Christianson Syndrome across the Lifespan: An International Longitudinal Study in Children, Adolescents, and Adults.

Mutations in the X-linked endosomal Na+/H+ Exchanger 6 (NHE6) causes Christianson Syndrome (CS). In the largest study to date, we examine genetic diversity and clinical progression, including cerebellar degeneration, in CS into adulthood. Data were collected as part of the International Christianson Syndrome and NHE6 (SLC9A6) Gene Network Study. Forty-four individuals with 31 unique NHE6 mutations, age 2 to 32 years, were followed prospectively, herein reporting baseline, 1-year follow-up, and retrospective natural history. We present data on the CS phenotype with regard to physical growth, adaptive and motor regression, and across the lifespan, including information on mortality. Longitudinal data on body weight and height were examined using a linear mixed model: the rate of growth across development was slow and resulted in prominently decreased age-normed height and weight by adulthood. Adaptive functioning was longitudinally examined: a majority of adult (18+ years) participants lost gross and fine motor skills over a 1-year follow-up. Previously defined core diagnostic criteria for CS (present in >85%) - namely nonverbal status, intellectual disability, epilepsy, postnatal microcephaly, ataxia, hyperkinesia - were universally present in age 6 to 16; however, an additional core feature of high pain tolerance was added (present in 91%), and furthermore, evolution of symptoms were noted across the lifespan, such that postnatal microcephaly, ataxia and high pain threshold were often not apparent prior to age 6, and hyperkinesis decreased after age 16. While neurologic exams were consistent with cerebellar dysfunction, importantly, a majority of individuals (>50% older than 10) also had corticospinal tract abnormalities. Three participants died during the period of the study. In this large and longitudinal study of CS, we begin to define the trajectory of symptoms and the adult phenotype, thereby identifying critical targets for treatment.

Bringing ultimate depth to scanning tunnelling microscopy: deep subsurface vision of buried nano-objects in metals.

A method for subsurface visualization and characterization of hidden subsurface nano-structures based on scanning tunelling microscopy/spectroscopy (STM/STS) has been developed. Nano-objects buried under a metal surface up to several tens of nanometers can be visualized through the metal surface and characterized with STM without destroying the sample. This non-destructive method exploits quantum well (QW) states formed by partial electron confinement between the surface and buried nano-objects. The specificity of STM allows for nano-objects to be singled out and easily accessed. Their burial depth can be determined by analysing the oscillatory behaviour of the electron density at the surface of the sample, while the spatial distribution of electron density can give additional information about their size and shape. The proof of concept was demonstrated with different materials such as Cu, Fe, and W in which the nanoclusters of Ar, H, Fe and Co were buried. For each material, the maximal depth of subsurface visualisation is determined by the material parameters and ranges from several nanometers to several tens of nanometers. To demonstrate the ultimate depth of subsurface STM-vision as the principal limit of our approach, the system of Ar nanoclusters embedded into a single-crystalline Cu(110) matrix has been chosen since it represents the best combination of the mean free path, smooth interface and inner electron focusing. With this system we experimentally demonstrated that Ar nanoclusters of several nanometers large buried as deep as 80 nm can still be detected, characterized and imaged. The ultimate depth of this ability is estimated to be 110 nm. This approach using QW states paves the way for enhanced 3D characterization of nanostructures hidden well below a metallic surface.

Content validation of observer-reported sickle cell pain diaries (SCPD-CS and SCPD-CN): results from interviews with caregivers.

BACKGROUND: Patients with sickle cell disease (SCD) experience daily pain and acute episodes known as sickle cell pain crises (SCPCs). The Sickle Cell Pain Diary-Caregiver Report (SCPD-C) is an observer-reported diary for use by caregivers of children ages < 12 years with SCD. This study reports on the content validity of the SCPD-C. METHODS: The SCPD-C was developed based on a literature review, measurement expert input, and a patient advisory board including clinicians. Three rounds of interviews (including both concept elicitation and cognitive debriefing methodologies) were conducted with caregivers of children with SCD aged < 12 to evaluate the content validity of the SCPD-C. RESULTS: Across three rounds of interviews, caregivers confirmed concepts in the SCPD-C and described observed impacts that were important and were added. Overall, caregivers evaluated the SCPD-C as easy to understand, with some minor adaptations for clarity. Additionally, the diary was split into two versions based on the child's age and school enrollment status (SCPD-CS for school-aged and SCPD-CN for non-school age children). CONCLUSIONS: Caregivers provided valuable input that led to important additions and changes to the measures. The SCPD-CS and SCPD-CN are appropriate and fit-for-purpose observer-reported outcome measures of SCPC-related pain frequency and severity, and impacts on health-related quality of life.

Content validation of a self-report daily diary in patients with sickle cell disease.

BACKGROUND: Sickle Cell Disease (SCD) is a genetic progressive vascular disease that impacts patients overall health and quality of life. Sickle-cell pain crises (SCPCs) are a hallmark clinical presentation of SCD and have been associated with increased morbidity and mortality. The Sickle Cell Pain Diary- Self Report (SCPD-S) was developed as a daily patient-reported outcome (PRO) measure primarily intended to capture the frequency and severity of SCD-related pain during and outside of a SCPC. The SCPD-S also examines the impact of the pain associated with an SCPC on other health-related quality of life concepts. The objective of this study was to investigate the content validity of the SCPD-S. METHODS: The content validation testing included 18 in-depth hybrid concept elicitation and cognitive debriefing interviews conducted with SCD patients in the US aged 12 years and older. Interviewers used a semi-structured interview guide and a think-aloud approach for the cognitive debriefing portion. All interviews were recorded, transcribed, coded and analyzed. RESULTS: Eighteen interviews across two rounds were conducted. Round 1 hybrid interviews (n = 12) resulted in the expansion of the SCPD-S from 13 to 19 items. Items on the impact of an SCPC on social and recreational activities, sleep, and emotional well-being were added. Five items were significantly revised, as were three response choice sets. Round 2 hybrid interviews (n = 6) confirmed the comprehensiveness of the revised diary, understandability of the wording, and appropriateness of the recall period and response sets. Saturation analyses specific to concept elicitation revealed that no additional interviews were needed. CONCLUSIONS: This study provided evidence to support the content validity of the SCPD-S, a self-report daily diary. Data gathered during patient interviews indicated that the SCPD-S is a fit for purpose measure of SCD and SCPC-related pain frequency and severity and the impact of this pain on other health-related quality of life concepts including fatigue and emotional health. The numerous changes to the SCPD-S as a result of the study findings highlight the importance of the content validation process when developing a PRO measure.

The development and validation of a revised version of the Medical Outcomes Study Sleep Scale (MOS Sleep-R).

BACKGROUND: The 12-item Medical Outcomes Study Sleep Scale (MOS Sleep Scale) has been used to capture patient-reported sleep problems in hundreds of studies. A revised version of the MOS Sleep Scale (MOS Sleep-R) was developed that uses simplified response sets, provides interpretable norm-based scoring, and has two recall versions (one-week or four-week). The objective of this study was to evaluate the psychometric properties (reliability and construct validity) of the MOS Sleep-R using data from a representative sample of U.S. adults. METHODS: Standardization of raw scores into norm-based T-scores (mean = 50, standard deviation = 10) was based on data from a 2009 U.S. internet-based general population survey. The internal consistency reliability of multi-item subscales and global sleep problems indices for both one-week and four-week recall forms of the MOS Sleep-R were examined using Cronbach's alphas and inter-item correlations. Construct validity was tested by comparing item-scale correlations between items within subscales with item-scale correlations across subscales. Scale-level convergent validity was tested using correlations with measures including generic health-related quality of life (i.e., SF-36v2) and other relevant outcomes (e.g., job performance, number of days in bed due to illness or injury, happiness/satisfaction with life, frequency of stress/pressure in daily life, the impact of stress/pressure on health, and overall health). RESULTS: The one-week and four-week recall forms of the MOS Sleep-R were completed by 2045 and 2033 respondents, respectively. The psychometric properties of the one-week and four-week forms were similar. All multi-item subscales and global index scores showed adequate internal consistency reliability (all Cronbach's alpha > 0.75). Patterns of inter-item and item-scale correlations support the scaling assumptions of the MOS Sleep-R. Patterns of correlations between MOS Sleep-R scores with criterion measures of health-related quality of life and other outcomes indicated adequate construct validity. CONCLUSIONS: The MOS Sleep-R introduces a number of revisions to the original survey, including simplified response sets, the introduction of a one-week recall form, and norm-based scoring that enhances interpretability of scores. Both the one-week and four-week recall period forms of the MOS Sleep-R demonstrated good internal consistency reliability and construct validity in a U.S. general population sample.

Childhood Physical Neglect Is Associated With Exaggerated Systemic and Intracellular Inflammatory Responses to Repeated Psychosocial Stress in Adulthood.

Experiences of child maltreatment are associated with a host of adverse mental and physical health outcomes in adulthood. Altered reactivity to psychosocial stress exposure may partially explain known associations between early experiences of maltreatment and later life health. The present study focuses on examining whether experiences of child maltreatment are associated with physiological reactions to initial and repeated psychosocial stress in adulthood. To this end, 44 healthy adults (52% male, aged 18-65) completed the Childhood Trauma Questionnaire to provide information about exposure to child maltreatment and completed the Trier Social Stress Test (TSST) on 2 consecutive days. Peripheral blood was collected prior to as well as 30 and 120 min following the TSST on each day. Plasma Interleukin-6 (IL-6) and gene expression of IL-6, IL-1ß, nuclear factor-kB (NF-kB), and inhibitor of kB (IkB) were measured from each blood sample. Total CTQ scores were unrelated to plasma IL-6 and gene expression (ps > .10) but a history of childhood physical neglect was associated with increased interleukin-1ß (ß =.35; p =.02; R2 =.19) and nuclear factor-kB (ß =.30; p =.046; R2 =.13) expression following initial stress. Following repeated exposure to the TSST, childhood physical neglect was associated with increased plasma IL-6 reactivity (ß =.34; p =.02; R2 =.16) and increased expression of nuclear factor-kB (ß =.31; p =.04; R2 =.08). Finally, childhood physical neglect was associated with decreased habituation following repeated exposure to the TSST. Other CTQ subscales were not related to plasma IL-6 and gene expression when considered individually. Results from this study are suggestive of a unique effect of childhood physical neglect on the physiological stress response following initial and repeated exposure to a common psychosocial stressor. This provides important directions for future research because the effect of childhood physical neglect on long-term neglect are not well understood and in need of further investigation.

Cytochrome oxidase assembly does not require catalytically active cytochrome C.

Cytochrome c oxidase (COX), the terminal enzyme of the mitochondrial respiratory chain, catalyzes the transfer of electrons from reduced cytochrome c to molecular oxygen. COX assembly requires the coming together of nuclear- and mitochondrial-encoded subunits and the assistance of a large number of nuclear gene products acting at different stages of maturation of the enzyme. In Saccharomyces cerevisiae, expression of cytochrome c, encoded by CYC1 and CYC7, is required not only for electron transfer but also for COX assembly through a still unknown mechanism. We have attempted to distinguish between a functional and structural requirement of cytochrome c in COX assembly. A cyc1/cyc7 double null mutant strain was transformed with the cyc1-166 mutant gene (Schweingruber, M. E., Stewart, J. W., and Sherman, F. (1979) J. Biol. Chem. 254, 4132-4143) that expresses stable but catalytically inactive iso-1-cytochrome c. The COX content of the cyc1/cyc7 double mutant strain harboring non-functional iso-1-cytochrome c has been characterized spectrally, functionally, and immunochemically. The results of these studies demonstrate that cytochrome c plays a structural rather than functional role in assembly of cytochrome c oxidase. In addition to its requirement for COX assembly, cytochrome c also affects turnover of the enzyme. Mutants containing wild type apocytochrome c in mitochondria lack COX, suggesting that only the folded and mature protein is able to promote COX assembly.