, placebo 7.7%). Only two subjects discontinued due to treatment-emergent adverse events, both during the OLE.
Conclusions
This study demonstrates superior efficacy of pancreatin 25 000 over placebo in patients with PEI after pancreatic surgery, measured by change in CFA. Pancreatin was generally well tolerated at the high dose administered (EudraCT registration number: 2005-004854-29).
doi:10.1111/apt.12236
PMCID: PMC3601428  PMID: 23383603
4.  Stability of 3-bromotyrosine in serum and serum 3-bromotyrosine concentrations in dogs with gastrointestinal diseases 
Background
3-Bromotyrosine (3-BrY) is a stable product of eosinophil peroxidase and may serve as a marker of eosinophil activation. A gas chromatography/mass spectrometry method to measure 3-BrY concentrations in serum from dogs has recently been established and analytically validated. The aims of this study were to determine the stability of 3-BrY in serum, to determine the association between peripheral eosinophil counts and the presence of an eosinophilic infiltrate in the gastrointestinal tract, and to compare serum 3-BrY concentrations in healthy dogs (n = 52) and dogs with eosinophilic gastroenteritis (EGE; n = 27), lymphocytic-plasmacytic enteritis (LPE; n = 25), exocrine pancreatic insufficiency (EPI; n = 26), or pancreatitis (n = 27).
Results
Serum 3-BrY concentrations were stable for up to 8, 30, and 180 days at 4°C, −20°C, and −80°C, respectively. There was no significant association between peripheral eosinophil count and the presence of eosinophils in the GI tissues (P = 0.1733). Serum 3-BrY concentrations were significantly higher in dogs with EGE (median [range] = 5.04 [≤0.63-26.26] μmol/L), LPE (median [range] = 3.60 [≤0.63-15.67] μmol/L), and pancreatitis (median [range] = 1.49 [≤0.63-4.46] μmol/L) than in healthy control dogs (median [range] = ≤0.63 [≤0.63-1.79] μmol/L; P < 0.0001), whereas concentrations in dogs with EPI (median [range] = 0.73 [≤0.63-4.59] μmol/L) were not different compared to healthy control dogs.
Conclusions
The present study revealed that 3-BrY concentrations were stable in serum when refrigerated and frozen. No relationship between peripheral eosinophil count and the presence of eosinophils infiltration in the GI tissues was found in this study. In addition, serum 3-BrY concentrations were increased in dogs with EGE, but also in dogs with LPE and pancreatitis. Further studies are needed to determine whether measurement of 3-BrY concentrations in serum may be useful to assess patients with suspected or confirmed EGE or LPE.
doi:10.1186/s12917-015-0321-0
PMCID: PMC4299803  PMID: 25595676
3-bromotyrosine; Canine; Eosinophilic gastroenteritis; Stability
5.  Faecal elastase 1: not helpful in diagnosing chronic pancreatitis associated with mild to moderate exocrine pancreatic insufficiency 
Gut  1998;42(4):551-554.
Background/Aim—The suggestion that estimation of faecal elastase 1 is a valuable new tubeless pancreatic function test was evaluated by comparing it with faecal chymotrypsin estimation in patients categorised according to grades of exocrine pancreatic insufficiency (EPI) based on the gold standard tests, the secretin-pancreozymin test (SPT) and faecal fat analysis. 
Methods—In 64 patients in whom EPI was suspected, the following tests were performed: SPT, faecal fat analysis, faecal chymotrypsin estimation, faecal elastase 1 estimation. EPI was graded according to the results of the SPT and faecal fat analysis as absent, mild, moderate, or severe. The upper limit of normal for faecal elastase 1 was taken as 200 µg/g, and for faecal chymotrypsin 3 U/g stool. Levels between 3 and 6 U/g stool for faecal chymotrypsin are usually considered to be suspicious for EPI. In this study, both 3 and 6 U/g stool were evaluated as the upper limit of normal. 
Results—Exocrine pancreatic function was normal in 34 patients, of whom 94, 91, and 79% had normal faecal elastase 1 and faecal chymotrypsin levels (<3 U/g and <6 U/g) respectively. Thirty patients had EPI, of whom 53, 37, and 57% had abnormal faecal enzyme levels (differences not significant). When EPI was graded as mild, moderate, or severe, 63% of patients had mild to moderate EPI, and 37% had severe EPI. In the latter group, between 73 and 91% of patients had abnormal faecal enzymes. In the group with mild to moderate EPI, abnormal test results were obtained for both faecal enzymes in less than 50% of the patients (differences not significant). Some 40% of the patients had pancreatic calcifications. There were no significant differences for either faecal enzyme between the two groups with and without pancreatic calcifications. In 62% of the patients who underwent an endoscopic retrograde cholangiopancreatography (ERCP), abnormal duct changes were found. Again, there were no significant differences for either faecal enzyme between the two groups with abnormal and normal ERCP. 
Conclusion—Estimation of faecal elastase 1 is not distinctly superior to the traditional faecal chymotrypsin estimation. The former is particularly helpful only in detecting severe EPI, but not the mild to moderate form, which poses the more frequent and difficult clinical problem and does not correlate significantly with the severe morphological changes seen in chronic pancreatitis. 


Keywords: faecal elastase 1; faecal chymotrypsin; secretin-pancreozymin test; faecal fat analysis; exocrine pancreatic insufficiency; diagnosis
PMCID: PMC1727065  PMID: 9616319
6.  13Carbon mixed triglyceride breath test and pancreatic enzyme supplementation in cystic fibrosis 
Archives of Disease in Childhood  1997;76(4):349-351.
Accepted 5 November 1996

Children with cystic fibrosis have variable degrees of exocrine pancreatic insufficiency which, if untreated, is the main cause of fat malabsorption. The impact of pancreatic enzyme supplementation on fat digestion was measured in 41 children with cystic fibrosis, 11 healthy controls, and five children with mucosal diseases by a non-invasive test of intraluminal lipolysis using 13carbon (13C) labelled mixed triglyceride (1,3-distearyl, 2[13C] octanoyl glycerol). The children with cystic fibrosis without pancreatic supplements had a median (range) 13C cumulative percentage dose recovered over six hours (cPDR) of 3.1% (0-31.7), the controls 31.0% (21.8-41.1), and the subjects with mucosal disease 27.8% (19.7-32.5). In 23 subjects with cystic fibrosis the usual dose of pancreatic enzyme supplements increased the cPDR to a median of 23.9% (0-45.6), and twice the usual dose of enteric coated microspheres increased the cPDR to 31.1% (11.1-47.8). There was no significant difference between the median cPDR of normal controls and children with mucosal disease, but there was a highly significant difference between these groups and children with untreated cystic fibrosis. Thirteen children with cystic fibrosis had no 13C recovery in their breath without enzymes and 10 showed marked increases with regular enzymes. In eight children doubling the dose of enzymes caused no or minimal improvement. The mixed triglyceride breath test offers a simple, non-invasive way of assessing the need for pancreatic enzyme supplementation in children with cystic fibrosis and could be used to optimise treatment.


PMCID: PMC1717143  PMID: 9166030
7.  Enteric coated microspheres of pancreatin in the treatment of cystic fibrosis: comparison with a standard enteric coated preparation. 
Thorax  1987;42(7):533-537.
In an open, randomised crossover study enteric coated microspheres of pancreatin were compared with a standard preparation of enteric coated pancreatin over two consecutive 28 day treatment periods in 23 adults with steatorrhoea due to cystic fibrosis. Lipase intake was equal to the patients' previous requirements and was the same during the two months. Patients performed 72 hour faecal collections at the end of each month and completed diary cards daily throughout. Comparison of the month of treatment with enteric coated microspheres with the month of standard enteric coated tablets showed a significant increase in body weight on microsphere capsules (p less than 0.02). There was also a reduced frequency of bowel actions (p less than 0.001) and abdominal pain (p less than 0.05), and improvement in stool character (p less than 0.001) on microsphere capsules. Faecal fat excretion was reduced by 44% with the microsphere capsules (p less than 0.01), and 86% of patients showed an increased coefficient of fat absorption (mean increase 13%, 95% confidence limits 6.5-19.1%; p less than 0.001). Eighty one per cent of patients preferred microsphere capsules of the two treatments. Thus enteric coated microsphere capsules are more effective in treating steatorrhoea in cystic fibrosis than standard enteric coated tablets.
PMCID: PMC460823  PMID: 3326213
8.  Efficacy and safety of a unique enteric-coated bicarbonate-buffered pancreatic enzyme replacement therapy in children and adults with cystic fibrosis 
Clinical investigation  2013;3(8):723-729.
Background
Pancreatic enzyme replacement therapy (PERT) is used to treat exocrine pancreatic insufficiency in cystic fibrosis.
Results/Methods
Efficacy and safety of a unique enteric-coated (EC) bicarbonate-buffered PERT product (PERTZYE®/PANCRECARB®; Digestive Care, Inc., Bethlehem, PA, USA) was studied in a randomized, double-blind, placebo-controlled cross-over design. Subjects were stabilized on EC-bicarbonate-buffered PERT and a high-fat diet. During two treatment periods, subjects were randomized to EC-bicarbonate-buffered PERT or placebo, followed by a 72-h stool collection employing an ingested stool dye marker. Mean coefficient of fat absorption with EC-bicarbonate-buffered PERT was 82.5% compared with 46.3% with the placebo (absolute difference 36.2%; p < 0.001), a 78.2% improvement for active over placebo. Similar improvements in nitrogen absorption were observed. Overall stool frequency and stool weight decreased (p < 0.001). No safety concerns were identified.
Summary
EC-bicarbonate-buffered PERT is effective in treating cystic fibrosis-associated exocrine pancreatic insufficiency.
doi:10.4155/cli.13.62
PMCID: PMC4157687  PMID: 25210613
bicarbonate-buffered pancrelipase; coefficient of fat absorption; cystic fibrosis; exocrine pancreatic insufficiency; pancreatic enzyme replacement therapy
9.  Screening and risk factors of exocrine pancreatic insufficiency in critically ill adult patients receiving enteral nutrition 
Critical Care  2013;17(4):R171.
Introduction
Malnutrition is a frequent problem associated with detrimental clinical outcomes in critically ill patients. To avoid malnutrition, most studies focus on the prevention of inadequate nutrition delivery, whereas little attention is paid to the potential role of exocrine pancreatic insufficiency (EPI). In this trial, we aim to evaluate the prevalence of EPI and identify its potential risk factors in critically ill adult patients without preexisting pancreatic diseases.
Methods
In this prospective cross-sectional study, we recruited 563 adult patients with critical illnesses. All details of the patients were documented, stool samples were collected three to five days following the initiation of enteral nutrition, and faecal elastase 1 (FE-1) concentrations were assayed using an enzyme-linked immunosorbent assay kit. Blood samples were also taken to determine serum amylase and lipase activity.
Results
The percentages of recruited patients with EPI (FE-1 concentration <200 μg/g) and severe EPI (FE-1 concentration <100 μg/g) were 52.2% and 18.3%, respectively. The incidences of steatorrhea were significantly different (P < 0.05) among the patients without EPI, with moderate EPI (FE-1 concentration = 100 to 200 μg/g) and severe EPI (FE-1 concentration < 100 μg/g). Both multivariate logistic regression analysis and z-tests indicated that the occurrence of EPI was closely associated with shock, sepsis, diabetes, cardiac arrest, hyperlactacidemia, invasive mechanical ventilation and haemodialysis.
Conclusions
More than 50% of critically ill adult patients without primary pancreatic diseases had EPI, and nearly one-fifth of them had severe EPI. The risk factors for EPI included shock, sepsis, diabetes, cardiac arrest, hyperlactacidemia, invasive mechanical ventilation and haemodialysis.
Trial registration
NCT01753024
doi:10.1186/cc12850
PMCID: PMC4057406  PMID: 23924602
10.  Effect of analgesic therapy on clinical outcome measures in a randomized controlled trial using client-owned dogs with hip osteoarthritis 
Background
Pain and impaired mobility because of osteoarthritis (OA) is common in dogs and humans. Efficacy studies of analgesic drug treatment of dogs with naturally occurring OA may be challenging, as a caregiver placebo effect is typically evident. However, little is known about effect sizes of common outcome-measures in canine clinical trials evaluating treatment of OA pain. Forty-nine client-owned dogs with hip OA were enrolled in a randomized, double-blinded placebo-controlled prospective trial. After a 1 week baseline period, dogs were randomly assigned to a treatment (ABT-116 – transient receptor potential vanilloid 1 (TRPV1) antagonist, Carprofen – non-steroidal anti-inflammatory drug (NSAID), Tramadol - synthetic opiate, or Placebo) for 2 weeks. Outcome-measures included physical examination parameters, owner questionnaire, activity monitoring, gait analysis, and use of rescue medication.
Results
Acute hyperthermia developed after ABT-116 treatment (P < 0.001). Treatment with carprofen (P ≤ 0.01) and tramadol (P ≤ 0.001) led to improved mobility assessed by owner questionnaire. Nighttime activity was increased after ABT-116 treatment (P = 0.01). Kinetic gait analysis did not reveal significant treatment effects. Use of rescue treatment decreased with treatment in the ABT-116 and Carprofen groups (P < 0.001). Questionnaire score and activity count at the end of treatment were correlated with age, clinical severity at trial entry, and outcome measure baseline status (SR ≥ ±0.40, P ≤ 0.005). Placebo treatment effects were evident with all variables studied.
Conclusion
Treatment of hip OA in client-owned dogs is associated with a placebo effect for all variables that are commonly used for efficacy studies of analgesic drugs. This likely reflects caregiver bias or the phenomenon of regression to the mean. In the present study, outcome measures with significant effects also varied between groups, highlighting the value of using multiple outcome measures, as well as an a priori analysis of effect size associated with each measure. Effect size data from the present study could be used to inform design of future trials studying analgesic treatment of canine OA. Our results suggest that analgesic treatment with ABT-116 is not as effective as carprofen or tramadol for treatment of hip arthritis pain in client-owned dogs.
doi:10.1186/1746-6148-8-185
PMCID: PMC3527270  PMID: 23035739
Dog; Hip; Osteoarthritis; Outcome measures; Clinical trial; Carprofen; Tramadol; ABT-116
11.  Fate of oral enzymes in pancreatic insufficiency. 
Gut  1993;34(5):708-712.
Oral pancreatic enzyme supplements, including those protected from gastric acidity by enteric coating, often achieve only partial correction of pancreatic steatorrhoea. To characterise the mechanisms involved in vivo, eight patients with steatorrhoea due to advanced pancreatic insufficiency and nine healthy controls were studied. Two sets of studies (small bowel intubation and five day faecal fat quantification) were randomly performed while patients were either on enteric coated pancreatin or equivalent placebo. A 260 cm long multilumen tube was used for double marker perfusion of two 20 cm segments located in the duodenum and in the ileum respectively. Luminal pH, flow, and trypsin and lipase activity outputs were measured at each segment for four hours postcibally. Placebo treated patients with pancreatic steatorrhoea had low enzyme outputs in the duodenal test segment and even lower outputs in the ileal segment. Pancreatin treatment significantly decreased steatorrhoea (p < 0.05) and increased luminal enzyme outputs (p < 0.05). The increase was much greater in the ileal than in the duodenal segment. Thus enteric coated pancreatin treatment abolished the normal gradient between postcibal duodenal and ileal lipase output. The results suggest that enteric coated pancreatin nearly corrects severe pancreatic steatorrhoea. The ingested lipase was utilised inefficiently, however, as luminal enzyme activity in the ileum was enhanced to a greater extent than in the duodenum, and consequently the absorptive potential of the small bowel was only partially utilised.
PMCID: PMC1374195  PMID: 8504976
12.  Prevalence of congenital hereditary sensorineural deafness in Australian Cattle Dogs and associations with coat characteristics and sex 
Background
Congenital hereditary sensorineural deafness (CHSD) occurs in many dog breeds, including Australian Cattle Dogs. In some breeds, CHSD is associated with a lack of cochlear melanocytes in the stria vascularis, certain coat characteristics, and potentially, abnormalities in neuroepithelial pigment production. This study investigates phenotypic markers for CHSD in 899 Australian Cattle Dogs.
Results
Auditory function was tested in 899 Australian Cattle Dogs in family groups using brainstem auditory evoked response testing. Coat colour and patterns, facial and body markings, gender and parental hearing status were recorded.
Deafness prevalence among all 899 dogs was 10.8% with 7.5% unilaterally deaf, and 3.3% bilaterally deaf, and amongst pups from completely tested litters (n = 696) was 11.1%, with 7.5% unilaterally deaf, and 3.6% bilaterally deaf.
Univariable and multivariable analyses revealed a negative association between deafness and bilateral facial masks (odds ratio 0.2; P ≤ 0.001). Using multivariable logistic animal modelling, the risk of deafness was lower in dogs with pigmented body spots (odds ratio 0.4; P = 0.050).
No significant associations were found between deafness and coat colour.
Within unilaterally deaf dogs with unilateral facial masks, no association was observed between the side of deafness and side of mask. The side of unilateral deafness was not significantly clustered amongst unilaterally deaf dogs from the same litter. Females were at increased risk of deafness (odds ratio from a logistic animal model 1.9; P = 0.034) after adjusting for any confounding by mask type and pigmented body spots.
Conclusions
Australian Cattle Dogs suffer from CHSD, and this disease is more common in dogs with mask-free faces, and in those without pigmented body patches. In unilaterally deaf dogs with unilateral masks, the lack of observed association between side of deafness and side of mask suggests that if CHSD is due to defects in molecular pigment pathways, the molecular control of embryonic melanoblast migration from ectoderm to skin differs from control of migration from ectoderm to cochlea. In Australian Cattle Dogs, CHSD may be more common in females.
doi:10.1186/1746-6148-8-202
PMCID: PMC3489614  PMID: 23107143
13.  Delayed release pancrelipase for treatment of pancreatic exocrine insufficiency associated with chronic pancreatitis 
Pancreatic enzyme supplements (PES) are used in chronic pancreatitis (CP) for correction of pancreatic exocrine insufficiency (PEI) as well as pain and malnutrition. The use of porcine pancreatic enzymes for the correction of exocrine insufficiency is governed by the pathophysiology of the disease as well as pharmacologic properties of PES. Variability in bioequivalence of PES has been noted on in vitro and in vivo testing and has been attributed to the differences in enteric coating and the degree of micro-encapsulation. As a step towards standardizing pancreatic enzyme preparations, the Food and Drug Administration now requires the manufacturers of PES to obtain approval of marketed formulations by April 2010. In patients with treatment failure, apart from evaluating drug and dietary interactions and compliance, physicians should keep in mind that patients may benefit from switching to a different formulation. The choice of PES (enteric coated versus non-enteric coated) and the need for acid suppression should be individualized. There is no current standard test for evaluating adequacy of therapy in CP patients and studies have shown that optimization of therapy based on symptoms may be inadequate. Goals of therapy based on overall patient presentation and specific laboratory tests rather than mere correction of steatorrhea are needed.
PMCID: PMC2710383  PMID: 19707261
pancreatic exocrine insufficiency; chronic pancreatitis; pancreatic enzyme supplement
14.  IMPAIRED SMALL BOWEL BARRIER INTEGRITY IN THE PRESENCE OF LUMENAL PANCREATIC DIGESTIVE ENZYMES LEADS TO CIRCULATORY SHOCK 
Shock (Augusta, Ga.)  2012;38(3):262-267.
In bowel ischemia, impaired mucosal integrity may allow intestinal pancreatic enzyme products to become systemic and precipitate irreversible shock and death. This can be attenuated by pancreatic enzyme inhibition in the small bowel lumen. It is unresolved, however, whether ischemically-mediated mucosal disruption is the key event allowing pancreatic enzyme products systemic access, and whether intestinal digestive enzyme activity in concert with increased mucosal permeability leads to shock in the absence of ischemia. To test this possibility, the small intestinal lumen of non-ischemic rats was perfused for two hours with either digestive enzymes, a mucin disruption strategy (i.e., mucolytics) designed to increase mucosal permeability, or both, and animals were observed for shock. Digestive enzymes perfused included trypsin, chymotrypsin, elastase, amylase and lipase. Control (n=6) and experimental animals perfused with pancreatic enzymes only (n=6) or single enzymes (n=3 for each of the five enzyme groups) maintained stable hemodynamics. After mucin disruption using a combination of enteral N-acetylcysteine, atropine, and increased flow rates, rats (n=6) developed mild hypotension (p<0.001 compared to groups perfused with pancreatic enzymes only after 90 minutes) and increased intestinal permeability to intralumenally perfused FITC-dextrans-20kD (p<0.05) compared to control and enzyme-only groups, but there were no deaths. All animals perfused with both digestive enzymes and subjected to mucin disruption (n=6) developed hypotension and increased intestinal permeability (p<0.001 after 90 minutes). Pancreatic enzymes were measured in the intestinal wall of both groups subjected to mucin disruption, but not in the enzyme-only or control groups. Depletion of plasma protease inhibitors was found only in animals perfused with pancreatic enzymes plus mucin disruption, implicating increased permeability and intralumenal pancreatic enzyme egress in this group. These experiments demonstrate that increased bowel permeability via mucin disruption in the presence of pancreatic enzymes can induce shock and increase systemic protease activation in the absence of ischemia, implicating bowel mucin disruption as a key event in early ischemia. Digestive enzymes and their products, if allowed to penetrate the gut wall may trigger multiorgan failure and death.
doi:10.1097/SHK.0b013e31825b1717
PMCID: PMC3422435  PMID: 22576000
Autodigestion; small intestine permeability; pancreatic enzymes; inflammatory mediators
15.  Comparison of Microbiological, Histological, and Immunomodulatory Parameters in Response to Treatment with Either Combination Therapy with Prednisone and Metronidazole or Probiotic VSL#3 Strains in Dogs with Idiopathic Inflammatory Bowel Disease 
PLoS ONE  2014;9(4):e94699.
Background
Idiopathic inflammatory bowel disease (IBD) is a common chronic enteropathy in dogs. There are no published studies regarding the use of probiotics in the treatment of canine IBD. The objectives were to compare responses to treatment with either combination therapy (prednisone and metronidazole) or probiotic strains (VSL#3) in dogs with IBD.
Methodology and Principal Findings
Twenty pet dogs with a diagnosis of IBD, ten healthy pet dogs, and archived control intestinal tissues from three euthanized dogs were used in this open label study. Dogs with IBD were randomized to receive either probiotic (D-VSL#3, n = 10) or combination drug therapy (D-CT, n = 10). Dogs were monitored for 60 days (during treatment) and re-evaluated 30 days after completing treatment. The CIBDAI (P<0.001), duodenal histology scores (P<0.001), and CD3+ cells decreased post-treatment in both treatment groups. FoxP3+ cells (p<0.002) increased in the D-VSL#3 group after treatment but not in the D-CT group. TGF-β+ cells increased in both groups after treatment (P = 0.0043) with the magnitude of this increase being significantly greater for dogs in the D-VSL#3 group compared to the D-CT group. Changes in apical junction complex molecules occludin and claudin-2 differed depending on treatment. Faecalibacterium and Turicibacter were significantly decreased in dogs with IBD at T0, with a significant increase in Faecalibacterium abundance observed in the animals treated with VSL#3 strains.
Conclusions
A protective effect of VSL#3 strains was observed in dogs with IBD, with a significant decrease in clinical and histological scores and a decrease in CD3+ T-cell infiltration. Protection was associated with an enhancement of regulatory T-cell markers (FoxP3+ and TGF-β+), specifically observed in the probiotic-treated group and not in animals receiving combination therapy. A normalization of dysbiosis after long-term therapy was observed in the probiotic group. Larger scale studies are warranted to evaluate the clinical efficacy of VSL#3 in canine IBD.
doi:10.1371/journal.pone.0094699
PMCID: PMC3983225  PMID: 24722235
16.  Effect of intravenous GLutamine supplementation IN Trauma patients receiving enteral nutrition study protocol (GLINT Study): a prospective, blinded, randomised, placebo-controlled clinical trial 
BMJ Open  2011;1(2):e000334.
Background
Trauma patients are characterised by alterations in the immune system, increased exposure to infectious complications, sepsis and potentially organ failure and death. Glutamine supplementation to parenteral nutrition has been proven to be associated with improved clinical outcomes. However, glutamine supplementation in patients receiving enteral nutrition and its best route are still controversial. Previous trials have been limited by a small sample size, use of surrogate outcomes or a limited period of supplementation. The aim of this trial is to investigate if intravenous glutamine supplementation to trauma patients receiving enteral nutrition is associated with improved clinical outcomes in terms of decreased organ dysfunction, infectious complications and other secondary outcomes.
Methods/design
Eighty-eight critically ill patients with multiple trauma receiving enteral nutrition will be recruited in this prospective, triple-blind, block-randomised, placebo-controlled clinical trial to receive either 0.5 g/kg/day intravenous undiluted alanyl-glutamine or intravenous placebo by continuous infusion (24 h/day). Both groups will be receiving the same standard enteral nutrition protocol and the same standard intensive care unit care. Supplementation will continue until discharge from the intensive care unit, death or a maximum duration of 3 weeks. The primary outcome will be organ-dysfunction evaluation assessed by the pattern of change in sequential organ failure assessment score over a 10-day period. The secondary outcomes are: the changes in total sequential organ failure assessment score on the last day of treatment, infectious complications during the ICU stay, 60-day mortality, length of stay in the intensive care unit and body-composition analysis.
Discussion
This study is the first trial to investigate the effect of intravenous alanyl-glutamine supplementation in multiple trauma patients receiving enteral nutrition on reducing severity of organ failure and infectious complications and preservation of lean body mass.
Trial registration number
This trial is registered at http://www.clinicaltrials.gov. NCT01240291.
Article summary
Article focus
Glutamine supplementation has demonstrated improved clinical outcomes in patients receiving parenteral nutrition. However, its effect and the best route of administration remain inconclusive for patients receiving enteral nutrition.
Previous trials for patients receiving enteral nutrition had a number of limitations.
Key messages
This proposed research with other worldwide trials will have implications in improving the practice of glutamine supplementation in critically ill patients.
The results of this trial will provide pilot data for a large multicentre trial to investigate the effect of intravenous glutamine supplementation in multiple trauma patients receiving enteral nutrition on infectious complications and mortality.
Strengths and limitations of this study
This is the first trial to investigate the effect of intravenous glutamine supplementation in trauma patients receiving enteral nutrition on organ failure, infectious complications and body composition.
Supplementation is continued as long as the patient is in the intensive care unit or to a maximum duration of 21 days.
This is a single-centre trial, so it is not powered to investigate the effect of intravenous alanyl-glutamine supplementation on mortality.
Data will not be applicable to trauma patients with severe renal failure or hepatic impairment.
The long-term outcomes (eg, 6-month mortality) are not assessed.
doi:10.1136/bmjopen-2011-000334
PMCID: PMC3221292  PMID: 22102646
17.  Diagnosis and treatment of pancreatic exocrine insufficiency 
Pancreatic exocrine insufficiency is an important cause of maldigestion and a major complication in chronic pancreatitis. Normal digestion requires adequate stimulation of pancreatic secretion, sufficient production of digestive enzymes by pancreatic acinar cells, a pancreatic duct system without significant outflow obstruction and adequate mixing of the pancreatic juice with ingested food. Failure in any of these steps may result in pancreatic exocrine insufficiency, which leads to steatorrhea, weight loss and malnutrition-related complications, such as osteoporosis. Methods evaluating digestion, such as fecal fat quantification and the 13C-mixed triglycerides test, are the most accurate tests for pancreatic exocrine insufficiency, but the probability of the diagnosis can also be estimated based on symptoms, signs of malnutrition in blood tests, fecal elastase 1 levels and signs of morphologically severe chronic pancreatitis on imaging. Treatment for pancreatic exocrine insufficiency includes support to stop smoking and alcohol consumption, dietary consultation, enzyme replacement therapy and a structured follow-up of nutritional status and the effect of treatment. Pancreatic enzyme replacement therapy is administered in the form of enteric-coated minimicrospheres during meals. The dose should be in proportion to the fat content of the meal, usually 40-50000 lipase units per main meal, and half the dose is required for a snack. In cases that do not respond to initial treatment, the doses can be doubled, and proton inhibitors can be added to the treatment. This review focuses on current concepts of the diagnosis and treatment of pancreatic exocrine insufficiency.
doi:10.3748/wjg.v19.i42.7258
PMCID: PMC3831207  PMID: 24259956
Chronic pancreatitis; Pancreatic exocrine insufficiency; Pancreatic enzyme replacement therapy
18.  Monitoring enzyme replacement treatment in exocrine pancreatic insufficiency using the cholesteryl octanoate breath test. 
Gut  1990;31(11):1324-1328.
The cholesteryl-14C-octanoate breath test was used to monitor the intraluminal enzymatic activity of pancreatin preparations in six patients with severe pancreatic insufficiency. Conventional enzyme replacement, with cimetidine as an adjunct, was compared to supplementation with enteric coated microspheres. In healthy control subjects, 14CO2 excretion rose rapidly and peaked at 90-120 minutes; mean (SD) cumulative recovery at four hours was 51 (8)%. In patients with pancreatic insufficiency on no treatment mean (SD) cumulative recovery was only 6 (4)%. After pancreatin, with previous administration of cimetidine, it increased to 27 (11)% with a time course resembling that in controls. With 2 mm enteric coated microspheres, 14CO2 excretion did not rise significantly before 120 minutes and cumulative recovery after four hours was 15 (11)%. In a control study, 2 mm radio-opaque microspheres did not empty from the stomach until two hours after ingestion. The results suggest that the cholesteryl octanoate breath test can be successfully used to monitor the intraluminal enzymatic activity after treatment with different forms of enzyme replacement in pancreatic insufficiency. In contrast to treatment with conventional pancreatin and cimetidine as an adjunct, 2 mm enteric coated microspheres did not show in vivo enzymatic activity until two hours after administration.
PMCID: PMC1378708  PMID: 2253920
19.  Greater Response to Placebo in Children Than in Adults: A Systematic Review and Meta-Analysis in Drug-Resistant Partial Epilepsy 
PLoS Medicine  2008;5(8):e166.
Background
Despite guidelines establishing the need to perform comprehensive paediatric drug development programs, pivotal trials in children with epilepsy have been completed mostly in Phase IV as a postapproval replication of adult data. However, it has been shown that the treatment response in children can differ from that in adults. It has not been investigated whether differences in drug effect between adults and children might occur in the treatment of drug-resistant partial epilepsy, although such differences may have a substantial impact on the design and results of paediatric randomised controlled trials (RCTs).
Methods and Findings
Three electronic databases were searched for RCTs investigating any antiepileptic drug (AED) in the add-on treatment of drug-resistant partial epilepsy in both children and adults. The treatment effect was compared between the two age groups using the ratio of the relative risk (RR) of the 50% responder rate between active AEDs treatment and placebo groups, as well as meta-regression. Differences in the response to placebo and to active treatment were searched using logistic regression. A comparable approach was used for analysing secondary endpoints, including seizure-free rate, total and adverse events-related withdrawal rates, and withdrawal rate for seizure aggravation. Five AEDs were evaluated in both adults and children with drug-resistant partial epilepsy in 32 RCTs. The treatment effect was significantly lower in children than in adults (RR ratio: 0.67 [95% confidence interval (CI) 0.51–0.89]; p = 0.02 by meta-regression). This difference was related to an age-dependent variation in the response to placebo, with a higher rate in children than in adults (19% versus 9.9%, p < 0.001), whereas no significant difference was observed in the response to active treatment (37.2% versus 30.4%, p = 0.364). The relative risk of the total withdrawal rate was also significantly lower in children than in adults (RR ratio: 0.65 [95% CI 0.43–0.98], p = 0.004 by metaregression), due to higher withdrawal rate for seizure aggravation in children (5.6%) than in adults (0.7%) receiving placebo (p < 0.001). Finally, there was no significant difference in the seizure-free rate between adult and paediatric studies.
Conclusions
Children with drug-resistant partial epilepsy receiving placebo in double-blind RCTs demonstrated significantly greater 50% responder rate than adults, probably reflecting increased placebo and regression to the mean effects. Paediatric clinical trial designs should account for these age-dependent variations of the response to placebo to reduce the risk of an underestimated sample size that could result in falsely negative trials.
In a systematic review of antiepileptic drugs, Philippe Ryvlin and colleagues find that children with drug-resistant partial epilepsy enrolled in trials seem to have a greater response to placebo than adults enrolled in such trials.
Editors' Summary
Background.
Whenever an adult is given a drug to treat a specific condition, that drug will have been tested in “randomized controlled trials” (RCTs). In RCTs, a drug's effects are compared to those of another drug for the same condition (or to a placebo, dummy drug) by giving groups of adult patients the different treatments and measuring how well each drug deals with the condition and whether it has any other effects on the patients' health. However, many drugs given to children have only been tested in adults, the assumption being that children can safely take the same drugs as adults provided the dose is scaled down. This approach to treatment is generally taken in epilepsy, a common brain disorder in children in which disruptions in the electrical activity of part (partial epilepsy) or all (generalized epilepsy) of the brain cause seizures. The symptoms of epilepsy depend on which part of the brain is disrupted and can include abnormal sensations, loss of consciousness, or convulsions. Most but not all patients can be successfully treated with antiepileptic drugs, which reduce or stop the occurrence of seizures.
Why Was This Study Done?
It is increasingly clear that children and adults respond differently to many drugs, including antiepileptic drugs. For example, children often break down drugs differently from adults, so a safe dose for an adult may be fatal to a child even after scaling down for body size, or it may be ineffective because of quicker clearance from the child's body. Consequently, regulatory bodies around the world now require comprehensive drug development programs in children as well as in adults. However, for pediatric trials to yield useful results, the general differences in the treatment response between children and adults must first be determined and then allowed for in the design of pediatric RCTs. In this study, the researchers investigate whether there is any evidence in published RCTs for age-dependent differences in the response to antiepileptic drugs in drug-resistant partial epilepsy.
What Did the Researchers Do and Find?
The researchers searched the literature for reports of RCTs on the effects of antiepileptic drugs in the add-on treatment of drug-resistant partial epilepsy in children and in adults—that is, trials that compared the effects of giving an additional antiepileptic drug with those of giving a placebo by asking what fraction of patients given each treatment had a 50% reduction in seizure frequency during the treatment period compared to a baseline period (the “50% responder rate”). This “systematic review” yielded 32 RCTs, including five pediatric RCTs. The researchers then compared the treatment effect (the ratio of the 50% responder rate in the treatment arm to the placebo arm) in the two age groups using a statistical approach called “meta-analysis” to pool the results of these studies. The treatment effect, they report, was significantly lower in children than in adults. Further analysis indicated that this difference was because more children than adults responded to the placebo. Nearly 1 in 5 children had a 50% reduction in seizure rate when given a placebo compared to only 1 in 10 adults. About a third of both children and adults had a 50% reduction in seizure rate when given antiepileptic drugs.
What Do These Findings Mean?
These findings, although limited by the small number of pediatric trials done so far, suggest that children with drug-resistant partial epilepsy respond more strongly in RCTs to placebo than adults. Although additional studies need to be done to find an explanation for this observation and to discover whether anything similar occurs in other conditions, this difference between children and adults should be taken into account in the design of future pediatric trials on the effects of antiepileptic drugs, and possibly drugs for other conditions. Specifically, to reduce the risk of false-negative results, this finding suggests that it might be necessary to increase the size of future pediatric trials to ensure that the trials have enough power to discover effects of the drugs tested, if they exist.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050166.
This study is further discussed in a PLoS Medicine Perspective by Terry Klassen and colleagues
The European Medicines Agency provides information about the regulation of medicines for children in Europe
The US Food and Drug Administration Office of Pediatric Therapeutics provides similar information for the US
The UK Medicines and Healthcare products Regulatory Agency also provides information on why medicines need to be tested in children
The MedlinePlus encyclopedia has a page on epilepsy (in English and Spanish)
The US National Institute for Neurological Disorders and Stroke and the UK National Health Service Direct health encyclopedia both provide information on epilepsy for patients (in several languages)
Neuroscience for Kids is an educational Web site prepared by Eric Chudler (University of Washington, Seattle, US) that includes information on epilepsy and a list of links to epilepsy organizations (mainly in English but some sections in other languages as well)
doi:10.1371/journal.pmed.0050166
PMCID: PMC2504483  PMID: 18700812
20.  Updated canine infection rates for Dirofilaria immitis in areas of Brazil previously identified as having a high incidence of heartworm-infected dogs 
Parasites & Vectors  2014;7(1):493.
Background
Canine heartworm infections were frequently diagnosed in Brazil before the new millennium. After the year 2000, the frequency of diagnosis showed a sharp decline; however, a few years later, new evidence indicated that the parasite was still present and that canine infection rates seemed to be increasing. Therefore, an updated survey of canine heartworm prevalence was conducted in several locations in south, southeast, and northeast Brazil.
Methods
Dogs from 15 locations having previously reported a high prevalence of heartworm infection were included in the survey according to defined criteria, including the absence of treatment with a macrocyclic lactone for at least 1 year. Blood samples from 1531 dogs were evaluated by an in-clinic immunochromatography test kit (Witness® Heartworm, Zoetis, USA) for detection of Dirofilaria immitis antigen. At each location, epidemiologic data, including physical characteristics and clinical signs reported by owners or observed by veterinarians, were recorded on prepared forms for tabulation of results by location, clinical signs, and physical characteristics.
Results
The overall prevalence of canine heartworm infection was 23.1%, with evidence of heartworm-infected dogs detected in all 15 locations studied. There was a tendency for higher prevalence rates in environmentally protected areas, despite some locations having less-than-ideal environmental temperatures for survival of vector mosquitoes. Among physical characteristics, it was noted that dogs with predominantly white hair coats and residing in areas with a high (≥20%) prevalence of heartworm were less likely to have heartworm infection detected by a commercial heartworm antigen test kit than were dogs with other coat colors. In general, dogs older than 2 years were more frequently positive for D. immitis antigen than were younger dogs. Clinical signs of heartworm infections were rare or owners were unable to detect them, and could not be used for reliable prediction of the presence of heartworm.
Conclusions
These results indicate that the prevalence of D. immitis has increased in these areas of Brazil over the past few years. Small animal practitioners in these areas should include routine screening tests for heartworm infections in every dog’s annual evaluation protocol and make sure to have uninfected dogs on prevention.
doi:10.1186/s13071-014-0493-7
PMCID: PMC4229606  PMID: 25376238
Canine antigen tests; Canine heartworm; Clinical signs; Dirofilaria immitis
21.  Ensemble Modeling of the Likely Public Health Impact of a Pre-Erythrocytic Malaria Vaccine 
PLoS Medicine  2012;9(1):e1001157.
Using an ensemble modeling approach, Thomas Smith and colleagues find that targeted mass vaccination with a pre-erythrocytic malaria vaccine RTS,S in low-transmission settings might have better health effects than vaccination through national EPI programs.
Background
The RTS,S malaria vaccine may soon be licensed. Models of impact of such vaccines have mainly considered deployment via the World Health Organization's Expanded Programme on Immunization (EPI) in areas of stable endemic transmission of Plasmodium falciparum, and have been calibrated for such settings. Their applicability to low transmission settings is unclear. Evaluations of the efficiency of different deployment strategies in diverse settings should consider uncertainties in model structure.
Methods and Findings
An ensemble of 14 individual-based stochastic simulation models of P. falciparum dynamics, with differing assumptions about immune decay, transmission heterogeneity, and treatment access, was constructed. After fitting to an extensive library of field data, each model was used to predict the likely health benefits of RTS,S deployment, via EPI (with or without catch-up vaccinations), supplementary vaccination of school-age children, or mass vaccination every 5 y. Settings with seasonally varying transmission, with overall pre-intervention entomological inoculation rates (EIRs) of two, 11, and 20 infectious bites per person per annum, were considered. Predicted benefits of EPI vaccination programs over the simulated 14-y time horizon were dependent on duration of protection. Nevertheless, EPI strategies (with an initial catch-up phase) averted the most deaths per dose at the higher EIRs, although model uncertainty increased with EIR. At two infectious bites per person per annum, mass vaccination strategies substantially reduced transmission, leading to much greater health effects per dose, even at modest coverage.
Conclusions
In higher transmission settings, EPI strategies will be most efficient, but vaccination additional to the EPI in targeted low transmission settings, even at modest coverage, might be more efficient than national-level vaccination of infants. The feasibility and economics of mass vaccination, and the circumstances under which vaccination will avert epidemics, remain unclear. The approach of using an ensemble of models provides more secure conclusions than a single-model approach, and suggests greater confidence in predictions of health effects for lower transmission settings than for higher ones.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The World Health Organization estimates that there are over 200 million cases of malaria each year, and that more than three-quarters of a million people (mostly children living in sub-Saharan Africa) die as a result. Several Plasmodium parasites cause malaria, the most deadly being Plasmodium falciparum. Plasmodium parasites, which are transmitted to people through the bites of infected night-flying mosquitoes, cause recurring fever and can cause life-threatening organ damage. Malaria transmission can be prevented by using insecticides to control the mosquitoes that spread the parasite and by sleeping under insecticide-treated bed nets to avoid mosquito bites. Treatment with antimalarial drugs also reduces transmission. Together, these preventative measures have greatly reduced the global burden of malaria over recent years, but a malaria vaccine could be a valuable additional tool against the disease. At present there is no licensed malaria vaccine, but one promising vaccine—RTS,S—is currently undergoing phase III clinical trials (the last stage of testing before licensing) in infants and children in seven African countries.
Why Was This Study Done?
If the RTS,S vaccine fulfills its promise and is licensed, how should it be used to maximize its effect on the global malaria burden? Should it be given through the World Health Organization's Expanded Programme on Immunization (EPI), which aims to provide universal access to immunization against several infectious diseases during the first three months of life, for example, or through mass vaccination campaigns? Individual mathematical models have been used to investigate this type of question, but the predictions made by these models may be inaccurate because malaria immunity is poorly understood, because little is known about the levels of variability (heterogeneity) in host responses to malaria infection and in malaria transmission, and because it is unclear what the structure of models used to predict vaccine efficacy should be. In this study, the researchers use an “ensemble” approach to model the likely public health impact of the RTS,S malaria vaccine. That is, they simultaneously consider the effect of the vaccine in multiple models of P. falciparum dynamics. Ensemble modeling is widely used in weather forecasting and has been used to investigate several other infectious diseases.
What Did the Researchers Do and Find?
The researchers constructed an ensemble of 14 individual-based stochastic simulation models of P. falciparum dynamics that included different assumptions about immune decay, transmission heterogeneity, and access to treatment. Such models simulate the passage of thousands of hypothetical individuals through different stages of malaria infection; movement between stages occurs stochastically (by chance) at a probability based on field data. Each model was used to predict the health benefits over 14 years of RTS,S deployment through EPI (with and without catch-up vaccination for infants who were not immunized during their first three months of life), through EPI and supplementary vaccination of school children, and through mass vaccination campaigns every five years at malaria transmission levels of 2, 11, and 20 infectious bites per person per annum (low, medium, and high entomological inoculation rates [EIRs], respectively). The predicted benefits of EPI vaccination programs over the 14-year period were modest and similar over a wide range of settings. However, EPI with an initial catch-up phase averted the most deaths per vaccine dose at higher EIRs. At the lowest EIR, mass vaccination strategies substantially reduced transmission, leading to much greater health effects per dose than other strategies, even at modest coverage.
What Do These Findings Mean?
The ensemble approach taken here suggests that targeted mass vaccination with RTS,S in low transmission settings may have greater health benefits than vaccination through national EPI programs. Importantly, this computer-intensive approach, which used computers made available over the internet by volunteers, provides more secure predictions than can be obtained using single models. In addition, it suggests that predictions made about the health effects of RTS,S vaccination for low transmission settings are more likely to be accurate than those made for higher transmission settings. However, this study only reports the first stages of using ensemble modeling to predict the health effects of RTS,S vaccination. Future studies will need to combine the outputs of multiple models with economic analyses to provide a rational basis for the design of vaccine-containing malaria control and elimination programs.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001157.
Information is available from the World Health Organization on malaria and on malaria immunization; the 2010 World Malaria Report provides details on the current global malaria situation; WHO also provides information on its Expanded Programme on Immunization (EPI), and its Global Immunization Vision and Strategy (some information is available in several languages)
The US Centers for Disease Control and Prevention provide information on malaria (in English and Spanish), including a selection of personal stories about malaria
Information is available from the Roll Back Malaria Partnership on the global control of malaria and on malaria in Africa
The latest results from the phase III trial of RTS,S are available on the website of the PATH Malaria Vaccine Initiative, a global program of the international nonprofit organization PATH that aims to accelerate the development of malaria vaccines and ensure their availability and accessibility in the developing world
Wikipedia has a page on ensemble forecasting (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
OpenMalaria is the open source simulator of malaria epidemiology and control used in this study; BOINC is the open source software for volunteer computing and grid computing that was used to run the simulations
MedlinePlus provides links to additional information on malaria and on immunization (in English and Spanish)
doi:10.1371/journal.pmed.1001157
PMCID: PMC3260300  PMID: 22272189
22.  Alleles of the major histocompatibility complex play a role in the pathogenesis of pancreatic acinar atrophy in dogs 
Immunogenetics  2013;65(7):10.1007/s00251-013-0704-y.
Exocrine pancreatic insufficiency (EPI) is a disease wherein pancreatic acinar cells fail to synthesize and secrete sufficient amounts of digestive enzymes for normal digestion of food. EPI affects many dog breeds, with a dramatically higher prevalence in the German shepherd dog (GSD) population. In this breed and perhaps others, EPI most often results from degeneration of the acinar cells of the pancreas, a hereditary disorder termed pancreatic acinar atrophy (PAA). Evidence of lymphocytic infiltration indicates that PAA is an autoimmune disease, but the genetic etiology remains unclear. Data from global gene expression and single nucleotide polymorphism profiles in the GSD suggest the involvement of the major histocompatibility complex [MHC; dog leukocyte antigen (DLA)]. To determine if alleles of the MHC influence development of EPI, genotyping of polymorphic class I (DLA-88) and II loci (DLA-DRB1, DLA-DQA1, and DLA- DQB1) was carried out for 70 affected and 63 control GSDs, and four-locus haplotypes were determined. One haplotype containing a novel allele of DLA-88 is very highly associated with EPI (OR>17; P=0.000125), while two haplotypes were found to confer protection from EPI (P=0.00087 and 0.0115). Described herein is the genotyping of MHC class I and II loci in a GSD cohort, establishment of four-locus haplotypes, and association of alleles/haplotypes with EPI.
doi:10.1007/s00251-013-0704-y
PMCID: PMC3857963  PMID: 23604463
Autoimmune; Canine; Exocrine pancreatic insufficiency; Pancreatic acinar atrophy; Major histocompatibility complex
23.  Increase in EPI vaccines coverage after implementation of intermittent preventive treatment of malaria in infant with Sulfadoxine -pyrimethamine in the district of Kolokani, Mali: Results from a cluster randomized control trial 
BMC Public Health  2011;11:573.
Background
Even though the efficacy of Intermittent Preventive Treatment in infants (IPTi) with Sulfadoxine-Pyrimethamine (SP) against clinical disease and the absence of its interaction with routine vaccines of the Expanded Immunization Programme (EPI) have been established, there are still some concerns regarding the addition of IPTi, which may increase the work burden and disrupt the routine EPI services especially in Africa where the target immunization coverage remains to be met. However IPTi may also increase the adherence of the community to EPI services and improve EPI coverage, once the benefice of strategy is perceived.
Methods
To assess the impact of IPTi implementation on the coverage of EPI vaccines, 22 health areas of the district of Kolokani were randomized at a 1:1 ratio to either receive IPTi-SP or to serve as a control. The EPI vaccines coverage was assessed using cross-sectional surveys at baseline in November 2006 and after one year of IPTi pilot-implementation in December 2007.
Results
At baseline, the proportion of children of 9-23 months who were completely vaccinated (defined as children who received BGG, 3 doses of DTP/Polio, measles and yellow fever vaccines) was 36.7% (95% CI 25.3% -48.0%). After one year of implementation of IPTi-SP using routine health services, the proportion of children completely vaccinated rose to 53.8% in the non intervention zone and 69.5% in the IPTi intervention zone (P <0.001).
The proportion of children in the target age groups who received IPTi with each of the 3 vaccinations DTP2, DTP3 and Measles, were 89.2% (95% CI 85.9%-92.0%), 91.0% (95% CI 87.6% -93.7%) and 77.4% (95% CI 70.7%-83.2%) respectively. The corresponding figures in non intervention zone were 2.3% (95% CI 0.9% -4.7%), 2.6% (95% CI 1.0% -5.6%) and 1.7% (95% CI 0.4% - 4.9%).
Conclusion
This study shows that high coverage of the IPTi can be obtained when the strategy is implemented using routine health services and implementation results in a significant increase in coverage of EPI vaccines in the district of Kolokani, Mali.
Trial Registration
ClinicalTrials.gov NCT00766662
doi:10.1186/1471-2458-11-573
PMCID: PMC3155918  PMID: 21767403
malaria; intermittent preventive treatment; sulphadoxine-pyrimethamine; expanded program of immunization
24.  Evaluation of the effects of dietary soy phytoestrogens on canine health, steroidogenesis, thyroid function, behavior and skin and coat quality in a prospective controlled randomized trial 
Background
Phytoestrogens are non-steroidal compounds possessing estrogenic activity present in significant amounts in soy-based pet foods. There is speculation that long-term consumption of phytoestrogen-rich diets could have biological effects but this has never been evaluated in dogs.
Hypothesis
Soy-based diets may affect general health, adrenocortical function, thyroid function, behavior and skin/coat quality in adult dogs.
Animals
Fifteen normal dogs were divided into two groups and fed either high-isoflavone (HID) or a low-isoflavone (LID) soy-based diet.
Methods
In this prospective controlled randomized trial end points of general health were assessed at baseline and up to one-year by evaluating body and dermatological condition, hematology, biochemistry profiles, urine-analysis (UA), serum concentrations of adrenal and thyroid hormones, and behavior. Student’s t-test (2 time points) analysis of variance with repeated measures (3 time points) was used to analyze differences in these parameters from baseline between diets.
Results
No differences were found in measures of skin/coat, body condition, or behavior, in either group. Results of hematology, biochemical profiles and urinalysis showed no differences between the two groups. Analysis of variance in repeated measures was used to analyze differences in hair follicles from baseline between diets when there were 2 time points. No differences were found in the evaluation of the skin, hair follicle and hair diameter size. Most adrenal and thyroid hormones did not change over time nor were they different by diet (P>.1). However, total T4 differences were higher in HI than LI group (15.3 vs −1.4 p=.07) and post-ACTH estradiol concentration differences were also increased in HI compared to LI groups (19 vs −5.6 pg/ml at 1 year, p=.0006).
Conclusions and Clinical Importance
These data suggest long-term ingestion of soy phytoestrogens may influence endocrine function in dogs and this could potentially impact results of studies evaluating endocrine function in dogs although larger studies are needed for confirmation.
doi:10.2460/ajvr.70.3.353
PMCID: PMC2698128  PMID: 19254147
Dog; Endocrine; Isoflavones; Skin; Coat
25.  Treatment of canine visceral leishmaniasis by the vaccine Leish-111f+MPL-SE 
Vaccine  2010;28(19):3333-3340.
Immunotherapy of canine visceral leishmaniasis (CVL) may provide an alternative to both marginally effective chemotherapy and undesired euthanasia of infected dogs and could have a great impact not only on animal welfare, but also on control of human disease. Therefore, we examined the potential immunotherapeutic efficacy of the subunit vaccine Leish-111f + MPL-SE, which has undergone rigorous preclinical testing and been demonstrated safe in human clinical trials. Two separate trials were performed in Salvador, Brazil, to evaluate the vaccine for therapeutic efficacy against CVL caused by natural infection: an open trial and a blinded trial. In the open trial 59 dogs with clinically active CVL were sequentially allocated to four groups: group 1 received Leish-111f + MPL-SE; group 2 was treated with Glucantime; group 3 received a combination of the vaccine and Glucantime; and group 4 was given no treatment. At the 6-month assessment, the 13 non-treated dogs had either died or showed no clinical improvement. In contrast, most dogs in groups 1-3 showed initial improvement (100%, 80%, and 92% respectively). Upon evaluation for a mean of 36 months after therapy, the following cure rates were observed: 75% for group 1 dogs (exact 95% confidence interval [CI] 43-95%), 64% for group 2 dogs (exact 95% CI 31-89%), and 50% for group 3 dogs (exact 95% CI 19-81%). Therapeutic efficacy of the Leish-111f + MPL-SE vaccine was reconfirmed in a subsequent blinded trial. The vaccine was effective for mild cases of CVL and was compromised in dogs with severe disease. Although further studies are required to understand mechanisms of action, the Leish-111f + MPL-SE vaccine is a promising tool to control VL in both dogs and humans.
doi:10.1016/j.vaccine.2010.02.089
PMCID: PMC2874835  PMID: 20206667
visceral leishmaniasis; Leishmania infantum; dog; immunotherapy; vaccine; adjuvant

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