Cost-effectiveness of a family-based multicomponent outpatient intervention program for children with obesity in Germany.

OBJECTIVES: Facing an epidemic of childhood obesity and budget constraints, public health administrations are showing an urgent interest in interventions that are both health effective and cost-effective. Thus, this study intends to analyze the return on investment of these existing programs. STUDY DESIGN: All analyses are based on a comprehensive data set from 249 children with obesity and overweight children who participated in the Children's Health InterventionaL Trial (CHILT), an 11-month outpatient multidisciplinary family-based program. METHODS: Cost-effectiveness was assessed by comparing estimated savings associated with a reduction in weight and improvement of obesity-related health parameters with intervention costs. Projected future savings in health care expenditures were modeled on existing research, using estimates of health care costs associated with juvenile obesity and remission thresholds of obesity-related disease. RESULTS: On average, participants achieved a 0.19-unit reduction in the body mass index standard deviation score, showed reduction in their blood pressure values (systolic = -1.76 mmHg, diastolic = -2.82 mmHg), and showed improvement in their high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol values (HDL = +1.31 mg/dL, LDL = -4.82 mg/dL). The intervention costs were 1799€ per participant, and the benefits of avoided future health care costs varied by individual. On an aggregated level, future savings amounted to between 1859€ and 1926€ per person, translating into a return on investment of 3.3-7.0%. CONCLUSIONS: This study shows that a multicomponent obesity intervention, such as the CHILT, not only results in weight loss and improves important health parameters but also is cost-effective.

Immuno-driven and Mechano-mediated Neotissue Formation in Tissue Engineered Vascular Grafts.

In vivo development of a neovessel from an implanted biodegradable polymeric scaffold depends on a delicate balance between polymer degradation and native matrix deposition. Studies in mice suggest that this balance is dictated by immuno-driven and mechanotransduction-mediated processes, with neotissue increasingly balancing the hemodynamically induced loads as the polymer degrades. Computational models of neovessel development can help delineate relative time-dependent contributions of the immunobiological and mechanobiological processes that determine graft success or failure. In this paper, we compare computational results informed by long-term studies of neovessel development in immuno-compromised and immuno-competent mice. Simulations suggest that an early exuberant inflammatory response can limit subsequent mechano-sensing by synthetic intramural cells and thereby attenuate the desired long-term mechano-mediated production of matrix. Simulations also highlight key inflammatory differences in the two mouse models, which allow grafts in the immuno-compromised mouse to better match the biomechanical properties of the native vessel. Finally, the predicted inflammatory time courses revealed critical periods of graft remodeling. We submit that computational modeling can help uncover mechanisms of observed neovessel development and improve the design of the scaffold or its clinical use.

3D-Printed Biodegradable Polymeric Vascular Grafts.

Congenital heart defect interventions may benefit from the fabrication of patient-specific vascular grafts because of the wide array of anatomies present in children with cardiovascular defects. 3D printing is used to establish a platform for the production of custom vascular grafts, which are biodegradable, mechanically compatible with vascular tissues, and support neotissue formation and growth.

Contrasting biofunctionalization strategies for the enhanced endothelialization of biodegradable vascular grafts.

Surface modification of biodegradable vascular grafts is an important strategy to improve the in situ endothelialization of tissue engineered vascular grafts (TEVGs) and prevent major complications associated with current synthetic grafts. Important strategies for improving endothelialization include increasing endothelial cell mobilization and increased endothelial cell capture through biofunctionalization of TEVGs. The objective of this study was to assess two biofunctionalization strategies for improving endothelialization of biodegradable polyester vascular grafts. These techniques consisted of cross-linking heparin to graft surfaces to immobilize vascular endothelial growth factor (VEGF) or antibodies against CD34 (anti-CD34Ab). To this end, heparin, VEGF, and anti-CD34Ab attachment and quantification assays confirmed the efficacy of the modification strategy. Cell attachment and proliferation on these groups were compared to unmodified grafts in vitro and in vivo. To assess in vivo graft functionality, the grafts were implanted as inferior vena cava interpositional conduits in mice. Modified vascular grafts displayed increased endothelial cell attachment and activity in vivo, according to microscopy techniques, histological results, and eNOS expression. Inner lumen diameter of the modified grafts was also better maintained than controls. Overall, while both functionalized grafts outperformed the unmodified control, grafts modified with anti-CD34Ab appeared to yield the most improved results compared to VEGF-loaded grafts.

Computational model of the in vivo development of a tissue engineered vein from an implanted polymeric construct.

Advances in vascular tissue engineering have been tremendous over the past 15 years, yet there remains a need to optimize current constructs to achieve vessels having true growth potential. Toward this end, it has been suggested that computational models may help hasten this process by enabling time-efficient parametric studies that can reduce the experimental search space. In this paper, we present a first generation computational model for describing the in vivo development of a tissue engineered vein from an implanted polymeric scaffold. The model was motivated by our recent data on the evolution of mechanical properties and microstructural composition over 24 weeks in a mouse inferior vena cava interposition graft. It is shown that these data can be captured well by including both an early inflammatory-mediated and a subsequent mechano-mediated production of extracellular matrix. There remains a pressing need, however, for more data to inform the development of next generation models, particularly the precise transition from the inflammatory to the mechanobiological dominated production of matrix having functional capability.

Biaxial mechanical properties of the inferior vena cava in C57BL/6 and CB-17 SCID/bg mice.

Multiple murine models have proven useful in studying the natural history of neovessel development in the tissue engineering of vascular grafts. Nevertheless, to better understand longitudinal changes in the biomechanics of such neovessels, we must first quantify native tissue structure and properties. In this paper, we present the first biaxial mechanical data for, and nonlinear constitutive modeling of, &QJ;the inferior vena cava from two models used in tissue engineering: wild-type C57BL/6 and immunodeficient CB-17 SCID/bg mice. Results show that inferior vena cava from the latter are significantly stiffer in the circumferential direction, both materially (as assessed by a stored energy function) and structurally (as assessed by the compliance), despite a lower intramural content of fibrillar collagen and similar wall thickness. Quantifying the natural history of neovessel development in different hosts could lead to increased insight into the mechanisms by which cells fashion and maintain extracellular matrix in order to match best the host stiffness while ensuring sufficient vascular integrity.

Pharmacokinetics and pharmacodynamics of moist inhalation epinephrine using a mobile inhaler.

BACKGROUND: Intramuscular (L-)epinephrine is used as self-medication for serious hypersensitivity reactions. Inhalative administration has the theoretical advantage of a more rapid absorption and better controllability. OBJECTIVES: The current trial was conducted to explore pharmacokinetics and pharmacodynamics of two nebulized inhalative epinephrine doses (4 mg and 8 mg in aqueous solution) using a mobile pocket inhaler relative to intramuscular administration (0.3 mg) and placebo. METHODS: This randomized, open-label, change-over pilot study involved eight young healthy men and women. Noncompartmental pharmacokinetic and pharmacodynamic parameters were calculated from epinephrine plasma concentrations and hemodynamic parameters. RESULTS: Mean exposure to epinephrine decreased from the 8 mg dose to the 4 mg inhalative dose, and further with the 0.3 mg intramuscular dose, with active treatments showing significantly higher concentrations than placebo (geometric mean area under the curve AUC0-t(last) values: 282, 236, 204 and 81.6 hr*ng/L). Maximal concentrations were reached within approximately 15 min for all active treatments. Epinephrine effects for inhalative administrations on heart rates were significantly higher than those for the intramuscular or placebo administration, while no excessive effects occurred. Pronounced overall variability prohibited a definite assessment of relative bioavailability between treatments. However, results indicated that epinephrine concentrations obtained following the 8 mg inhalative dose were not inferior to those after 0.3 mg i.m. CONCLUSIONS: A relevant fraction of moist inhalation epinephrine doses is absorbed and mediates systemic effects. This suggests that administration of epinephrine via a suitable pocket inhaler device may be beneficial in ambulatory emergency treatment of systemic hypersensitivity reactions. EudraCT number: 2010-021493-11.

Functional null mutations in the gonosomal homologue gene TBL1Y are associated with non-syndromic coarctation of the aorta.

In patients with congenital heart defects, chromosomal anomalies are 100 times more frequent than in control subjects. Coarctation of the aorta can be detected in 15-20% of patients with Ullrich-Turner syndrome. By extensively reviewing literature involving breakpoint analysis of gonosomal deletions in Ullrich- Turner syndrome patients with and without coarctation of the aorta, we identified several gonosomal homolgous gene pairs of interest. Four of these homologous gene pairs were investigated by standard DNA sequencing in a cohort of 83 patients with non-syndromic coarctation of the aorta. Subsequently stability of mutant RNA and protein was analyzed to verify functional relevance of detected mutations. We identified two unreported missense mutations in Exon 8 (p.D69H) and 9 (p.R176W) of TBL1Y. Bioinformatic analysis and 3D modelling predicted that both mutations lead to TBL1Y loss of function. In RT-PCR and Western blot analyses of HEK293 cells transfected with a vector carrying the full-length TBL1Y (wild-type and mutant), we documented the predicted protein instability by showing protein decay for both mutant proteins. TBL1Y is similar to its gonosomal homologue, TBL1X, and its autosomal homologue, TBLR1, on chromosome 3. Both genes are part of co-repressor machineries and required for transcriptional activation by transcription factors that involve CtBP1/2, which contributes to Notch signaling. Several studies have shown that Notch signalling is important for proper development of the left ventricular outflow tract. Our findings suggest that TBL1Y is involved in the genesis of non-syndromic coarctation of the aorta.

SERIAL NONRIGID VASCULAR REGISTRATION USING WEIGHTED NORMALIZED MUTUAL INFORMATION.

Vascular registration is a challenging problem with many potential applications. However, registering vessels accurately is difficult as they often occupy a small portion of the image and their relative motion/deformation is swamped by the displacements seen in large organs such as the heart and the liver. Our registration method uses a vessel detection algorithm to generate a vesselness image (probability of having a vessel at any given voxel) which is used to construct a weighting factor that is used to modify the intensity metric to give preference to vascular structures while maintaining the larger context. Therefore, our proposing method uses fully data-driven calculated weights and needs no prior knowledge for the weight calculation. We applied our method to the registration of serial MRI lamb images obtained from studies on tissue engineered vascular grafts and demonstrate encouraging performance as compared to non-weighted registration methods.

Initial evaluation of the use of USPIO cell labeling and noninvasive MR monitoring of human tissue-engineered vascular grafts in vivo.

This pilot study examines noninvasive MR monitoring of tissue-engineered vascular grafts (TEVGs) in vivo using cells labeled with iron oxide nanoparticles. Human aortic smooth muscle cells (hASMCs) were labeled with ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles. The labeled hASMCs, along with human aortic endothelial cells, were incorporated into eight TEVGs and were then surgically implanted as aortic interposition grafts in a C.B-17 SCID/bg mouse host. USPIO-labeled hASMCs persisted in the grafts throughout a 3 wk observation period and allowed noninvasive MR imaging of the human TEVGs for real-time, serial monitoring of hASMC retention. This study demonstrates the feasibility of applying noninvasive imaging techniques for evaluation of in vivo TEVG performance.

Peripheral airway obstruction in primary pulmonary hypertension.

BACKGROUND: As there is controversy about changes in lung function in primary pulmonary hypertension (PPH), lung mechanics were assessed with a focus on expiratory airflow in relation to pulmonary haemodynamics. METHODS: A cross sectional study was performed in 64 controls and 171 patients with PPH (117 women) of mean (SD) age 45 (13) years, pulmonary artery pressure (PAPmean) 57 (15) mm Hg, and pulmonary vascular resistance 1371 (644) dyne.s/cm(5). RESULTS: Mean (SD) total lung capacity was similar in patients with PPH and controls (98 (12)% predicted v 102 (17)% predicted, mean difference -4 (95% confidence interval (CI) -7.89 to -0.11); residual volume (RV) was increased (118 (24)% predicted v 109 (27)% predicted, mean difference 9 (95% CI 1.86 to 16.14); and vital capacity (VC) was decreased (91 (16)% predicted v 102 (10)% predicted, mean difference -11 (95% CI 15.19 to -6.80). RV/TLC was increased (117 (27)% predicted v 97 (29)% predicted, mean difference 20 (95% CI 12.3 to 27.8)) and correlated with PAPmean (r=0.31, p<0.001). In patients with PAPmean above the median of 56 mm Hg, RV/TLC was further increased (125 (32)% predicted v 111 (22)% predicted, mean difference -14 (95% CI -22.2 to -5.8)). Expiratory flow-volume curves were reduced and curvilinear in patients with PPH. CONCLUSIONS: Peripheral airway obstruction is common in PPH and is more pronounced in severe disease. This may contribute to symptoms. Reversibility of bronchodilation and relation to exercise capacity need further evaluation.

[Impairment of ventilatory parameters and exercise capacity in patients with pulmonary hypertension and chronic heart insufficiency]. / Einschränkung der Ventilationsparameter und Belastbarkeit durch pulmonale Hypertonie bei chronischer Herzinsuffizienz.

BACKGROUND AND OBJECTIVE: Chronic heart failure often coincides with secondary pulmonary hypertension. In this study the influence of pulmonary hypertension on exercise capacity and ventilatory parameters in patients with chronic heart failure was examined. PATIENTS AND METHODS: 21 patients with chronic heart failure (six women, 15 men, mean age 55 +/- 10 years) and a left ventricular ejection fraction of 25 % +/- 5 % were studied by right heart catheterization, bodyplethysmography including carbonmonoxide diffusion testing and spiroergometry. Seven patients suffered from ischemic and 14 patients from dilative cardiomyopathy. Pulmonary hypertension (defined as pulmonary artery mean pressure > 25 mmHg) was found in ten patients. RESULTS: Patients with pulmonary hypertension showed a reduced vital capacity (75 % +/- 20 % of normal values vs. 93 % +/- 14 % of normal values, p < 0.001), a lower forced expiratory volume in one second (FEV1 68 % +/- 21 % of normal values vs. 91 % +/- 15 % of normal values, p < 0.001), and a reduced carbonmonoxide-diffusing capacity (58 % +/- 21 % vs. 77 % +/- 21 %, p < 0.001) compared to patients without pulmonary hypertension. Mean expiratory flow at 25 % and 75 % of the exspiration time was lower in patients with pulmonary hypertension (30 % +/- 13 % vs. 50 % +/- 29 % and 62 % +/- 25 % vs. 81 % +/- 20 %, each p < 0.05). In patients with pulmonary hypertension, the flow-volume diagram characteristically showed signs of "small airway disease". Spiroergometry revealed a significantly lower maximum oxygen-uptake (12.5 +/- 2.1 vs. 15.2 +/- 4.1 ml/min/kg, p < 0.05), oxygen-uptake at the anaerobic threshold (9.7 +/- 1.6 vs. 12.0 +/- 3.0 ml/min/kg, p < 0.05), carbon dioxide ventilatory efficiency (EqCO2 38 +/- 9 vs. 31 +/- 3, p < 0.05) and ventilatory reserve (39 % +/- 22 % vs 51 % +/- 21 %, p < 0.05) in patients with pulmonary hypertension. CONCLUSION: In patients with chronic heart failure the presence of pulmonary hypertension leads to a reduction of exercise capacity and impaired ventilatory parameters. Lung functional testing reveals bronchial obstruction, "small airway disease" and a reduced ventilatory efficiency.

Diagnosis of pulmonary arterial hypertension and pulmonary embolism with magnetic resonance angiography.

BACKGROUND: Pulmonary magnetic resonance angiography (PMRA) has been proven to be accurate for the diagnosis of suspected acute or chronic pulmonary embolism (PE). Only limited data exist on the reliability of PMRA for the diagnosis of acute and chronic pulmonary artery hypertension (PAH). The aim of this study was to determine the accuracy of PMRA in the differentiation between patients suffering from PAH of varying etiologies. METHODS: Fifty patients (21 women; mean [+/- SD] age, 52 +/- 16 years) were examined with gadolinium-enhanced PMRA for the evaluation of pulmonary artery (PA) disease. The diagnosis of PAH (ie, systolic PA pressure of > 35 mm Hg) was determined by Doppler echocardiography. The criteria for the diagnosis of chronic PAH by PMRA were dilated central PAs (diameter > 28 mm) and abnormal proximal-to-distal tapering of the PAs. The diagnostic criterion for acute and chronic PE was the presence of an intravascular filling defect. RESULTS: Chronic PAH was present in 18 patients, which was correctly identified by PMRA in 16 patients (sensitivity, 89%). All patients without PAH had normal findings on PMRA (specificity, 100%). Only 1 of 18 patients with normal findings on PMRA showed moderate chronic PAH (negative predictive value, 94%). PAH due to acute/subacute pulmonary thromboembolism (15 patients) was identified in all patients (sensitivity, 100%). Acute PAH was differentiated from chronic PAH in all cases by the detection of intravascular filling defects and the lack of abnormal proximal-to-distal tapering of PAs. CONCLUSIONS: PMRA is a promising noninvasive imaging modality for the identification of patients with acute or chronic PAH. This technique should be considered a sensitive and highly specific screening tool for suspected chronic PAH.

Silicosis-induced pulmonary artery stenosis: demonstration by MR angiography and perfusion MRI.

Silicosis is a common occupational disease. We present a 64-year-old male patient suffering from symptomatic silicosis due to compression of the pulmonary arteries by enlarged hilar lymph nodes. Clinical symptoms and diagnostic imaging modalities are described, with emphasis on cross-sectional imaging. MR angiography and perfusion MRI of the lung in silicosis are described, and their diagnostic value in pneumoconiosis is discussed.

Multiple aseptic pulmonary nodules with central necrosis in association with pyoderma gangrenosum.

Pulmonary manifestations of pyoderma gangrenosum are relatively rare. We report the case of a 45-year-old patient with multiple pulmonary nodules with central necrosis as assessed by CT scan. The patient had a 4-year history of pyoderma gangrenosum with only minor skin manifestations. A CT-guided, fine-needle biopsy of the lung revealed a nonspecific, inflammatory, aseptic necrotic process, which was comparable to the skin biopsy of one pyoderma lesion. Following the initiation of oral prednisolone therapy, a rapid resolution of the pulmonary nodules occurred. We conclude that pulmonary nodules represent a rare pulmonary manifestation of pyoderma gangrenosum.

[Pyoderma gangrenosum: successful topical therapy with tacrolimus (FK506)]. / Pyoderma gangraenosum: erfolgreiche topische Therapie mit Tacrolimus (FK506).

Pyoderma gangrenosum is a distinct clinical entity characterized by chronic, recurring, destructive ulcerations. Although the pathogenesis of pyoderma gangrenosum is unknown, immunologic aberrations of neutrophil granulocytes seem to be important. Systemic steroids and macrolide lactones such as cyclosporin A and tacrolimus have been reported to be useful in the clinical management of disease. Pyoderma gangrenosum has been found to be associated with several systemic diseases. The association with chronic ulcerative colitis is well known, but the diagnosis may be complicated by early administration of systemic steroids. Therefore, local immunosuppression with topically applied agents could be an efficient therapeutic alternative especially for mild or early cutaneous lesions.We describe the successful topical treatment of a patient with multiple lesions of pyoderma gangrenosum with 0,1% tacrolimus (FK506) ointment which is known to have better dermal penetration and higher immunosuppressive potency than topical cyclosporin A. In addition, other indications for topical tacrolimus are discussed.

The unpredictable character of congenital cystic lung lesions.

BACKGROUND: The spectrum of congenital cystic disease of the lung ranges from hydrops and neonatal respiratory distress to asymptomatic lesions. Surgical management is dictated by the presence of symptoms, recurrent infection, and the potential risk of malignant transformation. METHODS: Since 1995, all consecutive patients with congenital cystic lung lesions underwent follow-up for symptoms, treatment, and correlation of presumptive with pathological diagnosis. RESULTS: Twelve cystic lung lesions were identified. Seven were diagnosed with mediastinal shift in utero; in 6 of 7, the shift subsequently resolved. Overall, 6 of 7 lesions that were followed up serially decreased in size. Two patients were symptomatic in utero; 1 underwent thoracoamniotic shunting, 1 pleurocentesis for impending hydrops. Postnatally, these 2, and 2 other newborns required urgent surgery. Five of 8 asymptomatic patients had elective resection by 16 months, and 4 await operation. In 6 of the 9 surgical cases (67%), there was a discrepancy between preoperative and pathological diagnosis. There were 4 hybrid congenital cystic adenomatoid malformation (CCAM)/sequestrations. CONCLUSIONS: At least 6 of 7 congenital cystic lung lesions decreased in size regardless of gestational age or presence of mediastinal shift. Antenatal intervention is therefore rarely indicated. Hybrid morphology may necessitate resection of stable, asymptomatic lesions to prevent the theoretical concern for associated malignancies as well as other complications of CCAM.

[Remission of nocturnal pathological respiratory patterns after orthotopic heart transplantation. A case report and overview of current status of therapy]. / Sistieren nächtlicher pathologischer Atmungsmuster nach orthotoper Herztransplantation. Ein Fallbericht sowie eine Ubersicht über den aktuellen Stand der Therapie.

BACKGROUND: Cheyne-Stokes respiration is characterized by recurrent phases of central apneas during sleep alternating with a crescendo-decrescendo hyperventilation. This abnormal respiratory pattern is often observed in patients with severe congestive heart failure and associated with fragmentation of sleep, excessive daytime sleepiness, and a relatively high mortality. Increased peripheral and central chemosensitivity, prolonged circulation time, and reduced blood gas buffering capacity are the major factors contributing to the pathology. However, the exact pathophysiologic mechanisms are not clear yet. Respiratory stimulants, oxygen and continuous or bilevel positive airway pressure (CPAP or BiPAP) might reduce the severity of Cheyne-Stokes respiration but have little effect on daytime sleepiness and cardiac function. There is only limited data supporting the assumption that intensive heart failure therapy has an effect on Cheyne-Stokes respiration. CASE REPORT: A 55-year-old male patient with dilative cardiomyopathy (NYHA IV) suffered excessive daytime sleepiness (Epworth Sleepiness Scale: 24 points). The patient was a heavy snorer with a normal body mass index. Treatment was initiated including ACE-inhibitors, beta-receptor blockers, diuretics and digoxin. The patient underwent sleep analysis with a Somno-Check system which demonstrated Cheyne-Stokes breathing (Respiratory Disturbance Index RDI: 40/h, lowest desaturation 76%) and body position dependent snoring. Oxygen therapy (21/min) had no effect on daytime sleepiness. Due to the cardiac condition, the patient was accepted for heart transplantation. Three weeks after transplantation sleep analysis was repeated and demonstrated a lack of evidence for periodic breathing (RDI 1/h, no desaturations below 90%), while snoring remained unchanged. Daytime sleepiness improved significantly (Epworth Sleepiness Scale: 6 points). Three weeks after normalizing left ventricular function a complete recovery from severe Cheyne-Stokes respiration was observed. CONCLUSION: Adequate therapy of the underlying cause of Cheyne-Stokes breathing such as end-stage congestive heart failure might sufficiently abolish any breathing abnormalities.