Diaphragmatic ultrasound and patent ductus arteriosus in the newborn: A retrospective case series.

Background: Patent ductus arteriosus (PDA) and diaphragmatic dysfunction are frequently seen in newborn infants but their relationship remains unknown. We aimed to use point of care ultrasound to compare diaphragmatic kinetics in infants with a PDA compared to in those without a PDA. Methods: M-mode ultrasonography was used to measure the mean inspiratory velocity (V I) in newborn infants with and without a haemodynamically significant PDA admitted in the Neonatal Unit at King's College Hospital during a three month period. Results: Seventeen diaphragmatic ultrasound studies were reviewed from 14 infants with a median (IQR) gestational age of 26.1 (25.8-30.6) weeks, birth weight of 780 (660-1385) gr at a postnatal age of 18 (14-34) days. Eight scans had evidence of a PDA. The median (IQR) VI was significantly lower in scans with a PDA [1.01 (0.78-1.86) cm/s] compared to the ones without a PDA [3.21 (2.80-3.59) cm/s, p < 0.001]. The median (IQR) gestational age was lower in infants with a PDA [25.8 (25.6-27.3) weeks] compared to infants without a PDA [29.0 (26.1-35.1) weeks, p = 0.007]. Using multivariable linear regression analysis the VI was independently associated with a PDA (adjusted p < 0.001) but not with the gestational age (adjusted p = 0.659). Conclusions: Patent ductus arteriosus was associated with a lower mean inspiratory velocity in neonates and this effect was independent of gestational age.

Cytauxzoon felis in salivary glands of Amblyomma americanum.

Cytauxzoon felis is a tick-borne piroplasmid hemoparasite that causes life-threatening disease in cats. Despite the critical role that ticks play in pathogen transmission, our knowledge regarding the C. felis life cycle remains limited to the feline hosts. Specific life stages of C. felis within the tick host have never been visualized microscopically and previous investigations have been limited to molecular detection by polymerase chain reaction (PCR). Sporozoites are the infectious stage of piroplasmids that are transmitted by ticks. In other tick-borne piroplasmids, sporozoite-based vaccines play a key role in disease prevention and management. We believe sporozoites have similar potential for cytauxzoonosis. Therefore, the objective of this study was to use different molecular and microscopic techniques to detect and evaluate C. felis sporozoites in tick salivary glands (SG). A total of 140 Amblyomma americanum adults that were fed on C. felis-infected cats as nymphs were included for this study. Specifically, dissected SGs were quartered and subjected to C. felis RT-PCR, RNAscope® in situ hybridization (ISH), histology, direct azure staining, and transmission electron microscopy (TEM). Cytauxzoon felis RT-PCR was also performed on half tick (HT) carcasses after SG dissection. Cytauxzoon felis RNA was detected in SGs of 17/140 ticks. Of these, 7/17 ticks had microscopic visualization via ISH and/or TEM. The remaining 10/17 ticks had only molecular detection of C. felis in SGs via RT-PCR without visualization. Cytauxzoon felis RNA was detected solely in HT carcasses via RT-PCR in 9/140 ticks. In ISH-positive tick SGs, hybridization signals were present in cytoplasms of SG acinar cells. TEM captured rare C. felis organisms with characteristic ultrastructural features of sporozoites. This study describes the first direct visualization of any developing stage of C. felis in ticks. Forthcoming studies should employ a combination of molecular and microscopic techniques to investigate the C. felis life cycle in A. americanum.

Tau Phosphorylation and Aggregation in the Developing Human Brain.

Tau hyperphosphorylation, mostly at serine (Ser) or threonine (Thr) residues, plays a key role in the pathogenesis of Alzheimer disease (AD) and other tauopathies. Rodent studies show similar hyperphosphorylation in the developing brain, which may be involved in regulating axonal growth and plasticity, but detailed human studies are lacking. Here, we examine tau phosphorylation by immunohistochemistry and immunoblotting in human fetal and adult autopsy brain tissue. Of the 20 cases with sufficient tissue preservation, 18 (90%) showed positive staining for S214 (pSer214), with the majority also positive for CP13 (pSer202), and PHF-1 (pSer396/pSer404). AT8 (pSer202/pThr205) and RZ3 (pThr231) were largely negative while PG5 (pSer409) was negative in all cases. Immunoblotting showed tau monomers with a similar staining pattern. We also observed phospho-tau aggregates in the fetal molecular layer, staining positively for S214, CP13, and PHF1 and negative for thioflavin S. These corresponded to high-molecular weight (∼150 kD) bands seen on Western blots probed with S214, PHF1, and PG5. We therefore conclude that fetal phosphorylation overlaps with AD in some residues, while others (e.g. T231, S409) appear to be unique to AD, and that tau is capable of forming nontoxic aggregates in the developing brain. These findings suggest that the fetal brain is resilient to formation of toxic aggregates, the mechanism for which may yield insights into the pathogenesis of tau aggregation and toxicity in the aging brain.

Correlation of Symptoms with Bronchoscopic Findings in Children with a Prenatal Diagnosis of a Right Aortic Arch and Left Arterial Duct.

A right aortic arch (RAA) with a left arterial duct (LAD) together encircle the trachea and have the potential to cause tracheobronchial compression and published guidelines recommend bronchoscopy in symptomatic patients. The aim of the study was to describe the incidence of tracheal compression in a cohort of prenatally diagnosed RAA and LAD. Retrospective review of clinical course and imaging of prenatal cases of RAA and LAD assessed with flexible bronchoscopy over an 11-year period. 34 cases of prenatally diagnosed RAA with LAD underwent bronchoscopy at median age of 9 months (range 0.4-123) of whom 11 had respiratory symptoms and 23 were asymptomatic. In the neonatal period, three cases demonstrated respiratory symptoms. An aberrant left subclavian artery (ALSA) was identified in 29 cases. Pulsatile tracheal compression was identified in 32/34 (94%) cases and two cases showed normal tracheal appearances. Significant tracheal compression (> 70% occlusion) was present in 25/34 (74%) cases of which 16 were asymptomatic. Significant carinal compression (> 70% occlusion) was identified in 14/34 (42%) cases, an ALSA was observed in 13/14. Surgical relief of a vascular ring has been performed in 27 (79%) cases at a median age of 15 months (range 0.6-128 months). At surgery, a fibrous remnant of an atretic left aortic arch was identified in 11/27 (41%) cases. Significant tracheal compression may be present in infants even without symptoms. If early relief of airway compression is to be achieved to promote normal development of tracheal cartilage, early bronchoscopy should be considered.

Species traits modify the species-area relationship in ground-beetle (Coleoptera: Carabidae) assemblages on islands in a boreal lake.

Life-history traits influence colonization, persistence, and extinction of species on islands and are important aspects of theories predicting the geographical distribution and evolution of species. We used data collected from a large freshwater lake (1,413 km2) in central Canada to test the effects of island area and isolation on species richness and abundance of carabid beetles as a function of body size, wing length, and breeding season. A total of 10,018 individual beetles from 37 species were collected during the frost-free period of 2013 using transects of pitfall traps on 30 forested islands ranging in area from 0.2 to 980.7 ha. Life-history traits improved the predictive ability and significantly modified the shape of species-area and abundance-area curves. Abundance and richness of small-bodied (< 13.9 mm), macropterous (winged), and spring-breeding species decreased with island area and increased with isolation. In contrast, richness and abundance of larger-bodied (> 14.0 mm) and flightless species increased with area, but not isolation. Body size of female Carabus taedatus Fabricius, the largest-bodied species, was positively related to island area, while body size on the adjacent mainland was most similar to that on smaller islands. Overall, species with large body size and low dispersal ability, as indicated by flightlessness, were most sensitive to reductions in area. We suggest that large-bodied, flightless species are rare on small islands because habitat is less suitable for them and immigration rates are lower because they depend on freshwater drift for dispersal to islands.

Right ventricular systolic function in hypoplastic left heart syndrome: A comparison of manual and automated software to measure fractional area change.

BACKGROUND: Quantitative echocardiographic assessment of right ventricular function is important in children with hypoplastic left heart syndrome (HLHS). The aim of this study was to examine the repeatability of different echocardiographic techniques, both manual and automated, to measure fractional area change (FAC) in patients with HLHS and to correlate these measurements with magnetic resonance imaging (MRI)-derived ejection fraction (EF). METHODS: Fifty-one children with HLHS underwent transthoracic echocardiography and cardiac MRI under the same general anesthetic as part of routine inter-stage assessment. FAC was measured from the apical four-chamber view using three different techniques: velocity vector imaging (VVI) (Syngo USWP 3.0; Siemens Healthineers), QLAB (Q-lab R 10.0; Philips Healthcare), and manual endocardial contour tracing (Xcelera, Philips Healthcare). Intra- and inter-observer variability was calculated using intra-class correlation coefficient (ICC). FAC was correlated with MRI EF calculated using a single standard method. RESULTS: Fractional area change had a good correlation with MRI-derived EF with an R value for VVI, QLAB, and manual methods of .7, .6, and .4, respectively. Intra- and inter-observer variability for FAC was good for automated echocardiographic methods (ICC>.85) but worse for manual method particularly inter-observer variability of FAC and end-systolic area. Both automated techniques tended to produce higher FAC values compared with manual measurements (P<.001). CONCLUSION: Automation improves the repeatability of FAC in HLHS. There are some differences between automated software in terms of correlation with MRI-derived EF. Measurement bias and wide limits of agreement mean that the same echocardiographic technique should be used during the follow-up of individual patients.

Interstage somatic growth in children with hypoplastic left heart syndrome after initial palliation with the hybrid procedure.

Introduction The hybrid procedure is one mode of initial palliation for hypoplastic left heart syndrome. Subsequently, patients proceed with either the "three-stage" pathway - comprehensive second stage followed by Fontan completion - or the "four-stage" pathway - Norwood procedure, hemi-Fontan, or Fontan completion. In this study, we describe somatic growth patterns observed in the hybrid groups and a comparison primary Norwood group. METHODS: A retrospective analysis of patients who have undergone hybrid procedure and Fontan completion was performed. Weight-for-age and height-for-age z-scores were recorded at each operation. RESULTS: We identified 13 hybrid patients - eight in the three-stage pathway and five in the four-stage pathway - and 49 Norwood patients. Weight: three stage: weight decreased from hybrid procedure to comprehensive second stage (-0.4±1.3 versus -2.3±1.4, p<0.01) and then increased to Fontan completion (-0.4±1.5 versus -0.6±1.4, p<0.01); four stage: weight decreased from hybrid procedure to Norwood (-2.0±1.4 versus -3.3±0.9, p=0.06), then stabilised to hemi-Fontan. Weight increased from hemi-Fontan to Fontan completion (-2.7±0.6 versus -1.0±0.7, p=0.01); primary Norwood group: weight decreased from Norwood to hemi-Fontan (p<0.001) and then increased to Fontan completion (p<0.001). Height: height declined from hybrid procedure to Fontan completion in the three-stage group. In the four-stage group, height decreased from hybrid to hemi-Fontan, and then increased to Fontan completion. The Norwood group decreased in height from Norwood to hemi-Fontan, followed by an increase to Fontan completion. CONCLUSION: In this study, we show that patients undergoing the hybrid procedure have poor weight gain before superior cavopulmonary connection, before returning to baseline by Fontan completion. This study identifies key periods to target poor somatic growth, a risk factor of morbidity and worse neurodevelopmental outcomes.

Multiple Drug Treatments That Increase cAMP Signaling Restore Long-Term Memory and Aberrant Signaling in Fragile X Syndrome Models.

Fragile X is the most common monogenic disorder associated with intellectual disability (ID) and autism spectrum disorders (ASD). Additionally, many patients are afflicted with executive dysfunction, ADHD, seizure disorder and sleep disturbances. Fragile X is caused by loss of FMRP expression, which is encoded by the FMR1 gene. Both the fly and mouse models of fragile X are also based on having no functional protein expression of their respective FMR1 homologs. The fly model displays well defined cognitive impairments and structural brain defects and the mouse model, although having subtle behavioral defects, has robust electrophysiological phenotypes and provides a tool to do extensive biochemical analysis of select brain regions. Decreased cAMP signaling has been observed in samples from the fly and mouse models of fragile X as well as in samples derived from human patients. Indeed, we have previously demonstrated that strategies that increase cAMP signaling can rescue short term memory in the fly model and restore DHPG induced mGluR mediated long term depression (LTD) in the hippocampus to proper levels in the mouse model (McBride et al., 2005; Choi et al., 2011, 2015). Here, we demonstrate that the same three strategies used previously with the potential to be used clinically, lithium treatment, PDE-4 inhibitor treatment or mGluR antagonist treatment can rescue long term memory in the fly model and alter the cAMP signaling pathway in the hippocampus of the mouse model.

PDE-4 inhibition rescues aberrant synaptic plasticity in Drosophila and mouse models of fragile X syndrome.

Fragile X syndrome (FXS) is the leading cause of both intellectual disability and autism resulting from a single gene mutation. Previously, we characterized cognitive impairments and brain structural defects in a Drosophila model of FXS and demonstrated that these impairments were rescued by treatment with metabotropic glutamate receptor (mGluR) antagonists or lithium. A well-documented biochemical defect observed in fly and mouse FXS models and FXS patients is low cAMP levels. cAMP levels can be regulated by mGluR signaling. Herein, we demonstrate PDE-4 inhibition as a therapeutic strategy to ameliorate memory impairments and brain structural defects in the Drosophila model of fragile X. Furthermore, we examine the effects of PDE-4 inhibition by pharmacologic treatment in the fragile X mouse model. We demonstrate that acute inhibition of PDE-4 by pharmacologic treatment in hippocampal slices rescues the enhanced mGluR-dependent LTD phenotype observed in FXS mice. Additionally, we find that chronic treatment of FXS model mice, in adulthood, also restores the level of mGluR-dependent LTD to that observed in wild-type animals. Translating the findings of successful pharmacologic intervention from the Drosophila model into the mouse model of FXS is an important advance, in that this identifies and validates PDE-4 inhibition as potential therapeutic intervention for the treatment of individuals afflicted with FXS.

Effects of pitfall trap lid transparency and habitat structure on the catches of carabid beetles (Coleoptera: Carabidae) in tame pasture.

Captures of insects in pitfall traps are affected by features of trap design that may confound the interpretation of data. One such feature is a lid suspended over the opening of the trap to exclude debris and rainwater. In this study, we tested whether use of these lids affected captures of carabid beetles by altering the light conditions at the opening to the trap. In one experiment, we examined the effects of lid transparency (opaque, semitransparent, or transparent) on catch rates. In a second experiment, we manipulated the heights (high, medium, or low) of vegetation adjacent to the traps to test for lid transparency and vegetation height interactions. We found that significantly more carabids were captured with use of transparent lids compared with other lid transparencies. Fewest Agonum cupreum Dejean, 1831, were captured with use of opaque lids. No other effects were detected. Given these results, we advocate the use of transparent lids, which provide the benefits of traditional opaque lids while minimizing the effects of lid use on light conditions at the opening to the trap.

The Drosophila DmGluRA is required for social interaction and memory.

Metabotropic glutamate receptors (mGluRs) have well-established roles in cognition and social behavior in mammals. Whether or not these roles have been conserved throughout evolution from invertebrate species is less clear. Mammals have eight mGluRs whereas Drosophila has a single DmGluRA, which has both Gi and Gq coupled signaling activity. We have utilized Drosophila to examine the role of DmGluRA in social behavior and various phases of memory. We have found that flies that are homozygous or heterozygous for loss of function mutations of DmGluRA have impaired social behavior in male Drosophila. Futhermore, flies that are heterozygous for loss of function mutations of DmGluRA have impaired learning during training, immediate-recall memory, short-term memory, and long-term memory as young adults. This work demonstrates a role for mGluR activity in both social behavior and memory in Drosophila.

A potential role for the interaction of Wolbachia surface proteins with the Brugia malayi glycolytic enzymes and cytoskeleton in maintenance of endosymbiosis.

The human filarial parasite Brugia malayi harbors an endosymbiotic bacterium of the genus Wolbachia. The Wolbachia represent an attractive target for the control of filarial induced disease as elimination of the bacteria affects molting, reproduction and survival of the worms. The molecular basis for the symbiotic relationship between Wolbachia and their filarial hosts has yet to be elucidated. To identify proteins involved in this process, we focused on the Wolbachia surface proteins (WSPs), which are known to be involved in bacteria-host interactions in other bacterial systems. Two WSP-like proteins (wBm0152 and wBm0432) were localized to various host tissues of the B. malayi female adult worms and are present in the excretory/secretory products of the worms. We provide evidence that both of these proteins bind specifically to B. malayi crude protein extracts and to individual filarial proteins to create functional complexes. The wBm0432 interacts with several key enzymes involved in the host glycolytic pathway, including aldolase and enolase. The wBm0152 interacts with the host cytoskeletal proteins actin and tubulin. We also show these interactions in vitro and have verified that wBm0432 and B. malayi aldolase, as well as wBm0152 and B. malayi actin, co-localize to the vacuole surrounding Wolbachia. We propose that both WSP protein complexes interact with each other via the aldolase-actin link and/or via the possible interaction between the host's enolase and the cytoskeleton, and play a role in Wolbachia distribution during worm growth and embryogenesis.

Serial magnetic resonance imaging in hypoplastic left heart syndrome gives valuable insight into ventricular and vascular adaptation.

OBJECTIVES: This study sought to investigate changes in magnetic resonance imaging (MRI) ventricular volumes and vascular dimensions before hemi-Fontan (HF) and before total cavopulmonary connection (TCPC) in children with hypoplastic left heart syndrome (HLHS). BACKGROUND: The systemic right ventricle (RV) in HLHS is subject to significant changes in volume loading throughout the surgical stages of palliation, particularly after the HF. METHODS: Fifty-eight patients had paired pre-HF and pre-TCPC MRI for assessment of changes of RV volumes, neoaortic flow, and vascular dimensions. RESULTS: Comparison of pre-HF and pre-TCPC MRI results showed a decrease of indexed RV end-diastolic volume and end-systolic volume (98 ml/m(2) to 87 ml/m(2) and 50 ml/m(2) to 36 ml/m(2), respectively) with stroke volume remaining constant (49 ml/m(2) vs. 51 ml/m(2)), leading to an increased RV ejection fraction (51% vs. 59%). These findings persisted after excluding the 3 patients who underwent tricuspid valve repair as part of their HF procedure. Indexed RV end-diastolic volume plotted against neoaortic stroke volume demonstrated a Frank-Starling-like curve that shifted upward after HF. The indexed distal left and right cross-sectional pulmonary artery areas were reduced after HF. CONCLUSIONS: In HLHS, serial MRI shows the adaptation of the systemic RV after HF with volume reduction in the context of a preserved stroke volume and an increased ejection fraction. The staged palliation in HLHS may be a risk factor particularly for reduced left pulmonary artery growth in itself as no factors investigated in this study were found to significantly impact on this.

Subjective evaluation of right ventricular systolic function in hypoplastic left heart syndrome: how accurate is it?

BACKGROUND: The geometry and heterogeneity of the right ventricle in hypoplastic left heart syndrome makes objective echocardiographic assessment of systolic function challenging. Consequently, subjective echocardiographic assessment of right ventricular (RV) function is still routinely undertaken. The aims of this study were to compare this with magnetic resonance imaging (MRI), investigate the impact of experience and training on the accuracy of subjective assessment, and critically analyze the role of echocardiography to detect impaired systolic function. METHODS: A retrospective analysis of prospectively acquired data was performed. Children with hypoplastic left heart syndrome underwent routine preoperative cardiac MRI and echocardiography under the same general anesthetic. Echocardiograms were reviewed, and members of the congenital heart disease team with differing echocardiography experience subjectively graded RV systolic function (good, moderate, or poor). This was compared with MRI-derived ejection fraction. RESULTS: Twenty-eight patients at different palliative stages were included. Twenty-eight observers were divided into five experience categories (congenital heart disease junior trainees to attending cardiologists). Median agreement was 47.6% (range, 31.4%-58.2%), with the lowest agreement among junior trainees and the highest among attending cardiologists. When used as a screening test for poor RV systolic function, the median sensitivity of echocardiography was 0.89 (range, 0.86-0.96), and median specificity was 0.45 (range, 0.26-0.55). The highest sensitivity was observed among junior trainees but with the lowest specificity. The highest specificity was observed among attending cardiologists (0.55). CONCLUSIONS: Agreement between echocardiographic and MRI RV ejection fraction improves with experience but remains suboptimal. When used as a screening test for poor RV function, echocardiography is sensitive, but specificity is heavily influenced by operator experience.

Three-dimensional dual-phase whole-heart MR imaging: clinical implications for congenital heart disease.

PURPOSE: To identify which rest phase (systolic or diastolic) is optimum for assessing or measuring cardiac structures in the setting of three-dimensional (3D) whole-heart imaging in congenital heart disease (CHD). MATERIALS AND METHODS: The study was approved by the institutional review board; informed consent was obtained. Fifty children (26 male and 24 female patients) underwent 3D dual-phase whole-heart imaging. Cardiac structures were analyzed for contrast-to-noise ratio (CNR) and image quality. Cross-sectional measurements were taken of the aortic arch, right ventricular (RV) outflow tract (RVOT) and pulmonary arteries. Normally distributed variables were compared by using paired t tests, and categorical data were compared by using Wilcoxon signed-rank test. RESULTS: Mean CNR and image quality were significantly (all P < .05) greater in systole for the right atrium (CNR, 8.9 vs 7.5; image quality, 438 vs 91), left atrium (CNR, 8.0 vs 5.3; image quality, 1006 vs 29), RV (CNR, 10.6 vs 8.2; image quality, 131 vs 23), LV (CNR, 9.4 vs 7.7; image quality, 125 vs 28), and pulmonary veins (CNR, 6.2 vs 4.9; image quality, 914 vs 32). Conversely, diastolic CNR was significantly higher in the aorta (9.2 vs 8.2; P = .013) and diastolic image quality was higher for the left pulmonary artery (238 vs 62; P = .007), right pulmonary artery (219 vs 35; P < .001), and for imaging of an area after an arterial stenosis (164 vs 7; P < .001). All aortic arch and RVOT cross-sectional measurements were significantly (P < .05) greater in systole (narrowest point of arch, 70 vs 53 mm(2); descending aorta, 71 vs 58 mm(2); transverse arch, 293 vs 275 mm(2); valvar RVOT, 291 vs 268 mm(2); supravalvar RVOT, 337 vs 280 mm(2); prebifurcation RVOT, 329 vs 259 mm(2)). CONCLUSION: Certain structures in CHD are better imaged in systole and others in diastole, and therefore, the dual-phase approach allows a higher overall success rate. This approach also allows depiction of diameter changes between systole and diastole and is therefore preferable to standard single-phase sequences for the planning of interventional procedures.

Behavior in a Drosophila model of fragile X.

This chapter will briefly tie together a captivating string of scientific discoveries that began in the 1800s and catapulted us into the current state of the field where trials are under way in humans that have arisen directly from the discoveries made in model organisms such as Drosophila (fruit flies) and mice. The hope is that research efforts in the field of fragile X currently represent a roadmap that demonstrates the utility of identifying a mutant gene responsible for human disease, tracking down the molecular underpinnings of pathogenic phenotypes, and utilizing model organisms to identify and validate potential pharmacologic targets for testing in afflicted humans. Indeed, in fragile X this roadmap has already yielded successful trials in humans (J. Med. Genetic 46(4) 266-271; Jacquemont et al. Sci Transl Med 3(64):64ra61), although the work in studying these interventions in humans is just getting underway as the work in model organisms continues to generate new potential therapeutic targets.

Tissue Doppler time intervals and derived indices in hypoplastic left heart syndrome.

AIMS: To describe tissue Doppler time intervals and derived indices in hypoplastic left heart syndrome (HLHS) across surgical stages, taking account of age-related changes in the heart rate. Correlation of the myocardial performance index (MPI) and the systolic to diastolic (S:D) time ratio with other echocardiographic and magnetic resonance imaging (MRI) measures of cardiac performance. METHODS AND RESULTS: Fifty-seven patients at different stages of HLHS palliation were studied prospectively using tissue Doppler imaging of the right ventricular free wall, with simultaneous cardiac MRI in the majority. Both isovolumic contraction time and isovolumic relaxation time were prolonged compared with the normal left and right ventricle: median (range) z-scores for the tricuspid annulus 1.9 (-1.2 to 9.3) and 1.3 (-2.0 to 5.5), respectively. When adjusted for heart rate, the ejection, systolic, and diastolic times in HLHS were not significantly different from published normal data. The MPI was increased at all surgical stages in HLHS. Neither MPI nor heart rate-specific S:D time ratio z-score correlated with MRI ejection fraction or indexed cardiac output when the confounding effect of significant tricuspid regurgitation was taken into consideration. CONCLUSION: The prolongation in isovolumic relaxation and contraction times may be due to adaptation or reduced myocardial performance. Differences in the S:D time ratio between surgical stages can be accounted for by the heart rate alone. Neither MPI z-score nor S:D z-score correlated with MRI or other echocardiographic indices of systolic or diastolic function with the exception of a negative correlation between central venous pressure and S:D ratio z-score.

Pharmacological reversal of synaptic plasticity deficits in the mouse model of fragile X syndrome by group II mGluR antagonist or lithium treatment.

Fragile X syndrome is the leading single gene cause of intellectual disabilities. Treatment of a Drosophila model of Fragile X syndrome with metabotropic glutamate receptor (mGluR) antagonists or lithium rescues social and cognitive impairments. A hallmark feature of the Fragile X mouse model is enhanced mGluR-dependent long-term depression (LTD) at Schaffer collateral to CA1 pyramidal synapses of the hippocampus. Here we examine the effects of chronic treatment of Fragile X mice in vivo with lithium or a group II mGluR antagonist on mGluR-LTD at CA1 synapses. We find that long-term lithium treatment initiated during development (5-6 weeks of age) and continued throughout the lifetime of the Fragile X mice until 9-11 months of age restores normal mGluR-LTD. Additionally, chronic short-term treatment beginning in adult Fragile X mice (8 weeks of age) with either lithium or an mGluR antagonist is also able to restore normal mGluR-LTD. Translating the findings of successful pharmacologic intervention from the Drosophila model into the mouse model of Fragile X syndrome is an important advance, in that this identifies and validates these targets as potential therapeutic interventions for the treatment of individuals afflicted with Fragile X syndrome.

Pharmacological and genetic reversal of age-dependent cognitive deficits attributable to decreased presenilin function.

Alzheimer's disease (AD) is the leading cause of cognitive loss and neurodegeneration in the developed world. Although its genetic and environmental causes are not generally known, familial forms of the disease (FAD) are attributable to mutations in a single copy of the Presenilin (PS) and amyloid precursor protein genes. The dominant inheritance pattern of FAD indicates that it may be attributable to gain or change of function mutations. Studies of FAD-linked forms of presenilin (psn) in model organisms, however, indicate that they are loss of function, leading to the possibility that a reduction in PS activity might contribute to FAD and that proper psn levels are important for maintaining normal cognition throughout life. To explore this issue further, we have tested the effect of reducing psn activity during aging in Drosophila melanogaster males. We have found that flies in which the dosage of psn function is reduced by 50% display age-onset impairments in learning and memory. Treatment with metabotropic glutamate receptor (mGluR) antagonists or lithium during the aging process prevented the onset of these deficits, and treatment of aged flies reversed the age-dependent deficits. Genetic reduction of Drosophila metabotropic glutamate receptor (DmGluRA), the inositol trisphosphate receptor (InsP(3)R), or inositol polyphosphate 1-phosphatase also prevented these age-onset cognitive deficits. These findings suggest that reduced psn activity may contribute to the age-onset cognitive loss observed with FAD. They also indicate that enhanced mGluR signaling and calcium release regulated by InsP(3)R as underlying causes of the age-dependent cognitive phenotypes observed when psn activity is reduced.