Histamine H1-receptor modulation of inter-neuronal coupling among vasopressinergic neurons depends on nitric oxide synthase activation

Inter-neuronal coupling is a relatively recently documented property of a wide variety of cell groups in the mammalian central nervous system. For many of these groups there is evidence that the coupling can be modulated by synaptic inputs. Incidence of dye coupling among vasopressin (VP) neurons of the rat supraoptic nucleus (SON) has been shown to increase in response to either activation of histamine H(1)-receptors or to increased NO production. Both of these effects involve activation of cGMP-dependent pathways. We tested the hypothesis that activation of H(1)-receptors resulted in downstream activation of NO synthase, which then mediated the H(1)-receptor effects. Putative VP neurons were intracellularly recorded and dye-injected in horizontal slices of hypothalamus, in which monosynaptic connections from the tuberomammillary nucleus (TM) were intact and electrically stimulated. Single-pulse TM stimulation evoked EPSPs and repetitive stimulation resulted in a nearly 3-fold increase in coupling incidence over unstimulated slices. TM-stimulated increased coupling was completely blocked by inhibitors of NO synthase (L-NAME) or of soluble guanylyl cyclase (ODQ or methylene blue), or pyrilamine, suggesting that the H(1)-receptor is not directly linked to guanylyl cyclase. Addition of the NO precursor, L-arginine or the NO donor, SNP, in combination with TM stimulation produced increases in coupling that were not significantly larger than those seen with stimulation alone, supporting the idea that a common pathway was used. We conclude that H(1)-receptors activate NO synthase via G-protein-coupled pathways and that NO working though its receptor, induces the downstream cGMP-dependent processes that result in increased inter-neuronal coupling.     

44Sacral extracorporeal magnetic stimulation is an effective treatment for pelvic floor dyssynergia; Comparative study with biofeedback therapy

Background: Recent development of extracorporeal magnetic stimulation (ECMS) which uses current‐changing magnetic fields allows the induction of electrical stimulation in the desired deep tissue. Recent study showed the sacral nerve stimulation reduces corticoanal excitability that may play a functional role in anal continence mechanisms. Preliminary study shows that ECMS of sacral nerve can modify pelvic floor function and expel rectal balloon in patients with pelvic floor dyssynergia (PFD). Aims: To evaluate the effect of ECMS compared with biofeedback therapy (BF) in patients with PFD. Methods and Materials: Thirty‐eight patients who fulfilled Rome II criteria for PFD by colon transit time and anorectal function tests, were randomly treated with 8 sessions of ECMS (2/weeks; n = 19) at prone position or BF (2/weeks; n = 19) at sitting position. Stimulation parameters were set at 50–80% of maximum intensity, 10 and 50 Hz frequency, 3 s burst length with 3 and 6 s off using arm‐typed stimulator (BioCom‐1000, Mcube Co., Korea). Symptom scores for constipation with/without anorectal function test were repeatedly measured after each treatment. Response was defined as 50% or more decreased symptom score after treatment (partial response: 30–50%, poor: <30%). Results: Fifteen patients (age 49.1 ± 13.4 years, mean ± SD; 4 men) completed 8 session of BF and 14 patients (54.5 ± 17.6 years, 3 men) completed 8 session of ECMS. Four patients of BF group discontinued treatment due to unsatisfactory therapeutic effect (n = 1) and withdrew consent (n = 3) and 5 patients of ECMS group discontinued treatment because of same reasons (n = 1, 4). Total symptom scores were significantly decreased after treatment of 8 session in both treatment groups (13.4 ± 6.6 vs. 4.3 ± 4.0 for BF, p = 0.009; 14.9 ± 5.6 vs. 3.4 ± 4.0 for ECMS, p < 0.001). Bowel movements per week were also significantly increased after treatment in both groups (median 2 vs. 7 for BF, p = 0.035; median 2 vs. 7 for ECMS, p = 0.008). Thirteen out of 15 patients showed response in BF group and 12 out of 14 showed good response in ECMS group. No adverse effects in both groups. Conclusions: ECMS is as effective as BF for the treatment of PFD. Long‐term effect of ECMS for the patients with pelvic floor dyssynergia need to be evaluated in the near future.     

Multilayered optofluidics for sustainable buildings

Indoor climate control is among the most energy-intensive activities conducted by humans. A building facade that can achieve versatile climate control directly, through independent and multifunctional optical reconfigurations, could significantly reduce this energy footprint, and its development represents a pertinent unmet challenge toward global sustainability. Drawing from optically adaptive multilayer skins within biological organisms, we report a multilayered millifluidic interface for achieving a comprehensive suite of independent optical responses in buildings. We digitally control the flow of aqueous solutions within confined milliscale channels, demonstrating independent command over total transmitted light intensity (95% modulation between 250 and 2,500 nm), near-infrared-selective absorption (70% modulation between 740 and 2,500 nm), and dispersion (scattering). This combinatorial optical tunability enables configurable optimization of the amount, wavelength, and position of transmitted solar radiation within buildings over time, resulting in annual modeled energy reductions of more than 43% over existing technologies. Our scalable “optofluidic” platform, leveraging a versatile range of aqueous chemistries, may represent a general solution for the climate control of buildings.

Buildings are the costliest energy sinks on the planet (1, 2). For their daily operation, which largely entails trying to heat, cool, and light the indoor environment as exterior conditions change, buildings require 32% (32.4 PWh) of the energy and 50% of the electricity consumed globally (2), corresponding to about 25% (9.18 GtCO₂) of our greenhouse gas emissions (1).Moreover, the emissions associated with buildings may double or triple by mid-century with increased urbanization (1). Global air conditioning demand is set to triple by 2050 (3). Heating and cooling energy use is expected to grow by 79% and 84% in the same timeframe (1). In addition, electricity-based emissions from residential and commercial buildings have already quintupled and quadruped, respectively, in the last four decades (1).Underpinning this alarming and growing footprint is a fundamental unmet challenge in building design: existing facades cannot achieve selective, reconfigurable responses to their solar environment; no window, sunshade, or chromogenic technology is able to independently tune the amount (intensity), wavelength (spectrum), and dispersion (scattering) of incident sunlight as solar conditions change (a comprehensive review of available technologies and their optical properties is provided in SI Appendix, Table S1).Static windows, with or without permanent reflective coatings, for instance, cannot dynamically modulate solar intensity, spectrum, nor scattering (4–6). Manual or automated venetian blinds, on the other hand, can partially control intensity and scattering (with changing slat angle), but not independently (7). Adjustable window shades, which can be bent, rotated, or otherwise translated under mechanical (6, 8–12), electrical (13), hygroscopic (14, 15), or thermal (16) stimuli, can usually tune only total intensity (17), while more experimental chromogenic windows, including reorientable liquid crystal (18–20), suspended particle (21–23), as well as electro- (24–34), photo- (26, 28, 29, 31, 35), and thermochromic (26, 28, 29, 31, 35–37) devices, can generally only regulate total sunlight intensity or spectrum (32–34, 38).At the building interface, independent, synergistic control over transmitted light intensity, spectrum, and scattering is necessary to achieve optimized and climate-responsive functions (4, 6, 31, 39). Control of total light intensity would enable modulation of solar heat gain and illumination; control of spectrum and, in particular, switchable transmission of near-infrared-selective (NIR) sunlight would decouple infrared heating from visible daylighting (38, 40); while control of scattering would allow for the spatial tuning of transmitted photons within a room. In the current absence of a building material with this combinatorial functionality, interior heating, cooling, and lighting systems must bear the brunt of temperature and illumination control, compensating entirely for exterior environmental fluctuations and interior occupant changes, and by themselves consume more than 25% of the energy used in the developed world (4, 6, 31, 39, 41).To alter this energy-intensive paradigm (41), buildings would benefit from independent, switchable control over total transmittance, NIR-selective absorption, and scattering by the outer facade. Developing this scalable, combinatorial optical platform, with the ability to separately tune each of these three properties, might be considered the “holy grail” for building material design (42).Multilayered Optical Mechanisms in Biology.As a possible source of inspiration, certain biological organisms have evolved multilayered mechanisms within their skin to tune independent optical properties at their interface. In a few species of squid (e.g., Loligo plei), for instance, active camouflage is achieved through the independent and cooperative action of a pigmentary layer of chromatophore organs and a structural layer of protein cells (43–45), mediating surface color, spectral reflectance, and spatial patterning (46–50) (Fig. 1B). Large shifts in spectral reflection peaks occur along surface regions where both pigmentary and structural layers are overlaid (SI Appendix, Fig. S3 C–J), enabling combinatorial, additive, optical responses. The panther chameleon has also evolved a multilayered infrastructure within its skin, leveraging a two-tiered system of photonic crystals, each with an independent morphology and function (51) (Fig. 1A). Color change is regulated through the uppermost photonic layer, as chameleons actively manipulate the periodicity of guanine nanocrystals to selectively reflect light. Thermoregulation, on the other hand, is achieved through the lowermost photonic layer, where populations of regularly arranged iridophore cells strongly reflect radiation in the NIR region.Open in a separate windowFig. 1.Biological inspiration for fluidic multilayer. (A) Color change in the panther chameleon, achieved using a multilayer architecture of active photonic crystals. (B) Color change in the squid, achieved using coordinated actuations within a multilayer of pigmentary and structural elements. The top images are of Sepioteuthis lessoniana, whereas the bottom images are of Loligo pealeii. (C and D) Schematic for achieving independent multilayered switchable responses in building facades, where switchable fluid flow within distinct layers can enable multiple distinct optical functions. (E) Schematic exemplifying several functional or multifunctional states, achieved through coordinated fluid injections within a bilayer. The fluid multilayer acts as an additive light filter for incoming light. Scale bars: (A) white, 20 μm; black, 200 nm; (B) 1 mm; (D) 1 cm. Images in (A) reproduced from ref. 51, published under a Creative Commons license (http://creativecommons.org/licenses/by/4.0/). Images in (B) reproduced with permission from ref. 48, and under license from refs. 52 and 53.Independently tunable and multifunctional multilayer interfaces enable combinatorial physiological responses in organisms. We hypothesize that building-scale analogues of these multilayered, multifunctional biological systems might be capable of similarly dynamic optical behaviors (SI Appendix, Fig. S3). To achieve a scalable and sustainable material platform with general optical tunability, we propose moving away from traditional solid-state approaches and instead suggest the integration of confined aqueous fluids: a class of replenishable, recyclable, nontoxic materials with remarkable spatial configurability (54–57) and broadly tailorable optical programmability (58, 59). Conventional microfluidic devices are typically applied to chemical (60, 61), diagnostic (62, 63), and computational (64, 65) “lab on a chip” applications, but few examples take advantage of the optical characteristics of confined fluids, and over large planar dimensions. We suggest that a system of stacked channeled layers capable of confining a selectively designed collection of fluids can achieve versatile, multifunctional, and combinatorial optical functionality.Here, we demonstrate a large-area “optofluidic” platform for buildings, capable of achieving independent and combinatorial control of total light transmission, spectrally selective light absorption, and spatially directable light dispersion through coordinated digital fluid flows therein (Fig. 1 C–E). In simulation, we show that independent control over three sequential aqueous fluid layers within a building facade—to regulate optimal degrees of total light transmission, NIR light transmission, and visible light scattering in response to fluctuating solar conditions—can accomplish savings of 75% on heating energy, 20% on electric lighting energy, and 43% on total operational energy, compared with the best available electrochromic technology. These results point toward an exciting design paradigm for buildings, where confined, switchable fluid layers within a facade can behave in concert as functionally programmable optical and solar filters. Dynamic control of this versatile fluidic platform could significantly improve the way we build, operate, and interact with buildings.     

Neuronal sirtuin1 mediates retinal vascular regeneration in oxygen-induced ischemic retinopathy

Regeneration of blood vessels in ischemic neuronal tissue is critical to reduce tissue damage in diseases. In proliferative retinopathy, initial vessel loss leads to retinal ischemia, which can induce either regrowth of vessels to restore normal metabolism and minimize damage, or progress to hypoxia-induced sight-threatening pathologic vaso-proliferation. It is not well understood how retinal neurons mediate regeneration of vascular growth in response to ischemic insults. In this study we aim to investigate the potential role of Sirtuin 1 (Sirt1), a metabolically-regulated protein deacetylase, in mediating the response of ischemic neurons to regulate vascular regrowth in a mouse model of oxygen-induced ischemic retinopathy (OIR). We found that Sirt1 is highly induced in the avascular ischemic retina in OIR. Conditional depletion of neuronal Sirt1 leads to significantly decreased retinal vascular regeneration into the avascular zone and increased hypoxia-induced pathologic vascular growth. This effect is likely independent of PGC-1α, a known Sirt1 target, as absence of PGC-1α in knockout mice does not impact vascular growth in retinopathy. We found that neuronal Sirt1 controls vascular regrowth in part through modulating deacetylation and stability of hypoxia-induced factor 1α and 2α, and thereby modulating expression of angiogenic factors. These results indicate that ischemic neurons induce Sirt1 to promote revascularization into ischemic neuronal areas, suggesting a novel role of neuronal Sirt1 in mediating vascular regeneration in ischemic conditions, with potential implications beyond retinopathy.     

Drinking patterns, dependency and life-time drinking history in alcohol-related liver disease

Aims   To examine the hypothesis that increases in UK liver deaths are a result of episodic or binge drinking as opposed to regular harmful drinking.
Design   A prospective survey of consecutive in-patients and out-patients.
Setting   The liver unit of a teaching hospital in the South of England.
Participants   A total of 234 consecutive in-patients and out-patients between October 2007 and March 2008.
Measurements   Face-to-face interviews, Alcohol Use Disorders Identification Test, 7-day drinking diary, Severity of Alcohol Dependence Questionnaire, Lifetime Drinking History and liver assessment.
Findings   Of the 234 subjects, 106 had alcohol as a major contributing factor (alcoholic liver disease: ALD), 80 of whom had evidence of cirrhosis or progressive fibrosis. Of these subjects, 57 (71%) drank on a daily basis; only 10 subjects (13%) drank on fewer than 4 days of the week—of these, five had stopped drinking recently and four had cut down. In ALD patients two life-time drinking patterns accounted for 82% of subjects, increasing from youth (51%), and a variable drinking pattern (31%). ALD patients had significantly more drinking days and units/drinking day than non-ALD patients from the age of 20 years onwards.
Conclusions   Increases in UK liver deaths are a result of daily or near-daily heavy drinking, not episodic or binge drinking, and this regular drinking pattern is often discernable at an early age.     

Autopsies of sudden infant death syndrome—classification and epidemiology

An enquiry into sudden infant death syndrome (SIDS) in 1987 furnished us with detailed epidemiological data for 281 cases that underwent a thorough post-mortem examination. This analysis uses these data to evaluate the role the autopsy plays in explaining sudden death. The cases were classified into three diagnostic groups: explained causes of death (group 1), unexplained deaths with anomalies (group 2), and no anomaly (group 3). These 281 cases show the three essential features that characterize SIDS: over-representation of males, increased deaths during the second and third months of life, and increased deaths during winter. The autopsy examination revealed that many of these deaths had a medical explanation. Almost half were assigned to group 1. At the time of autopsy, no precise pathology could be diagnosed for 147 deaths; of these, 140 showed histological anomalies. There were only seven sudden deaths for which no abnormal sign was evident at the autopsy. These results are compared with those of similar studies and discussed in connection with three factors: the initial selection of cases, the nature and degree of the investigations, and the possible interpretations of the symptoms uncovered.     

Flashlamp-excited dye laser therapy of idiopathic vulvodynia is safe and efficacious

Objective: The management of chronic vulvovaginal pain, not explicable on specific histologic grounds, presents a major problem in referral centers for lower genital tract diseases.Study design: This article reports on a two-step protocol in a sample of 175 medical nonresponders, drawn from a 2-year cohort of 725 women with vulvovaginal pain. The first maneuver was the use of a flashlamp-excited dye laser to selectively photocoagulate symptomatic subepithelial blood vessels in 168 women; the second was the microsurgical removal of chronically painful Bartholin's glands in 52 women not responsive or not suited to flashlamp-excited dye laser photothermolysis.Results: Dye laser response rates werer independent of whether patients manifested macroscopic focl of painful erythema (“vestibular adenitis”) or just colposcopically apparent hyperemia-ectasia of the individual blood vessels (“pruritic papillomatosis”) (55% vs 45% after a single surgical procedure; 76% vs 65% after serial retreatment; p not significant). Conversely, response rates were much lower among women in whom pressure on the Bartholin's glands produced sharp, lancinating pain (15% vs 66% after a single surgical procedure; 22% vs 93% after serial retreatment; p < 0.001). Forty-two (85%) of 50 patients with flashlamp-excited dye laser failure had deep pain; however, the impasse to progress was broken by gland removal. Final response rates were 92.5% (complete response 62%; partial response 30%) in the “surface-only” group and 80.3% in the “surface-plus-deep” group (χ² = 14.9; p < 0.001). The major complication was acute bacterial cellulitis, occurring in the first postoperative week. Modification of the treatment protocol to include topical antibiotics with an occlusive dressing reduced the cellulitis rate from 17.2% to 2.5%. In four women (1.8%) Koebner-like exophytic condylomas also developed within 1 month of flashlamp-excited dye laser surgery.Conclusion: The availability of a safe, efficacious, and relatively noninvasive treatment should reduce the need for resective surgery in most patients with idiopathic vulvodynia. 1995; 172; 1684–1701.)     

Sudden infant death in France during the winter of 1986

From the statistics of the medical causes of deaths and the results of a retrospective survey carried out among the physicians who certified the deaths, an analysis of post-neonatal mortality during winter of 1986 was undertaken in order to know if the relative part of the sudden infant death syndrome (SIDS) had increased during that winter. It appeared that the deaths attributed to SIDS can be distinguished from deaths of other causes for several factors (place of death, former status of the baby). However, the low number of post mortem examinations performed does not allow in all the declared cases to assess SIDS as internationally defined. However, it is shown that sudden mortality was not higher during this special winter and that immunizations were not more frequently related to this cause than to other causes of death.     

Fractones and other basal laminae in the hypothalamus

The physiological role of basal laminae (BL) and connective tissue (meninges and their projections) in the adult brain is unknown. We recently described novel forms of BL, termed fractones, in the most neurogenic zone of the adult brain, the subependymal layer (SEL) of the lateral ventricle. Here, we investigated the organization of BL throughout the hypothalamus, using confocal and electron microscopy. New types of BL were identified. First, fractones, similar to those found in the lateral ventricle wall, were regularly arranged along the walls of the third ventricle. Fractones consisted of labyrinthine BL projecting from SEL blood vessels to terminate immediately beneath the ependyma. Numerous processes of astrocytes and of microglial cells directly contacted fractones. Second, another form of BL projection, termed anastomotic BL, was found between capillaries in dense capillary beds. The anastomotic BL enclosed extraparenchymal cells that networked with the perivascular cells coursing in the sheaths of adjacent blood vessels. Vimentin immunoreactivity was often detected in the anastomotic BL. In addition, the anastomotic BL overlying macrophages contained numerous fibrils of collagen. We also found that the BL located at the pial surface formed labyrinthine tube-like structures enclosing numerous fibroblast and astrocyte endfeet, with pouches of collagen fibrils at the interface between the two cell types. We suggest that cytokines and growth factors produced by connective tissue cells might concentrate in BL, where their interactions with extracellular matrix proteins might contribute to their effects on the overlying neural tissue, promoting cytogenesis and morphological changes and participating in neuroendocrine regulation.     

Anatomy of the brain neurogenic zones revisited: fractones and the fibroblast/macrophage network

Cytogenesis in adult peripheral organs, and in all organs during development, occurs nearby basal laminae (BL) overlying connective tissue. Paradoxically, cytogenesis in the adult brain occurs primarily in the subependymal layer (SEL), a zone where no particular organization of BL and connective tissue has been described. We have reinvestigated the anatomy of the area considered the most neurogenic in the adult brain, the SEL of the lateral ventricle, in zones adjacent to the caudate putamen, corpus callosum, and lateral septal nucleus. Here, we report structural (confocal microscopy using laminin as a marker) and ultrastructural evidence for highly organized extravascular BL, unique to the SEL. The extravascular BL, termed fractones because of their fractal organization, were regularly arranged along the SEL and consisted of stems terminating in bulbs immediately underneath the ependyma. Fractones contacted local blood vessels by means of their stems. An individual fractone engulfed in its folds numerous processes of astrocytes, ependymocytes, microglial cells, and precursor cell types. The attachment site (base) of stems to blood vessels was extensively folded, overlying large perivascular macrophages that belong to a fibroblast/macrophage network coursing in the perivascular layer and through the meninges. In addition, collagen-1, which is associated with BL and growth factors during developmental morphogenetic inductions, was immunodetected in the SEL and particularly regionalized within fractones. Because macrophages and fibroblasts produce cytokines and growth factors that may concentrate in and exert their effect from the BL, we suggest that the structure described is implicated in adult neurogenesis, gliogenesis, and angiogenesis.