The Global Atmosphere-aerosol Model ICON-A-HAM2.3-Initial Model Evaluation and Effects of Radiation Balance Tuning on Aerosol Optical Thickness.

The Hamburg Aerosol Module version 2.3 (HAM2.3) from the ECHAM6.3-HAM2.3 global atmosphere-aerosol model is coupled to the recently developed icosahedral nonhydrostatic ICON-A (icon-aes-1.3.00) global atmosphere model to yield the new ICON-A-HAM2.3 atmosphere-aerosol model. The ICON-A and ECHAM6.3 host models use different dynamical cores, parameterizations of vertical mixing due to sub-grid scale turbulence, and parameter settings for radiation balance tuning. Here, we study the role of the different host models for simulated aerosol optical thickness (AOT) and evaluate impacts of using HAM2.3 and the ECHAM6-HAM2.3 two-moment cloud microphysics scheme on several meteorological variables. Sensitivity runs show that a positive AOT bias over the subtropical oceans is remedied in ICON-A-HAM2.3 because of a different default setting of a parameter in the moist convection parameterization of the host models. The global mean AOT is biased low compared to MODIS satellite instrument retrievals in ICON-A-HAM2.3 and ECHAM6.3-HAM2.3, but the bias is larger in ICON-A-HAM2.3 because negative AOT biases over the Amazon, the African rain forest, and the northern Indian Ocean are no longer compensated by high biases over the sub-tropical oceans. ICON-A-HAM2.3 shows a moderate improvement with respect to AOT observations at AERONET sites. A multivariable bias score combining biases of several meteorological variables into a single number is larger in ICON-A-HAM2.3 compared to standard ICON-A and standard ECHAM6.3. In the tropics, this multivariable bias is of similar magnitude in ICON-A-HAM2.3 and in ECHAM6.3-HAM2.3. In the extra-tropics, a smaller multivariable bias is found for ICON-A-HAM2.3 than for ECHAM6.3-HAM2.3.

Clinical Experience of Neurological Mitochondrial Diseases in Children and Adults: A Single-Center Study.

The goal of the study was to retrospectively evaluate a cohort of children and adults with mitochondrial diseases (MDs) in a single-center experience. Neurological clinical examination, brain magnetic resonance imaging (MRI) and spectroscopy, muscle biopsy, metabolic and molecular-genetic analysis were evaluated in 26 children and 36 adult patients with MD in Slovenia from 2004 to 2018. Nijmegen MD criteria (MDC) were applied to all patients and the need for a muscle biopsy was estimated. Exome-sequencing was used in half of the patients. Twenty children (77.0%) and 12 adults (35.0%) scored a total of ≥8 on MDC, a result that is compatible with the diagnosis of definite MD. Yield of exome-sequencing was 7/22 (31.0%), but the method was not applied systematically in all patients from the beginning of diagnostics. Brain MRI morphological changes, which can be an imaging clue for the diagnosis of MD, were found in 17/24 children (71.0%). In 7/26 (29.0%) children, and in 20/30 (67.0%) adults, abnormal mitochondria were found on electron microscopy (EM) and ragged-red fibers were found in 16/30 (53.0%) adults. Respiratory chain enzymes (RCEs) and/or pyruvate dehydrogenase complex (PDHc) activities were abnormal in all the children and six adult cases. First, our data revealed that MDC was useful in the clinical diagnosis of MD, and second, until the use of NGS methods, extensive, laborious and invasive diagnostic procedures were performed to reach a final diagnosis. In patients with suspected MD, there is a need to prioritize molecular diagnosis with the more modern next-generation sequencing (NGS) method.

Development, behaviour and sensory processing in Marshall-Smith syndrome and Malan syndrome: phenotype comparison in two related syndromes.

BACKGROUND: Ultrarare Marshall-Smith and Malan syndromes, caused by changes of the gene nuclear factor I X (NFIX), are characterised by intellectual disability (ID) and behavioural problems, although questions remain. Here, development and behaviour are studied and compared in a cross-sectional study, and results are presented with genetic findings. METHODS: Behavioural phenotypes are compared of eight individuals with Marshall-Smith syndrome (three male individuals) and seven with Malan syndrome (four male individuals). Long-term follow-up assessment of cognition and adaptive behaviour was possible in three individuals with Marshall-Smith syndrome. RESULTS: Marshall-Smith syndrome individuals have more severe ID, less adaptive behaviour, more impaired speech and less reciprocal interaction compared with individuals with Malan syndrome. Sensory processing difficulties occur in both syndromes. Follow-up measurement of cognition and adaptive behaviour in Marshall-Smith syndrome shows different individual learning curves over time. CONCLUSIONS: Results show significant between and within syndrome variability. Different NFIX variants underlie distinct clinical phenotypes leading to separate entities. Cognitive, adaptive and sensory impairments are common in both syndromes and increase the risk of challenging behaviour. This study highlights the value of considering behaviour within developmental and environmental context. To improve quality of life, adaptations to environment and treatment are suggested to create a better person-environment fit.

Bounding Global Aerosol Radiative Forcing of Climate Change.

Aerosols interact with radiation and clouds. Substantial progress made over the past 40 years in observing, understanding, and modeling these processes helped quantify the imbalance in the Earth's radiation budget caused by anthropogenic aerosols, called aerosol radiative forcing, but uncertainties remain large. This review provides a new range of aerosol radiative forcing over the industrial era based on multiple, traceable, and arguable lines of evidence, including modeling approaches, theoretical considerations, and observations. Improved understanding of aerosol absorption and the causes of trends in surface radiative fluxes constrain the forcing from aerosol-radiation interactions. A robust theoretical foundation and convincing evidence constrain the forcing caused by aerosol-driven increases in liquid cloud droplet number concentration. However, the influence of anthropogenic aerosols on cloud liquid water content and cloud fraction is less clear, and the influence on mixed-phase and ice clouds remains poorly constrained. Observed changes in surface temperature and radiative fluxes provide additional constraints. These multiple lines of evidence lead to a 68% confidence interval for the total aerosol effective radiative forcing of -1.6 to -0.6 W m-2, or -2.0 to -0.4 W m-2 with a 90% likelihood. Those intervals are of similar width to the last Intergovernmental Panel on Climate Change assessment but shifted toward more negative values. The uncertainty will narrow in the future by continuing to critically combine multiple lines of evidence, especially those addressing industrial-era changes in aerosol sources and aerosol effects on liquid cloud amount and on ice clouds.

Free-carrier dynamics in Au2Pb probed by optical conductivity measurements.

We measured the optical reflectivity of the Dirac material Au2Pb in a broad frequency range (30-48 000 cm-1) for temperatures between 9 and 300 K. The optical conductivity, computed from the reflectivity, is dominated by free-carrier contributions from topologically trivial bulk bands at all temperatures. The temperature-independent total plasma frequency of these carriers is [Formula: see text] eV. Overall, optical response of Au2Pb is typically metallic with no signs of localization and bad-metal behavior.

Tasimelteon for the treatment of non-24-hour sleep-wake disorder.

Tasimelteon (Hetlioz®), a melatonin receptor agonist, is the first, and, at the time of the publication, the only drug to be approved by the U.S. Food and Drug Administration (FDA) for the treatment of non-24-hour sleep-wake disorder (non-24). This circadian rhythm disorder occurs most commonly in blind individuals without light perception, and it results from their inability to entrain to the 24-hour photoperiod, although the indication does not specify a particular patient population. Non-24 is characterized by a persistent cycle of nighttime insomnia and daytime sleepiness, alternating with asymptomatic periods depending on an individual's degree of circadian rhythm synchronization with the photoperiod at any particular time. Phase II clinical trials in healthy individuals confirmed the circadian phase-shifting potential of tasimelteon. Phase III trials in totally blind subjects diagnosed with non-24 demonstrated the efficacy of tasimelteon in reducing both nighttime wakefulness and daytime napping. Physiologic monitoring revealed that tasimelteon resulted in a higher proportion of individuals becoming entrained to the 24-hour cycle compared with placebo. Safety assessments indicated that tasimelteon is well tolerated, with the most common adverse events being headache, alanine aminotransferase elevation, nightmares or unusual dreams, and upper respiratory or urinary tract infections. Tasimelteon is available as a capsule in a single 20-mg dose and it must be obtained through Vanda Pharmaceutical's HetliozSolutions program with dispensing through a specialty pharmacy. Safety studies in blind individuals diagnosed with non-24 are ongoing and a future clinical trial with Smith-Magenis syndrome patients is planned.

Persistent Detwinning of Iron-Pnictide EuFe_{2}As_{2} Crystals by Small External Magnetic Fields.

Our comprehensive study on EuFe_{2}As_{2} reveals a dramatic reduction of magnetic detwinning fields compared to other AFe_{2}As_{2} (A=Ba, Sr, Ca) iron pnictides by indirect magnetoelastic coupling of the Eu^{2+} ions. We find that only ∼0.1 T are sufficient for persistent detwinning below the local Eu^{2+} ordering; above T_{Eu}=19 K, higher fields are necessary. Even after the field is switched off, a significant imbalance of twin domains remains constant up to the structural and electronic phase transition (190 K). This persistent detwinning provides the unique possibility to study the low temperature electronic in-plane anisotropy of iron pnictides without applying any symmetry-breaking external force.

Benign convulsions in newborns and infants: occurrence, clinical course and prognosis.

BACKGROUND: During early development severe epilepsies may appear, some with well established occurrence. Benign non-epileptic and epileptic paroxysmal syndromes with excellent prognosis occur in the same period. There are no exact data on their occurrence. AIM: We have reviewed medical histories of children with benign non-epileptic or benign epileptic events: benign myoclonus of early infancy, benign neonatal sleep myoclonus, benign sleep myoclonus in infancy, benign partial epilepsy in infancy (BPEI) and benign infantile familial convulsions (BIFC) were established. The occurrence, clinical characteristics and prognosis of these syndromes were evaluated. METHODS: Inclusion criteria were met in 31 children. Research included retrospective analysis of clinical characteristics, laboratory values, neuroimaging and neurophysiological assessments, followed by evaluation of psychosocial development with the use of the Strengths and Difficulties Questionnaire (SDQ), fulfilled by parents. RESULTS: In our group the incidence of benign non-epileptic convulsions was 6.69 per 10 000 live births and the incidence of benign epileptic convulsions was 1.35 per 10 000. Male/female ratio in the group of children with non-epileptic events was 2.1:1. Among non-epileptic group 5 out of 23 children and among epileptic group 3 out of 8 children had minimal, mild or moderate abnormalities at neurological assessment at the time of the first clinical examination. Nonspecific changes in laboratory values were seen in 6 out of 23 in the non-epileptic and in 1 out of 8 children in the epileptic group. Neurophysiological assessments showed subtle changes in 4/23 in the non-epileptic and 6/8 in the epileptic group. Neuroimaging was not optimal in 5/23 with non-epileptic and 3/8 with epileptic events. Analysis of SDQ did not show significant deviations in psyhosocial development. Statistically significant deviation was observed only in relations with peers (p = 0.009). CONCLUSIONS: Benign neonatal and infantile convulsions are more frequent than severe epilepsies of the same age period. Results show higher proportion of males with benign non-epileptic conditions. No deviations in further development was found. Laboratory values, neuroimaging and neurophysiological assessments were normal or nonspecifically changed.

Recording conventional and amplitude-integrated EEG in neonatal intensive care unit.

Neonatal electroencephalography (EEG) presents a challenge due to its difficult interpretation that differs significantly from interpretation in older children and adolescents. Also, from the technological point of view, it is more difficult to perform and is not a standard procedure in all neonatal intensive care units (NICUs). During recent years, long-term cerebral function monitoring by the means of amplitude-integrated EEG (aEEG) has become popular in NICUs because it is easy to apply, allows real-time interpretation by the neonatologist treating the newborn, and has predictive value for outcome. On the other side, to record conventional EEG (cEEG), which is still considered the gold standard of neonatal EEG, the EEG technician should not only be well trained in performing neonatal EEG but also has to adapt to suboptimal working conditions. These issues need to be understood when approaching the neonatal cEEG in NICU and the main structure of the article is dedicated to this technique. The authors discuss the benefits of the digitalization and its positive effects on the improvement of NICU recording. The technical aspects as well as the standards for cEEG recording are described, and a section is dedicated to possible artifacts. Thereafter, alternative and concomitant use of aEEG and its benefits are briefly discussed. At the end there is a section that presents a review of our own cEEG and aEEG recordings that were chosen as the most frequently encountered patterns according to Consensus statement on the use of EEG in the intensive care unit.

An international survey of sleeping problems in the general population.

OBJECTIVE: This international omnibus survey investigated the prevalence and characteristics of sleep problems, as well as strategies for resolving sleep problems, in the general population of the USA, France, Germany, Italy, Spain, the UK and Japan. RESEARCH DESIGN AND METHODS: A representative sample of the general population aged > or = 15 years was recruited from each country. Questions focused on the nature of sleeping problems, the impact of problems on daily functioning and behavior with regard to resolving sleeping problems. RESULTS: A total of 10 132 individuals were included in this survey. The prevalence of sleeping problems was 56% in the USA, 31% in Western Europe and 23% in Japan. Most individuals with sleeping problems considered these to have an impact on their daily functioning, with family life most affected in the Western European sample, personal activities in the US sample and professional activities in the Japanese sample. Almost half of individuals with sleep problems had never taken any steps to resolving them, and the majority of respondents had not spoken with a physician about their problems. Of those individuals who had consulted a physician, drug prescriptions had been given to approximately 50% in Western Europe and the USA and 90% in Japan. CONCLUSIONS: Sleeping problems continue to present a considerable burden across Western Europe, the USA and Japan. Despite this, they are under-reported and under-treated, with almost half of affected individuals not taking any steps to resolve their sleeping problems.

The "Child in the Barrel syndrome"--severe pharyngeal-cervical-brachial variant of Guillain-Barre Syndrome in a toddler.

One week after a flu-like prodrome, an 18-month-old boy developed acute severe, symmetrical, painless weakness and wasting of the shoulder girdle and upper limbs, drooling, dysphagia, dysarthria, atrophy and fasciculations of the tongue. Milder paresis involved the mimic muscles and the neck extensors. The legs were intact with brisk reflexes. The flail immobile upper limbs produced the appearance that the boy was restrained in a narrow barrel. Electrodiagnostic findings suggested demyelinating motor neuropathy sparing the legs. CSF (45 days after onset) was normal. Initial recovery was observed but 70 days after onset the child suffered severe relapse and died from respiratory arrest. This is another rare case of the pharyngeal-cervical-brachial variant of Guillain-Barre syndrome in infancy with an unusual relapsing course leading to a fatal outcome.

Estimation of antiphospholipid antibodies in a prospective longitudinal study of children with migraine.

The aim of this study was to determine the prevalence and clinical significance of antiphospholipid antibodies (aPL) in children with migraine. The values of anticardiolipin (aCL) and antibeta2 glycoprotein I (antibeta2GPI) antibodies were assayed by an ELISA method in 52 children with migraine and 22 children with tension-type headache. The control group consisted of 61 apparently healthy children at regular preventive visits. Two monoclonal beta2GPI dependent aCL (HCAL and EY2C9) were used as calibrators. Lupus anticoagulant (LA) was determined by a modified dilute Russell viper venom time test. Persistently positive aPL were observed during the follow-up in 16.3% of children with migraine (9.3% for aCL, 7.0% for antibeta2GPI and 0% for LA) and in 16.7% of children with tension-type headache (11.1% for aCL, 5.6% for antibeta2GPI and 0% for LA). The prevalence of aPL did not differ significantly between patient groups and healthy children. The prevalence of aPL does not appear to be increased in an unselected group of children with migraine, however, the possible role of aPL in individual cases of paediatric migraine can not be excluded.

Motor activity during asymptomatic nocturnal hypoglycemia in adolescents with type 1 diabetes mellitus.

Nocturnal hypoglycemia is reported in 13%-56% of adolescents with type 1 diabetes mellitus. It may be asymptomatic in more than 50% of patients. No noninvasive method for detecting asymptomatic nocturnal hypoglycemia (ANH) has so far proven successful. The aim of the present study was to evaluate quantitative changes of motor activity by actigraphy during episodes of ANH in adolescents with type 1 diabetes mellitus. A total of 18 patients aged 10-16 years with a history of ANH were investigated. Blood was sampled at half-hourly intervals between 22.30 and 06.00 hours with a micropump, and an actigraph was fastened to the right wrist. Blood glucose concentrations were measured and compared to motor activity. Nocturnal hypoglycemia was recorded in 10 patients (55%), with blood glucose during periods of hypoglycemia of 3.00+0.17 mmol/l (range, 1.2-3.4 mmol/l), and duration of hypoglycemia of 1.95+1.34 hours (range, 0.5-5.0 hours). All periods of hypoglycemia were clinically asymptomatic. Regression analysis revealed a statistically significant linear correlation ( p=0.03) between blood glucose concentration and the respective 30-min activity counts. Activity counts in patients with nocturnal hypoglycemia were significantly (ANOVA, p<0.02) higher than in patients with normoglycemia. We conclude that low blood glucose was significantly correlated with an increase in motor activity as detected by actigraphy. This implies the possibility of noninvasive screening of asymptomatic nocturnal hypoglycemia.

Actigraphic assessment of sleep-wake rhythm during the first 6 months of life.

OBJECTIVES: To examine the validity of the "Gaehwiler" actigraph (Gaehwiler Electronics, model Z80-32k V(1)) for the assessment of sleep-wake (S/W) rhythm and sleep structure in infants during the first 6 months of life using an algorithm developed in our laboratory to differentiate sleep and wake states. METHODS: A continuous 72 h actigraphic recording was performed in 10 healthy infants at 1, 3 and 6 months of age. The actigraphic data were matched to direct observation of the infants' behavioural states. Using discriminant function analysis a scoring algorithm for automatic identification of S/W states from raw activity data was developed. The chi-square periodogram analysis was performed to estimate periodic components of S/W rhythm. RESULTS: The overall agreement rates between the actigraphic and observer scoring for S/W were between 87 and 95% for the infants after the third month of life, while for the 1-month-old infants they never exceeded 72%. The actigraphic discrimination between active and quiet sleep was the best in 3-month-old infants. The circadian influence on S/W rhythm was already present by the end of the first month of life. CONCLUSIONS: Using the "Gaehwiler" actigraph in our study, valid discrimination between sleep and wake states was obtained in infants during 3 and 6 months. The actigraph, however, did not provide valid active vs. quiet sleep state measures. The circadian rhythm of S/W was observed as early as during the first month of life.

Axonal regeneration into acellular nerve grafts is enhanced by degradation of chondroitin sulfate proteoglycan.

Although the peripheral nerve has the potential to regenerate after injury, degenerative processes may be essential to promote axonal growth into the denervated nerve. One hypothesis is that the nerve contains growth inhibitors that must be neutralized after injury for optimal regeneration. In the present study, we tested whether degradation of chondroitin sulfate proteoglycan, a known inhibitor of axon growth, enhances the growth-promoting properties of grafts prepared from normal donor nerves. Excised segments of rat sciatic nerve were made acellular by freeze-killing before treatment with chondroitinase ABC. Chondroitinase-dependent neoepitope immunolabeling showed that chondroitin sulfate proteoglycan was thoroughly degraded throughout the treated nerve segments. In addition, neuronal cryoculture assays revealed that the neurite-promoting activity of acellular nerves was significantly increased by chondroitinase treatment. Control and chondroitinase-treated acellular nerves were then used as interpositional grafts in a rat nerve injury model. Axonal regeneration into the grafts was assessed 4 and 8 d after implantation by growth-associated protein-43 immunolabeling. At both time points, the number of axons regenerating into acellular grafts treated with chondroitinase was severalfold greater than in control grafts. Growth into the chondroitinase-treated grafts was pronounced after only 4 d, suggesting that the delay of axonal growth normally associated with acellular grafts was attenuated as well. These findings indicate that chondroitinase treatment significantly enhanced the growth-promoting properties of freeze-killed donor nerve grafts. Combined with the low immunogenicity of acellular grafts, the ability to improve axonal penetration into interpositional grafts by preoperative treatment with chondroitinase may be a significant advancement for clinical nerve allografting.

Economic evaluation of Haemophilus influenzae type b vaccination in Slovenia.

The objective of the present study was to assess the economical impact of invasive Haemophilus influenzae type b infections in Slovenia, where the annual incidence of these infections is 16.4/100000 in children less than 5 years of age, and to compare it with the costs of a vaccination programme. The lifetime costs and benefits were estimated for the annual birth cohort of 18200 children. In the base-case model, the calculated benefit-to-cost ratios were 0.15, 0.98 and 1.38 taking into account 95% of savings in acute care costs, medical costs, and medical and non-medical costs, respectively. From the point of view of the Institute of Health Insurance of Slovenia, who pays all healthcare and vaccination costs, the vaccination programme per annual birth cohort of 18200 children would require an extra 7023 EUR or 0.40 EUR per cohort-child. The savings to society would represent 118410 EUR, indicating the rationale for inclusion of H. influenzae type b vaccination in the routine childhood immunisation programme in Slovenia.

A case of Zellweger syndrome with extensive MRI abnormalities and unusual EEG findings.

Differential diagnosis in a newborn with dysmorphic features and profound neurologic dysfunction should include the cerebro-hepato-renal syndrome of Zellweger. Its distinct clinical features, markedly elevated plasma levels of very long chain fatty acids and characteristic radiological findings support the diagnosis, which can now be confirmed by genetic markers. Quite consistent abnormalities of the neurophysiological studies in this syndrome have also been reported. We report a case with typical clinical and biochemical findings in whom distinctive brain MRI abnormalities were found. The results of neurophysiological studies with an unusual EEG pattern of continuous negative vertex sharp waves and spikes are discussed. We believe that such a pattern could be considered as a pathognomonic EEG finding, especially in cases of Zellweger syndrome with extensive brain abnormalities and may even be closely associated with cortical dysplasias.

Tumorigenic properties of neurofibromin-deficient neurofibroma Schwann cells.

Dermal and plexiform neurofibromas are peripheral nerve sheath tumors that arise frequently in neurofibromatosis type 1. The goal of the present study was to examine the tumorigenic properties of neurofibromin-deficient human Schwann cells (SCs) that were found to represent a subset of SCs present in approximately half of the total neurofibromas examined. Highly enriched SC cultures were established from 10 dermal and eight plexiform neurofibromas by selective subculture using glial growth factor-2 and laminin. These cultures had low tumorigenic potential in classical in vitro assays yet several unique preneoplastic properties were frequently observed, including delayed senescence, a lack of density-limited growth, and a strong propensity to spontaneously form proliferative cell aggregates rich in extracellular matrix. Western blot analysis failed to detect full-length neurofibromin in any of the neurofibroma SC cultures, indicating that neurofibromin-deficient SCs had a substantial growth advantage. Immunohistochemical staining of the originating tumors showed the majority were comprised principally of neurofibromin-negative SCs, whereas the remainder contained both neurofibromin-negative and neurofibromin-positive SCs. Lastly, engraftment of neurofibromin-deficient SC cultures into the peripheral nerves of scid mice consistently produced persistent neurofibroma-like tumors with diffuse and often extensive intraneural growth. These findings indicate that neurofibromin-deficient SCs are involved in neurofibroma formation and, by selective subculture, provide a resource for the development of an in vivo model to further examine the role of these mutant SCs in neurofibroma histogenesis.

A case of merosin-negative congenital muscular dystrophy with extensive white matter abnormalities and electroencephalographic changes in a Syrian boy.

Congenital muscular dystrophies are a group of heterogeneous disorders inherited as an autosomal recessive disease. In the Caucasians they are most frequently encountered as the so-called "pure" or occidental form. Recently it has been found that the severity of concomitant white matter changes depends on the presence or absence of merosin, the laminin isoform, in the skeletal muscle. The authors present a 2-year-old Syrian boy with congenital muscular dystrophy which proved to be merosin (laminin alpha2) deficient and believe that this is the first case described from Syria. The clinical picture, biochemical findings, neurophysiological investigations, biopsy findings and extensive abnormalities of white matter on magnetic resonance imaging (MRI) found in this case are presented. Peculiar electroencephalographic (EEG) pattern with fast rhythms in occipito-temporal regions is emphasized.