Steroid disorders in children: Congenital adrenal hyperplasia and apparent mineralocorticoid excess

Our research team and laboratories have concentrated on two inherited endocrine disorders, congenital adrenal hyperplasia (CAH) and apparent mineralocorticoid excess, in thier investigations of the pathophysiology of adrenal steroid hormone disorders in children. CAH refers to a family of inherited disorders in which defects occur in one of the enzymatic steps required to synthesize cortisol from cholesterol in the adrenal gland. Because of the impaired cortisol secretion, adrenocorticotropic hormone levels rise due to impairment of a negative feedback system, which results in hyperplasia of the adrenal cortex. The majority of cases is due to 21-hydroxylase deficiency (21-OHD). Owing to the blocked enzymatic step, cortisol precursors accumulate in excess and are converted to potent androgens, which are secreted and cause in utero virilization of the affected female fetus genitalia in the classical form of CAH. A mild form of the 21-OHD, termed nonclassical 21-OHD, is the most common autosomal recessive disorder in humans, and occurs in 1/27 Ashkenazic Jews. Mutations in the CYP21 gene have been identified that cause both classical and nonclassical CAH. Apparent mineralocorticoid excess is a potentially fatal genetic disorder causing severe juvenile hypertension, pre- and postnatal growth failure, and low to undetectable levels of potassium, renin, and aldosterone. It is caused by autosomal recessive mutations in the HSD11B2 gene, which result in a deficiency of 11β-hydroxysteroid dehydrogenase type 2. In 1998, we reported a mild form of this disease, which may represent an important cause of low-renin hypertension.

Degeneration of neurons, synapses, and neuropil and glial activation in a murine Atm knockout model of ataxia–telangiectasia

Neural degeneration is one of the clinical manifestations of ataxia–telangiectasia, a disorder caused by mutations in the Atm protein kinase gene. However, neural degeneration was not detected with general purpose light microscopic methods in previous studies using several different lines of mice with disrupted Atm genes. Here, we show electron microscopic evidence of degeneration of several different types of neurons in the cerebellar cortex of 2-month-old Atm knockout mice, which is accompanied by glial activation, deterioration of neuropil structure, and both pre- and postsynaptic degeneration. These findings are similar to those in patients with ataxia–telangiectasia, indicating that Atm knockout mice are a useful model to elucidate the mechanisms underlying neurodegeneration in this condition and to develop and test strategies to palliate and prevent the disease.

Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia

Ischemic stroke is the most common life-threatening neurological disease and has limited therapeutic options. One component of ischemic neuronal death is inflammation. Here we show that doxycycline and minocycline, which are broad-spectrum antibiotics and have antiinflammatory effects independent of their antimicrobial activity, protect hippocampal neurons against global ischemia in gerbils. Minocycline increased the survival of CA1 pyramidal neurons from 10.5% to 77% when the treatment was started 12 h before ischemia and to 71% when the treatment was started 30 min after ischemia. The survival with corresponding pre- and posttreatment with doxycycline was 57% and 47%, respectively. Minocycline prevented completely the ischemia-induced activation of microglia and the appearance of NADPH-diaphorase reactive cells, but did not affect induction of glial acidic fibrillary protein, a marker of astrogliosis. Minocycline treatment for 4 days resulted in a 70% reduction in mRNA induction of interleukin-1β-converting enzyme, a caspase that is induced in microglia after ischemia. Likewise, expression of inducible nitric oxide synthase mRNA was attenuated by 30% in minocycline-treated animals. Our results suggest that lipid-soluble tetracyclines, doxycycline and minocycline, inhibit inflammation and are neuroprotective against ischemic stroke, even when administered after the insult. Tetracycline derivatives may have a potential use also as antiischemic compounds in humans.

Localization of alpha type II calcium calmodulin-dependent protein kinase at glutamatergic but not gamma-aminobutyric acid (GABAergic) synapses in thalamus and cerebral cortex.

The alpha subunit of type II calcium/calmodulin-dependent protein kinase (CAM II kinase-alpha) plays an important role in longterm synaptic plasticity. We applied preembedding immunocytochemistry (for CAM II kinase-alpha) and postembedding immunogold labeling [for glutamate or gamma-aminobutyric acid (GABA)] to explore the subcellular relationships between transmitter-defined axon terminals and the kinase at excitatory and inhibitory synapses in thalamus and cerebral cortex. Many (but not all) axon terminals ending in asymmetric synapses contained presynaptic CAM II kinase-alpha immunoreactivity; GABAergic terminals ending in symmetric synapses did not. Postsynaptically, CAM II kinase-alpha immunoreactivity was associated with postsynaptic densities of many (but not all) glutamatergic axon terminals ending on excitatory neurons. CAM II kinase-alpha immunoreactivity was absent at postsynaptic densities of all GABAergic synapses. The findings show that CAM II kinase-alpha is selectively expressed in subpopulations of excitatory neurons and, to our knowledge, demonstrate for the first time that it is only associated with glutamatergic terminals pre- and postsynaptically. CAM II kinase-alpha is unlikely to play a role in plasticity at GABAergic synapses.

Mixed synapses discovered and mapped throughout mammalian spinal cord.

Previously, synaptic activity in the spinal cord of adult mammals was attributed exclusively to chemical neurotransmission. In this study, evidence was obtained for the existence, relative abundance, and widespread distribution of "mixed" (chemical and electrical) synapses on neurons throughout the spinal cords of adult mammals. Using combined confocal microscopy and "grid-mapped freeze fracture," 36 mixed synapses containing 88 "micro" gap junctions (median = 45 connexons) were found and mapped to 33 interneurons and motor neurons in Rexed laminae III-IX in cervical, thoracic, and lumbosacral spinal cords of adult male and female rats. Gap junctions were adjacent to presumptive active zones, where even small gap junctions would be expected to increase synaptic efficacy. Two morphological types of mixed synapse were discerned. One type contained distinctive active zones consisting of "nested" concentric toroidal deformations of pre- and postsynaptic membranes, which, because of their unusual topology, were designated as "synaptic sombreros." A second type had gap junctions adjacent to active zones consisting of broad, flat, shallow indentations of the plasma membrane. Morphometric analysis indicates that mixed synapses correspond to 3-5% of all synapses on the somata and proximal dendrites, but, because of their subcellular location and morphology, they could represent 30-100% of excitatory synapses. The relative abundance of mixed synapses on several classes of neurons in spinal cords of adult rats suggests that mixed synapses provide important but previously unrecognized pathways for bidirectional communication between neurons in the mammalian central nervous system.

Apolipoprotein E4 allele as a predictor of cholinergic deficits and treatment outcome in Alzheimer disease.

Apolipoprotein E (apoE) is critical in the modulation of cholesterol and phospholipid transport between cells of different types. Human apoE is a polymorphic protein with three common alleles, APO epsilon 2, APO epsilon 3, and APO epsilon 4. ApoE4 is associated with sporadic and late-onset familial Alzheimer disease (AD). Gene dose was shown to have an effect on risk of developing AD, age of onset, accumulation of senile plaques in the brain, and reduction of choline acetyltransferase (ChAT) activity in the hippocampus of AD subjects. To characterize the possible impact of the apoE4 allele on cholinergic markers in AD, we examined the effect of apoE4 allele copy number on pre- and postsynaptic markers of cholinergic activity. ApoE4 allele copy number showed an inverse relationship with residual brain ChAT activity and nicotinic receptor binding sites in both the hippocampal formation and the temporal cortex of AD subjects. AD cases lacking the apoE4 allele showed ChAT activities close or within age-matched normal control values. The effect of the apoE4 allele on cholinomimetic drug responsiveness was assessed next in a group (n = 40) of AD patients who completed a double-blind, 30-week clinical trial of the cholinesterase inhibitor tacrine. Results showed that > 80% of apoE4-negative AD patients showed marked improvement after 30 weeks as measured by the AD assessment scale (ADAS), whereas 60% of apoE4 carriers had ADAS scores that were worse compared to baseline. These results strongly support the concept that apoE4 plays a crucial role in the cholinergic dysfunction associated with AD and may be a prognostic indicator of poor response to therapy with acetylcholinesterase inhibitors in AD patients.

Long-term synaptic transformation of hippocampal CA1 gamma-aminobutyric acid synapses and the effect of anandamide.

Evidence is presented for a distinctive type of hippocampal synaptic modification [previously described for a molluscan gamma-aminobutyric acid (GABA) synapse after paired pre- and postsynaptic excitation]: transformation of GABA-mediated synaptic inhibition into synaptic excitation. This transformation persists with no further paired stimulation for 60 min or longer and is termed long-term transformation. Long-term transformation is shown to contribute to pairing-induced long-term potentiation but not to long-term potentiation induced by presynaptic stimulation alone. Further support for such mechanistic divergence is provided by pharmacologic effects on long-term transformation as well as these two forms of long-term potentiation by Cl- channel blockers, glutamate and GABA antagonists, as well as the endogenous cannabinoid ligand anandamide.

Madurez sintáctica: influencia de las TIC en sus índices y estudio comparativo entre las generaciones pre y post-internet

There is a growing concern about the poor quality of the writing of children and teenagers because of the continuous and constant exposure to the new technologies. Increasingly parents complain that their children spend too much time with their phones, tablets, computers, video games, etc. There is also an increase in the number of teachers who complain about their students’ writing skills. Some of the most prominent criticisms are loss of vocabulary, simplified syntax and the poor spelling of the compositions. To verify if these criticisms are motivated or not by the use of information and communication technologies (ICT) is what moved us to initiate this doctoral dissertation entitled “The influence of ICT on ratings of syntactic maturity: a comparative study between pre- and post-internet generations”. We aim to know if a daily and constant exposure to the ICT can affect the syntactic maturity rates of children and teenagers. We also want to find out if there are differences between the levels of syntactic maturity of today’s students and those of the 1990s, when there were no ICT and internet. In order to do this, we have carried out a quantitative analysis taking as a reference previous studies by generativist researchers in the Anglo-Saxon and Hispanic world and we have used the same units of measure (T-unit and clause). We collected a corpus of 382 essays, half argumentative and half descriptive, from 191 individuals. We have analyzed them according to ten dependent variables or syntactic maturity rates and other independent variables (Hours in internet, Course, Sex, Location, Type of school) by applying techniques of descriptive and inferential statistics...

Treatment Outcomes for Eating Disorder Patients With and Without Comorbid Substance Abuse Diagnoses

The impact of comorbid substance abuse and eating disorder diagnoses in an eating disorder treatment facility remains uncertain. Recent data suggest that in a substance abuse treatment setting, patients with comorbid eating disorders fared less favorably than patients without a comorbid diagnosis (Cohen et al., 2010; Glasner-Edwards et al., 2011). The purpose of this study is to compare eating disorder symptoms over the course of treatment for patients with and without comorbid substance abuse diagnoses in an eating disorder treatment facility. Archival data from an eating disorder treatment facility was used. Twenty-seven women with comorbid eating disorder and substance abuse diagnoses (EDSUD) were compared to twenty-seven women with an eating disorder diagnosis (ED) only. The subjects were compared on three scales from the Eating Disorder Inventory-III (EDI-3) by group, and pre- and post-treatment. The scales were Personal Alienation (PA), Interoceptive Deficits (ID), and Emotional Dysregulation (EmD). There was a significant decrease in symptoms post-treatment for all subjects on the PA and ID scales, and there was a significant difference between the EDSUD subjects and ED subjects on two scales. EDSUD subjects fared significantly less favorably on the ID and EmD scales. Women with EDSUD report more symptoms of Interoceptive Deficits and Emotional Dysregulation when compared to women with an ED diagnosis and no comorbid substance use. Subjects benefited from treatment in terms of less Personal Alienation and Interoceptive Deficits.

Support groups and cardiac rehabilitation: Effects of partner participation on anxiety and depression

This study analyzes the effect on levels of patient anxiety and depression of a partner joining a cardiac rehabilitation program support group, also taking into account the sex of the patient. The study was undertaken using a two-group comparison design with pre-and post-test measures in non-equivalent groups. The sample comprised patients in the cardiac rehabilitation program (CRP) at the Ramón y Cajal Hospital, Madrid (Spain). Analysis of covariance (ANCOVA) showed direct effects of sex and partner participation in support groups on the anxiety trait. Similarly, interaction effects were observed between the sex variable and partner participation. These results indicate the pertinence of designing separate groups for patients and partners. © 2014 Universidad Complutense de Madrid and Colegio Oficial de Psicólogos de Madrid.

The Eating Disorder Inventory-III Maturity Fears Scale and Treatment Outcome in an Intensive Outpatient Eating Disorder Program

Eating disorders present a significant physical and psychological problem with a prevalence rate of approximately six percent in the United States. Despite the extensive literature, identifying the consistent risk factors for predicting the course of treatment in eating disorders remains difficult. The present study explores the use of a standardized assessment, using the consistently validated Eating Disorder Inventory-III (EDI-3), in predicting treatment outcome. Specifically, the study investigates the particular scale of Maturity Fears (MF) on the EDI-3, hypothesizing that higher scores on the MF scale would predict lower rates of recovery and treatment completion. The participants were 52 eating disorder patients (19 AN, 18 BN, and 15 EDNOS), consecutively admitted to a five-month long intensive outpatient program (IOP). The participants completed an EDI-3 self-report at pre and post treatment, and their score on the MF scale did not show a significant predictive relationship to treatment completion or change in symptoms, as measured by the Eating Disorder Risk Composite (EDRC) scale on the EDI-3. This finding primarily suggests that maturity fears are not a significant predictive factor in an outpatient setting with adults, as compared to previous studies that found a relationship between maturity fears and treatment outcome, primarily with adolescent and inpatient populations.

Detection and mapping of burnt areas from time series of MODIS-derived NDVI data in a Mediterranean region

Moderate resolution remote sensing data, as provided by MODIS, can be used to detect and map active or past wildfires from daily records of suitable combinations of reflectance bands. The objective of the present work was to develop and test simple algorithms and variations for automatic or semiautomatic detection of burnt areas from time series data of MODIS biweekly vegetation indices for a Mediterranean region. MODIS-derived NDVI 250m time series data for the Valencia region, East Spain, were subjected to a two-step process for the detection of candidate burnt areas, and the results compared with available fire event records from the Valencia Regional Government. For each pixel and date in the data series, a model was fitted to both the previous and posterior time series data. Combining drops between two consecutive points and 1-year average drops, we used discrepancies or jumps between the pre and post models to identify seed pixels, and then delimitated fire scars for each potential wildfire using an extension algorithm from the seed pixels. The resulting maps of the detected burnt areas showed a very good agreement with the perimeters registered in the database of fire records used as reference. Overall accuracies and indices of agreement were very high, and omission and commission errors were similar or lower than in previous studies that used automatic or semiautomatic fire scar detection based on remote sensing. This supports the effectiveness of the method for detecting and mapping burnt areas in the Mediterranean region.

Channel Migration and Avulsion Hazards at Sunshine Point Campground, Mount Rainier National Park, Washington

In November 2006, the flood of record on the upper Nisqually River destroyed part of Sunshine Point Campground in Mount Rainier National Park, Washington. The Nisqually River migrated north and reoccupied five acres of its floodplain; Tahoma Creek partially avulsed into the west floodplain, topping banks of an undersized channel and flooding the campground. I assessed hazards to infrastructure at the old campground location, where the Park proposes to rebuild the remaining campground roads and sites. This assessment focuses on two major hazards: northward Nisqually River migration, which may reincorporate the floodplain into the river destroying infrastructure; and Tahoma Creek avulsions, which may flood the campgroud and deposit sediment burying campground infrastructure. I quantify northward migration by: estimating migration rates and changes to channel width; evaluating river occupation of the pre- and post-2006 campground; and estimating scour depths at revetments protecting the campground. I digitized the Nisqually River channels and channel centerlines from maps and images between 1955 and 2013 into a GIS, which I used to estimate migration rate and river width changes. Centerline migration rates average 9 ft/yr along the length of the Nisqually River study reach; at Sunshine Point lateral migration rates average 11 ft/yr. Maximum migration along the study reach was 19 ft/yr between 2006 and 2009. Greater than average migration rates and channel widths correspond to river confluences and include the Tahoma Creek confluence at Sunshine Point. To determine historical channel locations and the frequency that the river occupied different parts of its floodplain, I digitized the river from maps and images between 1903 and 2013. The Nisqually River flows through Sunshine Point Campground in eight out of 15 historical images. I assess scour at revetments protecting infrastructure from the Nisqually River during a 100-year recurrence interval flood using measured cross-sections. During a 100-year flood, the Nisqually River may scour up to 10 feet below the bed elevation. These scour depths can destabilize critical revetments leaving loose unconsolidated riverbanks exposed to Nisqually River flows. To determine the causes, locations, and frequency of flood hazards from Tahoma Creek avulsions, I field map avulsion channels and compare the results with imagery and channel width changes between 1955 and 2013. Mapped avulsion channels occur with swaths of dead vegetation or nascent vegetation; both dead and recent vegetation are visibly distinct from surrounding vegetation in aerial images. Times of changes to these vegetation anomalies correspond to increases in Tahoma Creek channel width. Avulsions have occurred at least three times in the study period: pre-1955, between 1979 and 1984, and in 2006. The 1984 and 2006 avulsions both occur after increases in Tahoma Creek reach averaged width. The NPS is considering two options to rebuild Sunshine Point Campground, both at the same location. The hazards posed by the Nisqually River and Tahoma Creek at Sunshine Point will affect both construction options equally. Migration hazards to the campground may be reduced by limiting the proposed campground infrastructure to an elevated ridge that has not been occupied by the Nisqually River since 1903. The hazards of damage from migration may be reduced by revetments, which were effective in preventing northward Nisqually River migration in 1959 and 1965. Tahoma Creek avulsions are related increased of Tahoma Creek reach averaged widths, which are near a 58- year maximum, and occurred during a 10-year flood in 1984. The campground may be as susceptible to flooding from avulsions during as little as a 10-year flood. A large avulsion may occur with the next significant Tahoma Creek width increase. Glacial retreat has been shown to increase debris flow activity and increase sediment delivery to Mount Rainier rivers. Increased sediment discharge has been correlated with aggradation, which will further encourage Tahoma Creek avulsions.

Analysis of the Hydrogeological Conditions and the Effects of Development on the Hydraulic Head at Redmond Ridge East

Redmond Ridge East (RRE) is a large-scale master plan community in East King County, WA. In this report, I evaluate the spatial variability of the Quaternary Advance Outwash (Qva) at RRE and the time-series data for 16 water wells with the intent to better understand groundwater below the RRE area. I investigate changes between pre- and post-development conditions through the determination of temporal changes in annual water level, annual water level fluctuations, hydraulic head response to precipitation, and ambient drainage of the aquifer. I also perform a basic analysis of the annual aquifer recharge and a determination for the storage through the implementation of the water table fluctuation (WTF) method. Associated Earth Sciences (AESI) was tasked with monitoring the geological and environmental impacts during the development of RRE and collected the data I use in this report. AESI involvement in monitoring began in 1998 and extends to the present. Sixteen wells were identified in the RRE area with adequate temporal data to conduct the analysis. A comparison of the well logs and aquifer testing data allowed local variations in the Qva to be mapped. The WTF was used to determine a range of reasonable specific yield values for locations where the Qva was unconfined. Yearly average of the seasonal water level high and lows, and the fluctuations were quantified. Temporal relationships were established through linear regression. The average water level was found to be increasing in some locations, and the corresponding fluctuations were found to decrease. However, no clear change between pre- and post-development was observed. The response of hydraulic head to precipitation was investigated through an analysis of hydrographs for ten wells. Periods of consistent response and the corresponding precipitation during each period were delineated. A linear relationship between precipitation and water level change was determined. The threshold precipitation under which there is a positive response in the hydraulic head was established. No observable changes were apparent between pre- and post-development conditions. The ambient drainage for the Qva was calculated using recessional periods on the hydrograph. The transmissivity of Qva varies with thickness of the overlying lodgment till and thickness of the Qva, itself. Water level fluctuations observed in the Qva are consistent with regional observations. Localized areas in the Qva display the large 10 foot fluctuations and these anomalies are likely due to a combination of the local variability in the storativity as well as the concentration and channeling of water due to geographical variations in the Qva and the overlying topography. All trends seen in the RRE area remained relatively constant through time. There was no evidence showing an effect of development on the hydraulic head at RRE. This implies that the style and distribution of infiltration has not changed as a result of development, and that any measures in place are properly mitigating the effects of development on the RRE region.

Teamwork in Health and Rehabilitation Sciences: Evaluation of a multiprofessional workshop

This paper outlines a multiprofessional education workshop piloted and subsequently conducted with a cohort of 81 graduate entry students of occupational therapy, physiotherapy, speech pathology and audiology. The rationale for, and format of, the workshop is outlined, followed by comparisons between students' knowledge about teamwork prior to and after the four-hour workshop. The workshop was based on a real case scenario of a child with Developmental Coordination Disorder (DCD). Students completed pre- and post-workshop questionnaires about their knowledge of DCD, teamwork and the roles of various professionals and parents; and a post-workshop questionnaire about their views regarding the utility of the workshop, its strengths, and learning outcomes. The evaluation indicated that the workshop was overwhelmingly successful from the students' perspective in: (1) enhancing their understanding about DCD and its multifaceted impact on school age children; (2) developing a deeper appreciation of the importance of teamwork itself; (3) refining their understanding of their own profession's role and (4) developing an appreciation of the role of other professions and parents in working with children with complex needs, and their families. Limitations of this study and directions for future research are discussed.