Functional Topography and Development of Inhibitory Reticulothalamic Barreloid Projections

The thalamic reticular nucleus (TRN) is the main source of inhibition to the somatosensory thalamus (ventrobasal nucleus, VB) in mice. However, the functional topography and development of these projections with respect to the VB barreloids has been largely unexplored. In this respect, to assist in the study of these projections, we have utilized a vesicular gamma-aminobutryic acid (GABA) transporter (VGAT)-Venus transgenic mouse line to develop a brain slice preparation that enables the rapid identification of inhibitory neurons and projections. We demonstrate the utility of our in vitro brain slice preparation for physiologically mapping inhibitory reticulothalamic (RT) topography, using laser-scanning photostimulation via glutamate uncaging. Furthermore, we utilized this slice preparation to compare the development of excitatory and inhibitory projections to VB. We found that excitatory projections to the barreloids, created by ascending projections from the brain stem, develop by postnatal day 2–3 (P2–P3). By contrast, inhibitory projections to the barreloids lag ~5 days behind excitatory projections to the barreloids, developing by P7–P8. We probed this lag in inhibitory projection development through early postnatal whisker lesions. We found that in whisker-lesioned animals, the development of inhibitory projections to the barreloids closed by P4, in register with that of the excitatory projections to the barreloids. Our findings demonstrate both developmental and topographic organizational features of the RT projection to the VB barreloids, whose mechanisms can now be further examined utilizing the VGAT-Venus mouse slice preparation that we have characterized

Functional Topography and Development of Inhibitory Reticulothalamic Barreloid Projections

The thalamic reticular nucleus (TRN) is the main source of inhibition to the somatosensory thalamus (ventrobasal nucleus, VB) in mice. However, the functional topography and development of these projections with respect to the VB barreloids has been largely unexplored. In this respect, to assist in the study of these projections, we have utilized a vesicular gamma-aminobutryic acid (GABA) transporter (VGAT)-Venus transgenic mouse line to develop a brain slice preparation that enables the rapid identification of inhibitory neurons and projections. We demonstrate the utility of our in vitro brain slice preparation for physiologically mapping inhibitory reticulothalamic (RT) topography, using laser-scanning photostimulation via glutamate uncaging. Furthermore, we utilized this slice preparation to compare the development of excitatory and inhibitory projections to VB. We found that excitatory projections to the barreloids, created by ascending projections from the brain stem, develop by postnatal day 2–3 (P2–P3). By contrast, inhibitory projections to the barreloids lag ~5 days behind excitatory projections to the barreloids, developing by P7–P8. We probed this lag in inhibitory projection development through early postnatal whisker lesions. We found that in whisker-lesioned animals, the development of inhibitory projections to the barreloids closed by P4, in register with that of the excitatory projections to the barreloids. Our findings demonstrate both developmental and topographic organizational features of the RT projection to the VB barreloids, whose mechanisms can now be further examined utilizing the VGAT-Venus mouse slice preparation that we have characterized.SVM CORP (Grant LAV 3487

Unusual Protrusion of Conjunctiva in Two Neonates with Harlequin Ichthyosis

Background: We present two patients who developed severe protrusion of the conjunctiva and chemosis secondary to Harlequin ichthyosis (HI). Case Reports: Case 1 was a male infant diagnosed with HI who had parchment-like appearance and conjunctival protrusion with severe chemosis. Case 2 was a female infant on whom HI had been suspected before birth through ultrasonography. She showed thickened skin over the entire body and conjunctival protrusion with severe chemosis. For both cases, a vitamin A derivative was applied and the hyperkeratotic layer was peeled off every day. Great care was taken to sterilize and moisten the ocular surface. The conjunctival protrusion gradually improved and other systemic conditions were successfully treated. HI is a rare condition, but affected infants are surviving longer than previously and hence guidelines for ocular management are now required. Conclusions: Gentle and patient debridement of the hyperkeratotic skin and moisturizing were important in treating the unusual conjunctival protrusion

Encoding of Temporal Information by Timing, Rate, and Place in Cat Auditory Cortex

A central goal in auditory neuroscience is to understand the neural coding of species-specific communication and human speech sounds. Low-rate repetitive sounds are elemental features of communication sounds, and core auditory cortical regions have been implicated in processing these information-bearing elements. Repetitive sounds could be encoded by at least three neural response properties: 1) the event-locked spike-timing precision, 2) the mean firing rate, and 3) the interspike interval (ISI). To determine how well these response aspects capture information about the repetition rate stimulus, we measured local group responses of cortical neurons in cat anterior auditory field (AAF) to click trains and calculated their mutual information based on these different codes. ISIs of the multiunit responses carried substantially higher information about low repetition rates than either spike-timing precision or firing rate. Combining firing rate and ISI codes was synergistic and captured modestly more repetition information. Spatial distribution analyses showed distinct local clustering properties for each encoding scheme for repetition information indicative of a place code. Diversity in local processing emphasis and distribution of different repetition rate codes across AAF may give rise to concurrent feed-forward processing streams that contribute differently to higher-order sound analysis

Interferon regulatory factor-4 activates IL-2 and IL-4 promoters in cooperation with c-Rel.

Interferon regulatory factor (IRF)-4 is a member of the IRF transcription factor family, whose expression is primarily restricted to lymphoid and myeloid cells. In T-cells, IRF-4 expression is induced by T-cell receptor (TCR) cross-linking or treatment with phorbol-12-myristate-13-acetate (PMA)/Ionomycin, and IRF-4 is thought to be a critical factor for various functions of T-cells. To elucidate the IRF-4 functions in human adult T-cell leukemia virus type 1 (HTLV-1)-infected T-cells, which constitutively express IRF-4, we isolated IRF-4-binding proteins from T-cells, using a tandem affinity purification (TAP)-mass spectrometry strategy. Fourteen proteins were identified in the IRF-4-binding complex, including endogenous IRF-4 and the nuclear factor-kappaB (NF-κB) family member, c-Rel. The specific association of IRF-4 with c-Rel was confirmed by immunoprecipitation experiments, and IRF-4 was shown to enhance the c-Rel-dependent binding and activation of the interleukin-4 (IL-4) promoter region. We also demonstrated that IL-2 production was also enhanced by exogenously-expressed IRF-4 and c-Rel in the presence of P/I, in T-cells, and that the optimal IL-2 and IL-4 productions in vivo was IRF-4-dependent using IRF-4-/- mice. These data provide molecular evidence to support the clinical observation that elevated expression of c-Rel and IRF-4 is associated with the prognosis in adult T-cell leukemia/lymphoma (ATLL) patients, and present possible targets for future gene therapy

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Peripheral representation of sound frequency in cricket auditory system : beyond tonotopy

Crickets provide a useful model system to study how animals analyze sound frequency. While much is known about how sound frequency is represented by central neurons and in behavior, little is yet known about auditory receptor neurons. I investigated physiological and anatomical properties of auditory receptor fibers (ARFs) and functional organization of their axon terminals, using single-unit recording and staining techniques. Behavioral experiments suggest that crickets are sensitive to two broad frequency ranges, centered at 4--5 kHz for acoustic communication and at 25--50 kHz for predator detection. However, cricket ARFs fall into three distinct populations, based on characteristic frequency (CF; low frequency, &sim;3--5.5 kHz; mid frequency, 9--12 kHz; ultrasound, &ge;18 kHz). One striking characteristic of single ARFs is the occurrence of multiple sensitivity peaks at different frequencies, which implies that the wide audible range of crickets is mediated by these multiple sensitivity peaks, even though CFs of ARFs are clustered at the three small ranges. To understand how populations of ARFs code sound intensity, level-response functions are examined. Physiological parameters derived from level-response functions are diverse, and are systematically related to threshold within each population. Low-frequency ARFs comprise two distinct anatomical types, based on the distributions of axon terminals, which also differ physiologically. Thus, based on CF and anatomy, cricket ARFs can be classified into four distinct populations. To understand how information flows from peripheral to central neurons, the positions of varicosities, i.e. output sites, of ARF axon terminals are mapped on a two-dimensional coordinate system. In crickets, the ARF axon terminals are functionally organized with respect to frequency and intensity. Anatomical organization with respect to threshold is related to physiological organization, which may reduce non-linear effects in postsynapti