Health impact in children and adolescents.

Obesity in children and adolescents is associated with multiple comorbidities, including metabolic, cardiovascular, gastrointestinal, pulmonary, orthopedic and psychological disorders. In fact, cardiovascular and metabolic impairments in childhood and adolescence constitute major risk factors for developing cardiovascular disease in adulthood. Thus, obesity in childhood and adolescence leads to a higher morbidity and mortality in adulthood. Therefore, strong emphasis must be laid on the prevention and therapy of childhood obesity. Treatment requires a multidisciplinary and multiphase approach including dietary management, physical activity, pharmacotherapy and bariatric surgery. This paper reviews the different comorbidities of childhood obesity supporting the notion of a multidisciplinary therapy concept.

[Does childhood obesity affect sexual development?]. / Beeinflusst die kindliche Adipositas die Pubertätsentwicklung?

The process of pubertal development is only partly understood and is influenced by many different factors. During the twentieth century there was a general trend toward earlier pubertal development. Fat mass is thought to be a major inducer of puberty. Owing to the rising epidemic of childhood obesity, the relationship between body composition in children and the rate and timing of puberty needs to be investigated. Some studies suggest that central obesity is associated with an earlier onset of pubertal development. Rapid weight gain in early life is linked to advanced puberty in both sexes. A clear correlation exists between increasing body mass index (BMI) and earlier pubertal development in girls. In boys the data are controversial: The majority of studies propose that there is an earlier puberty and voice break in obese boys, but some studies show the opposite. There are several factors and mechanisms that seem to link obesity and puberty, for example, leptin, adipocytokines, and gut peptides. Important players include genetic variation and environmental factors (e.g., endocrine-disrupting chemicals). This article presents the latest studies and evidence on this topic, underlining the inconsistencies in the data and, therefore, the need for further research in this area.

Leucocytes are a major source of circulating nicotinamide phosphoribosyltransferase (NAMPT)/pre-B cell colony (PBEF)/visfatin linking obesity and inflammation in humans.

AIMS/HYPOTHESIS: Nicotinamide phosphoribosyltransferase (NAMPT) is a multifunctional protein potentially involved in obesity and glucose metabolism. We systematically studied the association between circulating NAMPT, obesity, interventions and glucose metabolism and investigated potential underlying inflammatory mechanisms. METHODS: Fasting morning NAMPT serum levels were measured in cohorts of lean vs obese children, cohorts of intervention by lifestyle, exercise and bariatric surgery, and during an OGTT. In addition, mRNA expression, protein production and enzymatic activity of NAMPT were assessed from isolated leucocytes and subpopulations. RESULTS: Circulating NAMPT was significantly elevated in obese compared with lean children and declined after obesity interventions concomitantly with the decline in BMI, high-sensitivity C-reactive protein (hsCrP) and leucocyte counts. Circulating NAMPT significantly correlated with glucose metabolism and cardiovascular variables in univariate analyses, but only the association with glucose response during an OGTT was independent from BMI. We therefore assessed the NAMPT dynamic following an oral glucose load and found a significant decline of NAMPT levels to 77.0 ± 0.1% as a function of time, and insulin-to-glucose ratio during an OGTT in obese insulin-resistant adolescents. Circulating NAMPT was, however, most strongly associated with leucocyte counts (r = 0.46, p < 0.001). The leucocyte count itself determined significantly and independently from BMI insulin resistance in multiple regression analyses. We systematically evaluated NAMPT expression among several tissues and found that NAMPT was predominantly expressed in leucocytes. In subsequent analyses of leucocyte subpopulations, we identified higher NAMPT protein concentrations in lysates of granulocytes and monocytes compared with lymphocytes, whereas granulocytes secreted highest amounts of NAMPT protein into cell culture supernatant fractions. We confirmed nicotinamide mononucleotide enzymatic activity of NAMPT in all lysates and supernatant fractions. In monocytes, NAMPT release was significantly stimulated by lipopolysaccharide (LPS) exposure. CONCLUSIONS: Leucocytes are a major source of enzymatically active NAMPT, which may serve as a biomarker or even mediator linking obesity, inflammation and insulin resistance.

Retinol binding protein 4 (RBP4) is primarily associated with adipose tissue mass in children.

OBJECTIVE: Retinol binding protein 4 (RBP4) is a novel adipocytokine that may link obesity and insulin resistance. We aimed to discriminate between primary and secondary associations of RBP4 with obesity and related disease. DESIGN: We applied clinical and experimental approaches to investigate the association of RBP4 levels with normal development, obesity, metabolic and cardiovascular parameters in 68 lean and 61 obese children. RESULTS: RBP4 significantly increased with age and pubertal development in healthy lean children. Obese children had significantly higher RBP4 levels compared with lean controls (30.5±1.4 vs. 26.3±1.1 mg/L, P<0.05) and there was a clear association with BMI independent of age (r=0.33, P<0.0001). RBP4 levels correlated significantly with parameters of lipid and glucose metabolism, as well as cardiovascular parameters in univariate analyses. Multiple regression analyses confirmed the strong association of RBP4 with BMI z-score and age, while the association with most metabolic and cardiovascular parameters was abolished. To assess whether the association of RBP4 with obesity may be attributable to adipogenesis, we evaluated RBP4 expression and secretion during adipocyte differentiation using the human SGBS cell line. In preadipocytes, RBP4 mRNA expression was nearly undetectable but increased during differentiation up to approximately 1600-fold (P<0.05). Likewise, RBP4 secretion was restricted to mature adipocytes, further indicating that RBP4 is strongly related to differentiation of adipocytes. CONCLUSION: RBP4 is a marker of adipose tissue mass and obesity already evident in children. The association of RBP4 with metabolic and cardiovascular sequelae of obesity appears to be secondary to the underlying relationship wtih body fat.

Vaspin is related to gender, puberty and deteriorating insulin sensitivity in children.

BACKGROUND: Visceral adipose tissue-derived serine protease inhibitor (vaspin) has been suggested as a novel adipocytokine related to obesity and insulin sensitivity in adults. DESIGN: We quantified vaspin serum concentrations in 65 lean and 67 obese children and aimed to evaluate the relationship of vaspin with physical development, obesity, and metabolic and cardiovascular phenotypes in children. We further assessed the acute vaspin response to glucose provocation in 20 obese adolescents and evaluated tissue expression patterns of vaspin in humans. RESULTS: Vaspin levels were significantly higher in girls than in boys. In girls, vaspin increased with age and pubertal stage, whereas there was no change with development in boys. Obese girls had lower vaspin serum levels than those of lean controls, but there was no significant correlation with body mass index (BMI). Independent of sex, age and BMI, lower vaspin was associated with better insulin sensitivity, with higher systolic blood pressure and impaired endothelial function. In response to glucose provocation during an oral glucose tolerance test, vaspin serum levels declined by approximately 25% in adolescents with hyperinsulinemia, whereas there was no significant decline in normoinsulinemic patients. In support of our clinical data, we not only confirmed vaspin mRNA expression in adipose tissue but also found consistent expression of vaspin in the liver and indications for expression in the pancreas and the skin. CONCLUSION: We showed that gender differences in circulating vaspin levels develop during pubertal progression in girls. Although vaspin's association with obesity remains controversial, vaspin was increased with worsening insulin resistance already in children and was acutely down-regulated following glucose provocation in insulin-resistant adolescents independent of obesity. Besides adipose tissue, vaspin expression in the liver and the pancreas may potentially contribute to circulating vaspin levels and their regulation.

Early weight gain and outcome in Henoch-Schönlein nephritis.

BACKGROUND: Intrauterine growth restriction seems to be a risk factor for an aggravated course of secondary renal diseases in children. Catch-up growth after birth may play a critical role. We tested if there is an association between an aggravated course of nephritis in Henoch-Schönlein Purpura (PSHN) and low birth weight or early weight gain during infancy. PATIENTS: We retrospectively analysed the clinical course of 34 children with PSHN. METHODS: Patients were sorted according their birth weight standard deviation score (SDS) in tertiles. Early weight gain was defined as gain of weight standard deviation score >0.67 between birth and 2 years of age. RESULTS: Patients with higher birth weight needed Cyclophosphamide in a higher rate than low birth weight children. In the high weight gain group (SDS gain >0.67) 9 of the 11 patients compared to 7 of 22 patients in the low weight gain group (SDS gain <0.67) presented with arterial hypertension during the initial manifestation of PSH nephritis (p=0.01). Median systolic blood pressure SDS in the high weight gain group was 1.54 (-1.39-4.71) versus 0.29 (0.52-4.05) in the low weight gain group (p=0.008). Nevertheless, other clinical parameters during first manifestation and follow-up were not relevantly different. CONCLUSION: In contrast to the data of children with idiopathic nephrotic syndrome or IgA nephropathy, this study does neither provide evidence for an association between low birth weight nor early weight gain and the later course of PSHN. Interestingly, early weight gain was associated with a higher systolic blood pressure during the initial manifestation of PSHN.

[Topical anesthesia before vascular access in children. Comparison of a warmth-producing lidocaine-tetracaine patch with a lidocaine-prilocaine patch]. / Topische Anästhesie vor Venenpunktion bei Kindern. Vergleich eines wärmenden Lidocain-Tetracain- mit einem Lidocain-Prilocain-Pflaster.

BACKGROUND: Venepuncture is one of the most stressful situations for children during induction of general anesthesia. Therefore, many clinicians use a local anesthesia patch (EMLA) containing a mixture of lidocaine and prilocaine in order to reduce the stress for pediatric patients. This study compared the effect of a new heated topical anesthesia delivery system containing lidocaine and tetracaine (Rapydan) with the lidocaine/prilocaine patch EMLA. METHODS: The study design was prospective, randomized, single-blinded and monocenter. A total of 200 children aged from 3 to 13 years were randomized into group E (EMLA) or group R (Rapydan). The primary endpoint of the study was the overall incidence of pain. Additionally, the intensity of pain during venous puncture was evaluated by means of an investigator-based 4 point pain score: 0 no reaction, 1 gentle movement/grimacing, 2 moderate withdrawal of the arm/crying and 3 strong withdrawal/screaming. Furthermore, erythema of the skin, visibility of the veins and success rate of the punctures were assessed. RESULTS: Mean contact time of the patch with the skin was 35 min in both groups. The overall incidence of pain was 46% in group E and 12% in group R (p<0.001). The intensity of pain also differed significantly between the groups. A pain score of 1 was observed in 24% (group E) versus 10% (group R), a score of 2 was documented in 13% (group E) versus 1% (group R) and a score of 3 was observed in 9% (group E) versus 1% (group R; p<0.001). Erythema of the skin was observed more frequently in group R (p<0.001). Visibility of the veins and success rate of venous puncture did not differ significantly. CONCLUSIONS: After a contact time of 35 min the Rapydan patch led to superior analgesia during venous puncture than the EMLA patch. With regard to visibility of the veins and success rate of the punctures, differences between the two patches were not observed.

Considering laparoscopic salvage options--is pre-emptive omentectomy necessary in paediatric peritoneal patients?

BACKGROUND: In paediatric peritoneal dialysis patients, pre-emptive omentectomy is discussed controversially and literature provides only little data concerning this issue. Our aim was to evaluate the rate of omentum-majus-related problems in our patients, in whom omentectomy was generally not performed. Furthermore, we were interested in the success rates of laparoscopic adhesiolysis. PATIENTS AND METHODS: Between 09/2006 and 03/2008, we regularly saw 18 peritoneal dialysis patients in whom we retrospectively analysed medical records to determine the rate of catheter-related complications. In addition, we evaluated the success rates of laparoscopic adhesiolysis. RESULTS: During 355 dialysis months in 18 patients, we observed 7 omentum-majus-related obstructions in 6 patients (1/50.7 PM). The median age of the patients affected was 9 years, median filling volume at the time of the obstruction was 671 ml/m (2). Laparoscopic adhesiolysis was successful in 4 out of 7 episodes. In 3 cases, the catheter lumen was plugged by necrotic portions of the omentum and the catheters had to be replaced. CONCLUSION: Our data confirm omentum-majus-related catheter obstruction as a major cause of catheter dysfunction. However, in comparison to literature, it remains unclear to which extent omentectomy can reduce the incidence of catheter obstruction in general (including e. g. obstruction due to coagulation). Thus, the decision to perform an omentectomy should be taken individually after careful consideration. In case of omentum-majus-associated obstruction, early but not late laparoscopic intervention proved to be a successful, minimally invasive technique to restore catheter function.

Experience with mycophenolate mofetil as maintenance therapy in five pediatric patients with severe systemic lupus erythematosus.

Maintenance therapy of severe pediatric systemic lupus erythematosus (SLE) usually consists of azathioprine and prednisone . In adult SLE patients mycophenolate mofetil (MMF) is successfully used, superiority to azathioprine has not been shown yet. We hypothesized that a maintenance therapy with MMF is able to decrease disease activity as well as the dose of glucocorticoid needed in children and adolescents with SLE. Five girls with a mean age of 13.9 (range 12-15) years were treated with 1.2+/-0.20 g/m (2) MMF daily on individual medical decision. Three patients had severe renal (WHO IV) and one severe cerebral involvement. Three patients with frequent flares on azathioprine maintenance therapy were switched to MMF, two patients with severe renal and cerebral manifestation received MMF additionally after induction therapy. Flares, steroid dosage, and disease activity (SLEDAI) were monthly registered in all patients. The number of flares decreased from 1.28 to 0.25 episodes per patient year during a mean follow-up period of 39 (range 36-42) months after MMF initiation. In parallel prednisone dose could be reduced from 10.80+/-5.25 to 3.25+1.18 mg/d (p<0.01). SLEDAI score dropped from 15.20+/-2.8 before MMF to 3.60+/- 0.9 at the last visit under MMF (p<0.001). No severe adverse event occurred. In our cohort of five pediatric patients MMF was effective and safe for maintenance therapy of SLE over a period of 3.5 years. MMF seems to be successful in preventing flares even in adolescents having unfavorable course on azathioprine treatment before. This observation should be confirmed by a randomized multicenter clinical trial.

[Slim despite a genetic predisposition for obesity--influence of environmental factors as chance? A case report]. / Schlank trotz genetischer Prädisposition für Adipositas--Beeinflussung von Umweltfaktoren als Chance? Eine Kasuistik.

CASE HISTORY AND CLINICAL FINDINGS: A 4-year-old, slightly overweight (BMI 18 kg/m2, BMI SDS 1.29 approximately 90.1 (th) percentile) and otherwise healthy girl presented with accelerated linear growth (99.6 (th) percentile) and hyperphagia due to loss of satiety feeling. These findings are consistent with melanocortin-4 receptor ( MC4R) mutations. GENETIC ANALYSIS AND DIAGNOSIS: We found the partially inactivating mutation Arg (165)Trp by direct sequencing of the MC4R coding region. Interestingly, the patient's mother is also heterozygous for this mutation, but lean (BMI 19 kg/m2). TREATMENT AND COURSE: Carriers of MC4R mutations develop hyperphagia due to lack of satiety feeling as a result of central dysregulation. The reduction of energy intake and the encouragement of physical activity can be successful to control the body weight. CONCLUSION: Early diagnosis can promote lifestyle intervention to prevent the development of obesity even in the presence of a genetic predisposition.

Encouraging survival of infants with terminal renal failure combining dialysis and succeeding early transplantation.

Dialysis in newborns and infants is a very challenging field in pediatric nephrology and still associated with high mortality. This article is designed for pediatricians who advise parents of newborns with renal failure. It aims to provide information about the difficulties during the period of dialysis and outcome after successful transplantation. We report upon five patients who proceeded to end-stage renal failure within the first year of life. All patients received peritoneal dialysis; however, two had to be switched to hemodialysis for several months. Four patients received percutaneous endoscopic gastric tubes (PEG) to enable high caloric diet. At the age of 1.5 to 5 years all children were successfully transplanted achieving good renal function. With regard to severe complications, hospitalisation time and somatic development all patients showed a substantial improvement after renal transplantation. Growth velocity increased to above SDS +2 after transplantation and all children reached the milestones of development in due time. In conclusion, after renal replacement therapy is initialised in infants with end-stage renal failure, sufficient nutrition to improve weight gain and to achieve the earliest possible transplantation is mandatory. Early transplantation results in a catch-up of developmental delay in short time.

Patient with antibody-negative relapse of Goodpasture syndrome.

Smoking in young men may trigger anti-GBM disease manifesting with hemoptysis. We present a male adolescent in whom hemoptysis was mistaken to be a sign of airway infection for several months and who later on underwent an unusual antibody-negative relapse. The 16-year-old patient had a history of smoking and therapy-refractant hemoptysis and, later, acute macrohematuria with renal insufficiency necessitating hemodialysis (initial creatinine 4.2 mg/ dl). Chest X-ray showed diffuse lung infiltration. Renal biopsy revealed linear IgG deposits along the glomerular basement membrane (GBM) and cellular crescents in 13/16 glomeruli, simultaneously increased anti-GBM antibodies were detected. Thus, anti-GBM glomerulonephritis was diagnosed. After treatment with prednisone, oral cyclophosphamide and plasmapheresis, chest X-ray and hemoptysis improved, but renal failure persisted. Anti-GBM antibodies were negative. 4 weeks later, the patient presented again with a clinical relapse of severe hemoptysis and respiratory insufficiency after smoke exposition. Despite negative anti-GBM antibodies, he was treated similarly to a relapse and after the second course of plasmapheresis the patients' general condition improved and hemoptysis subsided. During the next 10 months the patient was stable with negative antibodies. He was under intermittent hemodialysis until laboratory measurements showed improved renal function. Now, 30 months after the acute episode, the patient is off dialysis for 17 months with stable creatinine values of 1.9 - 2.4 mg/dl, and is currently being treated with antihypertensive medicaments, calcitriol, calciumacetate, natriumhydrogencarbonate and allopurinol. The prognosis of anti-GBM glomerulonephritis depends on serum creatinine and the need of dialysis at initial presentation. In these patients, one-year survival rate is 67% and 5% for kidney function. Of note, despite the unfavorable prognosis in our patient, renal function recovered after 1 year of hemodialysis treatment. It is important to consider that in patients with anti-GBM disease antibody-negative relapses are possible.

Nitric oxide stimulates adrenomedullin secretion and gene expression in endothelial cells.

Adrenomedullin, a peptide with vasorelaxant activity, stimulates nitric oxide (NO) synthesis. We tested whether or not NO regulates the function of the adrenomedullin system. Human umbilical vein endothelial cells (HUVEC) were incubated with the NO donors sodium nitroprusside (SNP), morpholinosydnonimine (SIN-1) and the phospodiesterase V inhibitor zaprinast. In HUVEC, adrenomedullin concentration in the supernatant was measured by radioimmunoassay and mRNA expression was studied by Northern blot and competitive quantitative PCR. SNP, SIN-1, and zaprinast (100 micromol/l each) significantly increased adrenomedullin concentration in the supernatant of HUVEC twofold. The same concentrations increased adrenomedullin mRNA expression four- to tenfold. Similar results were obtained by both quantitative PCR and Northern blot. Thus, NO donor exposure in vitro increases both adrenomedullin secretion and mRNA expression in a dose-dependent manner.

Anti-TNF therapy and malignancy - a critical review.

The roles of tumour necrosis factor (TNF) and anti-TNF therapy in malignancy are reviewed, including an overview of baseline risk factors for malignancy in inflammatory diseases and the incidences of malignancies observed in clinical trials of an anti-TNF-a therapy, infliximab. The preclinical data and early clinical experience presented for infliximab do not provide evidence for a causal relationship between TNF-a antagonism and the development of lymphoid or nonlymphoid cancers.

Hypogastric artery embolization in endovascular abdominal aortic aneurysm repair.

PURPOSE: Iliac artery anatomy is a central factor in endoluminal abdominal aortic aneurysm therapy. It serves as the conduit for graft deployment and as the region of distal graft seal. Thirty-eight percent of iliac vessels in our patients require special treatment because of aneurysms, tortuosity, or small size. Bilateral hypogastric artery exclusion has been avoided because of concerns of colorectal ischemia, hip/buttock claudication, and impotence. We suggest that elective, staged, bilateral hypogastric embolization can be performed safely with reasonably low morbidity and can expand the anatomic boundaries for stent-graft abdominal aortic aneurysm repair. METHODS: This study was performed as a retrospective chart review of patients requiring hypogastric artery embolization for endovascular repair of abdominal aortic aneurysms between June 1998 and June 2000. Patients with otherwise appropriate anatomy and common iliac artery aneurysms were informed of the option for stent-graft repair with internal iliac artery embolization with its risks of impotence, hip/buttock claudication, and bowel ischemia. Patients underwent unilateral or staged bilateral coil embolizations of their proximal hypogastric arteries with an approximate 1-week interval between procedures. Hospital and office records were reviewed; phone interviews were performed. Follow-up ranged from 1 to 12 months. RESULTS: During a 24-month period, 65 patients underwent endovascular abdominal aortic aneurysm repair; 18 patients (28%) required hypogastric artery embolization. Seven (39%) of these patients underwent bilateral embolization. There were no episodes of clinically evident bowel ischemia. Lactate levels were normal in all measured patients. Postoperative fevers (> 101.0 degrees F) were documented in 10 (56%) of 18 patients. The average white blood cell count was 12.8 x 10(9)/L (range, 8.5-22.9). There were no positive blood culture results. The return to the full preoperative diet occurred in 1 to 3 days. Hip/buttock claudication occurred in approximately 50% of patients with persistent but improved symptoms at 6 months. Eighty-seven percent of patients had preoperative erectile dysfunction. Only two patients noted worsening of erectile function postoperatively. CONCLUSIONS: Preliminary results indicate that bilateral hypogastric artery embolization can be performed, when necessary, with reasonable morbidity in patients undergoing stent-graft abdominal aortic aneurysm repair.

Alteration of neuronal and endothelial nitric oxide synthase and neuropeptide Y in congenital ureteropelvic junction obstruction.

PROBLEM: We investigated whether deranged nitric oxide synthase (NOS) and neuropeptide Y (NPY) expression is detectable in the stenotic segments of patients with congenital ureteropelvic junction obstruction. METHODS: Using real-time reverse transcription-polymerase chain reaction (RT-PCR), we quantified mRNA amounts of NPY, neuronal (n), endothelial (e) and inducible (i) NOS in the stenotic segments of 20 patients with congenital ureteropelvic junction obstruction (aged 5.1+/-7.0 years) and of 21 unaffected controls (aged 23.5+/-24.2 years). Additionally, mRNAs of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), smooth muscle alpha-actin (Smactin), endothelial cell marker (CD31), and protein gene product 9.5 (PGP 9.5) were evaluated. Immunohistochemistry was made for NPY, nNOS, eNOS, iNOS, PGP 9.5, and CD 31. RESULTS: The mRNA of nNOS was significantly reduced in the obstructed junctions when related to the mRNAs of Smactin (P < 0.001) or GAPDH (P < 0.05), respectively. A significant reduction was also obtained for eNOS mRNA when standardized to CD31 (P < 0.05), GAPDH or Smactin mRNA (P < 0.05, and P < 0.001, respectively). NPY, PGP 9.5 and iNOS mRNAs were found in comparable quantities in both groups. In the stenotic segments, Smactin mRNA level was about twofold higher than in our control specimens, as shown by the lower CT values for the patients in real-time PCR (16.9+/-2.0 vs 17.9+/-2.6, P < 0.05). Furthermore, Smactin, nNOS, iNOS, eNOS, and NPY mRNA levels in specimens of unaffected ureteropelvic junctions were independent of age. Major differences between control and stenotic tissues were detected by immunohistochemistry: There was a dramatic reduction of innervation density as evidenced by nNOS and NPY labeling. CONCLUSION: Taken together, we found alterations in NOS gene expression and NPY innervation in tissue specimens of patients with congenital ureteropelvic junction obstruction.

Effects of saponins on the water solubility of different model compounds.

The influence of saponins on the water solubility of compounds having poor aqueous solubility was investigated with the model compounds digitoxin, rutin and aesculin. The saponins that were tested represent the most abundant structural types. Only slight effects on aqueous solubility were obtained for all the model compounds. These effects include both enhancements and reductions in aqueous solubility depending on the saponin, the concentration of the saponin solution and the model compound. Structure-activity relationships of general significance were not observed. Hence, saponins generally should not be regarded as solubilizers.

Tetanus: lest we forget.

Tetanus is a life threatening infection that is rarely encountered in clinical practice. Knowledge of the condition is necessary to ensure optimal management. A 30-year-old male presented with classic signs and symptoms of the disease, including trismus, risus sardonicus, paroxysmal muscle spasms and autonomic instability. The pathophysiology and modern management of this condition are reviewed.