Amygdala DCX and blood Cdk14 are implicated as cross-species indicators of individual differences in fear, extinction, and resilience to trauma exposure.

Doublecortin (DCX) has long been implicated in, and employed as a marker for, neurogenesis, yet little is known about its function in non-neurogenic brain regions, including the amygdala. This study sought first to explore, in rodents, whether fear learning and extinction modulate amygdala DCX expression and, second, to assess the utility of peripheral DCX correlates as predictive biomarkers of trauma response in rodents and humans. Pavlovian conditioning was found to alter DCX protein levels in mice 24 h later, resulting in higher DCX expression associated with enhanced learning in paradigms examining both the acquisition and extinction of fear (p < 0.001). This, in turn, is associated with differences in freezing on subsequent fear expression tests, and the same relationship between DCX and fear extinction was replicated in rats (p < 0.001), with higher amygdala DCX levels associated with more rapid extinction of fear. RNAseq of amygdala and blood from mice identified 388 amygdala genes that correlated with DCX (q < 0.001) and which gene ontology analyses revealed were significantly over-represented for neurodevelopmental processes. In blood, DCX-correlated genes included the Wnt signaling molecule Cdk14 which was found to predict freezing during both fear acquisition (p < 0.05) and brief extinction protocols (p < 0.001). High Cdk14 measured in blood immediately after testing was also associated with less freezing during fear expression testing (p < 0.01). Finally, in humans, Cdk14 expression in blood taken shortly after trauma was found to predict resilience in males for up to a year post-trauma (p < 0.0001). These data implicate amygdala DCX in fear learning and suggest that Cdk14 may serve as a predictive biomarker of trauma response.

Estrogen-dependent association of HDAC4 with fear in female mice and women with PTSD.

Women are at increased risk of developing post-traumatic stress disorder (PTSD) following a traumatic event. Recent studies suggest that this may be mediated, in part, by circulating estrogen levels. This study evaluated the hypothesis that individual variation in response to estrogen levels contributes to fear regulation and PTSD risk in women. We evaluated DNA methylation from blood of female participants in the Grady Trauma Project and found that serum estradiol levels associates with DNA methylation across the genome. For genes expressed in blood, we examined the association between each CpG site and PTSD diagnosis using linear models that adjusted for cell proportions and age. After multiple test correction, PTSD associated with methylation of CpG sites in the HDAC4 gene, which encodes histone deacetylase 4, and is involved in long-term memory formation and behavior. DNA methylation of HDAC4 CpG sites were tagged by a nearby single-nucleotide polymorphism (rs7570903), which also associated with HDAC4 expression, fear-potentiated startle and resting-state functional connectivity of the amygdala in traumatized humans. Using auditory Pavlovian fear conditioning in a rodent model, we examined the regulation of Hdac4 in the amygdala of ovariectomized (OVX) female mice. Hdac4 messenger RNA levels were higher in the amygdala 2 h after tone-shock presentations, compared with OVX-homecage control females. In naturally cycling females, tone-shock presentations increased Hdac4 expression relative to homecage controls for metestrous (low estrogen) but not the proestrous (high estrogen) group. Together, these results support an estrogenic influence of HDAC4 regulation and expression that may contribute to PTSD in women.

Functional evaluation of a PTSD-associated genetic variant: estradiol regulation and ADCYAP1R1.

Posttraumatic stress disorder (PTSD) affects 5-10% percent of the US adult population with a higher prevalence among women compared with men. Although it remains unclear how biological sex associates with susceptibility to PTSD, one mechanism may involve a role for estrogen in a gene by environment interaction. We previously demonstrated a sex-dependent association between the pituitary adenylate cyclase-activating polypeptide type 1 receptor (PAC1) and PTSD, where carriers of a C allele at single-nucleotide polymorphism (SNP) rs2267735 within the PAC1 receptor gene (ADCYAP1R1) have increased symptoms of PTSD. This SNP is located within a predicted estrogen response element (ERE), which regulates gene transcription when bound to estradiol (E2) activated estrogen receptor alpha (ERα). In the current study, we examined E2 regulation of ADCYAP1R1 in vitro, in cell culture, and in vivo in mice and humans. We find in mice that fear conditioning and E2 additively increase ADCYAP1R1 expression. In vitro, we show that E2/ERα binds to the ADCYAP1R1 ERE, with less efficient binding to an ERE containing the C allele of rs2267735. In women with low serum E2, the CC genotype associates with lower ADCYAP1R1 expression, which further associates with higher PTSD symptoms. These findings lead to a model in which E2 induces the expression of ADCYAP1R1 through binding of ERα at the ERE as an adaptive response to stress. Inhibition of E2/ERα binding to the ERE containing the rs2267735 risk allele results in reduced expression of ADCYAP1R1, diminishing estrogen regulation as an adaptive stress response and increasing risk for PTSD.

The detection of a population of submillimeter-bright, strongly lensed galaxies.

Gravitational lensing is a powerful astrophysical and cosmological probe and is particularly valuable at submillimeter wavelengths for the study of the statistical and individual properties of dusty star-forming galaxies. However, the identification of gravitational lenses is often time-intensive, involving the sifting of large volumes of imaging or spectroscopic data to find few candidates. We used early data from the Herschel Astrophysical Terahertz Large Area Survey to demonstrate that wide-area submillimeter surveys can simply and easily detect strong gravitational lensing events, with close to 100% efficiency.

Encoding and retrieval are differentially processed by the anterior cingulate and prelimbic cortices: a study based on trace eyeblink conditioning in the rabbit.

A growing body of literature suggests that structures along the midline of the prefrontal cortex (mPFC), including Brodmann's area 32 (prelimbic cortex) and area 24 (anterior cingulate cortex) in the rabbit play a role in retrieval of learned information. The present studies compared the effects of post-training lesions produced either immediately or 1-week following learning, to either prelimbic (area 32) or anterior cingulate (area 24) cortex on trace eyeblink (EB) conditioning. Further, because recent evidence suggests that the mPFC may play an even greater role in learning and memory when emotional arousal is low, these studies compared the effects of lesions in groups conditioned with either a relatively low-arousal corneal airpuff, or a more aversive periorbital eyeshock unconditioned stimulus (US). A total of six groups were tested, which received selective ibotenic acid or "sham" control lesions to either area 32 or 24, immediately or 1-week following asymptotic learning, and conditioned with an eyeshock US or an airpuff US. Results showed that the greatest lesion deficits were found when conditioning with the less aversive airpuff US. Further, lesions produced to area 32 one-week, but not immediately following learning, caused significant deficits in performance, while lesions produced to area 24 immediately, but not 1-week following learning, caused significant deficits in performance. These findings add to the body of evidence which shows that area 32 of the mPFC regulates retrieval, but not acquisition or storage of information, while area 24 mediates a less specific reacquisition process, but not permanent storage or retrieval of information during relearning of memories abolished by mPFC damage. These findings were, however, specific to those experiments in which the relatively non-aversive airpuff was the US.

Prefrontal control of trace eyeblink conditioning in rabbits: role in retrieval of the CR?

Rabbits (Oryctolagus cuniculus) were trained on a trace eyeblink (EB) conditioning task to a criterion of 10 consecutive EB conditioned responses (CRs). One week later, ibotenic acid or sham lesions were made in the mPFC centered on the prelimbic region (Brodmann's area 32) or the cingulate cortex (Brodmann's area 24). Following a 1-week postoperative recovery period, all animals were retrained for 4 consecutive days using the same parameters as during acquisition, given 1 week off, and retrained for another 4 days. Mean EB conditioning deficits in the group with area 32 lesions occurred on the first and second days of each retraining period. However, by the third and fourth days of retraining, these lesioned animals were performing at a level comparable to that of the sham group. Lesions of area 24 did not produce deficits at either retesting period. These findings were interpreted to indicate that area 32, but not area 24, is involved in retrieval processes, rather than consolidation or storage, in that the animals were impaired at both retesting times, but were able to relearn the task.

Ibotenic acid lesions to ventrolateral thalamic nuclei disrupts trace and delay eyeblink conditioning in rabbits.

Intact cerebellar structures (i.e., deep nuclei and perhaps cortex) are essential for acquisition of both simple delay and trace eyeblink (EB) conditioning. However, successful trace conditioning also requires intact cortico-limbic structures (i.e., hippocampus, medial thalamus, and medial prefrontal cortex, mPFC). A direct connection between the cerebellum and ventrolateral thalamic nuclei (VLTN) has been demonstrated in several species. Since VLTN projects to both premotor and prefrontal cortex, it may be an essential link in a cerebellar-thalamic-prefrontal circuit that provides the CNS substrate for acquisition of the trace EB CR. The current studies thus assessed the role of the VLTN on trace EB conditioning in New Zealand albino rabbits. We first verified afferent connections to the mPFC (Brodmann's area 32) from the VLTN, by injecting the retrograde tracer Flourogold(c) into area 32. Strong labeling in VLTN from terminal projections to mPFC were found. We next assessed the role of VLTN in trace eyeblink conditioning in animals that received either sham or ibotenic acid VLTN lesions. EB conditioning began with 10 consecutive daily sessions of trace conditioning, followed immediately by 4 days of extinction, and then 4 days of delay conditioning. VLTN lesions significantly impaired acquisition of both trace and delay conditioning, and impaired extinction. These findings, thus confirm the importance of the VLTN in a postulated cerebellar-thalamic-prefrontal circuit that underlies successful trace, as well as delay EB conditioning.

New upper limit on the total neutrino mass from the 2 degree field galaxy redshift survey.

We constrain f(nu) identical with Omega(nu)/Omega(m), the fractional contribution of neutrinos to the total mass density in the Universe, by comparing the power spectrum of fluctuations derived from the 2 Degree Field Galaxy Redshift Survey with power spectra for models with four components: baryons, cold dark matter, massive neutrinos, and a cosmological constant. Adding constraints from independent cosmological probes we find f(nu)<0.13 (at 95% confidence) for a prior of 0.1

A measurement of the cosmological mass density from clustering in the 2dF Galaxy Redshift Survey.

The large-scale structure in the distribution of galaxies is thought to arise from the gravitational instability of small fluctuations in the initial density field of the Universe. A key test of this hypothesis is that forming superclusters of galaxies should generate a systematic infall of other galaxies. This would be evident in the pattern of recessional velocities, causing an anisotropy in the inferred spatial clustering of galaxies. Here we report a precise measurement of this clustering, using the redshifts of more than 141,000 galaxies from the two-degree-field (2dF) galaxy redshift survey. We determine the parameter beta = Omega0.6/b = 0.43 +/- 0.07, where Omega is the total mass-density parameter of the Universe and b is a measure of the 'bias' of the luminous galaxies in the survey. (Bias is the difference between the clustering of visible galaxies and of the total mass, most of which is dark.) Combined with the anisotropy of the cosmic microwave background, our results favour a low-density Universe with Omega approximately 0.3.

Photophobia, epiphora, and torticollis: a masquerade syndrome.

Three young children presented with photophobia, epiphora, and torticollis as the initial manifestation of a posterior fossa tumor. In each case there was a delay in treatment due to the presumptive diagnosis of a local ocular inflammatory condition. We recommend that children with unexplained photophobia, epiphora, and torticollis undergo an imaging technique to evaluate the posterior fossa.

The antiseptic efficacy of chlorxylenol-containing vs. chlorhexidine gluconate-containing surgical scrub preparations.

The studies described here evaluate the efficacy of the chlorxylenol-containing surgical scrub formulations against the chlorhexidine gluconate-containing formulations using the Glove Juice Test, as recommended by the FDA's panel to develop guidelines for the study of antiseptic agents. Similar reports from the literature evaluating the relative efficacies of the iodophor-containing and the hexachlorophene-containing formulations are cited. Results fail to detect any significant differences in the efficacy of these two preparations, each significantly reducing the bacterial flora on the hands as indicated by immediate post-wash colony counts, and each demonstrating the continuing ability to significantly reduce bacterial growth with continued regular use.

Self-administration of medical modalities (SAMM): another method of rehabilitation education.

In order to train patients to carry out home pulmonary care adequately, we developed a hospital-based patient-education program we call Self-Administration of Medical Modalities (SAMM). This teaches patients about their pulmonary disease; about their medications' purposes, side effects and what to do if they occur, possible conflict with other medications, and the medication schedule; about use, care, and cleaning of aerosol inhalation devices and scheduling of aerosol medication treatments; and about chest physical therapy if it is indicated. Nurses, respiratory therapists, and physical therapists in the hospital teach and reinforce these concepts and evaluate the patient's progress in learning. The patient advances through three levels of competency. At Level I he is responsible only for keeping track of his medication and treatment schedules. At Level II the patient initiates requests for medication and treatments on schedule, takes them under supervision, and makes a written record of having done so. At Level III the patient's medications are kept at his bedside, he prepares and takes the medications himself, takes treatments himself, and he keeps written records. At this level the program simulates home conditions as much as possible. Patients have reported that they liked administering their own medications and treatments and that the SAMM Program was helpful in preparing them for self-care at home.

Effect of pH on the antimicrobial activity of some triphenylmethane dyes.

Four common dyes were tested as inhibitors of four types of bacteria over the pH range 5.0-9.0. Inhibition of the gram-negative types, Salmonella anatum and Enterobacter aerogenes, was markedly affected by the pH of the medium. These organisms tolerated concentrations of crystal violet and ethyl violet about 100-fold higher at pH 5.0 than at pH 9.0. Above pH 7.0 brilliant green (BG) and malachite green (MG) were precipitated as their respective carbinols and lost their inhibitory properties with these two organisms. Two gram-positive types, Staphylococcus aureus and Bacillus cereus, were more sensitive to dyes and results were less affected by pH. The carbinol forms of MG and BG were nearly as inhibitory to these organisms as the ionized forms.

Effect of heat on the antimicrobial activity of brillant green dye.

Antimicrobial activity of brilliant green dye in Trypticase soy broth (BBL) is reduced and ultimately destroyed by prolonged autoclaving at 121 C. Loss of antimicrobial activity is accompanied by decolorization of the dye. This is consistent with other evidence that antimicrobial activity of brilliant green resides in the colored dye ion. The dye is not decolorized when heated in distilled water or peptone, but is decolorized by heating in glucose, glycine, or sodium dodecyl sulfate, showing that decolorization results from reaction with components of the medium. To ensure optimal results, it is recommended that bacteriological media be sterilized by heat prior to addition of brilliant green dye.