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Most children with spinal muscular atrophy (SMA) develop spinal deformity, which may require surgical intervention. In addition to poor bone stock, vertebral body shape may hinder the placement of spinal implants resulting in complications and poor outcome. The aim of this study was to analyze whether vertebral body morphology of children and adolescents with SMA is altered in comparison to healthy age-matched controls.In this prospective cohort study, 17 children with SMA (mean age 8.7 ±1.0 years) and 13 adolescents with SMA (mean age 13.6 ±1.4 years), all with some degree of neuromuscular scoliosis, were analyzed by standardized radiographic measurements to evaluate vertebral body height and depth. Results were compared with age-matched healthy controls (n = 10 children; mean age 9.1 ± 1.6 years; n = 20 adolescents, mean age 13.1 ± 0.5 years). Computed tomography scans of 27 adolescents with SMA (13.5 ±1.2 years) and 25 healthy age-matched controls (13.8 ±2.0 years) were analyzed to define pedicle diameters.All children and adolescents with SMA had decreased vertebral height and depth in comparison to age-matched healthy controls. In adolescents, reduced depth was more pronounced than height in the thoracic spine. Pedicle size was significantly reduced in the lower thoracic and lumbar area.Reduced vertebral body height and depth and pedicle size in children and adolescents with SMA may influence surgical treatment of spinal deformity. Surgeons should be aware of anatomical differences and choose implant devices accordingly.

Duchenne muscular dystrophy is a progressive disease usually associated with loss of ambulation and progressive scoliosis. Immobilisation and glucocorticoid treatment are predisposing factors for reduced bone mineral density (BMD). Analysis of quantitative computed tomography revealed low BMD in thoracic and lumbar vertebrae in comparison to age- and sex-matched healthy controls.Evaluation of vertebral bone mineral density (BMD) in Duchenne Muscular Dystrophy (DMD) adolescents with untreated advanced scoliosis and comparison with the BMD values of healthy age-matched controls, based on quantitative computer tomography.Thirty-seven DMD adolescents (age 15.6 ± 2.5 years) with spinal deformity were evaluated clinically and radiologically prior to definite spinal fusion and compared to 31 male and age-matched healthy individuals (age 15.7 ± 2.3 years). Data related to previous medical treatment, physiotherapy and ambulatory status was also analysed. Scoliotic curves were measured on plain sitting radiographs of the spine. The BMD Z-scores of the thoracic and lumbar vertebrae were calculated with QCTpro® (Mindways Software Inc., USA), based on data sets of preoperative, phantom pre-calibrated spinal computed tomography scans.A statistically significant lower BMD could be found in DMD adolescents, when compared to healthy controls, showing an average value for the lumbar spine of 80.5 ± 30.5 mg/cmDMD adolescents with scoliosis have strongly reduced BMD Z-scores, especially in the lumbar spine in comparison to healthy controls. These findings support the implementation of a standardised screening and treatment protocol. Level of evidence/clinical relevance: therapeutic level III.

In advanced Rett syndrome (RTT), limited or complete loss of ambulation, nutritional problems and scoliosis are unfavorable factors for bone mineral density (BMD). Still, there are few data available in this research area. Spinal quantitative computed tomography (QCT) allows an exact measurement of the volumetric BMD (vBMD) in this patient group. Two examiners measured vBMD of thoracic and lumbar vertebrae on asynchronous calibrated CTs that were acquired prior to surgical scoliosis correction (n = 21, age 13.6 ± 2.5 years). The values were compared to age- and sex-matched healthy controls to additionally derive Z-scores (n = 22, age 13.8 ± 2.0 years). The results showed the most significant reduction of vBMD values in non-ambulatory RTT patients, with p < 0.001 and average BMD-Z-score −1.5 ± 0.2. In the subgroup comparison, non-ambulatory patients with valproate treatment had significant lower values (p < 0.001) than ambulatory patients without valproate therapy, with an average BMD-Z-score of −2.3 ± 0.2. Comparison of the Z-scores to critical BMD thresholds of 120 and 80 mg/cm3 showed normal Z-scores in case of the ambulatory RTT subgroup, as opposed to BMD-Z-scores of the non-ambulatory RTT subgroups, which were partially below osteopenia-equivalent values. Furthermore, valproate treatment seems to have a direct effect on vBMD in RTT patients and when combined with loss of ambulation, BMD-Z-scores are reduced to osteoporosis-equivalent levels or even further.

Die kongenitale Pseudarthrose der Tibia (CPT) ist eine seltene Erkrankung, die Unfallchirurgen und Orthopaden seit langer Zeit herausfordert. Klinisch imponieren eine meist zunehmende Antekurvations- und Varusfehlstellung der Tibia im Sauglings- und im Kleinkindalter. Oft ist die CPT mit einer Neurofibromatose oder fibrosen Dysplasie vergesellschaftet. Eine Diskontunitat der Tibia und/oder Fibula kann bei Unkenntnis des Krankheitsbildes als einfache Fraktur fehlgedeutet werden. Histopathologische Untersuchungen lassen vermuten, dass eine pathologische Veranderung des Periosts im Bereich der Pseudarthrose, das Hamartom, im Wesentlichen fur dieses Krankheitsbild verantwortlich zu sein scheint. Somit muss zur Heilung der CPT auch eine Resektion des Hamartoms erfolgen. Multimodale Therapieansatze mit Vereinigung medikamentoser und operativer Ansatze wie z. B. die X‑Union-Technik von Paley scheinen im Verlauf eine gunstigere Prognose aufzuzeigen.

Magnetically controlled growing rods (MCGRs) are an effective treatment method for early-onset scoliosis (EOS). In recent years, increasing titanium wear was observed in tissue adjacent to implants and in blood samples of these patients. This study aims to investigate the potential correlation between amount of metal loss and titanium levels in blood during MCGR treatment as well as influencing factors for metal wear. In total, 44 MCGRs (n = 23 patients) were retrieved after an average of 2.6 years of implantation and analyzed using a tactile measurement instrument and subsequent metal loss calculation. Titanium plasma levels (n = 23) were obtained using inductively coupled plasma-mass spectrometry (ICP-MS). The correlation of both parameters as well as influencing factors were analyzed. Titanium abrasion on MCGRs was observed in the majority of implants. There was no correlation of metal implant wear or titanium plasma values to the duration of MCGR implantation time, number of external lengthening procedures, patient’s ambulatory status, gender, weight or height. Material loss on the MCGRs showed a positive correlation to titanium blood plasma values. The present study is one of the first studies to analyze retrieved MCGRs using high-precision metrological techniques and compare these results with ICP-MS analyses determining blood titanium values.

Background. Brace treatment is frequently used in adolescent idiopathic scoliosis (AIS). However, due to different brace models, long-term results on spinal deformity development at the end of Chneau brace treatment are not often described and differ in results. Aim. The aim of this work was to analyze clinical and radiological data of AIS patients treated with Chneau braces from the beginning of treatment until the end of growth and brace therapy in order to define realistic treatment results and expectations in an everyday setting. Materials and methods. 52 AIS patients with Chneau brace treatment were followed from the beginning of treatment until the end of growth. Clinical data such as the initial Risser sign, age at treatment, gender, curve patterns and body mass index were analyzed. Results. At the beginning of brace therapy, the average age was 13.1 years and patients showed a mean scoliotic curve angle of 30.9. Four months of brace use reduced the scoliotic curve to 20.1. Nine months after the end of brace treatment and an average treatment duration of 17 months, scoliosis has increased up to 30.3 again. In children with a lower maturity status, the initial scoliotic curve was less than in more mature patients leading to less spinal deformity at the end of treatment. In addition, obese children had less scoliosis correction during brace therapy than normalweight children. Conclusion. In patients with AIS treated with a Chneau brace, the initial curvature correction was 35%. Nine months after the end of brace treatment, scoliotic curves identical to the deformities at the beginning of treatment could be observed.

Skoliosen im Kindes- und Jugendalter benotigen haufig aufwendige konservative und operative Therapieverfahren. Zur Vermeidung unerfreulicher Verlaufe ist die detaillierte Kenntnis des Wachstumsverhaltens, der Prognose und von Begleitproblematiken unerlasslich. Kenntnisse zu Atiologie, Prognose, Diagnostik und Therapie von Wirbelsaulendeformitaten im Wachstumsalter sollen vermittelt werden. Die vorliegende Arbeit beruht auf einer selektiven Literaturrecherche und auf den Ergebnissen mehrerer eigener prospektiver und retrospektiver Untersuchungen. Abhangig von Atiologie und Patientenalter ist eine detaillierte und interdisziplinare Diagnostik notig. Konservative Therapien, z. B. die Versorgung mithilfe eines Cheneau-Korsetts, konnen Krummungen bestenfalls aufhalten, aber nicht auf lange Sicht umkehren. Operative Therapien mit wachstumsfreundlichen Implantaten sind aufwendig sowie mit Komplikationen und Mehrfacheingriffen verbunden. Von extern zu verlangernde, magnetische Implantate vermindern die Zahl notwendiger operativer Eingriffe, tragen aber nicht zur Erhohung der Lebensqualitat bei. Unterschiedliche Formen der Skoliose benotigen verschiedene Therapieansatze. Wichtig ist die Kenntnis von der Art der Skoliose und dem wahrscheinlichen Verlauf. Abhangig davon muss die Familie entsprechend beraten und ein Therapiekonzept entwickelt werden. Wachstumsfreundliche Implantate werden als Ubergangslosung bis zur Wirbelsaulenversteifung eingesetzt.

Spinal muscular atrophy (SMA) is a fatal neurodegenerative disease of newborns and children caused by mutations or deletions of the survival of motoneuron gene 1 resulting in low levels of the SMN protein. While neuromuscular degeneration is the cardinal symptom of the disease, the reduction of the ubiquitously expressed SMN additionally elicits non-motoneuron symptoms. Impaired bone development is a key feature of SMA, but it is yet unknown whether this is an indirect functional consequence of muscle weakness or caused by bone-intrinsic mechanisms. Therefore, we radiologically examined SMA patients in a prospective, non-randomized cohort study characterizing bone size and bone mineral density (BMD) and performed equivalent measurements in pre-symptomatic SMA mice. BMD as well as lumbar vertebral body size were significantly reduced in SMA patients. This growth defect but not BMD reduction was confirmed in SMA mice by μCT before the onset of neuromuscular symptoms indicating that it is at least partially independent of neuromuscular degeneration. Interestingly, the number of chondroblasts in the hypertrophic zone of the growth plate was significantly reduced. This was underlined by RNAseq and expression data from developing SMA mice vertebral bodies, which revealed molecular changes related to cell division and cartilage remodeling. Together, these findings suggest a bone intrinsic defect in SMA. This phenotype may not be rescued by novel drugs that enhance SMN levels in the central nervous system only.

Reduktion und Retention des Krummungswinkels bei Kindern mit neuromuskularen Erkrankungen und progredienten Wirbelsaulendeformitaten. Progressive neuromyopathische Skoliose, welche konservativ nicht beherrscht werden kann (v. a. beim nicht gehfahigen Kind), und/oder Entwicklung eines Thoraxinsuffizienzsyndroms (TIS). Ungenugende Weichteildeckung, Korpergewicht 25 oder >50 kg, fehlende knocherne Verankerungsstrukturen (Rippen), ausgewachsenes Skelett (normalerweise Alter 50 % erzielt und eine Progression uber Jahre effektiv verhindert werden. Bei 495 ambulanten Verlangerungsprozeduren betrug die Rate an operationspflichtigen implantatassoziierten Komplikationen 3,7 %. Im Verlauf erhielten 29 % der 45 Kinder eine operative Revision. Mit der vorgestellten operativen „No-touch“-Technik zur Skoliosekorrektur kindlicher neuromyopathischer Deformitaten kann eine effektive Reduktion des Skoliosekrummungswinkels erreicht und gehalten werden. Vorteile der Methode sind ein teilweiser Erhalt der Wirbelsaulenflexibilitat und eine Reduktion wirbelsaulennaher Ossifikationen, was die definitive dorsale Spondylodese als Endpunkt der Behandlung erleichtert.

Purpose Magnetically controlled implant systems have been established to treat severe progressive spinal deformity in children. The purpose of this study was to evaluate (1) the ratio between achieved and expected distraction length, (2) the complication rate and its risk factors as well as (3) the correlation of the distraction length and the length of the spine. Methods A total of 40 patients with an average follow-up of 34 (14 to 57) months were prospectively included in the study. Children underwent lengthening procedures every three months. The ratio between the distraction lengths was determined by comparing the measured distraction length of the rod on radiographs with the distraction length displayed on the external remote controller for the magnetically controlled growing rod (MCGR). Age, weight, height, and complications were repeatedly recorded. Results The analysis of 746 procedures showed the actual distraction to be 94.4% of the expected one. No difference between implants on the concave and convex spinal side was observed. The overall complication rate was 4.6% mainly because of failure of the implant or lack of implant extension, which was directly related to an increased BMI. There was also a strong correlation between achieved implant distraction length and gain in spinal length. Conclusions Our study demonstrates a high ratio (0.94) between achieved and expected distraction length of magnetically controlled spinal rods. The complication rate was low (4.6%) and correlated to a high BMI. The correlation between the achieved implant distraction length and spinal length indicates the efficiency of the MCGR therapy. Level of evidence Therapeutic Level IV.

Purpose In young children, growth-friendly spinal implants with bilateral rib to pelvis fixation are used to control progressive spinal deformity. Whereas curve progression, complications and side-effects have been extensively studied in this patient population, no data are available on gait pattern changes and postural body adjustments. Our study evaluates whether gait pattern changed for ambulatory children treated with bilateral rib to pelvis implants compared to age-matched healthy children. Methods In this small cohort study, gait analysis was performed using spatiotemporal and kinematic parameters of four ambulatory children with severe scoliosis and growth-friendly spinal implants using the bilateral rib to pelvis fixation. Data were statistically analyzed and compared to seven healthy age-matched children. Results Between both groups, no differences were seen in walking speed, cadence and stride length. The treated patients showed a lower range of motion of the pelvic obliquity and of the trunk obliquity and rotation, but a higher knee flexion. Conclusions Growth-friendly spinal implants with bilateral rib to pelvis fixation are commonly used in wheelchair children and rarely indicated in ambulatory patients. The presented data show reduced trunk and pelvis motion using this implant construct. These findings help to understand body postural adjustments and add valuable information for families and care providers when considering this surgery. Level of evidence Therapeutic level IV.

Flexible flatfoot is among the most common skeletal disorders in childhood. This study describes the dynamic and static correction effects of subtalar arthroereisis in adolescents with flexible symptomatic flatfeet in comparison to normal subjects as well as to results before and after removal of metal. Eighteen adolescents with 25 symptomatic flexible flatfeet were treated surgically with a subtalar arthroereisis at a mean of 12.5 (10-16) years. At follow-up (mean 3.9 years, range 0.4-8), patients filled out the American Orthopaedic Foot and Ankle Society questionnaire, received radiographs and were examined using dynamic and static pedobarography as well as static hindfoot axis examination. Results were compared to healthy controls (n = 13; 26 feet). Surgically treated feet (n = 25) had better questionnaire results after surgery than before, but lower scores than healthy feet. Radiological parameters improved significantly after surgery. Removal of metal did not influence post-surgical results (follow-up 2.8 years). Surgically treated feet had larger contact areas than normal feet with predominance to the midfoot region. The relative maximum force, relative peak pressure and contact time were higher in the midfoot of treated feet compared to controls. When comparing pedobarography data of treated versus untreated feet of the same patients (subgroup n = 11 feet), there were no differences. Subtalar arthroereisis was able to effectively treat symptomatic flexible flatfeet in this population. Results improved significantly evaluating a questionnaire, radiographs, dynamic and static weight distribution, but were still worse than results of healthy feet. There was no relapse after removal of metal.

Purpose Growth-friendly spinal implants (GFSI) were established for scoliotic children as an interim solution until definite spinal fusion could be performed during puberty. While deformity control was clearly proven, the effects on vertebral shape and morphology are still unclear. Our prospective study assesses the effect of GFSI with continuous distraction on vertebral body shape and volume in SMA children in comparison with previously untreated age-matched SMA patients. Methods Cohort I (n = 19, age 13.2 years) were SMA patients without prior surgical scoliosis treatment. Cohort II (n = 24, age 12.4 years) were children, who had continuous spinal distraction with GFSI for 4.5 years. Radiographic measurements and computed tomography (CT) 3D volume rendering were performed before definite spinal fusion. For cohort II, additional radiographs were analyzed before the first surgical implantation of GFSI, after surgery and every year thereafter. Results Our analysis revealed decreased depth and volume in scoliotic patients with prior GFSI compared to scoliotic patients without prior implants. This difference was significant for the lower thoracic and entire lumbar spine. Vertebral body height and pedicle size were unchanged between the two cohorts. Conclusion CT data showed volume reduction in the vertebral body in scoliotic children after GFSI treatment. This effect was more severe in the lumbar and lower thoracic area. While vertebral height was identical in both groups, vertebral depth was reduced in the GFSI-treated group. Reduced vertebral depth and altered vertebral morphology should be considered before instrumenting the spine in previously treated scoliotic SMA children. Level of evidence III Diagnostic: individual cross-sectional studies with consistently applied reference standard and blinding.

ZusammenfassungDer kindliche Knick-Senk-Fuß ist eine 3-dimensionale Fußfehlstellung mit vermehrter Valgusstellung der Ferse, Abflachung der medialen Längswölbung und Abduktion des Vorfußes. Man unterscheidet die flexible von der kontrakten (rigiden) Form. Die Diagnostik gliedert sich in Anamnese, klinische Untersuchung, apparative Diagnostik wie Pedobarografie und die Ganganalyse sowie bildgebende Verfahren. Wichtig ist die Einbeziehung in ein Therapieschema von eventuell vorliegenden pädiatrischen oder neuropädiatrischen Erkrankungen (z. B. Muskeldystrophien, Ehlers-Danlos- oder Marfan-Syndrom u. Ä.). Es zeigt sich, dass bei Kindern ≤ 6 Jahre der flexible Knick-Senk-Fuß fast ausschließlich physiologisch vorkommt (bei 97% aller 19 Monate alten Kinder). Bis zum Alter von 10 Jahren bildet sich die mediale Fußlängswölbung zunehmend aus. Bei einem kleinen Anteil (10-jährige Kinder 4%) persistiert der Knick-Senk-Fuß oder wird progredient. Oberhalb von 10 Jahren besteht die Gefahr der Dekompensation mit zunehmender Rigidität. Nur die Minderheit der Kinder entwickelt eine Schmerzsymptomatik (

Background Context In several studies, vertical expandable prosthetic titanium rib (VEPTR) implants have shown good scoliosis control in children with the longest reported follow-up of 3.6 years. For growing rods, recent studies suggest a decreased efficiency of correction starting just after that time. To our knowledge, no long-term results of children with VEPTR treatment are available. Purpose This study aimed to evaluate spinal deformity in scoliotic children and to investigate correction potential of VEPTR implants at several time points of treatment, particularly after long-term follow-up. Study Design/Setting We performed a retrospective case series of 32 children with spinal deformity and VEPTR treatment with analysis of clinical and radiological data pre- and post-VEPTR implantation and every 2 years during the follow-up period. Patient Sample Thirty-two patients with spinal deformity and VEPTR treatment comprised the patient sample. Outcome Measures Patients had a primary VEPTR implantation due to spinal deformity and thoracic insufficiency syndrome and repeated lengthening procedures every 6 months. Clinical data were assessed and radiological parameters were analyzed. The main thoracic scoliotic curve and associated curves as well as kyphosis, lordosis, pelvic obliquity, and spinal length were measured in all radiographs until the end of VEPTR treatment or the last available examination. Methods Development of the different parameters during follow-up was evaluated and statistical analysis was performed with Statistica version 13.0. No funding was obtained for this study. The authors have no conflicts of interest to declare. Results Directly after VEPTR implantation, thoracic and lumbar curves corrected significantly, were stable at 2.8-year follow-up, and increased at 5.5-year follow-up, whereas cervical scoliosis was not affected by the treatment. The sagittal profile was initially improved both in kyphosis and lordosis. However, at 5.5-year follow-up, hyperkyphosis had deteriorated beyond the initial deformity. Pelvic obliquity was significantly restored especially in neuromuscular patients, and increasing spinal length was achieved within the 5.5-year follow-up. Conclusion In children with spinal deformity, implantation of the VEPTR device sufficiently corrected the deformity in all planes. During long-term follow-up, scoliosis increased slightly and was rather well controlled, whereas the implant system was not able to prevent deterioration of hyperkyphosis. Pelvic obliquity was well balanced and spinal lengthening was achieved during long-term follow-up.

BACKGROUND Almost all children with spinal muscular atrophy (SMA) develop a scoliosis during childhood and adolescence. In the last decades, growth-friendly spinal implants have been established as an interim solution for these patients until definite spinal fusion can be performed. The effect of those implants on the final outcome has yet to be described. OBJECTIVE To assess the effect of prior growth-friendly spinal surgical treatment on the outcome after spinal fusion in SMA children in comparison to untreated SMA patients through the prospective study. METHODS A total of 28 SMA patients with (n = 14) and without (n = 14) prior surgical treatment with growth-friendly implants were included. Average surgical treatment prior to definite spinal fusion was 4.9 yr. Scoliotic curve angle, pelvic obliquity, spinal length, kyphosis, and lordosis were evaluated for children with prior treatment and before and after dorsal spondylodesis for all children. RESULTS The curve angle before definite spinal fusion averaged at 104° for SMA patients without prior treatment and 71° for patients with prior treatment. Spondylodesis reduced the scoliotic curve to 50° and 33°, respectively, which equals a correction of 52% vs 54%. Pelvic obliquity could be improved by spinal fusion in all patients with better results in the pretreated group. Results for spinal length, kyphosis, and lordosis were similar in both groups. CONCLUSION These data show the positive effect of prior growth-friendly surgical treatment on radiographic results of spinal fusion in children with SMA. Both scoliotic curve angles and pelvic obliquity showed significantly better values when patients had growth-friendly implants before definite spinal fusion.

Cohen syndrome (CS) is a rare autosomal recessive disorder associated with mutations in the vacuolar protein sorting 13 homolog B (VPS13B; formerly COH1) gene. The core clinical phenotype comprises a characteristic facial gestalt, marked developmental delay, and myopia. Additional, nonobligatory features include obesity, microcephaly, short stature, muscular hypotonia, scoliosis, narrow hands and feet, progressive retinopathy, as well as neutropenia. Here we report a novel homozygous nonsense mutation in the VPS13B gene and previously undescribed clinical features in a 19-year-old woman with developmental delay, intellectual disability, and a particular facial appearance. The patient showed several features consistent with CS. In addition, the parents observed congenital alacrima and anhidrosis persisting until onset of puberty. The diagnosis was not established based on the clinical phenotype. We performed whole-genome sequencing and identified a novel homozygous nonsense mutation c.62T>G (NM_152564.4), p.(Leu21*) in the VPS13B gene. Our findings extended the previously reported phenotype of CS. We conclude that transient, prepubertal alacrima and anhidrosis are part of the phenotypic spectrum of CS associated with a novel homozygous nonsense mutation in the VPS13B gene. peerReviewed

Eighty and sixty maize fields were sampled in 1994 and 1995, respectively, to monitor Aspergillus infection and aflatoxin contamination of preharvest maize in Benin. Three Aspergillus species were isolated from different agroecological zones, with A. flavus being the most prevalent. The countrywide mean percentage of kernel infection was about 20% in both years. Aflatoxin was extracted from maize in at least 30% of the fields sampled. Toxin concentrations exhibited a distinct zonal variation, with relatively high levels in the Guinea Savanna. There was a trend toward higher rate of aflatoxin accumulation per percentage A. flavus infection from the south to the north. Damage by the ear borer, Mussidia nigrivenella, increased aflatoxin accumulation in maize. Hence, the geographic pattern observed in the occurrence of A. flavus and aflatoxin may be related to the incidence of M. nigrivenella.

ZusammenfassungAngeborene vaskuläre Malformationen sind häufig mit Problemen des muskuloskeletalen Systems vergesellschaftet. Stimulatives Wachstum führt zu Hypertrophien und Mehrwachstum, wie dies beispielsweise beim Klippel-Trenaunay-Syndrom mit einer zunehmenden Beinlängendifferenz vorkommt. Eine frühzeitige engmaschige klinische und radiologische kinderorthopädische Betreuung ist nötig, um rechtzeitig konservative oder operative Maßnahmen durchzuführen. Gravierende Beinlängendifferenzen im Wachstumsalter können in der Folge zu Skoliosen, aber auch rigiden Kontrakturen führen. Nach entsprechender Beobachtung und Planung sind wachstumshemmende operative Maßnahmen wie beispielsweise eine temporäre Epiphyseodese aufwändigeren verlängernden Verfahren oder Operationen nach Wachstumsabschluss vorzuziehen. Im Vorfeld einer Operation müssen zur Vermeidung von Komplikationen sorgfältige interdisziplinäre Abklärungen und Interventionen erfolgen beispielsweise zur Behandlung von Koagulopathien oder vorbereitenden Embolisationen im Operationsgebiet.

The objective of this study was to evaluate the presence of Aspergillus section Flavi and A. section Nigri in cashew nuts harvested in the Northern Guinea (NG) and Southern Sudanian (SS) agro-ecological zones of Benin. Also, the presence of aflatoxins was investigated. For detection of fungal contamination, a total of 100 kernels/sample (with disinfection) and 40 kernels/sample (without disinfection) were plated. Seventy samples from fourteen villages were used. Aflatoxins occurrence was analysed on 84 samples by ultraehigh performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). The average water content and the cashew nuts count were respectively 8.6% and 172 nuts/kg in NG and 8.7% and 174 nuts/kg in SS. Significant differences between villages in both zones were found for both water content and nuts count. In disinfected samples, strains of Aspergillus section Nigri were predominant, in NG and SS zones (90.2% and 87.2%) respectively. When non disinfected kernels were plated, A. section Nigri was predominant in both NG and SS zones, with percentages of 89.7% and 93.4%, respectively. None of the 84 nuts samples were positive for natural occurrence of aflatoxins with a detection limit of 0.05 e0.2 mg/kg.

OBJECTIVEDuring childhood, early-onset scoliosis (EOS) may show severe progressive deformity, which consequently leads to aggressive treatment strategies, such as serial casting, long-term bracing, or surgical interventions. The latter usually includes repeated surgeries for implant lengthening every 6 months in order to allow sufficient growth of the thorax and spine. In 2011, the 24-item Early-Onset Scoliosis Questionnaire (EOSQ-24) was introduced to measure health-related quality of life for this patient group and their families. Since then, cross-culturally adapted versions of the EOSQ-24 have been published in Spanish, Turkish, traditional Chinese, and Norwegian. The purpose of the study was to transculturally adapt the original English version of the EOSQ-24 into the German language and evaluate the reliability of the German version.METHODSAfter adaptation and forward/backward translation, the German version of the EOSQ-24 was given to the parents or caregivers of 67 EOS patients (33 male, 34 female) Data quality was evaluated by mean, standard deviation, percentage of data missing, and extent of ceiling and floor effects. Reliability was estimated by internal consistency using Cronbach α and item-total correlations.RESULTSIn the study group (n = 67), 12 children were either observed (n = 7) or treated with a brace (n = 5). The other 55 patients were treated surgically with growth-friendly implants. The item response to the German EOSQ-24 was high with a minimum of missing data (1.7%). All items showed very good to excellent internal consistencies (0.879–0.903). Floor effects for the 24 items were between 0% and 31% and ceiling effects between 9% and 78%. The calculated Cronbach α for the 24-item scale was 0.9003, indicating excellent reliability.CONCLUSIONSThe German adaptation of the EOSQ-24 shows excellent reliability and therefore is a valid tool to measure objective health-related quality of life in children with EOS.

Children with severe spinal deformity frequently are managed with growth-friendly implants. After initial surgery, externally controlled magnetic rods allow spinal deformity correction during growth without further surgical intervention. The ability to lengthen the spine without additional surgical procedures is especially beneficial in high-risk children, such as those with spinal muscular atrophy (SMA). The purpose of the present study was to assess the level of control of spinal deformity in a homogeneous group of patients with SMA who were managed with magnetically controlled implants for 2 years.This prospective, nonrandomized study included 21 non-ambulatory children with type-II SMA and progressive scoliosis who were managed bilaterally with a magnetically controlled implant that was inserted parallel to the spine with use of rib-to-pelvis hook fixation. Radiographic measurements of scoliotic curves, kyphosis, lordosis, pelvic obliquity, and spinal length were performed before and after implantation of the magnetically controlled device and during external lengthening. The mean duration of follow-up was 2 years.The mean main curve of patients without prior vertical expandable prosthetic titanium rib (VEPTR) treatment decreased from 70° before implantation of the magnetically controlled device to 30° after implantation of the device. Correction was maintained during the follow-up period, with a mean curve of 31° at the time of the latest follow-up at 2.2 years. Pelvic obliquity was surgically corrected by 76% (from 17° to 4°) and remained stable during follow-up. Thoracic kyphosis could not be corrected within the follow-up period. Spinal length of children without prior spinal surgery increased by50 mm immediately after device implantation and steadily increased at a rate of 13.5 mm/yr over the course of treatment. During treatment, 4 general complications occurred and 6 lengthening procedures failed, with 3 patients requiring surgical revision.Bilateral implantation of an externally controlled magnetic rod with rib-to-pelvis fixation represents a safe and efficient method to control spinal deformity in children with SMA, achieving sufficient and stable curve correction as well as increased spinal length. The complication rate was lower than those that have been described for VEPTR and other growing rod instrumentation strategies.Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Background The impact of backpack carrying on body postural changes in schoolchildren has been discussed intensively. However, findings are inconsistent mainly due to the lack of long-term results. Objective The purpose of this investigation was to study the influence of backpack weight on body posture and prevalence of back pain. Methods In our prospective, comparative study, we investigated the influence of backpack weight on 77 schoolchildren (average age 10.8 ± 0.7 years) over a 1-year period. Participants were evaluated at the beginning of the study by clinical examination and formal static posture analysis. Forty-nine students comprised the control group while 28 students in the intervention cohort had the weight of their backpacks reduced by 2 kg. All students were reevaluated after 6 and 12 months by formal postural examination. Results Children with reduced backpack weights had a significantly improved bending posture when wearing their backpacks when compared to the participants of the control group, whereas the analysis of the children while they did not wear their backpacks revealed no difference between the groups. Within the follow-up period all postural changes were reversible once the backpack weight was removed. Conclusions Schoolchildren with heavy backpack loads show postural changes while carrying their backpack but this impact was reversible when backpacks were removed. Continuous reduction of backpack loads minimizes prevalence of back pain.

Patients with psychiatric disorders of significant neurodevelopmental origin, such as schizophrenia and autism frequently experience genuine motor abnormalities, such as neurological soft signs (NSS). Previous MRI studies in patients with schizophrenia have shown that NSS are associated with abnormal cortical, thalamic and cerebellar structure and function. So far, however, no neuroimaging study focused on the role of the local gyrification index (LGI) in the pathophysiology of NSS. This study sought to explore the relationship between NSS and folding patterns of the cerebral cortex that are thought to be established during early brain development. In this study, whole brain high-resolution magnetic resonance imaging (MRI) at 3 Tesla was used to investigate the LGI in 33 patients with recent-onset schizophrenia. Cortical reconstruction was performed with the Freesurfer image analysis suite. NSS were examined on the Heidelberg Scale and related to LGI. Age, gender, years of education and medication were considered as potential confounding variables. In summary, higher NSS scores were positively associated with morphological changes of LGI predominantly in parietal and occipital areas. Our results confirm the hypothesis of a significant relationship between LGI changes and the NSS expression in schizophrenia. Investigation of LGI may help to explain subtle motor symptoms such as NSS in schizophrenia.

Spine-based fixation of magnetically controlled lengthening devices has been successfully performed for children with early-onset scoliosis. However, spinal manipulation may lead to ossifications, stiffness, and autofusion as previously described. To avoid these problems, a surgical technique combining bilateral externally controlled magnetic device implantation with a rib cradle and pelvic hook fixation was introduced by us in 2011. By using a bilateral single-rib or double-rib cradle fixation and a pelvic hook, the magnetic device is percutaneously inserted. The spine corrects indirectly without further manipulation. In small rib diameter or severe osteoporosis, double-rib cradles are used. Our introduced technique enables modification of the rib vertebral angle, which may be beneficial in children with spinal muscular atrophy and rib-cage deformity. This nonrandomized prospective study describes 18 children with neuromuscular scoliosis treated first by this method. All patients followed the same protocol, with expansion procedures being performed 5 months after surgery and every 3 months thereafter. Clinical, radiologic, and complication data were analyzed, showing a significant reduction in scoliosis and pelvic obliquity and an increase in spinal length, which could be maintained over a follow-up period of 1.2 years. The overall complication rate was lower than previously described, with 8%, 2 of them requiring surgery.

Bacterial colonization of spinal implants may cause severe complications in patients with early-onset scoliosis. Correct diagnosis and detection of microbiologic formation is crucial to prevent delayed infections caused by bacterial colonization. The purposes of this study were to estimate the rate and risk factors of colonization of vertical expandable prosthetic titanium rib (VEPTR) implants in children and to compare the different methods for detecting microbiologic formation on the spinal implants.We evaluated prospectively a group of 42 children with spinal deformities with an overall of 95 lengthening surgeries and applied different methods to detect potential bacterial colonization of VEPTR implants: swab of the implant, swab with culture of tissue, analysis of the removed lock, polymerase chain reaction (PCR), and confocal microscopy. Potential risk factors were evaluated.Of 42 patients, 17 (40%) were rated positive for bacterial colonization with Propionibacterium acnes and coagulase-negative staphylococci being the most commonly found bacteria. Risk factors for colonization were increasing age, body height, and weight. The swab with culture of removed tissue yielded most positive results, whereas direct microscopy and PCR were the least sensitive detection methods. Furthermore, commonly used infectious blood parameters were inconclusive.Although the impact of bacterial colonized implants on the health of the patients is not fully elucidated, clinicians aim for prevention of microbiologic formation on implanted devices. Therefore, reliable, inexpensive, and easy to apply diagnostic tools are indispensable to detect colonization. Based on our data, the swab together with tissue culture has the potential to become the method of choice for future diagnosis.

Frakturen des proximalen Radiusendes im Wachstumsalter weisen 3 Besonderheiten auf: Das Radiuskopfchen artikuliert mit 2 Gelenkpartnern und ist somit fur eine ungestorte Ellbogenfunktion unerlasslich. Die Versorgung des proximalen Radiusendes erfolgt durch periostale Gefase im Sinne einer Endstrombahn. Hieraus resultiert eine extreme Vulnerabilitat, sodass bei schweren Traumata – sei es durch Unfall oder Behandlung – Teil- oder Vollnekrosen mit Verplumpungen im Kopf-Hals-Bereich entstehen. Irreversible Komplikationen bilden die radioulnare Synostose und die chronische Epiphysenlosung, welche auch nach exzessiver Physiotherapie entstehen kann. Trotz einer niedrigpotenten Fuge zeigt das proximale Radiusende beim jungen Patienten eine enorme Spontankorrektur von Abkippungen. Seit-zu-Seit-Verschiebungen werden allerdings nicht remodelliert. Therapeutisch sollte moglichst atraumatisch vorgegangen werden. Wegen der Blutversorgungssituation sollten bei entsprechender Indikation unbedingt die Spontankorrektur und eine kurze Ruhigstellungszeit ohne Physiotherapie in ein Therapiekonzept integriert werden. Falls operiert werden muss, sind wiederholte traumatisierende Repositionsmanover zu unterlassen, im Zweifelsfall kann mit einem intramedullaren Nagel geschlossen oder schonend offen reponiert werden. Um den Besonderheiten des proximalen Radiusendes therapeutisch gerecht zu werden, mussen Vulnerabilitat und Korrekturpotenz gegeneinander abgewogen werden. Die Therapie muss so atraumatisch wie moglich sein. Das Spontankorrekturpotenzial sollte in die Primartherapie integriert werden, ohne dieses Potenzial in Bezug auf Ausmas und Alter der Patienten zu uberfordern.

Cassava chips were stored for 8 months in PICS bags, with half of the bags having a natural initial insect infestation, and the other half having this initial natural infestation augmented with 50 Prostephanus truncatus adults. Chips stored in traditional woven polypropylene bags served as controls. Oxygen levels varied during storage from 19.98 to 17.56%, 20.4 to 18.40%, and 20.24 to 19.92%, respectively, in PICS bags with augmented infestation (PICS-A), PICS bags under natural infestation levels (PICS-N) and polypropylene bags (WPP). Carbon dioxide levels varied from 0.73 to 3.90%, 0.65–3.56%, and 0.20–0.61%, respectively, in the three types of bags. P. truncatus populations were significantly higher in PICS-A reaching 98.66 ± 7.21 individuals/kg at the end of storage, compared to 92.66 ± 4.71 in PICS-N and 100.55 ± 3.56 in WPP. Dinoderus spp. density was significantly higher in WPP with 270.55 ± 20.59 individuals/kg after 8 months. The number of holes on chips and weight losses also increased with storage duration in all three treatments, but were significantly higher in WPP. Holes created by insects were noticed in PICS bags and were more important in the inner HDPE (high-density polyethylene) layer than in the outer HDPE layer. Up to 1913.00 ± 114.13 holes were observed on the inner HDPE layer of PICS bags and 1039.00 ± 29.40 in the outer HDPE layer. Hermetic storage bags prolong the storability of chips by approximately 1 month. PICS efficacy was probably affected by the large size of traditional cassava chips with large airspaces between individual chips, leading to a large oxygen store for insects which could not be used up through biotic activity, so that bags were not hermetic. In conclusion, PICS bags cannot be recommended for the storage of large sized traditional cassava chips.

A total of 420 samples were collected from agrarian households. Whereas 51% (215/420) of the samples were contaminated with one or more toxins, the contamination rates for maize, peanut, and cassava products were 74, 62, and 24%, respectively. The fumonisins (20-5412 μg/kg), aflatoxin B1 (6-645 μg/kg), roquefortine C (1-181 μg/kg), and deoxynivalenol (27-3842 μg/kg) were the most prevalent contaminants in maize. For peanut samples, aflatoxin B1 (6-125 μg/kg) and ochratoxin A (0.3-12 μg/kg) were the main contaminants, whereas aflatoxin B1 (6-194 μg/kg) and penicillic acid (25-184 μg/kg) were detected in the cassava products. Exposures calculated through maize intake for fumonisin B1 and aflatoxin B1 were several-fold higher (2-5 for fumonisin B1 and 10(4)-10(5) for aflatoxin B1) than the health-based guidance values of 2 μg/kg bw/day and 0.15 ng/kg bw/day, respectively. The study design constitutes a good model that can be implemented in other sub-Saharan African countries.

The purpose of this research is to screen different processes that could potentially decrease or even eliminate rotenone, a toxic isoflavonoid, from Pachyrhizus seeds. Yam bean seeds have very interesting nutritional characteristics, especially their high protein and lipid contents, and could potentially increase food security in under-nourished populations. However, they contain rotenone, a natural molecule previously used as an insecticide inhibiting the respiratory mitochondrial chain. It was also proven to be toxic to mammals as chronic exposure leads to the development of Parkinson-like symptoms in rats. As the thermosensitivity of rotenone had been reported, this study tested different processes (drying, roasting, boiling, frying, alcohol extraction), tegument removal, and traditional Beninese culinary recipes. Rotenone was then quantified in end-products by a validated method, associating microwave extraction, solid phase extraction (SPE), and HPLC-UV. With these processes a rotenone removal of up to 80% was obtained. The most effective methods were the drying and roasting of the seeds and the maceration of their flour in local alcohol. Rotenone degradation and elimination were confirmed by cytotoxic assays, effectively inducing a decrease in sample toxicity.

Study Design. Retrospective analysis of 1328 spinal radiographs of 57 patients after vertical expandable prosthetic titanium rib (VEPTR) implantation with an average follow-up of 30 months. Objective. To evaluate the incidence, time of onset, as well as the underlying factors influencing the occurrence of ossifications in children treated with VEPTR. Summary of Background Data. Spontaneous spinal fusions and ossifications are well known in children treated with spinal implants. In theory, children with spinal deformity and VEPTR implantation are less likely to develop these complications because of either little or no implant contact to the spine. Methods. Fifty-seven patients had a primary VEPTR implantation due to spinal deformity and thoracic insufficiency syndrome and repeated lengthening procedures. The mean age at the time of primary surgery was 7.7 years, the mean duration of follow-up was 29.8 months, and the mean number of operations was 5.9. A total of 1328 spinal radiographs were analyzed with respect to the occurrence and growth of ossifications, implant migration, and other complications. Results. Overall, 24% of the patients (n = 13) had ossifications, which affected in 92% the main load sharing VEPTR implant. The fusions involved in 54% of cases the lumbar spine and in each 23% the ribs and the iliac crest. Ossifications developed in 11% of children within the first year of treatment and increased by about the same rate per annum. After 53 months, 48% of the radiographs showed some ossifications. There was a significant correlation to the stiffness of the deformity and the number of surgical procedures. Conclusion. Contrary to previous assumptions, it was shown that in children treated with the VEPTR system, 48% of children showed ossifications after 53 months. Ossifications were observed significantly more often in children with stiff deformities and after multiple surgical procedures. It is a much more common problem than previously thought. Conclusion. Level of Evidence: 3

Fungal contaminants in major food staples in Kenya have negatively impacted food security. The study sought to investigate peanut market characteristics and their association with levels of aflatoxin in peanuts from Western, Nyanza and Nairobi Provinces of Kenya. Data were collected from 1263 vendors in various market outlets using a structured questionnaire, and peanuts and peanut products from each vendor were sampled and analyzed for aflatoxin levels. Thirty seven per cent of the samples exceeded the 10 μg/kg regulatory limit for aflatoxin levels set by the Kenya Bureau of Standards (KEBS). Raw podded peanuts had the lowest (χ2 = 167.78; P 10 μg/kg of aflatoxin. Over 70% of all storage structures were poorly ventilated and dusty. Sorting comprised 53% of the various crop protection measures used by traders post-harvest. To reduce aflatoxin exposure to consumers, set standards need to be complemented by strict monitoring systems and education of producers, processors and consumers in crop commodities other than maize, which has received the most attention in Kenya. Alternative uses of contaminated produce need to be explored.

Study design Case Series. Objective To describe the post-VEPTR (vertical expandable prosthetic titanium rib) treatment changes in early-onset spinal deformity (EOSD), which may influence the final correction spondylodesis. Summary of background data The VEPTR device, originally developed for the treatment of congenital rib cage malformation, is nowadays more widely used in the treatment of EOSD. At present, only a few reports describe the possible complications that may occur with repeated lengthening procedures of the VEPTR, thereby making the final spondylodesis more complicated and less satisfactory. Methods X-rays of 5 children treated for EOSD with 2 unilateral VEPTR (each rib to rib and rib to lumbar lamina) were analyzed for curve patterns and Cobb angles before, during, and at the end of VEPTR treatment, and after the final spondylodesis. Intraoperative observations during the spondylodesis, which influenced the possibilities of the curve correction, were documented. Results All patients showed a marked decompensation of the frontal balance and a high degree of rigidity of the main curve and the compensatory curves after treatment with the VEPTR device. Because of this spontaneous autofusion of spinal segments, migration of the rib cradles and/or the laminar hook, and a change in the curve patterns, the final fusion had to be longer in all patients than the primary deformity would have intended. Conclusions If an EOSD is treated with VEPTR, the curve progression and, in particular, the development of a high thoracic hyperkyphosis or rotation of the main curve should be critically observed. Autofusion of ribs and vertebral bodies may make the final correction spondylodesis even more challenging and risky for the patient and the end result less satisfactory.

Maize was artificially infested with either 10 or 25 individual Prostephanus truncatus (Horn) and Sitophilus zeamais (Motschulsky) or a mixture of both, and stored in a hermetic grain bag (HGB) or a woven polypropylene bag (WPB) for 150 days. Population growth of P. truncatus and S. zeamais during storage was low in HGB, while in WPB, the insect population increased significantly with storage duration. Mortality rate during storage was significantly higher in HGB than in WPB. After 60 days of storage, the average mortality rate of 99.50% was observed in HGB infested with 25 P. truncatus, and 100% for S. zeamais at the same infestation density after 90 days of storage. Grain losses were significantly lower in HGB compared with WPB. Less than 0.5 and 6.0% losses were obtained, respectively, for S. zeamais and P. truncatus in HGB infested with 25 individual insects after 150 days of storage, whereas losses of 19.2% (infestation with S. zeamais) and 27.1% (infestation with P. truncatus) were observed in WPB. HGB seems to be resistant to the perforation of S. zeamais, but not to P. truncatus. The moisture content of maize grains stored in HGB remained practically the same during storage, compared with the levels in WPB, which reduced with storage time. WPB could be used for maize storage, protecting it against insect infestation without the need for insecticide use.

Mycotoxins contamination in some agricultural food commodities seriously impact human and animal health and reduce the commercial value of crops. Mycotoxins are toxic secondary metabolites produced by fungi that contaminate agricultural commodities pre- or postharvest. Africa is one of the continents where environmental, agricultural and storage conditions of food commodities are conducive of Aspergillus fungi infection and aflatoxin biosynthesis. This paper reviews the commodity-wise aetiology and contamination process of aflatoxins and evaluates the potential risk of exposure from common African foods. Possible ways of reducing risk for fungal infection and aflatoxin development that are relevant to the African context. The presented database would be useful as benchmark information for development and prioritization of future research. There is need for more investigations on food quality and safety by making available advanced advanced equipments and analytical methods as well as surveillance and awareness creation in the region.

In West Africa, the most damaging lepidopteran pest of maize ears is the pyralid Mussidia nigrivenella . Although it is mostly described as a field pest, it can be found feeding on maize stored for up to 4 months. A survey was conducted in Benin in 2006 to assess M. nigrivenella infestations in different maize storage systems in the Southern (SGS) and Northern Guinea Savanna (NGS). In SGS and NGS the percentage of infested stores decreased from 86.7% to 26.7% and from 51.4% to 14.3%, respectively, during the first 28 weeks of storage. During the same time, mean numbers of M. nigrivenella per cob decreased from 0.36 to 0.04 across both zones. All larval stages, but mostly 3rd–5th instars, were frequently found even after more than 12 weeks, indicating that M. nigrivenella may have reproduced in storage, although reinfestation or delayed development could also explain this observation. The highest M. nigrivenella incidences of 16.8% and 14.4% were found in the “Ava” and crib stores, respectively. Infestations were highest in “Ava” and lowest in maize grain stored in polyethylene bags or in mud silos. In a laboratory experiment, the presence of post-harvest beetles negatively affected the bionomics of M. nigrivenella , indicating strong interspecific competition.

Fungal infection and aflatoxin contamination was evaluated on 180 samples of dried vegetables such as okra, hot chilli, tomato, melon seeds, onion and baobab leaves from Benin, Togo and Mali collected in September to October 2006. These products are dried to preserve them for lean periods and decrease their perishability. Fungal contamination was evaluated after plating on selective media with a total of 561 fungal isolates identified, ranging from 18 in tomato and 218 in baobab leaves. Baobab leaves, followed by hot chilli and okra showed high incidence of fungal contamination compared to the other dried vegetables, while shelled melon seeds, onion leaves and dried tomato had lower levels of fungal contamination. Species of Aspergillus were dominant on all marketed dried vegetables irrespective of country. Mycotoxin assessment by Reversed-Phase High Performance Liquid Chromatography showed that only okra and hot chilli were naturally contaminated with aflatoxin B(1) and aflatoxin B(2), at concentrations of 6.0 microg/kg on okra and 3.2 microg/kg on hot pepper. This is the first time that mycotoxigenic fungi and resultant toxins were found on dried vegetable products sampled from African markets. Previous reports have mostly highlighted the risk of mycotoxin exposure from staple crops in Africa, but such risks now need to be evaluated for other products such as dried vegetables.

Erectile dysfunction (ED) is often associated with increased cardiovascular risk. There is increasing evidence suggesting that dysfunction of the vascular endothelium with reduced bioavailability of nitric oxide (NO) may be the pathogenetic link between ED and cardiovascular disease. The crucial importance of the NO-guanylatecyclase-cGMP-phosphodiesterase pathway for penile erection is mirrored by the efficacy of phosphodiesterase-5 (PDE5) inhibitors in the treatment of ED. In contrast to other currently available PDE5 inhibitors with a half-life time of about 4 h Tadalafil has a half-life time of about 17.5 h resulting in erectile responsiveness for up to 36 h after 1 single dose. Most clinical experience has been reported with on-demand use of PDE-5 inhibitors, but meanwhile several studies were able to demonstrate that Tadalafil given daily in low (2.5 and 5 mg) doses is both highly effective and well-tolerated. In three randomized, double-blind, placebo-controlled multi-center trials, various validated measures of erectile function indicated that once daily Tadalafil at doses of 2.5, 5, and 10 mg was significantly superior to placebo.In another mono-center trial, once daily Tadalafil has shown significant efficacy even after failure of on-demand treatment. In a controlled cross-over study of on-demand versus daily Tadalafil treatment, 72% of the patients preferred once daily administration, mainly because of superior and longer efficacy allowing a more spontaneous sexual life. Interestingly in a pilot study of on-demand versus chronic administration of Tadalafil for 4 weeks, only regular dosing improved several markers of endothelial function.