MicroRNA and hyperaggregability of platelets in women with sticky platelet syndrome and pregnancy complications.

AIMS: We aimed to characterize relationship between the expression profiles of platelet miR-96, miR-126 and miR-223 and platelet function examination in patients with sticky platelet syndrome (SPS) and in healthy controls. BACKGROUND: MicroRNAs (miRNA, miR) are a group of small and non-coding RNAs involved in many mechanisms as regulators of post-transcriptional protein expression in platelets. SPS is defined as platelet hyperaggregability after administration of low doses of adenosine diphosphate and/or epinephrine. Clear genetic abnormality of this syndrome is not known yet. METHODS: We examined 45 patients with SPS and 30 healthy volunteers. For functional platelet examination we used light transmission aggregometry, and qRT-PCR was used to determine the expression of the miRNAs. RESULTS: We observed no relationship of the platelet miRNA expression with functional platelet examination in the entire cohort of patients with SPS. However, in a group of patients with SPS and pregnancy complications, we found that the expression of platelet miR-96 (p = 0.009) was up-regulated. CONCLUSION: In spite of the multiple limitations of the study, it can be considered that the increased expression of platelet miR-96 found in a group of patients with SPS and pregnancy complications could be related to the hyperaggregability in these selected patients (Tab. 2, Ref. 31).

Hyaluronic acid application vs arthroscopy in treatment of internal temporomandibular joint disorders.

AIMS: The goal of this study was to compare the treatment outcome after two different treatment modalities in cases of disc displacement of the temporomandibular joint diagnosed via magnetic resonance technique, namely surgical procedure in form of arthroscopic lysis and lavage vs. hyaluronic acid superior joint space application. MATERIALS AND METHODS: Magnetic resonance imaging was performed before and one year after treatment. Simultaneously, pre- and post-treatment visual analogue scales and maximal mouth opening distance were documented. RESULTS: In our study, out of the total of 145 patients who were initially diagnosed with magnetic resonance imaging to have internal derangements and treated with arthroscopic lysis and lavage or hyaluronic acid application, we observed progression of internal derangement in 27 cases (18.6 %), improvement in 37 cases (25.5 %) and stationary state in 81 patients (55.9 %). Both treatment methods significantly improved the followed maximal mouth opening distance and visual analogue scale, as confirmed upon the 12­month follow-up examination. Maximal mouth opening was 4.7mm for hyaluronic acid application and 12.2mm for arthroscopic lysis and lavage (p<0.005). The mean visual analogue scale values decreased from 6.2 to 2.1 for hyaluronic acid application and from 6.9 to 1.2 for arthroscopic lysis and lavage (p<0.005). CONCLUSION: Our study shows that both arthroscopic lysis and lavage and hyaluronic acid injections are effective and safe in the treatment of disc displacement in the temporomandibular joint (Tab. 3, Ref. 30).

Isolated orbital mucoceles in the absence of obstructive sinus disease.

Orbital surgeons are quite familiar with the diagnosis and management of paranasal sinus mucoceles due their frequent involvement of the orbit. These benign masses form and expand following sinus outflow obstruction secondary to various causes including trauma, inflammation and malignancy, amongst others. The authors present two cases of isolated orbital mucoceles without associated sinus outflow obstruction. There were notably no connections between the paranasal sinuses and the lesions. The mucoceles were diagnosed following orbitotomies and excisional biopsies with confirmatory histopathology. These rare orbital lesions should be considered when evaluating cystic orbital lesions, and the orbital surgeon should be familiar with the proposed pathophysiology and treatment recommendations.

Activity of coagulation factor XI in patients with spontaneous miscarriage: the presence of risk alleles.

The aim of this study was to compare the activity of coagulation factor XI (FXI) between patients with spontaneous miscarriage versus control group with no history of miscarriage and thrombosis, and then we evaluated the occurrence of risk alleles in the relation to miscarriage. FXI activity was determined using a coagulometer (Sysmex, CA 1500, Japan). Single nucleotide polymorphisms (SNPs) of F11 and CYP4V2 genes were evaluated. We examined 55 patients versus 31 control subjects. We found significantly higher activity of FXI (p = 0.04) in patients versus control subjects. The occurrence of two SNPs (rs2289252 and rs2036914) of the F11 gene and SNP (rs13146272) of CYP4V2 gene was not significantly different between both groups. Increased activity of FXI may be a potential risk factor for miscarriage. High activity of FXI diagnosed in women with history of miscarriage is not probably caused by the presence of studied SNPs.

Reflecting Before, During, and After the Heat of the Moment: A Review of Four Approaches for Supporting Health Staff to Manage Stressful Events.

Being a healthcare professional in both paediatric and adult hospitals will mean being exposed to human tragedies and stressful events involving conflict, misunderstanding, and moral distress. There are a number of different structured approaches to reflection and discussion designed to support healthcare professionals process and make sense of their feelings and experiences and to mitigate against direct and vicarious trauma. In this paper, we draw from our experience in a large children's hospital and more broadly from the literature to identify and analyse four established approaches to facilitated reflective discussions. Each of the four approaches seeks to acknowledge the stressful nature of health professional work and to support clinicians from all healthcare professions to develop sustainable skills so they continue to grow and thrive as health professionals. Each approach also has the potential to open up feelings of uncertainty, frustration, sorrow, anguish, and moral distress for participants. We argue, therefore, that in order to avoid unintentionally causing harm, a facilitator should have specific skills required to safely lead the discussion and be able to explain the nature, scope, safe application, and limits of each approach. With reference to a hypothetical but realistic clinical case scenario, we discuss the application and key features of each approach, including the goals, underpinning theory, and methods of facilitation.

Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis.

Niemann-Pick type C (NP-C) disease, a fatal neurovisceral disorder, is characterized by lysosomal accumulation of low density lipoprotein (LDL)-derived cholesterol. By positional cloning methods, a gene (NPC1) with insertion, deletion, and missense mutations has been identified in NP-C patients. Transfection of NP-C fibroblasts with wild-type NPC1 cDNA resulted in correction of their excessive lysosomal storage of LDL cholesterol, thereby defining the critical role of NPC1 in regulation of intracellular cholesterol trafficking. The 1278-amino acid NPC1 protein has sequence similarity to the morphogen receptor PATCHED and the putative sterol-sensing regions of SREBP cleavage-activating protein (SCAP) and 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase.

Mild antithrombin deficiency and risk of recurrent venous thromboembolism: results from the MEGA follow-up study.

Essentials Mild antithrombin deficiency may increase the risk of recurrent venous thromboembolism (VTE). In a cohort study, we stratified patients with VTE to various cut-off antithrombin levels. A 1.6-3.7-fold increased risk of recurrent VTE was observed in the lowest antithrombin categories. Mild antithrombin deficiency (activity < 5th percentile of normal) increases recurrent VTE risk. SUMMARY: Background Mild antithrombin deficiency (previously defined as antithrombin activity below 70% or 80%) has been associated with a 2.4-3.5-fold increased risk of recurrent venous thromboembolism (VTE). This finding may have implications for duration of antithrombotic therapy in VTE patients with mild antithrombin deficiency. Objectives To externally validate whether mild antithrombin deficiency is a risk factor for recurrent VTE. Methods In a population-based cohort study, patients with a first VTE (n = 2357) were stratified according to percentile cut-off antithrombin levels (< 5th [< 87%], 5-10th [87-92%], > 10th percentile [> 92%]) and functional antithrombin levels (< 70%, 70-80%, > 80%). Results During a median follow-up of 7.4 years, 361 recurrent events occurred (incidence rate, 2.5/100 patient-years). We observed an increased risk of recurrent VTE in the lowest antithrombin activity category (< 5th percentile; < 87%) as compared with antithrombin activity that was > 10th percentile (> 92%), with an adjusted hazard ratio (HR) of 1.5 (95%CI, 1.0-2.3). When analyses were stratified to antithrombin cut-off criteria of< 70% vs. patients with antithrombin activity > 80%, the adjusted HR for venous recurrence was 3.7 (95% CI, 1.4-9.9). Mild antithrombin deficiency was able to predict recurrent VTE over at least 8 years of follow-up and the association remained present when the population was stratified to the presence or absence of thrombosis risk factors. Restriction analyses, where patients who used anticoagulation at time of blood draw and those who reported drinking ≥ 5 glasses alcohol daily were excluded, did not materially affect these outcomes. Conclusion This study confirms that mild antithrombin deficiency is a risk factor for recurrent VTE.

Type C Niemann-Pick disease: dimethyl sulfoxide moderates abnormal LDL-cholesterol processing in mutant fibroblasts.

Biochemical and cytochemical studies have revealed that abnormal processing of low-density-lipoprotein (LDL) cholesterol can be reversed in mutant Niemann-Pick C (NP-C) fibroblasts when 2% dimethyl sulfoxide (DMSO) is added to the culture medium. Both the excessive lysosomal accumulation of LDL cholesterol and the delayed induction of cellular homeostatic responses associated with the uptake of LDL by the mutant cells were substantially reversed by DMSO. DMSO appears to accelerate the intracellular mobilization of LDL-derived cholesterol through effects that may reflect enhanced membrane permeability or cholesterol solubilization.

Carbamazepine in Fabry's disease: effective analgesia with dose-dependent exacerbation of autonomic dysfunction.

Seven patients with Fabry's disease and severe pain received carbamazepine (CMZ). Five of 7 patients had moderate to complete relief based upon self-assessment of pain levels. Preexisting autonomic dysfunction was exacerbated by CMZ in 2. Complications encountered were ileus, urinary retention, and gastrointestinal disturbance. Although CMZ was useful in treatment of pain, caution should be employed in this disease.

Clinical spectrum of Niemann-Pick disease type C.

Analysis of the neurologic symptomatology in 22 patients with Niemann-Pick disease type C revealed 3 phenotypes: (1) an early-onset, rapidly progressive form associated with severe hepatic dysfunction and psychomotor delay during infancy and later with supranuclear vertical gaze paresis, ataxia, marked spasticity, and dementia; (2) a delayed-onset, slowly progressive form heralded by the appearance, usually in early childhood, of mild intellectual impairment, supranuclear vertical gaze paresis, and ataxia, and later associated with dementia and, variably, seizures and extrapyramidal deficits; (3) a late-onset slowly progressive form distinguished from the 2nd pattern by later age of onset (adolescence or adulthood) and a much slower rate of progression. The existence of the 1st and 2nd phenotypes within the same sibship suggests that they are variant expressions of the same clinicopathologic disorder. Niemann-Pick disease type C should be considered not only in infants and children who present with organomegaly and a progressive neurodegenerative course, but also in adolescents and adults who have insidiously progressive neurologic dysfunction and only slight organomegaly. Associated with the disease is a marked deficiency in the ability of cultured fibroblasts to esterify exogenously supplied cholesterol. Assay of this deficiency is particularly useful for confirming the diagnosis in patients with atypical presentation.

Gender-related differences exist in cortical [3H]nisoxetine binding and are not affected by prenatal morphine exposure.

The present study was designed to test the hypothesis that prenatal morphine, which differentially affects hypothalamic norepinephrine content and turnover in male and female rats, has sexually dimorphic effects on the density of hypothalamic norepinephrine uptake sites in adult offspring. The binding characteristics of norepinephrine transporters were examined in the hypothalamus, preoptic area and frontal cortex of adult male and female rats exposed to morphine (5-10 mg/kg, twice daily) or saline on gestation days 11-18. There was a gender-related difference in the density of norepinephrine uptake sites measured by [3H]nisoxetine binding in the frontal cortex of saline controls, with control males having significantly fewer binding sites than control females. Prenatal morphine administration did not reverse or eliminate this difference. Additionally, prenatal morphine exposure had no effects on either the binding capacity or the affinity of norepinephrine uptake sites in the hypothalamus, preoptic area or frontal cortex of adult progeny. Thus, alterations in hypothalamic norepinephrine content and turnover following prenatal morphine exposure are not reflected in alterations in norepinephrine uptake sites. However, recent immunocytochemical work in our laboratory correlated reductions in hypothalamic norepinephrine content and turnover rate with reductions in tyrosine hydroxylase and dopamine-beta-hydroxylase fiber density in the hypothalamus of morphine-exposed female rats. Therefore, the present results may suggest that compensatory mechanisms increase the density of norepinephrine uptake sites in hypothalamic terminal fields of morphine-exposed females.

Layer-by-layer desquamation of corneal epithelium and maturation of tear-facing membranes.

A method to devitalize single layers of apically exposed rabbit corneal epithelial cells through the use of digitonin is described. Devitalized cells exfoliate spontaneously as loosely cohesive, trypan-blue-stained layers, exposing underlying viable cells. Repeated application of this devitalization-exfoliation methodology results in the gradual elimination of each of the epithelial cells. The generation of corneal surfaces composed of the tear-facing membranes of all intraepithelial cell types--subsurface, wing, and basal--is thus attainable. Exposed surfaces were studied with respect to microanatomy, the binding of lectins, and the adherence of Pseudomonas aeruginosa. Microprojections (microvilli or microplicae) were absent in the basal cells but were present in all suprabasal layers, and increased gradually in density as cells approached the surface position. Wheat germ agglutinin and concanavalin A were found to bind to the tear-facing membranes of all suprabasal cell layers. The tear-facing membrane of the basal cells, in contrast, was not labeled. Within each labeled layer, the magnitude of lectin binding differed markedly from cell to cell; lectin binding decreased as the cellular area exposed to the tear surface increased. Pseudomonas were found exclusively at microprojection-free cellular areas, suggesting that inhibition of attachment is linked to the ontogeny of these microprojections.

Reduced trabecular meshwork height in juvenile primary open-angle glaucoma.

OBJECTIVE: To compare trabecular meshwork height in a series of patients with juvenile primary open-angle glaucoma (JPOAG) with that in normal control patients. METHODS: Ultrasound biomicroscopy and A-scan biometry were performed on 16 eyes with JPOAG and 24 normal eyes. A radial, perpendicular image in the horizontal temporal meridian detailing the line of Schwalbe, scleral spur, and angle anatomy was obtained for each eye by a single examiner. Trabecular meshwork height was defined as the distance from the scleral spur to the Schwalbe line. RESULTS: Mean patient age (P = .85, t test), refractive error (P = .68), sex distribution (P = .26, Fisher exact test) and axial length (P = .39) were similar between the groups. Mean +/- SE trabecular meshwork heights were 0.36 +/- 0.03 mm (range, 0.19-0.53 mm) for JPOAG and 0.58 +/- 0.02 mm (range, 0.40-0.80 mm) for controls (P < .001). Eyes with greater axial length tended to have larger trabecular meshworks in both groups (P = .012, multivariate regression). A trabecular meshwork height-axial length ratio of 0.021 or less was associated with a significantly increased risk for JPOAG being present (odds ratio, 57; 95% confidence interval, 6.0-541). CONCLUSIONS: The trabecular meshwork is smaller in eyes with JPOAG compared with that in normal eyes. This finding suggests a structural abnormality that may underlie the reduced outflow.

ECLS in pertussis: does it have a role?

OBJECTIVES: To investigate the value of extracorporeal circulatory life support (ECLS) in paediatric patients with severe Bordetella pertussis infection. DESIGN: Single case report and a review of the ECLS database. SETTING: Tertiary referral hospital paediatric intensive care unit. PATIENTS AND PARTICIPANTS: A single case report of an infant with B. pertussis infection is described. Despite receiving ECLS, this infant died from overwhelming cardiac and cerebral insults. Outcome for children receiving ECLS registered on the Extracorporeal Life Support Organization database is reviewed. MEASUREMENTS AND RESULTS: The mortality of infants receiving ECLS for B. pertussis infection is high, with only 5 survivors reported among 22 registered cases. The majority of nonsurvivors had evidence of circulatory collapse in addition to severe respiratory failure, and these patients commonly died of hypoxic-ischaemic cerebral insult. These data suggest the existence of a subgroup of patients with respiratory failure only, who may benefit from ECLS, and a larger subgroup who suffer ischaemic cardiac and cerebral insults which are unlikely to be improved by ECLS. CONCLUSIONS: The value of ECLS in patients with B. pertussis infection who present with major cardiac dysfunction is questionable. Such patients almost invariably have a poor outcome despite maximal therapy.

Increase in iris-lens contact after laser iridotomy for pupillary block angle closure.

PURPOSE: To quantitate changes in anterior ocular segment anatomy after laser iridotomy for pupillary block angle closure. METHODS: We prospectively performed ultrasound biomicroscopy and A-scan biometry in 13 eyes of 13 consecutive untreated patients with relative pupillary block and appositional angle closure, without peripheral anterior synechiae on indentation gonioscopy. A radial, perpendicular image in the horizontal temporal meridian was obtained with ultrasound biomicroscopy before and one week after laser iridotomy in each eye. RESULTS: Mean age of the 13 patients was 69.3 +/- 1.8 (S.E.) years, mean refractive error was +1.37 +/- 0.39 diopters, and mean axial length was 22.54 +/- 0.20 mm. In 13 eyes, before and after laser iridotomy measurements of angle-opening distance (0.11 +/- 0.02 vs. 0.18 +/- 0.02 mm) (P = .0004; paired t test), angle aperture (8.3 +/- 1.3 vs 18.6 +/- 2.8 degrees) (P = .0003) and iris-lens contact distance (0.58 +/- 0.06 vs 1.18 +/- 0.14 mm) (P = .0003) were greater postoperatively, but anterior chamber depth was unchanged (P = .7). CONCLUSIONS: Flattening of the iris after laser iridotomy for pupillary block causes an increase in iris-lens contact. The change in angle configuration after iridotomy results more from an alteration in aqueous pressure gradients across the iris rather than from posterior lens movement.

Sleep structure and nocturnal disordered breathing in familial dysautonomia.

In 13 patients with familial dysautonomia sleep recordings were obtained to investigate the possibility that autonomic nervous system dysfunction plays a role in disordered breathing during sleep. Sleep structure in some of our patients was abnormal, showing decreased amount of REM sleep and increased REM latencies. All patients showed breathing disorders in sleep. The average number of apneic spells was 73.4 per night; 77% of the patients had more than 50 apneic spells per night. Abnormal breathing patterns were not uniform and were independent of patient's primary complaints. Typically, even severe respiratory irregularities were not associated with the usual cardiac response, indicating that our patients had "cardiac dysautonomia".

Determination of tetracycline antibiotics in animal tissues of food-producing animals by high-performance liquid chromatography using solid-phase extraction.

A high-performance liquid chromatographic (HPLC) method was developed for the determination of oxytetracycline (OTC), tetracycline (TC) and chlortetracycline (CTC) residues in bovine and porcine muscles. The method involved the homogenization of the sample in EDTA-McIlvaine buffer with added n-hexane and dichloromethane, centrifugation, precipitation of the supernatant using trichloroacetic acid and filtration. Preconcentration on Separcol SI C18 cartridges improved the clean-up and the recovery of tetracyclines that were separated by HPLC using the optimized mobile phase of 0.01 M oxalic acid-acetonitrile-methanol (45:35:20) on a Spherisorb ODS 2 column (250 x 4 mm I.D.). UV detection at 360 nm was applied with a detection limit of about 50 ng/g. The diode-array spectra confirmed the applicability of this method to the study of tetracycline residues in carcasses.

Prenatal morphine exposure differentially alters learning and memory in male and female rats.

The present study tested the hypothesis that exposure to morphine on prenatal days 11-18 impairs performance on tasks requiring learning and memory in adult male and female rats. In Experiment 1, a symmetrical maze was used to measure learning. In Experiment 2, an eight-arm radial maze was used to assess working spatial memory. The results of Experiment 1 demonstrated that prenatal morphine exposure reduces the time needed to complete the trials, but does not affect the accuracy of performance in male rats. In contrast, prenatal drug treatment had no effects on either the time or the accuracy of performance in female rats. In Experiment 2, both male and female morphine-exposed rats needed more time to complete regular trials (no delay) than controls; however, morphine exposure in male rats did not affect performance on tasks requiring memory, measured with delay trials, but hindered it in ovariohysterectomized (OVX) female rats. In OVX females, replacement injections of both estrogen and progesterone restored the impairment of performance on delay trials produced by prenatal morphine exposure. Thus, the present study demonstrates that prenatal morphine exposure differentially alters performance of adult male and female rats on tasks requiring learning and spatial memory.

Inhaled nitric oxide for acute hypoxemic respiratory failure in children and adults.

BACKGROUND: Acute hypoxemic respiratory failure affects all age groups and may result from a number of systemic diseases. It continues to be associated with high mortality and morbidity. Initial studies examining the effect of inhaled nitric oxide in respiratory failure demonstrated transient improvement in oxygenation but did not examine mortality or other significant morbidity outcomes. OBJECTIVES: To systematically examine randomized controlled trials addressing the effect of inhaled nitric oxide, compared with placebo inhaled gas, on mortality and morbidity in patients with acute hypoxemic respiratory failure. SEARCH STRATEGY: Randomized controlled trials were identified from electronic databases: The Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 2, 2002;MEDLINE (January 1966-August 2002); EMBASE (1980-March 2001); CINAHL (1982-July 2002), as well as from bibliographies of retrieved articles. Relevant journals and conference proceedings were hand searched and authors published in this field were contacted for knowledge of unpublished ongoing trials. SELECTION CRITERIA: Randomized controlled trials comparing inhaled nitric oxide with maximal conventional therapy and inhaled placebo, in either children or adults with acute hypoxemic respiratory failure. DATA COLLECTION AND ANALYSIS: Qualitative assessment of each trial was made and analyses performed according to statistical methods in Review Manager MetaView 4.1. A sub-group analysis was performed to assess the impact of inhaled nitric oxide at varied doses. MAIN RESULTS: Five randomized controlled trials were evaluated, assessing 535 patients with acute hypoxemic respiratory failure (Age range not provided). Lack of data prevented assessment of all outcomes. There was no significant difference of nitric oxide on mortality in trials without cross-over (RR 0.98, 95%CI 0.66,1.44). Published evidence from one study demonstrated nitric oxide to transiently improve oxygenation in the first 72 hours of treatment. Limited data demonstrated no significant difference in ventilator-free days between treatment and placebo groups, and no specific dose of nitric oxide was significantly advantageous over another. Other clinical indicators of effectiveness, such as duration of hospital and intensive care stay, were inconsistently reported. There were no significant complications directly attributable to this treatment. REVIEWER'S CONCLUSIONS: Nitric oxide did not demonstrate any statistically significant effect on mortality and transiently improved oxygenation in patients with hypoxemic respiratory failure. Lack of data prevented assessment of other clinically relevant end points. If further trials comparing inhaled nitric oxide with an inhaled placebo are to proceed, they should be stratified for primary disease, assess the impact of other combined treatment modalities for respiratory failure, and must specifically evaluate clinically relevant outcomes, before any benefit of inhaled nitric oxide for respiratory failure can be excluded.

Inhaled nitric oxide for acute hypoxemic respiratory failure in children and adults.

OBJECTIVES: To determine the effect of iNO, compared with inhaled placebo, on outcome in AHRF in children and/or adults. SEARCH STRATEGY: Randomised controlled trials (RCT's) were identified from electronic databases; MEDLINE, EMBASE, the Cochrane Library, and CINAHL, as well as from bibliographies of retrieved articles. Relevant journals and conference proceedings were hand searched and authors published in this field were contacted for knowledge of unpublished ongoing trials. SELECTION CRITERIA: RCT's comparing iNO with maximal conventional therapy and inhaled placebo, for AHRF in either children or adults. DATA COLLECTION AND ANALYSIS: Data were extracted and the analyses performed independently by two reviewers. All 5 authors were contacted for missing data. Qualitative assessment of each trial was made according to methodology described by Schulz (Schulz 1995), and analyses according to statistical methods in Review Manager MetaView 3.1. The fixed effect model was applied. Where possible, sub-group analyses were performed to assess the impact of iNO in varied doses. MAIN RESULTS: Five RCT's were evaluated, assessing 535 patients with AHRF. Inhaled nitric oxide made no impact on mortality in trials without cross-over (RR 0.98, 95%CI 0.66, 1.44), or with cross-over of treatment failures to open-label iNO (RR 1.22, 95%CI 0.65, 2.29). Published evidence from one study demonstrated that iNO resulted in a transient improvement in oxygenation in the first 24 hours of treatment: the oxygenation index (OI) showed a mean difference of -3 [95% CI -5.354, -0.646], and PaO2/FiO2 ratio, a mean difference of 35 [95% CI 20.236, 49.764]. Limited data demonstrated no difference in ventilator-free days between treatment and placebo groups, and no specific dose of iNO was significantly advantageous over another. Other clinical indicators of effectiveness, such as duration of hospital and intensive care stay, were inconsistently reported. There were no complications reported to be directly attributable to this treatment. REVIEWER'S CONCLUSIONS: From the data provided to date, iNO had no effect on mortality and only transiently improved oxygenation in AHRF in children and/or adults. There was a lack of data to assess other end points. The long term adverse effects of this drug are not known, as no long term follow-up of trial participants has been reported. If further trials comparing iNO with an inhaled placebo are to proceed, they should be stratified for primary disease and must specifically evaluate clinically relevant outcomes, before any benefit of iNO in AHRF can be excluded.