Visual Impairment and Functional Classification in Children with Cerebral Palsy.

BACKGROUND: Cerebral palsy (CP) is the most common motor impairment in childhood and often accompanied by a broad spectrum of comorbidities. Data are sparse concerning visual impairment (VI) and functional classification among CP children. OBJECTIVE: The objective of this study was to analyze the prevalence of VI among children with CP and to investigate a possible association between VI and Gross Motor Function Classification System (GMFCS) and the Bimanual Fine Motor Function (BFMF). METHODS: In this hospital-based study, records of 200 children with CP aged 2 to 17 years were reviewed. RESULTS: Overall, VI was found in 59.5% of children with CP. Prevalence of VI was higher when compared with non-CP children. A correlation between GMFCS as well as BFMF and severity of VI was found. Children with severe CP were at greater risk for severe VI, especially cerebral VI compared with children with mild CP. CONCLUSION: VI is a significant problem in children with CP and is correlated with motor function. Children with CP should undergo detailed ophthalmologic and orthoptic assessment to enable early intervention.

[Identification of rheumatological health apps in the Apple app store applying the "semiautomatic retrospective app store analysis" method : A longitudinal observation]. / Identifikation rheumatologischer Gesundheits-Apps im Apple App Store mit der Methode der "semiautomatischen retrospektiven App Store-Analyse" : Eine longitudinale Betrachtung.

BACKGROUND: The Apple and Google app stores offer a wide range of health apps. It is still a challenge to find valuable and qualified apps. OBJECTIVE: Can German language apps be identified using the "semiautomated retrospective app store analysis" (SARASA) method for the field of rheumatology? MATERIAL AND METHOD: The SARASA is a semiautomated method to select and characterize apps listed in the app store. After the first application in February 2018 SARASA was applied again to the Apple app store in February 2020. RESULTS: In February 2018 it was possible to acquire metadata for 103,046 apps and in February 2020 data for 94,735 apps that were listed in the category "health and fitness" or "medicine" in Apple's app store frontend for Germany. After applying the search terms 59 apps with a German language app description were identified for the field of rheumatology in 2018 and 53 apps in 2020. For these, more detailed manual reviews seem worthwhile. In 2018, the apps found were more likely to address patients than physicians and this was more balanced in 2020. In addition, it became apparent that for certain diseases there was no app developer activity. The percentage breakdown of matches by search term revealed substantial fluctuations in the app market when comparing 2018 to 2020. DISCUSSION: The SARASA method provides a useful tool to identify apps from app stores that meet predefined, formal criteria. Subsequent manual checks of the quality of the contents are still necessary. Further development of the SARASA method and consensus and standardization of quality criteria are worthwhile. Quality criteria should be considered for offers of mobile health apps in app stores.

Piroxicam inhibits herpes simplex virus type 1 infection in vitro.

Piroxicam is a potent, nonsteroidal, anti-inflammatory agent (NSAID) which also exhibits antipyretic activity. The antiviral effect of piroxicam against herpes simplex virus type 1 (HSV-1) was examined in vitro on RC-37 monkey kidney cells using a plaque reduction assay. Piroxicam was dissolved in ethanol or dimethylsulfoxide (DMSO) and the 50% inhibitory concentration (IC50) was determined at 4 µg/ml and 75 µg/ml, respectively. The IC50 for the standard antiherpetic drug acyclovir was determined at 1.6 µM. At non-cytotoxic concentrations of these piroxicam solutions, plaque formation was significantly reduced by 62.4% for ethanolic piroxicam and 72.8% for piroxicam in DMSO. The mode of antiviral action of these drugs was assessed by time-on-addition assays. No antiviral effect was observed when cells were incubated with piroxicam prior to infection with HSV-1 or when HSV-1 infected cells were treated with dissolved piroxicam. Herpesvirus infection was, however, significantly inhibited when HSV-1 was incubated with piroxicam prior to the infection of cells. These results indicate that piroxicam affected the virus before adsorption, but not after penetration into the host cell, suggesting that piroxicam exerts a direct antiviral effect on HSV-1. Free herpesvirus was sensitive to piroxicam in a concentration-dependent manner and the inhibition of HSV-1 appears to occur before entering the cell but not after penetration of the virus into the cell. Considering the lipophilic nature of piroxicam, which enables it to penetrate the skin, it might be suitable for topical treatment of herpetic infections.

[Future trend medical apps. From the apps store directly into medical practice?]. / Zukunftstrend "Medical Apps". Vom App-Store direkt in die medizinische Anwendung?

In day to day medical care, patients, nursing staff and doctors currently face a bewildering and rapidly growing number of health-related apps running on various "smart" devices and there are also uncountable possibilities for the use of such technology. Concerning regulation, a risk-based approach is applied for development and use (including safety and security considerations) of medical and health-related apps. Considering safety-related issues as well as organizational matters, this is a sensible approach but requires honest self-assessment as well as a high degree of responsibility, networking and good quality management by all those involved. This cannot be taken for granted. Apart from regulatory aspects it is important to not only consider what is reasonable, helpful or profitable. Quality aspects, safety matters, data protection and privacy as well as liability issues must also be considered but are often not adequately respected. If software quality is compromised, this endangers patient safety as well as data protection, privacy and data integrity. This can for example result in unwanted advertising or unauthorized access to the stored data by third parties; therefore, local, regional and international regulatory measures need to be applied in order to ensure safe use of medical apps in all possible areas, including the operating room (OR) with its highly specialized demands. Lawmakers need to include impulses from all stakeholders in their considerations and this should include input from existing private initiatives that already deal with the use and evaluation of apps in a medical context. Of course, this process needs to respect pre-existing national, European as well as international (harmonized) standards.

Anatomic double-bundle ACL reconstruction restricts knee extension in knees with hyperextension.

PURPOSE: Double-bundle ACL reconstruction has been demonstrated to be at least as effective as single-bundle reconstruction in terms of restoring knee rotational and translational stability. Until now, the influence on knees with hyperextension has not been evaluated. It was the purpose of this study to evaluate whether double-bundle ACL reconstruction restricts extension in hyperextendable knees. METHODS: Hamstring tendon reconstructions of 10 human cadaveric knees with the ability of hyperextension (age: 48 ± 14 years) were performed as single bundle (SB) on one side and double bundle (DB) on the other side. A surgical navigation system (BrainLab, Germany) was used to assess the kinematics of each knee at the intact and reconstructed state. A difference with regard to the anterior-to-posterior translation (AP) and rotational stability at 30° of knee flexion, 90° of flexion and the hyperextension capability of each specimen was analysed. RESULTS: The difference in AP translation before and after the reconstruction was not significantly different in 30° and 90° of flexion (n.s). Both single- and double-bundle reconstructions restored the preoperative kinematics at 30° and 90° of knee flexion (n.s). The knee extension was 4° ± 1.8° with the intact ACL and 4° ± 1.7° after reconstruction in the SB group (n.s). The knee extension was 5° of hyperextension ± 1.1° with the intact ACL and 0° ± 0.4° after reconstruction in the DB group; the limitation of the extension was significantly larger in this group (p = 0.013). CONCLUSION: Both single- and double-bundle ACL reconstruction techniques are capable of restoring knee anteroposterior and rotational stability. Double-bundle reconstructions significantly reduce knee extension in knees with hyperextension capability. Care must be taken when using double-bundle techniques in patients with knee hyperextension as this procedure may limit the knee extension after double-bundle ACL reconstruction.

Requirement for Wnt3 in vertebrate axis formation.

Several studies have implicated Wnt signalling in primary axis formation during vertebrate embryogenesis, yet no Wnt protein has been shown to be essential for this process. In the mouse, primitive streak formation is the first overt morphological sign of the anterior-posterior axis. Here we show that Wnt3 is expressed before gastrulation in the proximal epiblast of the egg cylinder, then is restricted to the posterior proximal epiblast and its associated visceral endoderm and subsequently to the primitive streak and mesoderm. Wnt3-/- mice develop a normal egg cylinder but do not form a primitive streak, mesoderm or node. The epiblast continues to proliferate in an undifferentiated state that lacks anterior-posterior neural patterning, but anterior visceral endoderm markers are expressed and correctly positioned. Our results suggest that regional patterning of the visceral endoderm is independent of primitive streak formation, but the subsequent establishment of anterior-posterior neural pattern in the ectoderm is dependent on derivatives of the primitive streak. These studies provide genetic proof for the requirement of Wnt3 in primary axis formation in the mouse.

Imprinted expression of the murine Angelman syndrome gene, Ube3a, in hippocampal and Purkinje neurons.

Angelman syndrome (AS) is a human genetic disorder characterized by mental retardation, seizures, inappropriate laughter, abnormal galt, tremor and ataxia. There is strong genetic evidence that the disorder is associated with a maternally expressed, imprinted gene mapping to chromosome 15q11-13. Affected patients demonstrate varied molecular abnormalities, including large maternal deletions, uniparental paternal disomy (UPD). Imprinting mutations and loss of function mutations of E6-associated-protein (E6-AP) ubiquitin-protein ligase (UBE3A). All of these abnormalities are associated with loss of maternal expression of UBE3A. Although mutations in UBE3A cause AS, indicating that maternal-specific expression of UBE3A is essential for a normal phenotype, evidence for maternal-specific expression of UBE3A has been lacking. Using mice with partial paternal UPD encompassing Ube3a to differentiate maternal and paternal expression, we found by in situ hybridization that expression of Ube3a in Purkinje cells, hippocampal neurons and mitral cells of the olfactory bulb in UPD mice was markedly reduced compared to non-UPD littermates. In contrast, expression of Ube3a in other regions of the brain was only moderately or not at all reduced in UPD mice. The major phenotypic features of AS correlate with the loss of maternal-specific expression of Ube3a in hippocampus and cerebellum as revealed in the mouse model.

[Implant-free tibial fixations of the posterior cruciate ligament. Development and biomechanical testing]. / Implantatfreie tibiale Fixierung des hinteren Kreuzbandes. Entwicklung und biomechanische Testung.

BACKGROUND: A secure tibial press fit technique in posterior cruciate ligament reconstructions may be a relevant alternative to common techniques because no hardware is necessary. Up to the present point in time no biomechanical data exist for a tibial press fit posterior cruciate ligament (PCL) reconstruction. This study compares the biomechanical properties of hamstring and quadriceps tendon grafts using a press fit technique with those of an interference screw fixation. METHODS: Quadriceps and hamstring tendons of 20 human cadavers (age 49.2±18.5 years) were used. A press fit fixation with a knot in the semitendinosus tendon (K) and a quadriceps tendon bone block graft (Q) were compared to an interference screw fixation (I) in 27 porcine tibiae. In each group, nine constructs were cyclically stretched and then loaded until failure. Maximum load to failure, stiffness and elongation during failure testing and cyclical loading were investigated. RESULTS: The maximum load to failure was 518±157 N (387-650 N) for the K group, 558±119 N (466-650 N) for the I group and 620±102 N (541-699 N) for the Q group. The stiffness was 55±27 N/mm (18-89 N/mm) for the K group, 117±62 N/mm (69-165 N/mm) for the I group and 65±21 N/mm (49-82 N/mm) for the Q group. The stiffness of the I group was significantly larger (ANOVA on ranks, P=0.01). The elongation during cyclical loading was significantly larger for all groups from the 1st to the 5th cycle compared to the elongation in between the 5th and the 20th cycle (P<0.03). CONCLUSION: All techniques exhibited larger elongation during initial loading. Load to failure and stiffness were significantly different between the fixations. The Q fixation showed equal biomechanical properties compared to a pure tendon fixation (I) with an interference screw. The results of group K were inferior. All three investigated fixation techniques exhibit comparable biomechanical properties. Preconditioning of the constructs is critical. Future randomized, clinical trials have to investigate the biological effectiveness of these fixation techniques.

The circadian system and mood related behavior in mice.

Most organisms on earth have evolved an internal clock in order to predict daily recurring events. This clock called circadian clock has a period of about 24 h and allows organisms to organize biochemical and physiological processes over one day. Changes in lighting conditions as they occur naturally over seasons, or man made by jet lag or shift work, advance or delay clock phase in order to synchronize an organism's physiology to the environment. A misalignment of the clock to its environment results in sleep disturbances and mood disorders. Although there are strong associations between the circadian clock and mood disorders such as depression, the underlying molecular mechanisms are not well understood. This review describes the currently known molecular links between circadian clock components and mood related behaviors in mice, which will help to understand the causal links between the clock and mood in humans in the future.

The fixation strength of tibial PCL press-fit reconstructions.

PURPOSE: A secure tibial press-fit technique in posterior cruciate ligament reconstructions is an interesting technique because no hardware is necessary. For anterior cruciate ligament (ACL) reconstruction, a few press-fit procedures have been published. Up to the present point, no biomechanical data exist for a tibial press-fit posterior cruciate ligament (PCL) reconstruction. The purpose of this study was to characterize a press-fit procedure for PCL reconstruction that is biomechanically equivalent to an interference screw fixation. METHODS: Quadriceps and hamstring tendons of 20 human cadavers (age: 49.2 ± 18.5 years) were used. A press-fit fixation with a knot in the semitendinosus tendon (K) and a quadriceps tendon bone block graft (Q) were compared to an interference screw fixation (I) in 30 porcine femora. In each group, nine constructs were cyclically stretched and then loaded until failure. Maximum load to failure, stiffness, and elongation during failure testing and cyclical loading were investigated. RESULTS: The maximum load to failure was 518 ± 157 N (387-650 N) for the (K) group, 558 ± 119 N (466-650 N) for the (I) group, and 620 ± 102 N (541-699 N) for the (Q) group. The stiffness was 55 ± 27 N/mm (18-89 N/mm) for the (K) group, 117 ± 62 N/mm (69-165 N/mm) for the (I) group, and 65 ± 21 N/mm (49-82 N/mm) for the (Q) group. The stiffness of the (I) group was significantly larger (P = 0.01). The elongation during cyclical loading was significantly larger for all groups from the 1st to the 5th cycle compared to the elongation in between the 5th to the 20th cycle (P < 0.03). CONCLUSION: All techniques exhibited larger elongation during initial loading. Load to failure and stiffness was significantly different between the fixations. The Q fixation showed equal biomechanical properties compared to a pure tendon fixation (I) with an interference screw. All three fixation techniques that were investigated exhibit comparable biomechanical properties. Preconditioning of the constructs is critical. Clinical trials have to investigate the biological effectiveness of these fixation techniques.

Comparison of three suture techniques and three suture materials on gap formation and failure load in ruptured tendons: a human cadaveric study.

INTRODUCTION: There is a large variety of ruptures of tendons and ligaments in trauma surgery. Reliable data about the most appropriate suture technique and suture material for ruptured tendons are sparse. This human cadaveric study compares the biomechanical properties of three suture materials and three suture techniques for semitendinosus tendon repair. METHOD: Sixty-three human cadaver hamstring tendons underwent tenotomy and repair with either Baseball suture, Kessler suture, or a novel "Hannover" suture, using either PDS 2-0, Ethibond 2-0, or Fiberwire 2-0. Biomechanical analysis included pretensioning the constructs with 2 N for 50 s, then cyclic loading of 500 cycles between 2 and 15 N at 1 Hz in a servohydraulic testing machine with measurement of elongation. After this, ultimate failure load and failure mode analysis was performed. RESULTS: Ruptures repaired by Fiberwire™ as suture material and the Baseball suture technique were able to withstand significantly higher maximum failure loads (72.8 ± 22.0 N, p < 0.001) than the Kessler suture and the Hannover suture, while ruptures repaired by Fiberwire and the Kessler suture technique showed the lowest elongation after cyclic loading (14.6 ± 3.8 mm, p = 0.15). CONCLUSION: These findings may be of relevance for the future clinical treatment of tendon ruptures. Further in vivo clinical application studies are desirable for the future.

Successful implementation of classical ketogenic dietary therapy in a patient with Niemann-Pick disease type C.

BACKGROUND: Niemann-Pick disease type C (NP-C) is a neurodegenerative disease for which only palliative treatment exists, and only miglustat is effective in stabilizing neurological manifestations of NP-C. Ketogenic dietary therapies (KDT) are successfully used in patients with seizure disorders, including those associated with various inherited metabolic diseases (IMD), to reduce seizure frequency and medication requirement as well as to confer neuroprotection. Since patients with NP-C suffer pharmacorefractory seizures associated with ongoing neurodegeneration, KDT might be beneficial. The concomitant use of miglustat and KDT in patients with NP-C has not been reported. CASE PRESENTATION: We describe our experience in a now 17-year-old female with NP-C manifest early in childhood who has been successfully and continuously treated with miglustat and KDT in a palliative care setting for 3y. Although the neurodegeneration of NP-C progressed, she benefited from a reduction in seizure activity, fewer hospital stays related to seizure exacerbation, and increased alertness. CONCLUSION: KDT could be safely deployed in our patient with NP-C, in whom its effects have been beneficial. Generally KDT is demonstratedly efficacious in patients with epilepsy and IMD. It reduces seizure activity and medication requirements and confers neuroprotection. Intracellular cholesterol trafficking and regulation of cholesterol biosynthesis are impaired in NP-C, which may prompt caution with respect to dietary lipid intake.

Quantitative detection of Clostridium difficile in hospital environmental samples by real-time polymerase chain reaction.

C. difficile-associated diarrhoea occurs commonly in hospitals and is a significant cause of morbidity and mortality. Hospital surfaces are often contaminated with nosocomial pathogens and may be responsible for cross-transmission, especially if hardy Gram-positive and spore-forming organisms are involved. The aim of this study was to quantify C. difficile in the hospital environment near C. difficile-positive and -negative patients using a quantitative real-time polymerase chain reaction. A total of 531 samples was collected from the clinical environment and classified into three groups according to patient and ward status for C. difficile. As expected, there were significantly higher counts of C. difficile on the floor and in the near environment of C. difficile patients. However, a significant correlation was found between C. difficile counts on the floor and on the hands of patients and healthcare workers (HCWs) in wards without evidence of C. difficile. This suggests that asymptomatic carriage among patients and HCWs can also contribute towards C. difficile transmission in hospitals. In conclusion, C. difficile can be transmitted via personal contact or via contaminated areas of the hospital environment.

Stroke-like episodes in propionic acidemia caused by central focal metabolic decompensation.

Propionic acidemia caused by propionyl-CoA carboxylase deficiency frequently leads to neurologic complications. Herein we report an eleven-year-old patient with propionic acidemia having three stroke-like episodes during a period of 13 months characterized by acute reversible hemiplegia and vegetative symptoms like bradycardia or drowsiness. No biochemical signs of severe metabolic decompensation were detectable in plasma. At all three episodes, EEG was not indicative for status epilepticus, but in the acute episode it showed slowing of background activity emphasized on one side. MRI revealed reversible hyperintensities in cortical grey matter and basal ganglia. During the third episode a lumbar puncture was done in parallel with venous puncture. Concentrations of glutamine (902 micromol/L), glycine (24 micromol/L) and alanine (78 micromol/L) were elevated in CSF. In plasma glycine (1 859 micromol/L) and alanine (608 micromol/L) concentrations were also elevated, whereas the glutamine (458 micromol/L) concentration was normal. CSF/plasma ratios were elevated for glutamine (1.97) and alanine (0.13) and normal for glycine (0.01). We assume that the stroke-like episodes in our patient may be caused by an acute focal cerebral metabolic decompensation, which is detectable by unspecific changes in MRI and by measuring amino acids and lactate in CSF versus plasma.

Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation.

The E6-AP ubiquitin ligase (human/mouse gene UBE3A/Ube3a) promotes the degradation of p53 in association with papilloma E6 protein, and maternal deficiency causes human Angelman syndrome (AS). Ube3a is imprinted with silencing of the paternal allele in hippocampus and cerebellum in mice. We found that the phenotype of mice with maternal deficiency (m-/p+) for Ube3a resembles human AS with motor dysfunction, inducible seizures, and a context-dependent learning deficit. Long-term potentiation (LTP) was severely impaired in m-/p+ mice despite normal baseline synaptic transmission and neuroanatomy, indicating that ubiquitination may play a role in mammalian LTP and that LTP may be abnormal in AS. The cytoplasmic abundance of p53 was increased in postmitotic neurons in m-/p+ mice and in AS, providing a potential biochemical basis for the phenotype through failure to ubiquitinate and degrade various effectors.

Circadian rhythms: a fine c(l)ocktail!

The central pacemaker of circadian behavior in mammals is located in the suprachiasmatic nuclei, each neuron of which has its own circadian rhythm. Recent studies shed light on the integration of these individual cellular rhythms and on novel genetic determinants that have been found to influence circadian behavior.

The lissencephaly gene product Lis1, a protein involved in neuronal migration, interacts with a nuclear movement protein, NudC.

Important clues to how the mammalian cerebral cortex develops are provided by the analysis of genetic diseases that cause cortical malformations [1-5]. People with Miller-Dieker syndrome (MDS) or isolated lissencephaly sequence (ILS) have a hemizygous deletion or mutation in the LIS1 gene [3,6]; both conditions are characterized by a smooth cerebral surface, a thickened cortex with four abnormal layers, and misplaced neurons [7,8]. LIS1 is highly expressed in the ventricular zone and the cortical plate [9,10], and its product, Lis1, has seven WD repeats [3]; several proteins with such repeats have been shown to interact with other polypeptides, giving rise to multiprotein complexes [11]. Lis1 copurifies with platelet-activating factor acetylhydrolase subunits alpha 1 and alpha 2 [12], and with tubulin; it also reduces microtubule catastrophe events in vitro [13]. We used a yeast two-hybrid screen to isolate new Lis1-interacting proteins and found a mammalian ortholog of NudC, a protein required for nuclear movement in Aspergillus nidulans [14]. The specificity of the mammalian NudC-Lis1 interaction was demonstrated by protein-protein interaction assays in vitro and by co-immunoprecipitation from mouse brain extracts. In addition, the murine mNudC and mLis1 genes are coexpressed in the ventricular zone of the forebrain and in the cortical plate. The interaction of Lis1 with NudC, in conjunction with the MDS and ILS phenotypes, raises the possibility that nuclear movement in the ventricular zone is tied to the specification of neuronal fates and thus to cortical architecture.

The circadian clock, metabolism and obesity.

In the last decades, obesity has been on the rise becoming a burden for health care systems. The reasons behind this rise are most likely caused by lifestyle rather than by an increase in gene mutations, because manifestations of genetic alterations would take longer than just a few decades. Lifestyle has a great impact on the circadian system and therefore on the body internal organization of physiological and biochemical processes, regulating various aspects of behavior and metabolism. In the following, I will discuss recent studies delineating relationships between metabolic processes and the circadian system, how metabolites and nutrients regulate the circadian clock and how nuclear receptors can act as metabolic sensors and clock regulators. Finally, I will discuss how clock modulation and feeding patterns influence the development of obesity.

Differential effects of vasodilatory prostaglandins on focal adhesions, cytoskeletal architecture, and migration in human aortic smooth muscle cells.

OBJECTIVE: Cyclooxygenases 1 and 2 are expressed in atherosclerotic arteries, and local generation of prostacyclin and prostaglandin E2 (PGE2) occurs. However, the role of cyclooxygenases and individual prostaglandins during plaque progression is currently uncertain. The present study characterizes the effect of vasodilatory prostaglandins on morphology, focal adhesion (FA) function, and migration in human aortic smooth muscle cells (SMCs). METHODS AND RESULTS: The stable prostacyclin analog iloprost transiently induced: (1) disassembly of FA and stress fibers, (2) partial retraction and rounding of SMCs, (3) hypophosphorylation of FA kinase (FAK) and paxillin, and (4) inhibition of platelet-derived growth factor-BB-induced migration. Inhibition of FAK phosphorylation and morphological changes were mimicked by forskolin, inhibited by H89, and prevented by the protein tyrosine phosphatase inhibitor vanadate and by calpeptin. PGE2 was by far less efficient with respect to all parameters investigated. This difference correlated with the respective cAMP induction in response to iloprost and PGE2. CONCLUSIONS: Inhibition of FAK phosphorylation and FA function is a new target of vasodilatory prostaglandins, which might be causally involved in the antimigratory effects of prostaglandins. Importantly, prostacyclin analogs and PGE2 differ dramatically with respect to dephosphorylation of FAK and inhibition of migration, which might be of relevance for their respective functions in atherosclerosis.