Lean body weight dosing avoids excessive systemic exposure to proton pump inhibitors for children with obesity.

BACKGROUND: Children with obesity are more likely to suffer gastroesophageal reflux disease, requiring acid-suppression therapy with proton pump inhibitors (PPIs) and no guidelines regarding dosing. OBJECTIVE: To prospectively evaluate lean-body-weight-based (LBW) dosing of the PPI pantoprazole for children with and without obesity. METHODS: Methods: Sixty-two children (6-17 years) received a one-time oral dose of liquid pantoprazole (1.2 mg kg-1 LBW). Plasma pantoprazole concentrations were measured at 10 time points over 8 h and pharmacokinetic (PK) profiles generated using non-compartmental techniques, in order to compare PK parameters of interest between children with and without obesity, while accounting for CYP2C19 genotype. RESULTS: Adjusted for milligram-per-kilogram total body weight (TBW) pantoprazole received, apparent drug clearance (CL/F) was reduced 50% in children with vs. without obesity (p=0.03). LBW-based dosing compensated for this reduction in CL/F (p = 0.15). CONCLUSION: To achieve comparable systemic PPI exposures for children with and without obesity, we recommend using LBW, rather than TBW-based dosing for pantoprazole.

Adhesive strength of bone-implant interfaces and in-vivo degradation of PHB composites for load-bearing applications.

Aim of this study was to evaluate the response of bone to novel biodegradable polymeric composite implants in the femora of growing rats. Longitudinal observation of bone reaction at the implant site (BV/TV) as well as resorption of the implanted pins were monitored using in vivo micro-focus computed tomography (µCT). After 12, 24 and 36 weeks femora containing the implants were explanted, scanned with high resolution ex vivo µCT, and the surface roughness of the implants was measured to conclude on the ingrowth capability for bone tissue. Scanning electron microscope (SEM) and energy dispersive X-ray spectroscopy (EDX) were used to observe changes on the surface of Polyhydroxybutyrate (PHB) during degradation and cell ingrowth. Four different composites with zirconium dioxide (ZrO2) and Herafill(®) were compared. After 36 weeks in vivo, none of the implants did show significant degradation. The PHB composite with ZrO2 and a high percentage (30%) of Herafill® as well as the Mg-alloy WZ21 showed the highest values of bone accumulation (increased BV/TV) around the implant. The lowest value was measured in PHB with 3% ZrO2 containing no Herafill®. Roughness measurements as well as EDX and SEM imaging could not reveal any changes on the PHB composites׳ surfaces. Biomechanical parameters, such as the adhesion strength between bone and implant were determined by measuring the shear strength as well as push-out energy of the bone-implant interface. The results showed that improvement of these mechanical properties of the studied PHBs P3Z, P3Z10H and P3Z30H is necessary in order to obtain appropriate load-bearing material. The moduli of elasticity, tensile strength and strain properties of the PHB composites are close to that of bone and thus promising. Compared to clinically used PLGA, PGA and PLA materials, their additional benefit is an unchanged local pH value during degradation, which makes them well tolerated by cells and immune system. They might be used successfully for personalized 3D printed implants or as coatings of rapidly dissolving implants.

Multiple pathological fractures and delayed union associated with lead exposure in a German Shepherd Dog.

CASE REPORT: An 8-year-old 40.8-kg intact male German Shepherd Dog was evaluated for bilateral antebrachial fractures. Radiographs revealed osteopenia and comminuted proximal diaphyseal fractures of the left radius and ulna, and proximal articular fracture of the right ulna. A dual energy X-ray absorptiometry scan confirmed decreased bone mineral density. Bone mineral analysis collected at the time of definitive surgical repair demonstrated high lead concentration. Analysis further demonstrated normal bone calcium and phosphorus concentrations. Serum lead concentration was normal. The left radial and ulnar fractures were surgically stabilised with an external fixator. The right ulnar fracture was splinted. The left antebrachial fractures were palpably unstable at 12 weeks after surgery. Moderate callus formation and incomplete bone union were present at 17 weeks postoperatively. The dog was re-presented 15 months later for right metacarpal and left metatarsal fractures, which were managed conservatively. Complete bone union of the right radial and ulnar fractures was not present at that time. CONCLUSION: Excessive lead accumulation in bone should be considered as a differential diagnosis for increased susceptibility to pathologic fracture and delayed fracture healing in dogs.

Patellar groove replacement in patellar luxation with severe femoro-patellar osteoarthritis.

OBJECTIVE: To report a novel method of treating femoro-patellar instability in association with severe femoro-patellar osteoarthritis, by substituting the femoral trochlear with a patellar groove replacement prosthesis. STUDY DESIGN: Retrospective case series. METHODS: Preoperative lameness was scored from 0-4, and radiographic studies including standard positions for patellar luxation were obtained for evidence of malalignment and femoro-patellar osteoarthritis. Cases with or without previous surgeries were included. The size of trochlear implant was determined by transparent templates and confirmed intra-operatively with trials. Radiographic images, together with clinical examinations, were reviewed immediately and at three months postoperatively and at longer term when available. RESULTS: Thirty-five cases of patellar luxation ranging from grades II to IV were included. Eleven of these cases had prior surgical interventions which failed to stabilize the patella. Fourteen dogs required additional surgical procedures in conjunction with patellar groove replacement. Complications occurred in six patients, of which three required revision. Complete resolution of subjectively-assessed lameness was evident in 24/35 cases by the third month and in another seven of 35 patients on the longer term re-evaluations. CLINICAL SIGNIFICANCE: Use of a patellar groove replacement prosthesis has the potential to decrease the lameness associated with severe femoro-patellar arthritis, to improve patellar stability, and to correct the alignment of the extensor mechanism.

Nutritional Changes and Micronutrient Supply in Patients with Phenylketonuria Under Therapy with Tetrahydrobiopterin (BH(4)).

BACKGROUND: Since 2008 patients with BH(4)-sensitive phenylketonuria can be treated with sapropterin dihydrochloride (Kuvan®) in addition to the classic phenylalanine (Phe) restricted diet. The aim of this study was to evaluate the nutritional changes and micronutrient supply in patients with phenylketonuria (PKU) under therapy with tetrahydrobiopterin (BH(4)). SUBJECTS AND METHODS: 19 children with PKU (4-18 years) and potential BH(4)-sensitivity were included, 14 completed the study protocol. Dried blood Phe concentrations as well as detailed dietary records were obtained throughout the study at preassigned study days. RESULTS: Eight patients could increase their Phe tolerance from 629 ± 476 mg to 2131 ± 1084 mg (P = 0.006) under BH(4) while maintaining good metabolic control (Phe concentration in dried blood 283 ± 145 µM vs. 304 ± 136 µM, P = 1.0), therefore proving to be BH(4)-sensitive. They decreased their consumption of special low protein products and fruit while increasing their consumption of high protein foods such as processed meat, milk and dairy products. Intake of vitamin D (P = 0.016), iron (P = 0.002), calcium (P = 0.017), iodine (P = 0.005) and zinc (P = 0.046) significantly declined during BH(4) treatment while no differences in energy and macronutrient supply occurred. CONCLUSION: BH(4)-sensitive patients showed good metabolic control under markedly increased Phe consumption. However, the insufficient supply of some micronutrients needs consideration. Long-term multicenter settings with higher sample sizes are necessary to investigate the changes of nutrient intake under BH(4) therapy to further evaluate potential risks of malnutrition. Supplementation may become necessary.

The necessity of broad consent and complementary regulations for the protection of personal data in biobanks: what can we learn from the German case?

In order to follow population-based approaches for certain causes and risks of illnesses, more and more biobanks have been set up during the last years. Here, samples and personal data of the donors are collected and saved, whereby concrete research aims, at the time of storage of the bio-probes and the related data, are mostly undetermined. Biobanks, therefore, have the character of a collection of material and data that can be used for initially undetermined research projects. Under legal aspects the question arises whether the data subjects can consent only to an already determined use of their samples and data or can consent to a general use for research. In this article, we discuss the validity of broad consent and in how far the arising deficits in data protection need to be and can be compensated. Broad consent is, in our opinion, generally legally valid. It leads, however, to an encroachment of the ruling basic principles of data protection law. The 5-pillar concept of the German Ethics Council therefore suggests additional regulations to compensate the lacks of broad consent. While other recommendations and opinions - as far as can be seen - do only describe in vague terms the conditions for statutory regulations, the opinion of the German Ethics Council comprises very concrete statements. It, therefore, might serve as a model in the international debate on privacy and biobanks. As a result of the current debate, we identify this as a paradigm shift in data protection in biobanks.

Tetrahydrobiopterin (BH4) in PKU: effect on dietary treatment, metabolic control, and quality of life.

BACKGROUND: Tetrahydrobiopterin (BH(4))-sensitive phenylketonuria (PKU) can be treated with sapropterin dihydrochloride. We studied metabolic control and health-related quality of life (HRQoL) in PKU patients treated with BH(4). SUBJECTS AND METHODS: Based on the review of neonatal BH(4) test results and mutation analysis in 41 PKU patients, 19 were identified as potentially BH(4)-sensitive (9 females, 10 males, age 4-18 years). We analyzed phenylalanine (phe) concentrations in dried blood samples, nutrition protocols, and HRQoL questionnaires (KINDL(®)) beginning from 1 year before, during the first 42 days, and after 3 months of BH(4) therapy. RESULTS: Eight BH(4)-sensitive patients increased their phe tolerance (629 ± 476 vs. 2131 ± 1084 mg, p = 0.006) while maintaining good metabolic control (phe concentration in dried blood 283 ± 145 vs. 304 ± 136 µM, p = 1.0). Six of them were able to stop dietary protein restriction entirely. BH(4)-sensitive patients had average HRQoL scores that were comparable to age-matched healthy children. There was no improvement in HRQoL scores after replacing classic dietary treatment with BH(4) supply, although personal reports given by the patients and their parents suggest that available questionnaires are inappropriate to detect aspects relevant to inborn metabolic disorders. DISCUSSION: BH(4) can allow PKU patients to increase their phe consumption significantly or even stop dietary protein restrictions. Unexpectedly, this does not improve HRQoL as assessed with KINDL(®), partly due to high scores even before BH(4) therapy. Specific questionnaires should be developed for inborn metabolic disorders.

Litter mixture effects on tropical tree seedling growth--a greenhouse experiment.

Decomposing litter provides critical nutrients for plants, particularly in nutrient-poor ecosystems such as tropical forests. We hypothesised that decomposing litter improves the performance of a variety of tropical tree seedlings, and that this litter effect varies depending on the species of litter present in litter mixtures. We addressed these hypotheses with a large pot experiment manipulating a range of different litter mixtures of contrasting quality and using seedlings of four tree species from the Amazonian forest of French Guiana. In contrast to our initial hypothesis, decomposing litter had either neutral or negative impacts on seedling growth, despite strongly different growth rates, biomass allocation patterns and leaf and root traits among tree species. Tree species varied in their responses to litter additions, which were further modified by species identity of the added litter. Our data show litter species-specific effects on growth, biomass allocation and leaf and root traits of tropical tree seedlings. These results suggest that a net nutrient release from decomposing litter does not necessarily improve tree seedling growth, even under nutrient-limiting conditions. In conclusion, litter layer composition may affect seedling establishment and recruitment success beyond litter-derived plant nutrient availability, which may contribute to tree species composition and dynamics in the studied tropical forest.

Unrestricted consumption of fruits and vegetables in phenylketonuria: no major impact on metabolic control.

BACKGROUND/OBJECTIVES: The treatment of phenylketonuria (PKU) requires consistent restriction of protein intake from natural sources. Therefore, protein from all foods has to be accounted for, even the small amounts in fruits and vegetables. We studied whether free consumption of fruits and vegetables containing less than 75 mg phenylalanine (phe) per 100 g affects metabolic control in children with PKU. SUBJECTS/METHODS: Fourteen children (2-10 years) were included in a cross-over study, with a two-week period of conventional treatment (accounting for protein from fruits and vegetables) and a two-week period with free fruit and vegetable consumption. The instruction to follow liberal fruit and vegetable consumption in the first or second study period was randomized. Detailed daily dietary records were obtained throughout the study. Phe and nutrient content was calculated. Dried-blood phe concentration was monitored daily. RESULTS: Although total phe intake increased by an average of 58 mg per day (P=0.037) during the 2 weeks of free fruit and vegetable consumption, dried-blood phe concentrations were unchanged. Total intake of fruits and vegetables did not increase, but patients instead used the higher phe tolerance to consume more of other foods, which were calculated and accounted for. CONCLUSION: Free consumption of fruits and vegetables does not impair metabolic control in PKU patients over a 2-week period.

The use of cyclosporine-A in dogs with chronic osteoarthritis: a pilot study.

OBJECTIVE: To evaluate the efficacy of cyclosporine-A in dogs with radiographic and physical evidence of chronic stifle osteoarthritis. MATERIALS AND METHODS: Ten hound-type dogs with osteoarthritis induced by surgical transection of a cranial cruciate ligament followed by immediate stabilization of the stifle four years prior to study start were randomized to two groups. Cyclosporine-A was administered orally once daily at 5 mg/kg to one group for one month while the other group served as control. After a two week wash-out period during which the animals were not treated, and the degree of lameness was allowed to return to baseline, the treatments were switched so that the second group received treatment with cyclosporine-A and the first group served as control. Ground reaction forces were measured using a force platform in all animals at day zero and then every two weeks until the end of the study. RESULTS: Cyclosporine-A did not alter the degree of lameness based on assessment of ground reaction forces. CONCLUSIONS: At a dose of 5 mg/kg/day for 28 days, cyclosporine-A was not effective in decreasing lameness of dogs with chronic osteoarthritis induced by surgical transection of the cranial cruciate ligament.

Transient hyperammonemia due to L-asparaginase therapy in children with acute lymphoblastic leukemia or non-Hodgkin lymphoma.

The standard treatment protocol for acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL) in childhood includes intravenous therapy with asparaginase (Asp), which may cause hyperammonemia. In this study, all patients receiving asparaginase therapy at the Hospital for Children and Adolescents of the University of Leipzig between January 2002 and December 2007 were reviewed for the occurrence of hyperammonemia. Fifty-four patients were identified (22 girls, 32 boys; mean age 5.8 years). Blood ammonia concentrations were determined in 4 patients due to suspicious clinical signs. All showed hyperammonemia with NH(3) concentrations between 260 and 700 µmol/L. They received specific acute detoxification therapy consisting in protein restriction, administration of benzoic acid, glucose/insulin. All 4 recovered completely. All patients receiving therapeutic regimes that include asparaginase (Asp) should be monitored for the development of transient hyperammonemia.

Tandem mass spectrometric determination of succinylacetone in dried blood spots enables presymptomatic detection in a case of hepatorenal tyrosinaemia.

Tyrosinaemia type I, or fumarylacetoacetase deficiency, causes hepatorenal damage by accumulation of fumarylacetoacetate. Patients are generally in good condition at birth, but are at risk of developing serious metabolic crises with liver failure and hepatic coma. An early start of treatment with NTBC and a tyrosine-balanced diet can prevent harm to the patients. The application of tandem mass spectrometry to newborn screening allows for easy determination of tyrosine to detect the presence of hypertyrosinaemia in the neonate, but most patients with tyrosinaemia type I do not present with high tyrosine levels at the time of newborn screening. We report on a 7-week-old girl presenting with acute hepatopathy and severe coagulopathy due to tyrosinaemia type I. The metabolic screening, which was performed by tandem mass spectrometry at the age of 48 h, had revealed normal values for tyrosine and methionine that were well within ranges observed in the general population and equally normal ratios of methionine/tyrosine and tyrosine/serine. In this patient even lowering the cut-off levels for tyrosine and methionine would not have provided better sensitivity. Residual blood spots from the newborn screening filter paper were retrospectively analysed using a specific mass-spectrometric method for the detection of succinylacetone and revealed a 5-fold elevated succinylacetone concentration. This indicates that identification of all newborns with hepatorenal tyrosinaemia is only possible by determination of succinylacetone as part of the newborn screening process.

Incidence of cholelithiasis in 125 continent urinary diversions.

PURPOSE: Several studies in animals and humans have demonstrated that ileal resection has an increased association with gallstone formation. However, little reported data exist in regard to continent diversion, and the incidence and relative risk of gallstones. We describe a single institution, single surgeon (J. W. W.) experience with 125 modified Indiana pouch continent urinary diversions constructed in a 14-year period and the subsequent association with gallstones. MATERIALS AND METHODS: We retrospectively reviewed the charts of 129 patients who underwent continent urinary diversion from March 1985 to August 1998 at our institution to assess postoperative cholelithiasis. Complete information was available in 125 of the 129 charts. All patients were followed yearly with ultrasound combined with telephone followup to ensure complete data. RESULTS: Cholelithiasis was present in 32 of the 125 reviewable patients (25.6%), including 53 men and 72 women. Three men and 8 women who underwent previous or concomitant cholecystectomy for gallstones were excluded from study. Therefore, cholelithiasis developed in 21 of the 114 remaining patients (18.4%), including 5 males (4.3%) and 16 females (14%). Five of the 50 remaining men (10%) and 16 of the remaining 64 women (25%) had gallstones. Mean age at surgery was 43.5 years (range 19 to 73) and mean age at gallstone development was 45 years (range 23 to 77). Mean time from surgery to gallstone development was 3 years (range 1.1 to 5.5). Mean followup via chart review was 41 months (range 1 to 127). The recent telephone followup reached 83 of the 125 patients (66.4%). However, 20 of the 42 patients who were not reached by the telephone followup had had clinic appointments at our institution in the last 11/2 years for an overall 82.4% followup rate (103 of 125 patients). Of the 21 patients with cholelithiasis 17 were identified by chart review and 4 were identified by telephone followup. CONCLUSIONS: The recent literature indicates a 10% and 20% incidence of gallstones in American men and women, respectively. Previous reports support a potential increase in cholelithiasis in patients who undergo ileal resection. Our data indicate no increased risk of gallstones in patients who undergo modified Indiana pouch urinary diversion. However, longer followup is required to verify these findings.

Single-step formation of structurally defined bicyclic peptides via S(N)Ar cyclization.

[structure: see text]. A solid-phase methodology for macrocyclization via an S(N)Ar reaction has been developed for the unambiguous formation of bicyclic peptidic compounds in a single cyclization step. The cyclization strategy involves the reaction of a 3,5-dihydroxybenzoyl group with two nitrofluorobenzoyl moieties. The symmetry of the dihydroxy aromatic ring results in a single product, and the remaining nitro groups are subsequently reduced to anilines and acylated.

Identification of the hyaluronan receptor for endocytosis (HARE).

Rat liver sinusoidal endothelial cells (LECs) express two hyaluronan (HA) receptors, of 175 and 300 kDa, responsible for the endocytic clearance of HA. We have characterized eight monoclonal antibodies (mAbs) raised against the 175-kDa HA receptor partially purified from rat LECs. These mAbs also cross-react with the 300-kDa HA receptor. The 175-kDa HA receptor is a single protein, whereas the 300-kDa species contains three subunits, alpha, beta, and gamma at 260, 230, and 97 kDa, respectively (Zhou, B., Oka, J. A., and Weigel, P. H. (1999) J. Biol. Chem. 274, 33831-33834). The 97-kDa subunit was not recognized by any of the mAbs in Western blots. Based on their cross-reactivity with these mAbs, the 175-, 230-, and 260-kDa proteins appear to be related. Two of the mAbs inhibit (125)I-HA binding and endocytosis by LECs at 37 degrees C. All of these results confirm that the mAbs recognize the bone fide LEC HA receptor. Indirect immunofluoresence shows high protein expression in liver sinusoids, the venous sinuses of the red pulp in spleen, and the medullary sinuses of lymph nodes. Because the tissue distribution for this endocytic HA receptor is not unique to liver, we propose the name HARE (HA receptor for endocytosis).

Radiographic, densitometric, and biomechanical effects of recombinant canine somatotropin in an unstable ostectomy gap model of bone healing in dogs.

OBJECTIVE: To determine the effect of recombinant canine somatotropin (STH) on radiographic, densitometric, and biomechanical aspects of bone healing using an unstable ostectomy gap model. STUDY DESIGN: After an ostectomy of the midshaft radius, bone healing was evaluated over an 8-week period in control dogs (n = 4) and dogs receiving recombinant canine STH (n = 4). ANIMALS OR SAMPLE POPULATION: Eight sexually intact female Beagle dogs, 4 to 5 years old. METHODS: Bone healing was evaluated by qualitative and quantitative evaluation of serial radiographs every 2 weeks. Terminal dual-energy x-ray absorptiometry and three-point bending biomechanical testing were also performed. RESULTS: Dogs receiving STH had more advanced radiographic healing of ostectomy sites. Bone area, bone mineral content, and bone density were two to five times greater at the ostectomy sites of treated dogs. Ultimate load at failure and stiffness were three and five times greater in dogs receiving STH. CONCLUSIONS: Using the ostectomy gap model, recombinant canine STH enhanced the radiographic, densitometric, and biomechanical aspects of bone healing in dogs. CLINICAL RELEVANCE: Dogs at risk for delayed healing of fractures may benefit from treatment with recombinant canine STH.