Improving Care for Families and Children with Neurodevelopmental Disorders and Co-occurring Chronic Health Conditions Using a Care Coordination Intervention.

OBJECTIVE: This clinical intervention study aimed to improve care integration and health service delivery for children with concurrent neurodevelopmental disorders and chronic health conditions. This population has significant unmet needs and disproportionate deficits in service delivery. A lack of coordination across child service sectors is a common barrier to successful treatment and support of children with neurodevelopmental disorders with complex medical needs. METHODS: This project implemented an innovative care coordination model, involving one-on-one supports from a trained care coordinator who liaised with the broader intersectoral care team to improve joint care planning, integration of services, and the experience of both families and care providers. To evaluate the impact of care coordination activities, a single-group interventional study was conducted using a repeated-measures framework (at 0, 6, and 12 months) using previously established outcome measures. RESULTS: Over 2 years, this project provided care coordination to 84 children and their families, with an age range from 2 to 17 years. The care coordination intervention demonstrated positive impacts for children, families, and care teams and contributed to clinical efficiencies. Children had fewer visits to the emergency department and less frequent acute care use. Improvement in access to services, joint care planning and communication across providers, and better linkage with school supports were demonstrated. Families reported that the program decreased their stress around coordinating care for their child. CONCLUSION: This work demonstrated that intersectoral care coordination is attainable through innovative and collaborative practice for children with complex neurodevelopmental and medical needs.

Valley Subband Splitting in Bilayer Graphene Quantum Point Contacts.

We report a study of one-dimensional subband splitting in a bilayer graphene quantum point contact in which quantized conductance in steps of 4e^{2}/h is clearly defined down to the lowest subband. While our source-drain bias spectroscopy measurements reveal an unconventional confinement, we observe a full lifting of the valley degeneracy at high magnetic fields perpendicular to the bilayer graphene plane for the first two lowest subbands where confinement and Coulomb interactions are the strongest and a peculiar merging or mixing of K and K^{'} valleys from two nonadjacent subbands with indices (N,N+2), which are well described by our semiphenomenological model.

Responder and nonresponder patients exhibit different peripheral transcriptional signatures during major depressive episode.

To date, it remains impossible to guarantee that short-term treatment given to a patient suffering from a major depressive episode (MDE) will improve long-term efficacy. Objective biological measurements and biomarkers that could help in predicting the clinical evolution of MDE are still warranted. To better understand the reason nearly half of MDE patients respond poorly to current antidepressive treatments, we examined the gene expression profile of peripheral blood samples collected from 16 severe MDE patients and 13 matched controls. Using a naturalistic and longitudinal design, we ascertained mRNA and microRNA (miRNA) expression at baseline, 2 and 8 weeks later. On a genome-wide scale, we detected transcripts with roles in various biological processes as significantly dysregulated between MDE patients and controls, notably those involved in nucleotide binding and chromatin assembly. We also established putative interactions between dysregulated mRNAs and miRNAs that may contribute to MDE physiopathology. We selected a set of mRNA candidates for quantitative reverse transcriptase PCR (RT-qPCR) to validate that the transcriptional signatures observed in responders is different from nonresponders. Furthermore, we identified a combination of four mRNAs (PPT1, TNF, IL1B and HIST1H1E) that could be predictive of treatment response. Altogether, these results highlight the importance of studies investigating the tight relationship between peripheral transcriptional changes and the dynamic clinical progression of MDE patients to provide biomarkers of MDE evolution and prognosis.

Suppression of autophagy and activation of glycogen synthase kinase 3beta facilitate the aggregate formation of tau.

Neurofibrillary tangle (NFT) is a characteristic hallmark of Alzheimer's disease. GSK3ß has been reported to play a major role in the NFT formation of tau. Dysfunction of autophagy might facilitate the aggregate formation of tau. The present study examined the role of GSK3ß-mediated phosphorylation of tau species on their autophagic degradation. We transfected wild type tau (T4), caspase-3-cleaved tau at Asp421 (T4C3), or pseudophosphorylated tau at Ser396/Ser404 (T4-2EC) in the presence of active or enzyme-inactive GSK3ß. Trehalose and 3-methyladenine (3-MA) were used to enhance or inhibit autophagic activity, respectively. All tau species showed increased accumulation with 3-MA treatment whereas reduced with trehalose, indicating that tau undergoes autophagic degradation. However, T4C3 and T4-2EC showed abundant formation of oligomers than T4. Active GSK3ß in the presence of 3-MA resulted in significantly increased formation of insoluble tau aggregates. These results indicate that GSK3ß-mediated phosphorylation and compromised autophagic activity significantly contribute to tau aggregation.

Suppression of Autophagy and Activation of Glycogen Synthase Kinase 3beta Facilitate the Aggregate Formation of Tau

Neurofibrillary tangle (NFT) is a characteristic hallmark of Alzheimer's disease. GSK3beta has been reported to play a major role in the NFT formation of tau. Dysfunction of autophagy might facilitate the aggregate formation of tau. The present study examined the role of GSK3beta-mediated phosphorylation of tau species on their autophagic degradation. We transfected wild type tau (T4), caspase-3-cleaved tau at Asp421 (T4C3), or pseudophosphorylated tau at Ser396/Ser404 (T4-2EC) in the presence of active or enzyme-inactive GSK3beta. Trehalose and 3-methyladenine (3-MA) were used to enhance or inhibit autophagic activity, respectively. All tau species showed increased accumulation with 3-MA treatment whereas reduced with trehalose, indicating that tau undergoes autophagic degradation. However, T4C3 and T4-2EC showed abundant formation of oligomers than T4. Active GSK3beta in the presence of 3-MA resulted in significantly increased formation of insoluble tau aggregates. These results indicate that GSK3beta-mediated phosphorylation and compromised autophagic activity significantly contribute to tau aggregation.

A controlled comparison of brachial artery flow mediated dilation (FMD) and digital pulse amplitude tonometry (PAT) in the assessment of endothelial function in systemic lupus erythematosus.

The utility of flow mediated dilation (FMD) a measure of endothelial function is limited by operator dependence. Pulse amplitude tonometry (PAT) is a novel, less operator-dependent technique to assess endothelial function. This study compares PAT to FMD in SLE and controls. Thirty women with SLE and 31 controls were enrolled. Medications, cardiovascular disease and risk factors, SLE activity (SLAM-R) and damage (SLICC-DI) were recorded. FMD and PAT were performed simultaneously. Endothelium-independent function was assessed with nitroglycerin. Average age was 48.3 +/- 10.1 years, SLE duration 16.2 years, SLAM-R 8.3 and SLICC-DI 1.0. Framingham Risk Scores were < or =2% in most subjects. There were no differences between SLE cases and controls in FMD, PAT or response to nitroglycerin. This study found no association between FMD and PAT in SLE or controls. In the 17 SLE cases with a history of Raynaud's, correlation between FMD and PAT was 0.50 (P = 0.04). There was no difference in endothelial function assessed by FMD or PAT in SLE cases versus controls. FMD did not correlate with PAT except in SLE cases with a history of Raynaud's. Correlation between FMD and PAT may be stronger in populations with greater variation in endothelial function and more cardiovascular risk factors.

Proposed response criteria for neurocognitive impairment in systemic lupus erythematosus clinical trials.

The objective of this study was to identify reliable and valid instruments to measure cognitive impairment in systemic lupus erythematosus (SLE), and to define minimally important change of cognitive impairment in SLE for clinical trials. Neurocognitive measures used in randomized clinical trials in SLE were reviewed, and response criteria were developed using consensus expert opinion. The definition of cognitive impairment in the ACR nomenclature for neuropsychiatric lupus syndrome was adopted. Cognitive impairment is a deficit of 2.0 or more standard deviations (SD) below the mean, compared to normative data, in the key domains of attention, memory and psychomotor speed. Cognitive decline is defined as a deficit of 1.5-1.9 SD below the mean. Focal decline is defined if impairment exists in one or more measures within one domain, and multifocal decline if impairment exists on measures spanning two or more domains. The combination of ACR neuropsychological battery and the Cognitive Symptoms Inventory (CSI) is recommended to quantitate cognitive function. A clinically important response is defined as an improvement of > or = 1.0 SD with an effect size of 1.0 in the key domains of the ACR neuropsychological testing, and an improvement of > or = 1.0 SD with an effect size of 1.0 in functional performance of the CSI.

Central precocious puberty: clinical and laboratory features.

OBJECTIVE: To determine whether the initial presentation of patients with central precocious puberty (CPP) varies according to the aetiology, whether this permits the differentiation between idiopathic and organic forms, and whether the body mass index (BMI) and plasma leptin concentrations are linked to gonadotrophin secretion. DESIGN: The clinical and laboratory features of 256 patients (26 boys and 230 girls) with CPP were studied separately in boys and girls. We compared patients with idiopathic CPP (seven boys and 186 girls) to those with organic CPP, whose pubertal development revealed a central nervous system (CNS) lesion (five boys and 11 girls), and to patients with organic CPP associated with a previously treated CNS lesion (14 boys and 33 girls). RESULTS: Boys with organic CPP, having revealed or treated CNS lesions, started their puberty earlier (3.0 +/- 1.0 years and 6.7 +/- 0.5 years) than boys with idiopathic CPP (8.5 +/- 0.2 years, P < 0.01 and < 0.05). Boys with organic CPP associated with a treated CNS lesion had lower luteinizing hormone (LH)/follicle stimulating hormone (FSH) peaks ratio after stimulation with gonadotrophin releasing hormone (GnRH) (1.6 +/- 0.5) than did boys with idiopathic CPP (2.2 +/- 0.3, P < 0.05). Girls with organic CPP revealing a CNS lesion started their puberty earlier (3.6 +/- 0.9 years) than girls with idiopathic CPP (6.6 +/- 0.1 years, P < 0.0 l) and had higher LH (P < 0.01) and FSH peaks (< 0.05). Girls with organic CPP associated with a treated CNS lesion had higher BMI (1.8 +/- 0.2 z-score) than did girls with idiopathic CPP (1.3 +/- 0.1 zs, P < 0.05), higher leptin concentrations (11.7 +/- 1.8 microg/l vs. 7.7 +/- 0.5 microg/l, P < 0.0 l), LH peak (P < 0.01), FSH peak (P < 0.05) and LH/FSH peaks ratio (1 +/- 0.1 vs. 0.8 +/- 0.1, P < 0.05). Only 12.4% of the girls with idiopathic CPP had BMI-zs < 0, and their plasma leptins were positively correlated with BMI (P < 0.0001). CONCLUSIONS: The features of central precocious puberty vary according to the aetiology, but it is impossible to exclude a central nervous system lesion in a given patient with central precocious puberty without performing central nervous system imaging. This imaging remains necessary in all cases of central precocious puberty. Most of the girls with idiopathic central precocious puberty had increased BMI, but we found no correlation between plasma leptin concentrations and gonadotrophin secretion.

Comparison of the TEMPO+ ear-level speech processor and the cis pro+ body-worn processor in adult MED-EL cochlear implant users.

A study was conducted to compare the new MED-EL TEMPO+ ear-level speech processor with the CIS PRO+ body-worn processor in the COMBI 40/COMBI 40+ implant system. Speech tests were performed in 46 experienced subjects in two test sessions approximately 4 weeks apart. Subjects were switched over from the CIS PRO+ to the TEMPO+ in the first session and used only the TEMPO+ in the time between the two sessions. Speech tests included monosyllabic word tests and sentence tests via the telephone. An adaptive noise method was used to adjust each subject's scores to approximately 50%. Additionally, subjects had to complete a questionnaire based on their 4 weeks of experience with the TEMPO+. The speech test results showed a statistically significant improvement in the monosyllabic word scores with the TEMPO+. In addition, in the second session, subjects showed a significant improvement when using the telephone with the TEMPO+, indicating some learning in this task. In the questionnaire, the vast majority of subjects found that the TEMPO+ allows equal or better speech understanding and rated the sound quality of the TEMPO+ higher. All these objective and subjective results indicate the superiority of the TEMPO+ and are mainly attributed to a new coding strategy called CIS+ and its implementation in the TEMPO+. In other words, based on the results of this study, it appears that after switching over from the CIS PRO+ to the TEMPO+, subjects are able to maintain or even improve their own speech understanding capability.

[Hair cell function diagram in premature and mature newborn infants]. / Haarzellfunktionsdiagramme bei Früh- und Reifgeborenen.

BACKGROUND: The grade of maturation of the cochlear function must be taken into account when the cochlear function is investigated in premature infants and neonates. Quantitative analysis has not yet been performed. METHODS: Using the otodynamic analyzer ILO 88/92, we therefore determined haircell functional diagrams and the echo 65 dB levels in 35 healthy neonates as well as 30 healthy premature infants with a median gestational age (GA) of 32 weeks (28-35 weeks) 2-3 days post natum. Follow up investigations were performed in 10 neonates and 16 premature infants. RESULTS: The mean echo 65 dB levels were 4.88 +/- 4.22 dB for the right ears and 5.72 +/- 5.16 dB for the left ears in premature infants < or = 32 weeks of GA, 10.25 +/- 3.89 dB and 10.69 +/- 5.55 dB respectively in premature infants > 32 weeks of GA, and 16.01 +/- 4.99 and 14.90 +/- 4.41 dB respectively in neonates. There was no significant difference between neonates at day 2 and 4 post natum. In 16 premature infants the echo 65 dB levels increased from 4.92 dB for the right ears and 4.79 dB for the left ears at the second day of life to 11.72 dB and 11.73 dB respectively at the age of 4 weeks. CONCLUSION: We present therefore strong evidence for a maturation of the cochlear function in premature infants with increasing age. The individual grade of maturation of the cochlea is of relevance for the auditive stimulation of very premature infants.

[Laryngeal manifestations in patients with Parkinson disease]. / Kehlkopfbefunde bei Patienten mit Morbus Parkinson.

BACKGROUND: Impairments of articulation, respiration, and phonation are a common symptom of Parkinson's disease and may result in reduced communication. Previous observations have shown a high incidence of laryngeal abnormalities. However, no relevant data were available for gender differences of laryngeal abnormalities in Parkinson's disease. METHOD: Thirty-nine female and 61 male patients with Parkinson's disease were examined. The laryngeal function was explored by laryngoendoscopy and laryngostroboscopy in respiration and production of [i:] during normal pitch and normal loudness. RESULTS: Abnormal function of vocal cord abduction and adduction were observed in 54% of the women and 39% of the men; more patients had reduced abduction. Bilateral vocal fold atrophy was seen in 36% of the women and 56% of the men, while 41% of the women and 57% of the men had a bilateral hypertrophy ventricular fold. Phase closure incompetence was found in 60.5% of the women and 49% of the men. Abnormal amplitude and mucosal waveform were seen in more male patients, while 30.7% of the women and 25% of the men had a laryngeal tremor. Gender differences were observed with respect to common laryngeal symptoms. CONCLUSION: This study concludes that laryngeal abnormalities in Parkinson's disease show a high degree of gender differences. The percentage of patients with abnormal abduction of the vocal cord was higher than has been reported in other studies. Vocal-fold bowing appear to be related to vocal fold atrophy. Although patients with Parkinson's disease frequently exhibit vocal fold atrophy, other mechanisms and causes should be discussed. Patients with tremor and common laryngeal symptoms were observed. These findings were not expected and further studies of this phenomena would be useful.

Results of cochlear implantation in patients with severe to profound hearing loss--implications for patient selection.

In patients with some residual hearing and minor benefit from conventional hearing aids, the benefits of cochlear implantation have to be weighed carefully against eventual adverse effects. In this study, pre- and post-operative thresholds as well as functional results after cochlear implantation are reported; 17 of 44 implanted adults had residual hearing pre-operatively (mean threshold(250 to 4000 Hz): 106 dB HL) in the implanted ear. Residual hearing in the implanted ear could not, in general, be preserved post-operatively. Seventeen of 44 implanted children had some amount of residual hearing in the implanted ear pre-operatively (implanted ear: 114 dB HL; contralateral ear: 109.9 dB HL; mean thresholds(250 to 4000 Hz))). Contrary to the results in adults, residual hearing in the implanted ear remained statistically unchanged. Hearing in the contralateral ear increased significantly from 109.9 to 101.9 dB HL post-operatively. This increase was mainly attributed to maturation of the central auditory pathway. In adults with residual hearing, the monosyllable word recognition scores increased significantly from 9 per cent pre-operatively to 42 per cent post-operatively. Children with residual hearing tended to perform better on speech-related test material compared to children without prior auditory experience. Cochlear implantation is indicated in adults and children with residual hearing and minor benefit from conventional amplification. The contralateral ear in children should be considered for additional acoustical stimulation.

Data preparation for transient evoked otoacoustic emissions.

Recently the measurement of transient evoked otoacoustic emissions (TEOAEs) has been universally accepted as a noninvasive, objective method for the detection of cochlear damage. We present a computerized data preparation method which facilitates the comparison of several measurements of otoemissions for different stimuli. By comparing signals at different stimuli for corresponding time intervals it is possible to detect characteristic cochlear emissions at lower stimulus levels. Especially in case of ambiguous test results detecting typical emission waves by comparison helps to improve the reliability of TEOAE measurement.

A follow-up study of long-term results after cochlear implantation in children and adolescents.

The time course of speech development in children after cochlear implantation may extend over many years, thus making long-term studies necessary to evaluate any outcome. We report our long-term results after cochlear implantation in children and adolescents. Mean follow-up was 28 months, ranging from 1 to 5 years. After at least 1 year of experience all children were found to benefit from their cochlear implants. The majority of children scored above chance in speech identification tasks requiring closed set word and sentence understanding). At the 4-year interval, all children tested including prelingually deaf children had developed open set sentence understanding. The most relevant factor accounting for differences in the results was the duration of implant use in all groups. Even beyond 3 years the results continued to improve. Peri- or postlingually deafened children tended to have favorable results. For prelingually deaf children, duration of deafness and age at implantation were correlated negatively with the results.

[Results of neonatal hearing screening with transitory evoked otoacoustic emissions]. / Ergebnisse eines Neugeborenen-Hörscreenings mittels transitorisch evozierter otoakustischer Emissionen.

From 1. 10. 1992-31. 12. 1993 a hearing screening was performed in 994 preterm and term babies (765 healthy neonates and 229 neonates with risk factors for hearing loss) by means of transient evoked otoacoustic emissions (TEOAE). There was a bilateral absent of emissions in 4.3% of the healthy neonates and 11.8% of the risk babies. 8 from 32 healthy neonates and 10 from 22 risk babies also had a negative test result in the control investigation. 16 of these children showed in 7 cases a severe hearing impairment in expanded pedaudiological investigations. The registration of TEOAE is a recommendable method for a hearing screening in neonates.

[Improved evaluation of transitory evoked otoacoustic emissions by correlation filtering]. / Verbesserte Auswertbarkeit transitorisch evozierter otoakustischer Emissionen durch Korrelationsfilterung.

Hearing screening as well as evaluation of cochlear function under therapy with ototoxic agents or patients with various diseases is increasingly done by registration of transient evoked otoacoustic emissions (TEOAE). Usually the standard system ILO 88 Otodynamic Analyser is used, where until now emissions were analyzed subjectively. However, evaluation of signals may be difficult mainly in the hearing threshold area. In this article we describe a method to mathematically analyze registered emissions by correlation-filtering. This allows to better identify small specific responses, to further increase the sensitivity of TEOAE, and offers a more objective means for audiologic diagnoses.