Review of Conventional and High Dose Rate Brain Radiation (FLASH): Neurobehavioural, Neurocognitive and Assessment Issues in Rodent Models.

Ionising radiation causes secondary tumours and/or enduring cognitive deficits, especially in children. Proton radiotherapy reduces exposure of the developing brain in children but may still cause some lasting effects. Recent observations show that ultra-high dose rate radiation treatment (≥40 Gy/s), called the FLASH effect, is equally effective at tumour control but less damaging to surrounding tissue compared with conventional dose rate protons (0.03-3 Gy/s). Most studies on the FLASH effect in brain and other tissues with different radiation modalities (electron and photon radiation), show FLASH benefits in these preclinical rodent models, but the data are limited, especially for proton FLASH, including for dose, dose rate and neurochemical and neurobehavioural outcomes. Tests of neurocognitive outcomes have been limited despite clinical evidence that this is the area of greatest concern. The FLASH effect in the context of proton exposure is promising, but a more systematic and comprehensive approach to outcomes is needed.

MR Imaging Characteristics of Intraocular Perfluoro-n-Octane.

We describe the unique MR imaging characteristics of intraocular perfluoro-n-octane, a liquid used for intraoperative and postoperative tamponade in the context of complex retinal detachment repair, and contrast it with other intraocular pathologies. Because trace amounts of perfluoro-n-octane may be left in the globe postoperatively, it may be confused for other abnormalities, such as foreign bodies or tumors.

Cognitive deficits and increases in creatine precursors in a brain-specific knockout of the creatine transporter gene Slc6a8.

Creatine transporter (CrT; SLC6A8) deficiency (CTD) is an X-linked disorder characterized by severe cognitive deficits, impairments in language and an absence of brain creatine (Cr). In a previous study, we generated floxed Slc6a8 (Slc6a8 flox ) mice to create ubiquitous Slc6a8 knockout (Slc6a8-/y ) mice. Slc6a8-/y mice lacked whole body Cr and exhibited cognitive deficits. While Slc6a8-/y mice have a similar biochemical phenotype to CTD patients, they also showed a reduction in size and reductions in swim speed that may have contributed to the observed deficits. To address this, we created brain-specific Slc6a8 knockout (bKO) mice by crossing Slc6a8flox mice with Nestin-cre mice. bKO mice had reduced cerebral Cr levels while maintaining normal Cr levels in peripheral tissue. Interestingly, brain concentrations of the Cr synthesis precursor guanidinoacetic acid were increased in bKO mice. bKO mice had longer latencies and path lengths in the Morris water maze, without reductions in swim speed. In accordance with data from Slc6a8 -/y mice, bKO mice showed deficits in novel object recognition as well as contextual and cued fear conditioning. bKO mice were also hyperactive, in contrast with data from the Slc6a8 -/y mice. The results show that the loss of cerebral Cr is responsible for the learning and memory deficits seen in ubiquitous Slc6a8-/y mice.

Phosphodiesterase-1b deletion confers depression-like behavioral resistance separate from stress-related effects in mice.

Phosphodiesterase-1b (Pde1b) is highly expressed in striatum, dentate gyrus, CA3 and substantia nigra. In a new Floxed Pde1b × CreCMV global knockout (KO) mouse model, we show an immobility-resistance phenotype that recapitulates that found in constitutive Pde1b KO mice. We use this new mouse model to show that the resistance to acute stress-induced depression-like phenotype is not the product of changes in locomotor activity or reactivity to other stressors (learned helplessness, novelty suppressed feeding or dexamethasone suppression), and is not associated with anhedonia using the sucrose preference test. Using tamoxifen inducible Cre, we show that the immobility-resistant phenotype depends on the age of induction. The effect is present when Pde1b is Reduced from conception, P0 or P32, but not if reduced as adults (P60). We also mapped regional brain expression of PDE1B protein and of the Cre driver. These data add to the suggestion that PDE1B may be a target for drug development with therapeutic potential in depression alone or in combination with existing antidepressants.

Weighing up the evidence -- a systematic review of measures used for the sensation of breathlessness in obesity.

Breathlessness on exertion is common in people with obesity. Assessments of breathlessness may include sensation (intensity, sensory quality or unpleasantness) and/ or the behavioral/emotional consequences of the sensation (respiratory-related functional impairment, disability or quality of life). This systematic review of primary studies published since 2005 evaluated how has the sensation of breathlessness been assessed in adults with increased adiposity. A total of 41 articles were retained from the systematic search strategy resulting in 20 instruments. The Modified Borg Scale (perceived exertion-intensity), the Medical Research Council (MRC) Scale and Baseline Dyspnea Index (BDI; both assess respiratory-related functional impairment) were, respectively, the most frequently reported instruments. Few instruments had been tested for reliability and validity in people with increased adiposity. Visual Analog Scale, Modified Borg Scale, descriptors of sensory quality, MRC and BDI can be recommended as instruments based on their psychometric properties (reliability (correlations >0.8) and concurrent validity (correlation with severity of airways obstruction and walking distance)). A greater number of instruments were identified that assessed the consequences of the breathlessness rather than breathlessness as a sensation. If sensation drives behavior, comprehensive data on the sensation of breathlessness might assist in understanding the behavioral consequences of interventions.

Development of primary human nasal epithelial cell cultures for the study of cystic fibrosis pathophysiology.

Cultured primary epithelial cells are used to examine inflammation in cystic fibrosis (CF). We describe a new human model system using cultured nasal brushings. Nasal brushings were obtained from 16 F508del homozygous patients and 11 healthy controls. Cells were resuspended in airway epithelial growth medium and seeded onto collagen-coated flasks and membranes for use in patch-clamp, ion transport, and mediator release assays. Viable cultures were obtained with a 75% success rate from subjects with CF and 100% from control subjects. Amiloride-sensitive epithelial Na channel current of similar size was present in both cell types while forskolin-activated CF transmembrane conductance regulator current was lacking in CF cells. In Ussing chambers, cells from CF patients responded to UTP but not to forskolin. Spontaneous and cytomix-stimulated IL-8 release was similar (stimulated 29,448 ± 9,025 pg/ml; control 16,336 ± 3,308 pg/ml CF; means ± SE). Thus nasal epithelial cells from patients with CF can be grown from nasal brushings and used in electrophysiological and mediator release studies in CF research.

Symptom Dimensions in Two Samples of Africans Americans with Obsessive-Compulsive Disorder.

Obsessive-compulsive disorder (OCD) is a leading cause of disability worldwide, however, there is a lack of research that includes African Americans, thus it is unclear whether findings about symptom dimensions can be generalized to this population. A sample of adult African Americans with OCD (N=74) was recruited at the University of Pennsylvania (Penn) and administered the Yale Brown Obsessive-Compulsive checklist (YBOCS) to better understand the phenomenology of OCD in African Americans. Frequencies of symptoms are reported and compared to findings from the National Survey of American Life (NSAL; N=54). A principal components analysis of YBOCS categories and items was performed on the Penn sample. A six-component solution was found, that included Contamination & Washing, Hoarding, Sexual Obsessions & Reassurance, Aggression & Mental Compulsions, Symmetry & Perfectionism, and Doubt & Checking, explaining 59.1% of the variance. Factors identified were similar to those of previous studies in primarily white samples. African Americans with OCD reported more contamination symptoms and were twice as likely to report excessive concerns with animals as European Americans with OCD. The results indicate the presence of cultural differences, which is consistent with findings among non-clinical samples. Implications of these findings are discussed.

A new model of Pde4d deficiency: genetic knock-down of PDE4D enzyme in rats produces an antidepressant phenotype without spatial cognitive effects.

Phosphodiesterases (PDEs) are a superfamily of intracellular second messenger cyclic nucleotide hydrolyzing enzymes composed of 12 families. The Pde4 family has been implicated in depression and cognition, and PDE4 inhibitors have been evaluated as antidepressants and possible cognitive enhancers. Pde4d(-/-) mice show an antidepressant phenotype and learning enhancement on some tests, but not others as do mice treated with PDE4 inhibitors. Here, we report for the first time the behavioral phenotype of a new Pde4d knock-down (KD) rat model of PDE4D deficiency. Consistent with other data on PDE4D deficiency, Pde4d KD rats showed depression resistance in the Porsolt forced swim test and hyperreactivity of the acoustic startle response with no differential response on prepulse inhibition, suggesting no sensorimotor gating defect. Pde4d KD rats also exhibited a small exploratory activity reduction but no difference following habituation, and no enhanced spatial learning or reference memory in the Morris water maze. A selective improvement in route-based learning in the Cincinnati water maze was seen as well as enhanced contextual and cued fear conditioning and a more rapid rate of cued extinction from their higher freezing level that declined to wild-type (WT) levels only after ∼20 extinction trials. The rat model confirms Pde4d's role in depression but not in spatial learning or memory enhancement and shows for the first time higher fear conditioning and altered extinction compared with controls. The new model provides a tool by which to better understand the role of PDE4D in neuropsychiatric disorders and for the development of alternate treatment approaches.

Effect of vitamin C deficiency during postnatal development on adult behavior: functional phenotype of Gulo-/- knockout mice.

Organisms using oxygen for aerobic respiration require antioxidants to balance the production of reactive oxygen species during metabolic processes. Various species--including humans and other primates--suffer mutations in the GULO gene encoding L-gulono-γ-lactone oxidase; GULO is the rate-limiting enzyme in the biosynthesis of ascorbate, an important cellular antioxidant. Animals lacking the ability to synthesize vitamin C develop scurvy without dietary supplementation. The Gulo-/- knockout (KO) mouse requires oral supplemental vitamin C; without this supplementation the animal dies with a scorbutic condition within several weeks. Vitamin C is known to be most abundant in the brain, where it is believed to play important roles in neuroprotection, neurotransmission and neuromodulation. We therefore hypothesized that ascorbate deficiency in Gulo-/- KO mice might lead to an abnormal behavioral phenotype. We established the amount of ascorbate in the drinking water (220 ppm) necessary for generating a chronic low-ascorbate status in the brain, yet clinically the mice appeared healthy throughout 100 days postpartum at which time all behavioral-phenotyping tests were completed. Compared with Gulo+/+ wild-type littermates, ascorbate-deficient Gulo-/- mice were found to be less active in moving in their environment; when in water, these mice swam more slowly in some tests, consistent with a mild motor deficit. We found no evidence of cognitive, anxiety or sensorimotor-gating problems. Despite being less active, Gulo-/- mice exhibited exaggerated hyperactivity to the dopaminergic agonist methamphetamine. The subnormal movement, combined with hypersensitivity to a dopamine agonist, point to developmental ascorbate deficiency causing long-term striatal dysfunction.

Neurotoxic (+)-methamphetamine treatment in rats increases brain-derived neurotrophic factor and tropomyosin receptor kinase B expression in multiple brain regions.

Methamphetamine (MA) is an abused stimulant which can result in cognitive deficits and monoamine depletions. Animal models of neurotoxic MA exposure show reductions in dopamine, serotonin, and their associated transporters. MA abuse can result in long-term attention, working memory, and executive function deficits in humans and deficits in route-based egocentric learning, novel object recognition, and novel odor preference in rodents. MA has also been shown to affect brain-derived neurotrophic factor (BDNF) in humans and rodents. This experiment examined the effects of a MA binge dosing regimen (10 mg/kg x 4 at 2 h intervals, s.c.) in Sprague-Dawley rats on BDNF, tropomyosin receptor kinase B (TrkB), and tyrosine hydroxylase (TH) mRNA expression, and plasma corticosterone. Tissues were collected 1, 7, and 24 h following the last MA dose. Expression of BDNF and TrkB mRNA was analyzed using in situ hybridization with cRNA probes. Frontal, parietal, and entorhinal cortical BDNF mRNA expression were increased by MA exposure at all time-points. Increases in BDNF mRNA were also seen in the hippocampal CA1, prefrontal cortex (PFC), piriform cortex, and locus coeruleus but only at specific times. TrkB mRNA expression was modified in several subregions of the hippocampus as well as in PFC and striatum. TH mRNA was increased at the 1 h time-point in the substantia nigra pars compacta with no differences noted at the other times. Corticosterone levels were increased at all three time-points. The findings suggest that BDNF and its receptor may be upregulated as a compensatory mechanism after MA exposure.

Middle ear osteoma: a rare cause of conductive hearing loss with normal tympanic membrane.

Osteomas of the temporal bone are benign osseous tumors usually located to the external auditory canal. Osteomas involving the middle ear are very rare. We report the case of a patient presenting with a progressive hearing loss caused by a middle ear osteoma involving the incus and contiguous to the tympanic segment of the facial nerve. This report highlights the value of CT scan in the work-up of conductive or mixed hearing loss with normal tympanic membrane. The management of middle ear osteoma is discussed.

Heliox, dyspnoea and exercise in COPD.

One of the most important determinants of physical and mental well-being of people with chronic obstructive pulmonary disease (COPD) is participation in physical activity. The ability to alter the sensation of dyspnoea during exercise may improve both exercise duration and intensity. Despite the low density, inert nature, strong safety profile and multiple applications of helium gas, the potential benefit of helium-oxygen gas mixtures as an adjunct therapy to modify disease symptoms and exercise capabilities in obstructive lung diseases has only recently been explored. This is a systematic review of the available peer-reviewed evidence exploring whether symptom modification (perceived levels of dyspnoea) and exercise performance in COPD (either intensity or duration of work) are modified by inhalation of Heliox. Eight experimental studies met inclusion for this review. A variety of methodologies and outcome variables were used negating meta-analysis and hampering direct comparison between interventions. Overall, there was high level of evidence with a low risk of bias supporting Heliox's effectiveness in improving the intensity and endurance of exercise when compared to room air for people with COPD. Little conclusive evidence was found to determine whether Heliox altered the sensation of dyspnoea during exercise.

Effects on plasma corticosterone levels and brain serotonin from interference with methamphetamine-induced corticosterone release in neonatal rats.

Methamphetamine (MA) induces multiple effects in rats including alterations to corticosterone (CORT) and adrenocorticotropic hormone (ACTH). This effect is age dependent showing a U-shaped function similar to that of other stressors during the stress hyporesponsive period. Neonatal MA treatment leads to adult learning and memory impairments, but whether these are related to MA-induced CORT release is unknown. Here in, four methods were tested in neonatal rats previously established in adult rats for inhibiting stress-induced CORT release: inhibiting synthesis (metyrapone (MET) or ketoconazole (KTZ)) or surgically by adrenalectomy or adrenal autotransplantation (ADXA). Pretreatment on postnatal day 11 with MET or KTZ prior to four doses of 10 mg/kg of MA initially suppressed MA-induced increases in plasma CORT, but 24 h later, even with additional inhibitor treatment, a large CORT increase was seen which exceeded that of MA alone. Adrenalectomy blocked MA-induced increases in CORT but caused a secondary effect on brain serotonin (5-HT) and dopamine (DA), causing greater reductions than those caused by MA alone. ADXA inhibited MA-induced CORT release without causing a 24-h CORT increase and did not produce additional effects on brain 5-HT or DA. Neonatal ADXA is a new model for developmental drug or stress experiments designed to test the role of CORT in mediating early effects on later outcomes.

Mouse plasmacytoma-expressed transcript 1 knock out induced 5-HT disruption results in a lack of cognitive deficits and an anxiety phenotype complicated by hypoactivity and defensiveness.

Serotonin (5-HT) is involved in many developmental processes and influences behaviors including anxiety, aggression, and cognition. Disruption of the serotonergic system has been implicated in human disorders including autism, depression, schizophrenia, and ADHD. Although pharmacological, neurotoxin, and dietary manipulation of 5-HT and tryptophan hydroxylase has added to our understanding of the serotonergic system, the results are complicated by multiple factors. A newly identified ETS domain transcription factor, Pet-1, has direct control of major aspects of 5-HT neuronal development. Pet-1 is the only known factor that is restricted in the brain to 5-HT neurons during development and adulthood and exerts dominant control over 5-HT neuronal phenotype. Disruption of Pet-1 produces an approximately 80% loss of 5-HT neurons and content and results in increased aggression in male Pet-1(-/-) mice [Hendricks TJ, Fyodorov DV, Wegman LJ, Lelutiu NB, Pehek EA, Yamamoto B, Silver J, Weeber EJ, Sweatt JD, Deneris ES (2003) Neuron 37:233-247]. We hypothesized that Pet-1(-/-) mice would also exhibit changes in anxiety and cognition. Pet-1(-/-) mice were hypoactive which may have affected the observed lack of anxious behavior in the elevated zero maze and light-dark test. Pet-1(-/-) mice, however, were more defensive during marble burying and showed acoustic startle hyper-reactivity. No deficits in spatial, egocentric, or novel object recognition learning were found in Pet-1(-/-) mice. These findings were unexpected given that 5-HT depleting drugs given to adult or developing animals result in learning deficits [Mazer C, Muneyyirci J, Taheny K, Raio N, Borella A, Whitaker-Azmitia P (1997) Brain Res 760:68-73; Morford LL, Inman-Wood SL, Gudelsky GA, Williams MT, Vorhees CV (2002) Eur J Neurosci 16:491-500; Vorhees CV, Schaefer TL, Williams MT (2007) Synapse 61:488-499]. Lack of differences may be the result of compensatory mechanisms in reaction to a constitutive knock out of Pet-1 or 5-HT may not be as important in learning and memory as previously suspected.

A national study of the availability and use of electrophysical agents by Australian physiotherapists.

Electrophysical agents (EPAs) are a core part of physiotherapy practice and entry level education. With the increase in the number of EPAs over time, their availability and use in contemporary physiotherapy practice is an important consideration when determining entry level curricula. Thus, the aim of the study was to ascertain the current availability and usage of EPAs in Australian physiotherapy practice. A purpose-designed questionnaire was mailed to all registered physiotherapists in Australia. A response rate of 27% was obtained (n=3,538). Nonresponder analyses indicated that the results were representative of the total population of Australian physiotherapists. Over 70% of respondents had access to ultrasound, cold packs/ice, heat packs, electrical stimulation for sensory stimulation, and interferential therapy. Two main groups of EPAs were used relatively frequently. The first group was used daily or monthly by 60% of respondents (ultrasound, hot packs, and cold packs/ice), and a second group (electromyographic and pressure biofeedback, interferential therapy, and electrical stimulation for sensory stimulation) was used on a daily or monthly basis by between 30% and 45% of the sample. A group of EPAs, including ultraviolet light, microwave, and shortwave diathermy, was not used by over 90% of the sample. The study has provided contemporary national data on EPA availability and use in Australia.

[Superior semicircular canal dehiscence mimicking otosclerosis: usefulness of imaging]. / Déhiscence du canal semi-circulaire antérieur mimant une otospongiose: intérêt de l'imagerie.

OBJECTIVES: To emphasize the role of computerized tomography (CT) in the etiologic work-up of stapes surgery failure. MATERIAL AND METHODS: Helical high resolution CT scan of the temporal bone with axial and coronal views and multiplanar reconstructions was performed in a patient who had undergone unsuccessful stapedectomy. RESULTS: CT scan demonstrated a well located prosthesis, the absence of the radiological hallmarks of otosclerosis, and revealed a superior semicircular canal dehiscence (SSCD). The diagnosis of SSCD was retrospectively considered accountable for the preoperative clinical and audiometric presentation that had mimicked otosclerosis. CONCLUSION: CT is the diagnostic test of choice in elucidating stapes surgery failure (with persistent or recurrent conductive hearing loss), whereas SSCD should be systematically considered among its causes.

[Imaging in adult chronic otitis]. / Imagerie des otites chroniques de l'adulte.

Chronic otitis media (COM) can be divided into two subtypes: COM with cholesteatoma (including precholesteatomatous states) is an aggressive form of otitis. Surgical treatment is mandatory because of the risk for labyrinthine or cerebromeningeal complications. CT is very important in the preoperative work-up (extension of cholesteatoma, anatomic variants). In patients who have undergone middle ear surgery, CT and presently MRI play an increasing role in the detection of recurrent or relapsing cholesteatoma. COM without cholesteatoma does not have an osteolytic potential, but may leave auditive sequelae that in selected cases may warrant surgical treatment to improve hearing. CT is useful in the etiological work-up of patients with severe hypoacusis. CT also plays an important role in cases of surgical failure, to detect a dislocation of the ossiculoplasty or impairment of the middle ear caused by fluid effusion. The objective of this paper is to specify the indications, the results and the limits of pre- and postoperative imaging in COM.

Phosphodiesterase 1B differentially modulates the effects of methamphetamine on locomotor activity and spatial learning through DARPP32-dependent pathways: evidence from PDE1B-DARPP32 double-knockout mice.

Mice lacking phosphodiesterase 1B (PDE1B) exhibit an exaggerated locomotor response to D-methamphetamine and increased in vitro phosphorylation of DARPP32 (dopamine- and cAMP-regulated phosphoprotein, M r 32 kDa) at Thr34 in striatal brain slices treated with the D1 receptor agonist, SKF81297. These results indicated a possible regulatory role for PDE1B in pathways involving DARPP32. Here, we generated PDE1B x DARPP32 double-knockout (double-KO) mice to test the role of PDE1B in DARPP32-dependent pathways in vivo. Analysis of the response to d-methamphetamine on locomotor activity showed that the hyperactivity experienced by PDE1B mutant mice was blocked in PDE1B-/- x DARPP32-/- double-KO mice, consistent with participation of PDE1B and DARPP32 in the same pathway. Further behavioral testing in the elevated zero-maze revealed that DARPP32-/- mice showed a less anxious phenotype that was nullified in double-mutant mice. In contrast, in the Morris water maze, double-KO mice showed deficits in spatial reversal learning not observed in either single mutant compared with wild-type mice. The data suggest a role for PDE1B in locomotor responses to psychostimulants through modulation of DARPP32-dependent pathways; however, this modulation does not necessarily impact other behaviors, such as anxiety or learning. Instead, the phenotype of double-KOs observed in these latter tasks may be mediated through independent pathways.

Usefulness of delayed postcontrast magnetic resonance imaging in the detection of residual cholesteatoma after canal wall-up tympanoplasty.

OBJECTIVES/HYPOTHESIS: Imaging takes an increasing place in the follow-up of patients who have undergone surgery for cholesteatoma, with computed tomography (CT) as the first line imaging technique. However, in case of complete opacity of the tympanomastoid cavities, CT is not able to differentiate residual cholesteatoma from postoperative scar tissue. The aim of this study was to assess the usefulness of magnetic resonance imaging (MRI) using delayed postcontrast T1-weighted images for the detection of residual cholesteatoma after canal wall-up tympanoplasty (CWU) in cases where CT was not conclusive. STUDY DESIGN: Prospective study. METHODS: MRI, with delayed postcontrast T1-weighted images (30-45 minutes after contrast injection), was performed before revision surgery in 41 consecutive patients who had undergone CWU for cholesteatoma and presenting with a nonspecific complete opacity of the mastoid bowl on CT. In all the cases, imaging results were compared with operative findings at surgical revision. RESULTS: A residual cholesteatoma was found in 19 of 41 patients at revision surgery and was correctly detected on MRI in 17 patients. In the two remaining cases, cholesteatoma pearls smaller than 3 mm were not seen. There was no false-positive case. Statistics were as follows: sensitivity 90%; specificity 100%; positive predictive value 100%; negative predictive value 92%. CONCLUSION: When postoperative CT is not conclusive because of complete opacity of the tympanomastoid cavities, MRI with delayed postcontrast T1-weighted images is a reliable additional technique for the detection of a residual cholesteatoma when its diameter is at least 3 mm.