NLRP3 mutation and cochlear autoinflammation cause syndromic and nonsyndromic hearing loss DFNA34 responsive to anakinra therapy.

The NLRP3 inflammasome is an intracellular innate immune sensor that is expressed in immune cells, including monocytes and macrophages. Activation of the NLRP3 inflammasome leads to IL-1ß secretion. Gain-of-function mutations of NLRP3 result in abnormal activation of the NLRP3 inflammasome, and cause the autosomal dominant systemic autoinflammatory disease spectrum, termed cryopyrin-associated periodic syndromes (CAPS). Here, we show that a missense mutation, p.Arg918Gln (c.2753G > A), of NLRP3 causes autosomal-dominant sensorineural hearing loss in two unrelated families. In family LMG446, hearing loss is accompanied by autoinflammatory signs and symptoms without serologic evidence of inflammation as part of an atypical CAPS phenotype and was reversed or improved by IL-1ß blockade therapy. In family LMG113, hearing loss segregates without any other target-organ manifestations of CAPS. This observation led us to explore the possibility that resident macrophage/monocyte-like cells in the cochlea can mediate local autoinflammation via activation of the NLRP3 inflammasome. The NLRP3 inflammasome can indeed be activated in resident macrophage/monocyte-like cells in the mouse cochlea, resulting in secretion of IL-1ß. This pathway could underlie treatable sensorineural hearing loss in DFNA34, CAPS, and possibly in a wide variety of hearing-loss disorders, such as sudden sensorineural hearing loss and Meniere's disease that are elicited by pathogens and processes that stimulate innate immune responses within the cochlea.

Persistence, distribution, and impact of distinctly segmented microparticles on cochlear health following in vivo infusion.

Delivery of pharmaceuticals to the cochleae of patients with auditory dysfunction could potentially have many benefits from enhancing auditory nerve survival to protecting remaining sensory cells and their neuronal connections. Treatment would require platforms to enable drug delivery directly to the cochlea and increase the potential efficacy of intervention. Cochlear implant recipients are a specific patient subset that could benefit from local drug delivery as more candidates have residual hearing; and since residual hearing directly contributes to post-implantation hearing outcomes, it requires protection from implant insertion-induced trauma. This study assessed the feasibility of utilizing microparticles for drug delivery into cochlear fluids, testing persistence, distribution, biocompatibility, and drug release characteristics. To allow for delivery of multiple therapeutics, particles were composed of two distinct compartments; one containing polylactide-co-glycolide (PLGA), and one composed of acetal-modified dextran and PLGA. Following in vivo infusion, image analysis revealed microparticle persistence in the cochlea for at least 7 days post-infusion, primarily in the first and second turns. The majority of subjects maintained or had only slight elevation in auditory brainstem response thresholds at 7 days post-infusion compared to pre-infusion baselines. There was only minor to limited loss of cochlear hair cells and negligible immune response based on CD45+ immunolabling. When Piribedil-loaded microparticles were infused, Piribedil was detectable within the cochlear fluids at 7 days post-infusion. These results indicate that segmented microparticles are relatively inert, can persist, release their contents, and be functionally and biologically compatible with cochlear function and therefore are promising vehicles for cochlear drug delivery. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 1510-1522, 2016.

WITHDRAWN: Home-based support for disadvantaged adult mothers.

BACKGROUND: Babies born to socio-economically disadvantaged mothers are at higher risk of a range of problems in infancy. Home visiting programs are thought to improve outcomes, both for mothers and children, largely through advice and support. OBJECTIVES: To assess the effectiveness of home visiting programmes for women who have recently given birth and who are socially or economically disadvantaged. SEARCH STRATEGY: We searched the following electronic databases: The Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 3, 2006); MEDLINE (1966 to March 2006); EMBASE (1980 to 2006 week 12); CINAHL (1982 to March week 4 2006); PsycINFO (1872 to March week 4 2006); ASSIA (1987 to March 2006); LILACS (1982 to March 2006); and Sociological Abstracts(1963 to March 2006). We searched grey literature using ZETOC (1993 to March 2006); Dissertation Abstracts International (late 1960s to 2006); and SIGLE (1980 to March 2006). We also undertook communication with published authors about ongoing or unpublished research. SELECTION CRITERIA: Included studies were randomised controlled trials investigating the efficacy of home visiting directed at disadvantaged adult mothers. DATA COLLECTION AND ANALYSIS: Two reviewers (EC and JP or CB) independently assessed titles and abstracts identified in the search for eligibility. Data were extracted and entered into RevMan (EC, JP and CB), synthesised and presented in both written and graphical form (forest plots). Outcomes included in this review were established at the protocol stage by an international steering group. The review does not report on all outcomes reported in included studies. MAIN RESULTS: We included 11 studies with 4751 participants in this review. Data show no statistically significant differences for those receiving home visiting, either for maternal outcomes (maternal depression, anxiety, the stress associated with parenting, parenting skills, child abuse risk or potential or breastfeeding) or child outcomes (preventive health care visits, psychosocial health, language development, behaviour problems or accidental injuries. Evidence about uptake of immunisations is mixed, and the data on child maltreatment difficult to interpret. AUTHORS' CONCLUSIONS: This review suggests that for disadvantaged adult women and their children, there is currently no evidence to support the adoption of home visiting as a means of improving maternal psychosocial health, parenting or outcomes for children. For reasons discussed in the review, this does not amount to a conclusion that home visiting programmes are ineffective, but indicates a need to think carefully about the problems that home visiting might influence, and improvements in the conduct of outcome studies in this area.

WITHDRAWN: Home-based support for disadvantaged teenage mothers.

BACKGROUND: Babies born to socio-economically disadvantaged mothers are at higher risk of injury, abuse or neglect and health problems than babies born to more affluent mothers; disadvantaged teenage mothers are at particular risk of adverse outcomes. Home-visiting programs are thought to improve outcomes for both mothers and children, largely through advice and support. OBJECTIVES: To assess the effectiveness of home-visiting programmes for women who have recently given birth and who are socially or economically disadvantaged. SEARCH STRATEGY: The following electronic databases were searched: CENTRAL (2006, Issue 3); MEDLINE (1966 to March 2006); EMBASE (1980 to week 12 2006); CINAHL (1982 to March week 4 2006); PsycINFO (1872 to March week 4 2006); ASSIA (1987 to March 2006); LILACS (1982 to March 2006); and Sociological Abstracts (1963 to March 2006). Grey literature was also be searched using ZETOC (1993 to March 2006); Dissertation Abstracts International (late 1960s to 2006); and SIGLE (1980 to March 2006). Communication with published authors about ongoing or unpublished research was also undertaken. SELECTION CRITERIA: Included studies were randomised controlled trials investigating the efficacy of home visiting directed at teenage mothers. DATA COLLECTION AND ANALYSIS: Titles and abstracts identified in the search were independently assessed for eligibility by two review authors (EC and JP or CB). Data were extracted and entered into RevMan (EC, JP and CB), synthesised and presented in both written and graphical form (forest plots). Outcomes included in this review were established at the protocol stage by an international steering group. The review did not report on all outcomes reported in included studies. MAIN RESULTS: Five studies with 1838 participants were included in this review. Data from single studies provided support for the effectiveness of home visiting on some outcomes, but the evidence overall provided only limited support for the effectiveness of home visiting as a means of improving the range of maternal and child outcomes considered in this review. AUTHORS' CONCLUSIONS: This review suggests there is only limited evidence that home-visiting programmes of the kind described in this review can impact positively on the quality of parenting of teenage mothers or on child development outcomes for their offspring. For reasons discussed in the review, this does not amount to a conclusion that home-visiting programmes are ineffective but indicates a need to think carefully about the problems that home visiting might influence and about improvements in the conduct and reporting of outcome studies in this area.

Home-based support for disadvantaged adult mothers.

BACKGROUND: Babies born to socio-economically disadvantaged mothers are at higher risk of a range of problems in infancy. Home visiting programs are thought to improve outcomes, both for mothers and children, largely through advice and support. OBJECTIVES: To assess the effectiveness of home visiting programmes for women who have recently given birth and who are socially or economically disadvantaged. SEARCH STRATEGY: We searched the following electronic databases: The Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 3, 2006); MEDLINE (1966 to March 2006); EMBASE (1980 to 2006 week 12); CINAHL (1982 to March week 4 2006); PsycINFO (1872 to March week 4 2006); ASSIA (1987 to March 2006); LILACS (1982 to March 2006); and Sociological Abstracts(1963 to March 2006). We searched grey literature using ZETOC (1993 to March 2006); Dissertation Abstracts International (late 1960s to 2006); and SIGLE (1980 to March 2006). We also undertook communication with published authors about ongoing or unpublished research. SELECTION CRITERIA: Included studies were randomised controlled trials investigating the efficacy of home visiting directed at disadvantaged adult mothers. DATA COLLECTION AND ANALYSIS: Two reviewers (EC and JP or CB) independently assessed titles and abstracts identified in the search for eligibility. Data were extracted and entered into RevMan (EC, JP and CB), synthesised and presented in both written and graphical form (forest plots). Outcomes included in this review were established at the protocol stage by an international steering group. The review does not report on all outcomes reported in included studies. MAIN RESULTS: We included 11 studies with 4751 participants in this review. Data show no statistically significant differences for those receiving home visiting, either for maternal outcomes (maternal depression, anxiety, the stress associated with parenting, parenting skills, child abuse risk or potential or breastfeeding) or child outcomes (preventive health care visits, psychosocial health, language development, behaviour problems or accidental injuries. Evidence about uptake of immunisations is mixed, and the data on child maltreatment difficult to interpret. AUTHORS' CONCLUSIONS: This review suggests that for disadvantaged adult women and their children, there is currently no evidence to support the adoption of home visiting as a means of improving maternal psychosocial health, parenting or outcomes for children. For reasons discussed in the review, this does not amount to a conclusion that home visiting programmes are ineffective, but indicates a need to think carefully about the problems that home visiting might influence, and improvements in the conduct of outcome studies in this area.

Home-based support for disadvantaged teenage mothers.

BACKGROUND: Babies born to socio-economically disadvantaged mothers are at higher risk of injury, abuse or neglect and health problems than babies born to more affluent mothers; disadvantaged teenage mothers are at particular risk of adverse outcomes. Home-visiting programs are thought to improve outcomes for both mothers and children, largely through advice and support. OBJECTIVES: To assess the effectiveness of home-visiting programmes for women who have recently given birth and who are socially or economically disadvantaged. SEARCH STRATEGY: The following electronic databases were searched: CENTRAL (2006, Issue 3); MEDLINE (1966 to March 2006); EMBASE (1980 to week 12 2006); CINAHL (1982 to March week 4 2006); PsycINFO (1872 to March week 4 2006); ASSIA (1987 to March 2006); LILACS (1982 to March 2006); and Sociological Abstracts (1963 to March 2006). Grey literature was also be searched using ZETOC (1993 to March 2006); Dissertation Abstracts International (late 1960s to 2006); and SIGLE (1980 to March 2006). Communication with published authors about ongoing or unpublished research was also undertaken. SELECTION CRITERIA: Included studies were randomised controlled trials investigating the efficacy of home visiting directed at teenage mothers. DATA COLLECTION AND ANALYSIS: Titles and abstracts identified in the search were independently assessed for eligibility by two review authors (EC and JP or CB). Data were extracted and entered into RevMan (EC, JP and CB), synthesised and presented in both written and graphical form (forest plots). Outcomes included in this review were established at the protocol stage by an international steering group. The review did not report on all outcomes reported in included studies. MAIN RESULTS: Five studies with 1838 participants were included in this review. Data from single studies provided support for the effectiveness of home visiting on some outcomes, but the evidence overall provided only limited support for the effectiveness of home visiting as a means of improving the range of maternal and child outcomes considered in this review. AUTHORS' CONCLUSIONS: This review suggests there is only limited evidence that home-visiting programmes of the kind described in this review can impact positively on the quality of parenting of teenage mothers or on child development outcomes for their offspring. For reasons discussed in the review, this does not amount to a conclusion that home-visiting programmes are ineffective but indicates a need to think carefully about the problems that home visiting might influence and about improvements in the conduct and reporting of outcome studies in this area.

Altered neuroendocrine response and gastric dysmotility in the Flinders Sensitive Line rat.

In the search for animal models that can replicate some features of functional dyspepsia (FD) patients, we turned our interest to the Flinders Sensitive Line (FSL) rat. Gastric motility disturbances prevalent in FD patients as well as urine corticosterone and plasma prolactin were measured following buspirone challenge. Flinders Resistant Line (FRL) rat was used as control. The results show that the FSL rats have a disturbed gastric motility, reflected as both an increased gastric accommodation rate and gastric volume during gastric distension as well as a delayed gastric emptying, the latter possibly as a consequence of the former. Lipid administration resulted in a significant increase in maximal gastric volume only in the FRL rats. Both the corticosterone response to buspirone and the 24-h urinary output of corticosterone were normal in FSL rats. Similar to FD patients, the FSL rat showed supersensitivity to buspirone in the increase in prolactin release. Although FSL rats show some features similar to a subset of FD patients, the increased gastric accommodation contrasts to the reduced accommodation often seen in FD patients. Further studies are warranted to determine the relevance of this rat strain as a model for FD.

Integration of pharmacotherapy and psychotherapy for bipolar disorder.

There is no question that pharmacotherapy is the treatment of choice for bipolar disorder. However. an integration of psychotherapeutic techniques with pharmacotherapy has been recommended by the American Psychiatric Association practice guideline for the treatment of bipolar disorder. Psychotherapy aims to address risk factors and associated features that are difficult to address with pharmacotherapy alone. The most common psychotherapeutic approaches added to pharmacotherapy for bipolar disorder include psychoeducation, individual cognitive-behavioral therapy, marital and family interventions, individual interpersonal therapy, and adjunctive therapies such as those for substance use. Each of these approaches is described in detail, and research regarding their efficacy is presented.

Microvascular effects of selective prostaglandin analogues in the eye with special reference to latanoprost and glaucoma treatment.

Prostaglandin F(2alpha) analogues have recently been introduced on the market for glaucoma treatment. While these drugs have a well-documented intraocular pressure reducing effect only a limited number of studies have been published regarding their effects on the microvasculature in the eye. Since many naturally occurring prostaglandins have marked effects on the cardiovascular system it is conceivable that synthetic prostaglandins used as glaucoma drugs may exert microvascular effects in the eye, even if they exhibit receptor selectivity. Latanoprost, the active principle of Xalatan((R)) eye drops, is a selective FP prostanoid receptor agonist, and much of the paper is focused on the microvascular effects of latanoprost and some closely related prostaglandin analogues. The purpose of the paper is to review the literature on the microvascular effects of prostaglandins in the eye, and to present some unpublished data on the effects of selective prostaglandin analogues. Most of the prostaglandin analogues studied exhibit selectivity for the FP prostanoid receptor. Results from studies with the following prostaglandin analogues are presented in the paper: PGF(2alpha)-isopropyl ester (PGF(2alpha)-IE), 17-phenyl-18,19,20-trinor-PGF(2alpha)-isopropyl ester (17-phenyl-PGF(2a)-IE), 15-keto-17-phenyl-18,19, 20-trinor-PGF(2alpha)-isopropyl ester (15-keto-17-phenyl-PGF(2a)-IE), 13,14-dihydro-17-phenyl-18,19,20-trinor-PGF(2alpha)-isopropy l ester (latanoprost), 13,14-dihydro-15R,S-17-phenyl-18,19, 20-trinor-PGF(2alpha)-isopropyl ester (PhXA34), 17-phenyl-18,19, 20-trinor-PGE(2)-isopropyl ester (17-phenyl-PGE(2)-IE), and 19R-hydroxy-PGE(2) (19R-OH-PGE(2)). The regional blood flow has been determined with radioactively labelled microspheres, the blood volume with (51)Cr labelled erythrocytes and the capillary permeability to albumin with (125)I and (131)I labelled albumin. PGF(2alpha)-IE has been shown to exert marked microvascular effects in the rabbit anterior segment including vasodilatation, increased capillary permeability, and a breakdown of the blood-aqueous barrier. 17-phenyl-PGF(2alpha)-IE, 15-keto-17-phenyl-PGF(2alpha)-IE, and PhXA34/latanoprost exerted significantly less vasodilatory effect, and little effect on capillary permeability was seen with the FP receptor agonists when studied with Evans blue. Intravenous administration of PhXA34 at a dose range of 1-100 microg/kg b.w. had no consistent effect on the regional blood flow in the eye indicating that FP receptors in the ocular blood vessels are not expressed in the rabbit, or alternatively are not functionally coupled to regulation of vascular tone. In cats topical application of PGF(2alpha)-IE had no significant effect the on the regional blood flow in cannulated eyes. No blood flow experiments were performed in intact eyes with PGF(2alpha)-IE. 17-phenyl-PGF(2alpha)-IE and latanoprost caused some vasodilation in the anterior segment. None of the analogues had any significant effect on the blood volume in the ocular tissues, but an increase in capillary permeability to albumin was seen in several tissues of the eye. However, in the eyelid, nictitating membrane and conjunctiva exposed to high concentrations of the prostaglandins no or only little leakage of albumin was detected. It appears that the intraocular microvasculature in the cat exhibits some sensitivity to FP prostanoid receptor agonists. (ABSTRACT TRUNCATED)

Effect of latanoprost on regional blood flow and capillary permeability in the monkey eye.

OBJECTIVE: To evaluate the effects of latanoprost on regional blood flow and capillary permeability in the monkey eye. METHODS: Anesthetized cynomolgus monkeys were unilaterally treated with a single dose containing 6 pg of latanoprost; or 10 microg of PhXA34 (13,14-dihydro-15R, S-17-phenyl-18,19,20-trinor-prostaglandin F2alpha [PGF2alpha]-isopropyl ester), which contains about 50% latanoprost. Regional blood flow in the eye was measured with radioactively labeled microspheres; capillary permeability was measured by determining the extravascular plasma-equivalent albumin space using 125I-albumin, 131I-albumin, and 51Cr-labeled erythrocytes. RESULTS: Latanoprost or PhXA34 had no or only a slight effect on the regional blood flow when measured 1, 2 1/2, 3, 4 1/2, and 6 hours after dose administration, with the exception of the anterior sclera, in which a moderate increase in blood flow was detected. No effect on capillary permeability to albumin was detected when studied 30 minutes to 2 1/2 hours and 5 to 6 hours after dose administration. CONCLUSION: Latanoprost, a selective prostaglandin F receptor agonist, exerted no or only slight vascular effects for up to 6 hours after dose administration in the monkey eye, with the exception of the anterior sclera, in which a moderate increase in blood flow was detected. CLINICAL RELEVANCE: Naturally occurring prostaglandins may cause marked microcirculatory changes in the eye that could be of clinical concern. Latanoprost, a selective prostaglandin F receptor agonist, seems to be devoid of such effects.

Effects of prostaglandin E2, F2alpha, and latanoprost acid on isolated ocular blood vessels in vitro.

The vascular effects of PGE2, PGF2alpha and latanoprost acid on isolated bovine long posterior ciliary arteries and episcleral veins have been investigated using a small vessel myograph. PGE2 caused vasorelaxation both in the ciliary artery and episcleral vein (EC50: 7.9x10(-9) M and 2.1x10(-8) M respectively). Blockade of thromboxane receptors with GR 32191B, a TP receptor antagonist, shifted the concentration-response curves to the left in both preparations, probably indicating a slight co-stimulation of TP receptors in these vessels. Blockade of tachykinin NK-1 receptors had no effect on the PGE2 concentration-response curve. PGF2alpha caused a concentration dependent contraction in half of the ciliary arteries examined and relaxation in the other half. In the presence of the thromboxane receptor antagonist (GR 3211B) PGF2alpha always induced relaxation of the ciliary artery (EC50:1.3x10[-5] M). At higher concentrations PGF2alpha tended to slightly constrict the episcleral veins, but in the presence of the TP receptor antagonist (GR 32191B) only relaxation was observed. Latanoprost acid contracted the ciliary artery at concentrations above 10(-6) M. This effect was completely abolished by the TP receptor antagonist (GR 32191B). In the episcleral vein latanoprost acid induced a slight relaxation but in the presence of the TP receptor antagonist (GR 32191B) no effect was observed. These results indicate that PGE2 invariably induces vasorelaxation of bovine ciliary arteries and episcleral veins, whereas both PGF2alpha and latanoprost acid at high concentrations can cause vasoconstriction probably by stimulating TP receptors. PGF2alpha causes marked relaxation of both ciliary arteries and episcleral veins in the presence of the TP blocker which seems unlikely to be mediated by FP receptors.

Mediation of prostaglandin f2 alpha-induced ocular surface hyperemia by sensory nerves in rabbits.

PURPOSE: Prostaglandin F2 alpha (PGF2 alpha) and several other prostaglandins cause surface hyperemia of the eye when applied topically. The purpose of the present study was to investigate the role of sensory nerves in prostaglandin-induced ocular hyperemia. METHODS: The ophthalmic branch of the trigeminal nerve was unilaterally electrocoagulated in rabbits using a stereotaxic technique. Two weeks later the animals received bilaterally one drop of PGF2 alpha-isopropyl ester (PGF2 alpha-IE) at a dose of 1 microgram/ eye. The blood flow to the different parts of the eye was measured with the radioactively labeled microsphere technique before, 30 and 60 min after treatment with PGF2 alpha-IE. RESULTS: In the control eyes with intact sensory innervation, PGF2 alpha-IE caused a marked increase in blood flow to the surface structures of the eye (conjunctiva, anterior sclera, eyelids and nictitating membrane) and the iris, and a moderate increase in the blood flow to the ciliary processes, but no increase in the choroidal blood flow. In the denervated eyes the increase in blood flow to the surface structures was almost completely abolished, and there was also a tendency toward less increase in blood flow in the anterior uvea. CONCLUSIONS: These results indicate that PGF2 alpha-induced ocular surface hyperemia, at least at the early stage, is mediated to a large extent by sensory nerves.

Analysis of variance of microspheres blood flow measurements in rabbits.

As part of a larger study on the interpretation of angiographically derived hemodynamic parameters, blood flow in several ocular tissues was measured using the radioactively labelled microspheres technique. As an unexpected secondary results, it was found that the microspheres data gave quantitative information on hyperaemic effects in the eye. This is the subject of the present paper. The measurements were made in 13 anaesthetized pigmented rabbits. In each animal, three blood flow measurements were performed at three different ocular perfusion pressures (60-15 mmHg). The perfusion pressures of the experimental eye were varied by changing the intra-ocular pressure. The contra-lateral eye served as a control. Labelled microspheres were used as a non-recirculating blood flow indicator, enabling the estimation of regional blood flows, in this case for the iris, ciliary body, peripheral choroid and peripapillary choroid separately. Using analysis of variance with perfusion pressure as covariate and taking into account the blood flow of the control eye, hyperaemia could be quantified in the experimental eye. Apart from a difference amongst animals, hyperaemia depended on tissue type. The amount of hyperaemia proved to be more pronounced in the anterior part of the eye, iris and ciliary body, and to decrease towards the posterior pole. With regard to the causes of this hyperaemia one could speculate about the invasive handling (anterior eye needles) topical administration of tropicamide, in combination with the general anaesthesia.

Fluorescein angiographic evaluation of the effect of latanoprost treatment on blood-retinal barrier integrity: a review of studies conducted on pseudophakic glaucoma patients and on phakic and aphakic monkeys.

Endogenous prostaglandins (PGs) have been claimed to play a role in the development of cystoid macular edema (CME). Two fluorescein angiographic studies evaluating the effect of latanoprost, a new ocular hypotensive PG analogue, on blood-retinal barrier integrity are, therefore, reviewed here. In the first study, six of eight unilaterally aphakic cynomolgus monkeys were treated bilaterally once daily for six months with 0.035% latanoprost (seven times the clinically used oculohypotensive concentration). Two of the animals served as controls. Fluorescein angiography of the fundus after one, three and six months of treatment revealed no leakage of fluorescein in any of the 16 eyes. In another study, pseudophakic eyes of 16 glaucoma patients who received twice-daily treatment with 0.006% latanoprost for four weeks were compared to eight patients treated with placebo. Biomicroscopic examination did not reveal any signs of CME and only one placebo-treated eye revealed a slight perifoveal leakage of fluorescein. These studies suggest that topically-applied latanoprost does not have a fluorescein angiographically detectable direct effect on the integrity of the blood-retinal barrier system in phakic or aphakic monkey eyes or in pseudophakic human eyes. This does not rule out the occurrence of CME in eyes more susceptible to CME, due to vitreous loss, posterior capsulotomy, or other postoperative situations. Especially in those eyes a study with latanoprost is proposed. Since, fluorescein angiography is a rather crude method of detecting abnormalities of the blood-retinal barriers, vitreous fluorometry in addition is suggested.

Mechanism of prostaglandin E2-, F2alpha- and latanoprost acid-induced relaxation of submental veins.

The mechanism of prostaglandin E2-, prostaglandin F2alpha- and latanoprost acid (13,14-dihydro-17-phenyl-18,19,20-trinor-prostaglandin F2alpha)-induced relaxation of the rabbit submental vein was studied. Prostaglandin E2 caused maximum relaxation of endothelin-1 precontracted vessels (EC50: 1.8 x 10(-8) M). Much of the relaxation could be abolished by denuding the endothelium with the nitric oxide synthase inhibitor, L-NAME (N(G)-Nitro-L-arginine methylester). CGRP-(8-37) (calcitonin gene-related peptide fragment (8-37)), a calcitonin gene-related peptide receptor antagonist, exhibited a partial blocking effect, whereas the tachykinin NK1 receptor blocker, GR 82334 ([D-Pro9[Spiro-gamma-Lactam]Leu10,Trp11]physalaemin (1-11)), markedly attenuated the response. Both prostaglandin F2alpha and the relatively selective FP receptor agonist, latanoprost acid, caused relaxation of the veins to about 50% of the precontracted state in the presence of GR 32191B ([1R-[1alpha(Z),2beta,3beta,5alpha]]-(+)-7-[5-([1,1'-b iphenyl]-4-ylmethoxy)-3-hydroxy-2-(1-piperidinyl)cyclopentyl]-4-he ptenoic acid), a thromboxane receptor antagonist (EC50: for prostaglandin F2alpha 7.9 x 10(-9) M, and for latanoprost acid 4.9 x 10(-9) M). L-NAME, as well as denuding the endothelium, completely abolished the effect. In addition, most or at least a large part of the relaxation was also blocked by CGRP-(8-37) as well as GR 82334. These results indicate that the FP receptor-mediated relaxation of veins is based on release of nitric oxide in addition to involvement of calcitonin gene-related peptide and substance P, or some other tachykinin, probably released from perivascular sensory nerves. The more pronounced relaxation induced by prostaglandin E2 could be due to vasodilator EP receptors in the smooth muscle layer of the veins.

Study of choroidal blood flow by comparison of SLO fluorescein angiography and microspheres.

Choroidal hemodynamics estimated with parameters describing the dye build-up curves obtained with video fluorescein angiography, were compared with a classical regional blood flow measurement: radioactively labelled microspheres. Video fluorescein angiograms (Rodenstock's SLO 101) and microspheres blood flow measurements were made in 13 anaesthetized pigmented rabbits. Ocular perfusion pressures were varied from 60 to 15 mmHg by changing the intraocular pressure. The angiographically derived dye build-up curves were described by means of an exponential model. One of the model parameters is the time constant tau theoretically reflecting local blood refreshment time. Labelled microspheres act as a non-recirculating blood flow indicator, enabling the estimation of regional blood flows. The relation between choroidal blood flow and perfusion pressure is nearly linear, suggesting the passive nature of choroidal vasculature. There is a significant correlation between tau and microspheres flow (R = 0.67, P < 0.01). According to the rheological model the product of blood flow and tau corresponds to the relevant blood volume. Hence, a function for the volume of the choriocapillaris as a function of perfusion pressure was established. The model parameter tau can be interpreted as the local blood refreshment time. Since the parameter tau, unlike microspheres, can be used clinically, tau may be used to retrieve information on choroidal hemodynamics in clinical practice. Information on the spatial distribution of choroidal hemodynamics is also obtained.

The prevalence of pain in a disabled population.

An estimated 1.7 million disabled adults (95% CI +/- 74,000), living in private households in Great Britain, reported pain symptoms which severely affected their daily activities. That is, the pain they experienced is so severe, unrelieved and recurring as to limit or prevent their ability to perform ordinary, everyday, activities. They represent 30% of disabled adults suggesting that pain is a substantial cause of disability and a major public health problem. The prevalence of severely limiting pain increased with age declining beyond age 55 though younger disabled adults, and women generally, reported more severe pain symptoms. Pain was associated with disabilities which commonly have a physical origin and directly affect bodily movement, compounding the problems of daily living for this population. Three-quarters of those whose lives were limited by pain said the worst bouts of pain occurred at least once a week; half took analgesic medicine every day. More than nine out of ten disabled people suffering pain had recent contact with primary and community health or hospital services.

Posttraumatic stress disorder and childhood abuse in battered women: comparisons with maritally distressed women.

In the present study, posttraumatic stress disorder (PTSD) prevalence rates were compared among 50 battered women and 37 maritally distressed women who had not experienced battering (N = 87). Participants were administered R. Spitzer and I. B. S. Williams's (1985) Structured Clinical Interview for the DSM-III-R (Diagnostic and Statistical Manual of Mental Disorders [3rd ed., rev.]) to assess PTSD status and previous traumatic experiences in addition to other standardized measures of PTSD and violence exposure. Battered women exhibited significantly higher rates of PTSD than maritally distressed women (58% vs. 18.9%). Although both groups had similar rates of previous trauma experiences, women with a PTSD-positive status (both battered women and maritally distressed women) were significantly more likely to have experienced self-reported childhood sexual abuse and a higher overall number of previous traumas than those with a PTSD-negative status. Battering exposure and childhood sexual abuse predicted 37% of the variance in overall PTSD intensity levels.

Role of nitric oxide in PGF2 alpha-induced ocular hyperemia.

The effect of nitric oxide synthase inhibition on prostaglandin F2 alpha (PGF2 alpha)-induced ocular hyperemia in the rabbit has been studied. PGF2 alpha was administered topically as the isopropyl ester (PGF2 alpha-IE) unilaterally, with the other eye serving as a control. The regional blood flow in the eye was determined with radioactively-labelled microspheres in conscious animals. Synthesis of nitric oxide (NO) was blocked by L-NMMA (200 mg kg-1 b.w., i.v.). PGF2 alpha-IE induced marked hyperemia of the surface structures of the eye (conjunctiva, eye lids, nictitating membrane, anterior sclera), as well as increased blood flow of the anterior uvea. L-NMMA blocked the hyperemia of the surface structures but not completely the increase in blood flow of the anterior uvea. PhXA41 (13,14-dihydro-17-phenyl-18,19,20-trinor-PGF2 alpha-isopropyl ester), a selective prostaglandin FP-receptor agonist, had no significant effect on the ocular blood flow. These results indicate that PGF2 alpha causes surface hyperemia of the eye by activating nitric oxide synthase, but this mechanism seems to be only partly involved in the increase in blood flow of the ciliary processes and the iris. The PGF2 alpha-induced ocular hyperemia is unlikely to be mediated by FP receptors.