Intracranial Pulsating Balloon-Based Cardiac-Gated ICP Modulation Impact on Brain Oxygenation: A Proof-of-Concept Study in a Swine Model.

BACKGROUND: Brain oxygenation improvement is a sought-after goal in neurocritical care patients. Previously, we have shown that cerebral blood flow improvement by cardiac-gated intracranial pressure (ICP) modulation using an intracranial pulsating balloon is feasible in a swine model. We sought to explore specific ICP modulation protocols to assess the feasibility of influencing brain oxygenation. METHODS: A previously presented electrocardiogram (ECG)-gated intracranial balloon pump in which volume, timing, and duty cycle of balloon inflation could be altered was used. Different protocols were tested in a swine model of normal and elevated ICP attained by intracranial fluid infusion with continuous monitoring of physiological parameters, and brain tissue oxygen tension (PbtO2) was measured at baseline and after device activation. RESULTS: We studied five swine, subjected to two main protocols differing in their phase relative to the cardiac cycle. In reduced brain perfusion status (ICP > 20 mm Hg, PbtO2 < 15 mm Hg), the late-diastolic-early-systolic (Inflation/deflation) protocol showed consistent elevation in PbtO2 (+ 9%, p < 0.01), coupled with ICP reduction (- 12%, p < 0.01), whereas the early-systolic-late-diastolic (inflation/deflation) protocol resulted in PbtO2 reduction (- 4%, p < 0.01), coupled with ICP increase (+ 5% above baseline, p < 0.01). No significant changes in brain oxygenation or ICP were observed at normal perfusion status (ICP < 20 mm Hg, PbtO2 > 15 mm Hg). CONCLUSIONS: Intracranial cardiac-gated balloon pump activation can influence cerebral oxygenation and raise PbtO2 above threshold values. This study supports the concept of late-diastolic pressure rise, coupled with early-systolic pressure drop, as a potential effector of flow augmentation leading to improve brain tissue oxygenation. Further studies are warranted to assess the translational potential of using an intracranial cardiac-gated balloon pump device to improve brain tissue oxygenation.

Atypical Auditory Brainstem Response and Protein Expression Aberrations Related to ASD and Hearing Loss in the Adnp Haploinsufficient Mouse Brain.

Autism is a wide spread neurodevelopmental disorder with growing morbidity rates, affecting more boys than girls worldwide. Activity-dependent neuroprotective protein (ADNP) was recently recognized as a leading gene accounted for 0.17% of autism spectrum disorder (ASD) cases globally. Respectively, mutations in the human ADNP gene (ADNP syndrome), cause multi-system body dysfunctions with apparent ASD-related traits, commencing as early as childhood. The Adnp haploinsufficient (Adnp+/-) mouse model was researched before in relations to Alzheimer's disease and autism. Adnp+/- mice suffer from deficient social memory, vocal and motor impediments, irregular tooth eruption and short stature, all of which corresponds with reported phenotypes in patients with the ADNP syndrome. Recently, a more elaborated description of the ADNP syndrome was published, presenting impediments such as hearing disabilities in > 10% of the studied children. Irregular auditory brainstem response (ABR) has been connected to ASD-related cases and has been suggested as a potential hallmark for autism, allowing diagnosis of ASD risk and early intervention. Herein, we present detriment hearing in the Adnp+/- mice with atypical ABR and significant protein expression irregularities that coincides with ASD and hearing loss studies in the brain.

Reduced changes in protein compared to mRNA levels across non-proliferating tissues.

BACKGROUND: The quantitative relations between RNA and protein are fundamental to biology and are still not fully understood. Across taxa, it was demonstrated that the protein-to-mRNA ratio in steady state varies in a direction that lessens the change in protein levels as a result of changes in the transcript abundance. Evidence for this behavior in tissues is sparse. We tested this phenomenon in new data that we produced for the mouse auditory system, and in previously published tissue datasets. A joint analysis of the transcriptome and proteome was performed across four datasets: inner-ear mouse tissues, mouse organ tissues, lymphoblastoid primate samples and human cancer cell lines. RESULTS: We show that the protein levels are more conserved than the mRNA levels in all datasets, and that changes in transcription are associated with translational changes that exert opposite effects on the final protein level, in all tissues except cancer. Finally, we observe that some functions are enriched in the inner ear on the mRNA level but not in protein. CONCLUSIONS: We suggest that partial buffering between transcription and translation ensures that proteins can be made rapidly in response to a stimulus. Accounting for the buffering can improve the prediction of protein levels from mRNA levels.

The GPSM2/LGN GoLoco motifs are essential for hearing.

The planar cell polarity (PCP) pathway is responsible for polarizing and orienting cochlear hair cells during development through movement of a primary cilium, the kinocilium. GPSM2/LGN, a mitotic spindle-orienting protein associated with deafness in humans, is a PCP effector involved in kinocilium migration. Here, we link human and mouse truncating mutations in the GPSM2/LGN gene, both leading to hearing loss. The human variant, p.(Trp326*), was identified by targeted genomic enrichment of genes associated with deafness, followed by massively parallel sequencing. Lgn (ΔC) mice, with a targeted deletion truncating the C-terminal GoLoco motifs, are profoundly deaf and show misorientation of the hair bundle and severe malformations in stereocilia shape that deteriorates over time. Full-length protein levels are greatly reduced in mutant mice, with upregulated mRNA levels. The truncated Lgn (ΔC) allele is translated in vitro, suggesting that mutant mice may have partially functioning Lgn. Gαi and aPKC, known to function in the same pathway as Lgn, are dependent on Lgn for proper localization. The polarization of core PCP proteins is not affected in Lgn mutants; however, Lgn and Gαi are misoriented in a PCP mutant, supporting the role of Lgn as a PCP effector. The kinocilium, previously shown to be dependent on Lgn for robust localization, is essential for proper localization of Lgn, as well as Gαi and aPKC, suggesting that cilium function plays a role in positioning of apical proteins. Taken together, our data provide a mechanism for the loss of hearing found in human patients with GPSM2/LGN variants.

Labor progress indices and dynamics of the individual uterine contraction during the active stage of labor.

AIM: To obtain and study new data on the dynamics of the labor process and to develop a contraction-based index of labor progress. METHODS: This study was carried out at the Delivery Room, Department of Obstetrics and Gynecology, Western Galilee Hospital, Nahariya, Israel, using a new device (Birth Track). We continuously monitored cervical dilatation (CD) and head descent (HD) in 30 nulliparaous women during active labor with (augmented group) and without (study group) oxytocin augmentation. This led to the development and validation of progress indices based on features extracted from continuous monitoring. RESULTS: There were no significant differences between the average of each parameter in the study and augmented groups, except for HD velocity. Average HD velocity was faster in the study group. Linear regression analyses demonstrated that head station (HS) amplitude and Toco amplitude were the best parameters for predicting HD velocity in both groups. In the study group, average HD velocity was also significantly related to Toco rate and contraction efficiency. In the augmented group, only a weak correlation with Toco rate was seen, and no correlation with contraction efficiency. CONCLUSION: With the assistance of the Birth Track device, we can obtain continuous data on the labor process and indices to estimate the labor progress process without the use of vaginal (manual) examination.

Limitation of cerebral blood flow by increased venous outflow resistance in elevated ICP.

Extensive investigation and modeling efforts have been dedicated to cerebral pressure autoregulation, which is primarily regulated by the ability of the cerebral arterioles to change their resistance and modulate cerebral blood flow (CBF). However, the mechanisms by which elevated intracranial pressure (ICP) leads to increased resistance to venous outflow have received less attention. We modified our previously described model of intracranial fluid interactions with a newly developed model of a partially collapsed blood vessel, which we termed the "flow control zone" (FCZ). We sought to determine the degree to which ICP elevation causing venous compression at the FCZ becomes the main parameter limiting CBF. The FCZ component was designed using nonlinear functions representing resistance as a function of cross-sectional area and the pressure-volume relations of the vessel wall. We used our previously described swine model of cerebral edema with graduated elevation of ICP to calculate venous outflow resistance and a newly defined parameter, the cerebral resistance index (CRI), which is the ratio between venous outflow resistance and cerebrovascular resistance. Model simulations of cerebral edema and increased ICP led to increased venous outflow resistance. There was a close similarity between model predictions of venous outflow resistance and experimental results in the swine model (cross-correlation coefficient of 0.97, a mean squared error of 0.087, and a mean absolute error of 0.15). CRI was strongly correlated to ICP in the swine model (r2 = 0.77, P = 0.00012, 95% confidence interval [0.15, 0.45]). A CRI value of 0.5 was associated with ICP values above clinically significant thresholds (24 mmHg) in the swine model and a diminished capacity of changes in arteriolar resistance to influence flow in the mathematical model. Our results demonstrate the importance of venous compression at the FCZ in determining CBF when ICP is elevated. The cerebral resistance index may provide an indication of when compression of venous outflow becomes the dominant factor in limiting CBF following brain injury.NEW & NOTEWORTHY The goal of this study was to investigate the effects of venous compression caused by elevated intracranial pressure (ICP) due to cerebral edema, validated through animal experiments. The flow control zone model highlights the impact of cerebral venous compression on cerebral blood flow (CBF) during elevated ICP. The cerebral venous outflow resistance-to-cerebrovascular resistance ratio may indicate when venous outflow compression becomes the dominant factor limiting CBF. CBF regulation descriptions should consider how arterial or venous factors may predominantly influence flow in different clinical scenarios.

Estimating intracranial parameters using an inverse mathematical model with viscoelastic elements that closely predicts complex ICP morphologies.

The quantitative relationship between arterial blood pressure (ABP) and intracranial pressure (ICP) waveforms has not been adequately explained. We hypothesized that the ICP waveform results from interferences between propagating and reflected pressure waves occurring in the cranium following the initiating arterial waveform. To demonstrate cranial effects on interferences between waves and generation of an ICP waveform morphology, we modified our previously reported mathematical model to include viscoelastic elements that affect propagation velocity. Using patient data, we implemented an inverse model methodology to generate simulated ICP waveforms in response to given ABP waveforms. We used an open database of traumatic brain injury patients and studied 65 pairs of ICP and ABP waveforms from 13 patients (five pairs from each). Incorporating viscoelastic elements into the model resulted in model-generated ICP waveforms that very closely resembled the measured waveforms with a 16-fold increase in similarity index relative to the model with only pure elasticity elements. The mean similarity index for the pure elasticity model was 0.06 ± 0.12 SD, compared to 0.96 ± 0.28 SD for the model with viscoelastic components. The normalized root mean squared error (NRMSE) improved substantially for the model with viscoelastic elements compared to the model with pure elastic elements (NRMSE of 2.09% ± 0.62 vs. 15.2% ± 4.8, respectively). The ability of the model to generate complex ICP waveforms indicates that the model may indeed reflect intracranial dynamics. Our results suggest that the model may allow the estimation of intracranial biomechanical parameters with potential clinical significance. It represents a first step in the estimation of inaccessible intracranial parameters.

Mechanisms of reduced cerebral blood flow in cerebral edema and elevated intracranial pressure.

A mechanism of elevated intracranial pressure (ICP) in cerebral edema and its effects on cerebral blood flow (CBF) are presented in this paper. To study and demonstrate these effects, a mathematical model of intracranial hydrodynamics was developed. The model simulates the intracranial hydrodynamics and the changes that occur when cerebral edema predominates. To account for an edema pathology, the model includes resistances to cerebrospinal fluid (CSF) and interstitial fluid (ISF) flows within the parenchyma. The resistances change as the intercellular space becomes smaller due to swelling of brain cells. The model demonstrates the effect of changes in these resistances on ICP and venous resistance to blood flow by accounting for the key interactions between pressure, volume, and flow in the intracranial compartments in pathophysiological conditions. The model represents normal intracranial physiology as well as pathological conditions. Simulating cerebral edema with increased resistance to cerebral ISF flow resulted in elevated ICP, increased brain volume, markedly reduced ventricular volume, and decreased CBF as observed in the neurointensive care patients. The model indicates that in high ICP values, alternation of the arterial-arteriolar resistance to flow minimally affects CBF, whereas at low ICP they have a much greater effect on CBF. The model demonstrates and elucidates intracranial mechanisms related to elevated ICP.NEW & NOTEWORTHY Study goal was to elucidate the role of "bulk flow" of ISF through brain parenchyma. A model was developed to simulate fluid shifts in brain edema, ICP elevation, and their effect on CBF. Bulk flow resistance affected by edema elevates ICP and reduces CBF. Bulk flow affects transmural pressure and volume distribution in brain compartments. Changes in bulk flow resistance result in increase of venous resistance to flow and decrease in CBF.

Genomic characterization and therapeutic utilization of IL-13-responsive sequences in asthma.

Epithelial responses to the cytokine interleukin-13 (IL-13) cause airway obstruction in asthma. Here we utilized multiple genomic techniques to identify IL-13-responsive regulatory elements in bronchial epithelial cells and used these data to develop a CRISPR interference (CRISPRi)-based therapeutic approach to downregulate airway obstruction-inducing genes in a cell type- and IL-13-specific manner. Using single-cell RNA sequencing (scRNA-seq) and acetylated lysine 27 on histone 3 (H3K27ac) chromatin immunoprecipitation sequencing (ChIP-seq) in primary human bronchial epithelial cells, we identified IL-13-responsive genes and regulatory elements. These sequences were functionally validated and optimized via massively parallel reporter assays (MPRAs) for IL-13-inducible activity. The top secretory cell-selective sequence from the MPRA, a novel, distal enhancer of the sterile alpha motif pointed domain containing E-26 transformation-specific transcription factor (SPDEF) gene, was utilized to drive CRISPRi and knock down SPDEF or mucin 5AC (MUC5AC), both involved in pathologic mucus production in asthma. Our work provides a catalog of cell type-specific genes and regulatory elements involved in IL-13 bronchial epithelial response and showcases their use for therapeutic purposes.

Reactivity of blood vessels in response to prostaglandin E2 in placentas from pregnancies complicated by fetal growth restriction.

OBJECTIVE: The authors aimed to study the contractility responses of normal and fetal growth restriction (FGR) placentas to prostaglandin E(2) (PGE(2) ) and to correlate the results to subsequent placental histological analysis. METHOD: A dual-perfused single cotyledon model was used. Placentas from pregnancies complicated by FGR and from normal pregnancies were obtained. Selected cotyledons were cannulated and dually perfused. Following stabilization, three concentrations of PGE(2) (0.05, 0.1, and 0.15 mg/mL) were administered to the fetal arterial side causing contraction/relaxation response. Fetal perfusion pressure was measured continuously during these contraction and relaxation phases. Following the perfusion experiments, the placentas were analyzed for fetal or maternal origin vascular lesions. RESULTS: A total of 21 complete experiments were performed (16 normal, 5 FGR). In response to PGE(2) , FGR placentas exhibited lower change in the perfusion pressure and lower relaxation time constant. Basal perfusion pressure did not differ significantly between the two groups. Placental histopathology lesions, fetal or maternal origin, were more common in the FGR compared with the controls placentas, 80% versus 25%, respectively, P= 0.047. CONCLUSIONS: The lower vascular reactivity in response to PGE(2) and the presence of fetal and maternal vascular placental lesions suggest a mechanism explaining the altered vascular supply in FGR.

Two-dimensional and three-dimensional Doppler assessment of fetal growth restriction with different severity and onset.

OBJECTIVES: To investigate the role of three-dimensional (3D) power Doppler ultrasonography in the assessment of fetal growth-restriction (FGR) with various degrees of severity and onset, and compare the results with the analysis of two-dimensional (2D) Doppler. STUDY DESIGN: Vascular indices extracted from 3D Doppler measurements of the placenta were compared with indices of flow-velocity waveforms extracted from 2D Doppler measurements of the major sites of the fetal circulation between FGR (study group) and uncomplicated pregnancies (control group) from 25 to 38 weeks' gestation. RESULTS: Three-dimensional indices were significantly lower in pregnancies complicated by FGR compared with uncomplicated pregnancies. When measured in placental periphery, vascularization index was 9.4 ± 9.6 in FGR pregnancies compared with 16 ± 14.7, P = 0.04. Flow index was 33.9 ± 6.9 compared with 38.7 ± 4.9, P = 0.03 and the vascularization-flow index was 3.8 ± 4.3 compared with 6.5 ± 6, respectively, P = 0.03. Among the conventional 2D indices, umbilical artery and middle cerebral artery pulsatility indices were not significantly different between the FGR and control groups. Higher rate of maternal or fetal compartment vascular lesions were detected in the FGR group. CONCLUSIONS: Three-dimensional Doppler was found to be more strongly associated with placental vascular compromise than conventional 2D Doppler, regardless of severity and onset of fetal growth restriction.

Interactions of brain, blood, and CSF: a novel mathematical model of cerebral edema.

BACKGROUND: Previous models of intracranial pressure (ICP) dynamics have not included flow of cerebral interstitial fluid (ISF) and changes in resistance to its flow when brain swelling occurs. We sought to develop a mathematical model that incorporates resistance to the bulk flow of cerebral ISF to better simulate the physiological changes that occur in pathologies in which brain swelling predominates and to assess the model's ability to depict changes in cerebral physiology associated with cerebral edema. METHODS: We developed a lumped parameter model which includes a representation of cerebral ISF flow within brain tissue and its interactions with CSF flow and cerebral blood flow (CBF). The model is based on an electrical analog circuit with four intracranial compartments: the (1) subarachnoid space, (2) brain, (3) ventricles, (4) cerebral vasculature and the extracranial spinal thecal sac. We determined changes in pressure and volume within cerebral compartments at steady-state and simulated physiological perturbations including rapid injection of fluid into the intracranial space, hyperventilation, and hypoventilation. We simulated changes in resistance to flow or absorption of CSF and cerebral ISF to model hydrocephalus, cerebral edema, and to simulate disruption of the blood-brain barrier (BBB). RESULTS: The model accurately replicates well-accepted features of intracranial physiology including the exponential-like pressure-volume curve with rapid fluid injection, increased ICP pulse pressure with rising ICP, hydrocephalus resulting from increased resistance to CSF outflow, and changes associated with hyperventilation and hypoventilation. Importantly, modeling cerebral edema with increased resistance to cerebral ISF flow mimics key features of brain swelling including elevated ICP, increased brain volume, markedly reduced ventricular volume, and a contracted subarachnoid space. Similarly, a decreased resistance to flow of fluid across the BBB leads to an exponential-like rise in ICP and ventricular collapse. CONCLUSIONS: The model accurately depicts the complex interactions that occur between pressure, volume, and resistances to flow in the different intracranial compartments under specific pathophysiological conditions. In modelling resistance to bulk flow of cerebral ISF, it may serve as a platform for improved modelling of cerebral edema and blood-brain barrier disruption that occur following brain injury.

Neonatal AAV gene therapy rescues hearing in a mouse model of SYNE4 deafness.

Genetic variants account for approximately half the cases of congenital and early-onset deafness. Methods and technologies for viral delivery of genes into the inner ear have evolved over the past decade to render gene therapy a viable and attractive approach for treatment. Variants in SYNE4, encoding the protein nesprin-4, a member of the linker of nucleoskeleton and cytoskeleton (LINC), lead to DFNB76 human deafness. Syne4-/- mice have severe-to-profound progressive hearing loss and exhibit mislocalization of hair cell nuclei and hair cell degeneration. We used AAV9-PHP.B, a recently developed synthetic adeno-associated virus, to deliver the coding sequence of Syne4 into the inner ears of neonatal Syne4-/- mice. Here we report rescue of hair cell morphology and survival, nearly complete recovery of auditory function, and restoration of auditory-associated behaviors, without observed adverse effects. Uncertainties remain regarding the durability of the treatment and the time window for intervention in humans, but our results suggest that gene therapy has the potential to prevent hearing loss in humans with SYNE4 mutations.

Absent from DNA and protein: genomic characterization of nullomers and nullpeptides across functional categories and evolution.

Nullomers and nullpeptides are short DNA or amino acid sequences that are absent from a genome or proteome, respectively. One potential cause for their absence could be their having a detrimental impact on an organism. RESULTS: Here, we identify all possible nullomers and nullpeptides in the genomes and proteomes of thirty eukaryotes and demonstrate that a significant proportion of these sequences are under negative selection. We also identify nullomers that are unique to specific functional categories: coding sequences, exons, introns, 5'UTR, 3'UTR, promoters, and show that coding sequence and promoter nullomers are most likely to be selected against. By analyzing all protein sequences across the tree of life, we further identify 36,081 peptides up to six amino acids in length that do not exist in any known organism, termed primes. We next characterize all possible single base pair mutations that can lead to the appearance of a nullomer in the human genome, observing a significantly higher number of mutations than expected by chance for specific nullomer sequences in transposable elements, likely due to their suppression. We also annotate nullomers that appear due to naturally occurring variants and show that a subset of them can be used to distinguish between different human populations. Analysis of nullomers and nullpeptides across vertebrate evolution shows they can also be used as phylogenetic classifiers. CONCLUSIONS: We provide a catalog of nullomers and nullpeptides in distinct functional categories, develop methods to systematically study them, and highlight the use of variability in these sequences in other analyses.

Cardiac-gated intracranial elastance in a swine model of raised intracranial pressure: a novel method to assess intracranial pressure-volume dynamics.

OBJECTIVE: Previous studies have demonstrated the importance of intracranial elastance; however, methodological difficulties have limited widespread clinical use. Measuring elastance may offer potential benefit in helping to identify patients at risk for untoward intracranial pressure (ICP) elevation from small rises in intracranial volume. The authors sought to develop an easily used method that accounts for the changing ICP that occurs over a cardiac cycle and to assess this method in a large-animal model over a broad range of ICPs. METHODS: The authors used their previously described cardiac-gated intracranial balloon pump and swine model of cerebral edema. In the present experiment they measured elastance at 4 points along the cardiac cycle-early systole, peak systole, mid-diastole, and end diastole-by using rapid balloon inflation to 1 ml over an ICP range of 10-30 mm Hg. RESULTS: The authors studied 7 swine with increasing cerebral edema. Intracranial elastance rose progressively with increasing ICP. Peak-systolic and end-diastolic elastance demonstrated the most consistent rise in elastance as ICP increased. Cardiac-gated elastance measurements had markedly lower variance within swine compared with non-cardiac-gated measures. The slope of the ICP-elastance curve differed between swine. At ICP between 20 and 25 mm Hg, elastance varied between 8.7 and 15.8 mm Hg/ml, indicating that ICP alone cannot accurately predict intracranial elastance. CONCLUSIONS: Measuring intracranial elastance in a cardiac-gated manner is feasible and may offer an improved precision of measure. The authors' preliminary data suggest that because elastance values may vary at similar ICP levels, ICP alone may not necessarily best reflect the state of intracranial volume reserve capacity. Paired ICP-elastance measurements may offer benefit as an adjunct "early warning monitor" alerting to the risk of untoward ICP elevation in brain-injured patients that is induced by small increases in intracranial volume.

Involvement of the autonomic nervous system in motor adaptation: acceleration or error reduction?

In the last few decades motor adaptation was extensively studied observing the invariant features of reaching movements. In a parallel neurobehavioral line of research emotional learning was studied under the umbrella of the 'two-factor theory of learning'. In this study we explore the relation between motor learning and the autonomic response (heart rate, HR) of subjects performing point to point reaching movements holding a computer mouse. We consider two alternative outcomes: one is that autonomic response correlates with the learning rate and the second is that the autonomic response correlates with the residual error at the steady state. Eighteen subjects performed reaching movements under perturbed visual feedback demonstrating learning and after effects of learning. The hand movement as well as an Electrocardiogram signal were recorded throughout the training and carefully analyzed offline to extract the trial by trial error as well as the heart period. The results show clear correlation between the change in HR and the residual error but no correlation between the change in HR and the learning rate supporting the second alternative that the sensitivity to errors but not the learning rate correlates with the autonomic response. A control group of another seven subjects underwent the same experiment without the perturbed visual feedback. This control group showed no change in the HR. Further studies are required to validate this hypothesis and unravel the mechanism by which the autonomic response correlates with the residual motor error.

Cerebral blood flow augmentation using a cardiac-gated intracranial pulsating balloon pump in a swine model of elevated ICP.

OBJECTIVE: Augmenting brain perfusion or reducing intracranial pressure (ICP) dose is the end target of many therapies in the neuro-critical care unit. Many present therapies rely on aggressive systemic interventions that may lead to untoward effects. Previous studies have used a cardiac-gated intracranial balloon pump (ICBP) to model hydrocephalus or to flatten the ICP waveform. The authors sought to sought to optimize ICBP activation parameters to improve cerebral physiological parameters in a swine model of raised ICP. METHODS: The authors developed a cardiac-gated ICBP in which the volume, timing, and duty cycle (time relative to a single cardiac cycle) of balloon inflation could be altered. They studied the ICBP in a swine model of elevated ICP attained by continuous intracranial fluid infusion with continuous monitoring of systemic and cerebral physiological parameters, and defined two specific protocols of ICBP activation. RESULTS: Eleven swine were studied, 3 of which were studied to define the optimal timing, volume, and duty cycle of balloon inflation. Eight swine were studied with two defined protocols at baseline and with ICP gradually raised to a mean of 30.5 mm Hg. ICBP activation caused a consistent modification of the ICP waveform. Two ICBP activation protocols were used. Balloon activation protocol A led to a consistent elevation in cerebral blood flow (8%-25% above baseline, p < 0.00001). Protocol B resulted in a modest reduction of ICP over time (8%-11%, p < 0.0001) at all ICP levels. Neither protocol significantly affected systemic physiological parameters. CONCLUSIONS: The preliminary results indicate that optimized protocols of ICBP activation may have beneficial effects on cerebral physiological parameters, with minimal effect on systemic parameters. Further studies are warranted to explore whether ICBP protocols may be of clinical benefit in patients with brain injuries with increased ICP.

Mechano-electric feedback effects in a three-dimensional (3D) model of the contracting cardiac ventricle.

Mechano-electric feedback affects the electrophysiological and mechanical function of the heart and the cellular, tissue, and organ properties. To determine the main factors that contribute to this effect, this study investigated the changes in the action potential characteristics of the ventricle during contraction. A model of stretch-activated channels was incorporated into a three-dimensional multiscale model of the contracting ventricle to assess the effect of different preload lengths on the electrophysiological behavior. The model describes the initiation and propagation of the electrical impulse, as well as the passive (stretch) and active (contraction) changes in the cardiac mechanics. Simulations were performed to quantify the relationship between the cellular activation and recovery patterns as well as the action potential durations at different preload lengths in normal and heart failure pathological conditions. The simulation results showed that heart failure significantly affected the excitation propagation parameters compared to normal condition. The results showed that the mechano-electrical feedback effects appear to be most important in failing hearts with low ejection fraction.

DNA methylation dynamics during embryonic development and postnatal maturation of the mouse auditory sensory epithelium.

The inner ear is a complex structure responsible for hearing and balance, and organ pathology is associated with deafness and balance disorders. To evaluate the role of epigenomic dynamics, we performed whole genome bisulfite sequencing at key time points during the development and maturation of the mouse inner ear sensory epithelium (SE). Our single-nucleotide resolution maps revealed variations in both general characteristics and dynamics of DNA methylation over time. This allowed us to predict the location of non-coding regulatory regions and to identify several novel candidate regulatory factors, such as Bach2, that connect stage-specific regulatory elements to molecular features that drive the development and maturation of the SE. Constructing in silico regulatory networks around sites of differential methylation enabled us to link key inner ear regulators, such as Atoh1 and Stat3, to pathways responsible for cell lineage determination and maturation, such as the Notch pathway. We also discovered that a putative enhancer, defined as a low methylated region (LMR), can upregulate the GJB6 gene and a neighboring non-coding RNA. The study of inner ear SE methylomes revealed novel regulatory regions in the hearing organ, which may improve diagnostic capabilities, and has the potential to guide the development of therapeutics for hearing loss by providing multiple intervention points for manipulation of the auditory system.

A mathematical model of penile vascular dysfunction and its application to a new diagnostic technique.

A noninvasive diagnostic device was developed to assess the vascular origin and severity of penile dysfunction. It was designed and studied using both a mathematical model of penile hemodynamics and preliminary experiments on healthy young volunteers. The device is based on the application of an external pressure (or vacuum) perturbation to the penis following the induction of erection. The rate of volume change while the penis returns to its natural condition is measured using a noninvasive system that includes a volume measurement mechanism that has very low friction, thereby not affecting the measured system. The rate of volume change (net flow) is obtained and analyzed. Simulations using a mathematical model show that the device is capable of differentiating between arterial insufficiency and venous leak and indicate the severity of each. In preliminary measurements on young healthy volunteers, the feasibility of the measurement has been demonstrated. More studies are required to confirm the diagnostic value of the measurements.