A novel nonsense variant in REEP6 is involved in a sporadic rod-cone dystrophy case.

Rod-cone dystrophy (RCD), also called retinitis pigmentosa, is the most common form of progressive inherited retinal disorders secondary to photoreceptor degeneration. It is a genetically heterogeneous disease characterized by night blindness, followed by visual field constriction and, in most severe cases, total blindness. The aim of our study was to identify the underlying gene defect leading to severe RCD in a 60-year-old woman. The patient's DNA was investigated by targeted next generation sequencing followed by whole exome sequencing. A novel nonsense variant, c.267G>A p.(Trp89*), was identified at a homozygous state in the proband in REEP6 gene, recently reported mutated in 7 unrelated families with RCD. Further functional studies will help to understand the physiopathology associated with REEP6 mutations that may be linked to a protein trafficking defect.

ARL2BP mutations account for 0.1% of autosomal recessive rod-cone dystrophies with the report of a novel splice variant.

We report a novel ARL2BP splice site mutation after whole-exome sequencing (WES) applied to a Moroccan family including two sisters affected with autosomal recessive rod-cone dystrophy (arRCD). Subsequent analysis of 844 index cases did not reveal further pathogenic chances in ARL2BP indicating that mutations in ARL2B are a rare cause of arRCD (about 0.1%) in a large cohort of French patients.

Next-generation sequencing confirms the implication of SLC24A1 in autosomal-recessive congenital stationary night blindness.

Congenital stationary night blindness (CSNB) is a clinically and genetically heterogeneous retinal disorder which represents rod photoreceptor dysfunction or signal transmission defect from photoreceptors to adjacent bipolar cells. Patients displaying photoreceptor dysfunction show a Riggs-electroretinogram (ERG) while patients with a signal transmission defect show a Schubert-Bornschein ERG. The latter group is subdivided into complete or incomplete (ic) CSNB. Only few CSNB cases with Riggs-ERG and only one family with a disease-causing variant in SLC24A1 have been reported. Whole-exome sequencing (WES) in a previously diagnosed icCSNB patient identified a homozygous nonsense variant in SLC24A1. Indeed, re-investigation of the clinical data corrected the diagnosis to Riggs-form of CSNB. Targeted next-generation sequencing (NGS) identified compound heterozygous deletions and a homozygous missense variant in SLC24A1 in two other patients, respectively. ERG abnormalities varied in these three cases but all patients had normal visual acuity, no myopia or nystagmus, unlike in Schubert-Bornschein-type of CSNB. This confirms that SLC24A1 defects lead to CSNB and outlines phenotype/genotype correlations in CSNB subtypes. In case of unclear clinical characteristics, NGS techniques are helpful to clarify the diagnosis.

Management of Indigenous patients presenting with non ST-segment elevation acute coronary syndrome in South Australia: a retrospective cohort study.

AIM: Using Australian guidelines for management of acute coronary syndromes, we assessed the probability of an Indigenous patient receiving interventional and therapeutic care after presenting in two metropolitan hospitals. METHODS: A retrospective case note review of patients admitted through two Adelaide public tertiary hospital emergency departments from December 2007 to December 2009. The study cohort was 488 patients with high-risk clinical features without ST-segment elevation. RESULTS: Indigenous patients were significantly younger, present later in the disease process and have a higher burden of cardiovascular risk factors when compared with non-Indigenous patients. Indigenous patients were 54% more likely to receive angiography (Risk ratios (RR) = 1.54; 95% CI 1.31; 1.81) than non-Indigenous patients, however, this difference disappeared after adjustment for age, sex and propensity score. Indigenous patients were 20% more likely to receive the recommended medications (RR = 1.19, 95% CI 1.01; 1.40) compared with non-Indigenous patients. Patients over 65 years were 53% less likely to receive an angiogram (RR = 0.47, 95% CI 0.38; 0.56) and were 35% less likely to receive the recommended medications (RR = 0.65, 95% CI 0.54; 0.78) than a patient at the ages of 18-49. Women were almost 20% less likely to receive an angiogram (RR = 0.81, 95% CI 0.66; 0.99) and 20% less likely to receive the recommended medications (RR = 0.80, 95% CI 0.71; 0.91) when compared with men. The likelihood of receiving medications on discharge was significantly influenced by age, gender, ethnicity, comorbid burden and revascularisation. CONCLUSIONS: The younger age and significantly higher-risk profile of Indigenous adults presenting to SA hospitals with acute coronary syndromes appears to lead to different management decisions, which may well be led by patient factors. Many of these risk conditions can be better managed in the primary care setting.

Impact of age, gender and indigenous status on access to diagnostic coronary angiography for patients presenting with non-ST segment elevation acute coronary syndromes in Australia.

Using Australian guidelines for management of acute coronary syndromes, we investigated the proportion of high-risk patients enrolled in the Acute Coronary Syndromes Prospective Audit registry who received a coronary angiogram. A prospective nationwide multicentre registry involving 39 Australian hospitals was used. The study cohort were patients with high-risk clinical features without ST segment elevation (n = 1948) admitted from emergency departments between 1 November 2005 and 31 July 2007. Eighty nine per cent of patients with ST segment elevation myocardial infarction and only 53% of eligible patients with high-risk acute coronary syndromes with no ST elevation received a diagnostic angiogram. Increasing age was associated with lower rates of angiography; a high-risk patient at the age of ≥ 70 years was 19% less likely to receive an angiogram than one at the age of <70 years (risk ratio (RR) = 0.81 95% confidence interval (CI) 0.76, 0.76). Women were 26% less likely than men to receive an angiogram (RR = 0.74; 95% CI = 0.65, 0.83). The adjusted RR from the multivariate analysis suggests that a patient at the age of ≥ 70 years was 35% less likely to receive an angiogram than one at the age of <70 years (RR = 0.65, 95% CI = 0.60, 0.73), and that women were 13% less likely than men to receive an angiogram (RR = 0.87, 95% CI = 0.80, 0.96). Indigenous patients were as likely to access angiography as eligible non-indigenous patients (RR = 1.03, 95% CI 0.85, 1.25). There is underinvestigation of high-risk patients without ST segment elevation in Australian hospitals, particularly for women and older patients. Indigenous patients are younger and have poorer risk profiles, and represent a group that would benefit from greater investment in prevention strategies.

The complete form of X-linked congenital stationary night blindness is caused by mutations in a gene encoding a leucine-rich repeat protein.

X-linked congenital stationary night blindness (XLCSNB) is characterized by impaired scotopic vision with associated ocular symptoms such as myopia, hyperopia, nystagmus and reduced visual acuity. Genetic mapping in families with XLCSNB revealed two different loci on the proximal short arm of the X chromosome. These two genetic subtypes can be distinguished on the basis of electroretinogram (ERG) responses and psychophysical testing as a complete (CSNB1) and an incomplete (CSNB2) form. The CSNB1 locus has been mapped to a 5-cM linkage interval in Xp11.4 (refs 2,5-7). Here we construct and analyse a contig between the markers DXS993 and DXS228, leading to the identification of a new gene mutated in CSNB1 patients. It is partially deleted in 3 families and mutation analysis in a further 21 families detected another 13 different mutations. This gene, designated NYX, encodes a protein of 481 amino acids (nyctalopin) and is expressed at low levels in tissues including retina, brain, testis and muscle. The predicted polypeptide is a glycosylphosphatidylinositol (GPI)-anchored extracellular protein with 11 typical and 2 cysteine-rich, leucine-rich repeats (LRRs). This motif is important for protein-protein interactions and members of the LRR superfamily are involved in cell adhesion and axon guidance. Future functional analysis of nyctalopin might therefore give insight into the fine-regulation of cell-cell contacts in the retina.

[CRISPR/Cas9: From research to therapeutic application]. / CRISPR/Cas9 : de la recherche à l'application thérapeutique.

For several decades, genome engineering has raised interest among many researchers and physicians in the study of genetic disorders and their treatments. Compared to its predecessors, zinc-finger nucleases (ZFN) and transcription activator-like effectors (TALEN), clustered regularly interspaced short palindromic repeats (CRISPR/Cas9) is currently the most efficient molecular tool for genome editing. This system, originally identified as a bacterial adaptive immune system, is capable of cutting and modifying any gene of a large number of living organisms. Numerous trials using this technology are being developed to provide effective treatment for several diseases, such as cancer, cardiovascular and ophthalmic disorders. In research, this technology is increasingly used for genetic disease modelling, providing meaningful models of relevant studies as well as a better understanding of underlying pathological mechanisms. Many molecular tools are now available to put this technique into practice in laboratories, and despite the technical and ethical issues raised by manipulation of the genome, CRIPSR/Cas9 offers a new breath of hope for therapeutic research around the world.

Aetiology of resuscitated out-of-hospital cardiac arrest treated at hospital.

INTRODUCTION: Precipitating aetiology of out-of-hospital cardiac arrest (OHCA), as confirmed by diagnostic testing or autopsy, provides important insights into burden of OHCA and has potential implications for improving OHCA survivorship. This study aimed to describe the aetiology of non-traumatic resuscitated OHCAs treated at hospital within a local health network according to available documentation, and to investigate differences in outcome between aetiologies. METHODS: Observational retrospective cohort study of consecutive OHCA treated at hospital within a local health network between 2011-2016. Cases without sustained ROSC (≥20 minutes), unverified cardiac arrest, and retrievals to external acute care facilities were excluded. A single aetiology was determined from the hospital medical record and available autopsy results. Survival to hospital discharge was compared between adjudicated aetiologies. RESULTS: In the 314 included cases, distribution of precipitating aetiology was 53% cardiac, 18% respiratory, 3% neurological, 6% toxicological, 9% other, and 11% unknown. A presumed cardiac pre-hospital diagnosis was assigned in 235 (84%) cases, 20% of which were incorrect after exclusion of unknown cases. Rates of survival to hospital discharge varied significantly across aetiologies: cardiac 64%, respiratory 21%, neurological 0%, toxicological 58%, other 32% (p < 0.001). A two-fold difference in survival was observed between cardiac and non-cardiac aetiologies (64% versus 29%, excluding unknown, p < 0.001). CONCLUSIONS: Non-cardiac aetiologies represented a substantial burden of resuscitated OHCA treated at hospital within a local health network and were associated with poor outcome. The results confirmed that true aetiology was not evident on initial examination in 1 in 5 cases with a pre-hospital cardiac diagnosis.

Congenital stationary night blindness in a patient with mild learning disability due to a compound heterozygous microdeletion of 15q13 and a missense mutation in TRPM1.

The complete form of congenital stationary night blindness (cCSNB) represents a non-progressive retinal disorder characterized by night vision problems and often congenital nystagmus, reduced vision, high myopia, strabismus and normal fundus appearance. Clinically this form of CSNB can be diagnosed by full-field electroretinogram. The mode of inheritance can be X-linked and autosomal recessive with mutations in genes coding for proteins mainly present at the dendritic tips of ON-bipolar cells. Mutations in NYX, GRM6, GPR179, LRIT3 and TRPM1 lead to this condition. The latter gene defect represents the major form underlying cCSNBC. It codes for the melastatin-related transient receptor 1 expressed in the inner nuclear layer of the retina, with the protein localized in ON-bipolar cells. To date, various homozygous or compound heterozygous mutations in TRPM1 have been reported. Small chromosomal rearrangements are frequent cause of mental retardation. In rare cases deletions can overlap with a mutation on the remaining chromosome and lead to a recessive disorder. Here, we describe a patient with mild neurological deficiencies and cCSNB caused by a microdeletion on 15q32 overlapping with a TRPM1 variant.

First identification of ITM2B interactome in the human retina.

Integral Membrane Protein 2 B (ITM2B) is a type II ubiquitous transmembrane protein which role remains unclear. ITM2B mutations have been associated with different disorders: mutations leading to longer mutant proteins have been reported in two distinct Alzheimer-like autosomal dominant disorders with early-onset progressive dementia and cerebellar ataxia. Both disorders share neurological features including severe cerebral amyloid angiopathy, non-neuritic plaques, and fibrillary tangles as in Alzheimer disease. Our group reported a missense mutation in ITM2B, in an unusual retinal dystrophy with no dementia. This finding suggests a specific role of ITM2B in the retina. As the identification of retinal-specific ITM2B partners could bring new insights into the cellular functions of ITM2B, we performed quantitative proteomics of ITM2B interactome of the human retina. Overall, 457 ITM2B partners were identified with 8 of them involved in visual transduction. In addition, bulk Gene Ontology analyses showed that many ITM2B partners are involved in several other biological functions, such as microtubule organization, protein translation and interestingly, mitochondrial homeostasis. These data represent the first report of the ITM2B interactome in the human retina and may serve as a valuable inventory of new potential ITM2B partners for future investigations of ITM2B physiological functions and dysfunctions.

Unperceived treatment gaps in acute coronary syndromes.

BACKGROUND: Despite a strong evidence-base for several therapies recommended in the management of acute coronary syndromes (ACS), many patients do not receive these therapies. The barriers preventing translation of evidence into practice are incompletely understood. The aim of this study was to survey clinicians regarding barriers to implementing recommendations of recently published national clinical guidelines and to determine the extent to which these impact clinical practice. METHODS: A survey of clinicians at hospitals included in Australian Collaborative Acute Coronary Syndromes Prospective Audit (ACACIA, n = 3402, PML0051) was conducted, measuring self-stated knowledge, beliefs and guideline-concordant behaviours in relation to their care of ACS patients. Correlations between individual respondents' self-estimated rates and clinician's institutional rates of guideline-concordant behaviours were performed. RESULTS: Most respondents (n = 50/86, 58%) were aware of current guidelines and their scope, achieving 7/10 (Interquartile Range (IQR) = 2) median score on knowledge questions. Belief in benefits and agreement with guideline-recommended therapy was high. However, none of these factors correlated with increased use of guideline therapies. Apart from clopidogrel (r(s) = 0.28, p < 0.01) and early interventional therapy for high-risk non-ST elevation myocardial infarction (r(s) = 0.31, p < 0.01), there were no significant correlations between individual clinicians' self-estimated rates of guideline-concordant practice and rates recorded in ACACIA data for their respective institution. CONCLUSION: Beliefs about practice do not match actual practice. False beliefs regarding levels of evidence-based practice may contribute to inadequate implementation of evidence-based guidelines. Strategies such as continuous real-time audit and feedback of information for the delivery of care may help clinicians understand their levels of practice better and improve care.

Novel mutations in the folliculin gene associated with spontaneous pneumothorax.

Spontaneous pneumothorax is mostly sporadic but may also occur in families with genetic disorders, such as Birt-Hogg-Dubé syndrome, which is caused by mutations in the folliculin (FLCN) gene. The aim of the present study was to investigate the presence and type of mutation in a Swiss pedigree and in a sporadic case. Clinical examination, lung function tests and high-resolution computed tomography were performed. All coding exons and flanking intronic regions of FLCN were amplified by PCR and directly sequenced. The amount of FLCN transcripts was determined by quantitative real-time RT-PCR. Two novel mutations in FLCN were identified. Three investigated family members with a history of at least one spontaneous pneumothorax were heterozygous for a single nucleotide substitution (c.779G>A) that leads to a premature stop codon (p.W260X). Quantitative real-time RT-PCR revealed a reduction of FLCN transcripts from the patient compared with an unaffected family member. DNA from the sporadic case carried a heterozygous missense mutation (c.394G>A). Lung function of this patient was normal and computed tomography showed similar bilateral cysts, as observed in the two members of the unrelated Swiss family. Mutations in the folliculin gene are associated with cystic lung lesions in an otherwise morphological normal lung and predispose to spontaneous pneumothorax.

Temporal trends in major angioplasty complications: technical issues and the case for on-site coronary surgery.

The need for on-site cardiac surgery has been a component of guidelines for the practice of elective and emergency percutaneous coronary intervention (PCI). However, proportions of cases requiring emergency coronary artery bypass grafting (CABG) post-PCI have fallen. This audit of complications of PCI confirms the very low incidence of need for emergency CABG, despite increasingly complex PCI caseload. Although the availability of stents/antiplatelet pharmacotherapy probably has contributed to improved PCI outcomes, the avoidance of emergency CABG is not contingent on either extensive use of glycoprotein IIb/IIIa inhibitors or strategies of universal stenting.

Using the ability to perform CPR as a standard of fitness: a consideration of the influence of aging on the physiological responses of a select group of first aiders performing cardiopulmonary resuscitation.

OBJECTIVE: Previous research has suggested that the physical demands of performing cardiopulmonary resuscitation (CPR) are relatively low. However, the subjects studied have generally been of a young age. The aim of this study was to test the hypothesis, in null form, that the physiological responses to the performance of single operator CPR for 10 min are independent of age. Confirmation of the hypothesis would allow the use of a period of time performing CPR as a socially non-discriminatory means of testing ability across a wide spectrum of age. DESIGN: 33 St. John Operations Branch members (a sample of convenience), aged between 18 and 65 years, were examined whilst performing 10 min of single operator CPR on a manikin at St. John Ambulance Headquarters, Adelaide, South Australia. Heart rate and cardiac rhythm were monitored continuously. Blood pressure was recorded at baseline and the end of the 3rd, 6th and 9th min of CPR. Subjects also rated their perceived level of activity using the 15-point Borg rating scale every 3 min and at the end of the test. RESULTS: The calculated rate-pressure product did not vary significantly with age, either at rest or in response to performing CPR. The rate-pressure product increased significantly (P < 0.05) whilst performing CPR. There was no effect of age on the perceived level of exertion, which also increased significantly during CPR as compared with rest. CONCLUSION: There was no significant effect of age on the physiological responses to the performance of 10 min of single operator CPR in this select group.

Analysis of pesticides and PCBs in waste wood and house dust.

The use of the pesticides - DDT (1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane) and lindane (gamma-hexachlorocyclohexane) - and of PCBs (polychlorinated biphenyls) has been limited or forbidden for several decades. Nevertheless, due to their persistence and bioaccumulative potentials they are still ubiquitous in the environment. Therefore, the main objective of this study was to determine analytical methods to analyse the pesticides lindane and DDT, its metabolites DDD (1,1-dichloro-2,2-bis(4-chlorophenyl)ethane) and DDE (1,1-dichloro-2,2-bis(4-chlorophenyl)ethene), and PCBs in waste wood and house dust. An ultrasonic extraction was performed followed by a sample clean up by filtration or silica gel column. The prepared samples were measured by GC/MS. Quantification through internal standard calibration delivered low limits of detection. Specific amounts of the target compounds were detected in all analysed dust samples. The comparison of the contamination between dust samples of eastern Germany (former German Democratic Republic - GDR) and western Germany partly revealed significant differences of the contamination levels. Furthermore, it was examined whether older wooden material might cause a constant volatilisation of pesticides in apartments. Waste wood samples of different contamination categories were analysed. Apparently, these samples are potentially responsible for a constant DDX (Σ(DDT, DDD, DDE)) and lindane volatilisation, but not for PCBs.

A common NYX mutation in Flemish patients with X linked CSNB.

AIMS: The Schubert-Bornschein type of complete congenital stationary night blindness (CSNB) is a genetically heterogeneous retinal disorder. It is characterised by a non-progressive disease course, often associated with high myopia and nystagmus. So far, mutations in two genes, NYX (nyctalopin) and GRM6 (metabotropic glutamate receptor 6) have been associated with this form of CSNB. The purpose of this study was to identify the genetic defect in affected male patients from Flemish families with complete CSNB. METHODS: Probands with CSNB from three large Flemish families underwent ophthalmological examination. DNA was extracted from peripheral blood, and the coding region of NYX along with parts of the 5'UTR and 3'UTR and intronic regions covering the splice sites were PCR amplified and sequenced. RESULTS: In the affected individuals of three Flemish families with the complete form of CSNB a novel NYX mutation, c.855delG was identified. This deletion is predicted to lead to a frameshift mutation, p.Asp286ThrfsX62 causing a premature stop codon. CONCLUSION: Previously, both single families with different mutations in NYX as well as different families with an identical mutation, suggestive of a founder mutation, have been described. The c.855delG deletion in NYX seems to be a common mutation associated with CSNB in the Flemish population from Belgium. Thus, we suggest performing diagnostic testing for CSNB in the Flemish population initially directed towards the identification of this mutation. Subsequent screening for other mutations in NYX or GRM6 could be performed as a second step.

cDNA subtraction cloning reveals novel genes whose temporal and spatial expression indicates association with trophoblast invasion.

Trophoblast invasion is a critical process in development of most mammals that shares similarities with the invasive behavior of tumor cells. In the present investigation, a cDNA subtraction library was constructed between invasive trophoblast at day 8 of murine development and mature noninvasive placenta at day 18 of gestation. One of the differentially expressed clones, Epcs26, was mapped to the X chromosome and revealed no homology to any known gene. It was predominantly expressed in parietal endoderm, undifferentiated cells of the ectoplacental cone, and a few trophoblast giant cells. Another gene, designated Epcs50, was mapped to chromosome 19. It exhibited homologies to the mouse Mps1 gene and, like Mps1, may have a distant relationship to the lytic protein perforin. High expression was detected in parietal endoderm cells and in a subset of secondary trophoblast giant cells. Two sequences, Epcs24 and Epcs68, exhibited an extensive open reading frame that shared the common features of the cysteine proteinase cathepsin L. Expression was confined to an undefined subpopulation of trophoblast giant cells. Both genes were mapped to chromosome 13 in close proximity to cathepsins L and J. The known functions of MPS1 and cathepsin L proteins indicate that the related proteins EPCS50, EPCS24, and EPCS68 participate in conferring invasive properties to the mouse trophoblast.

DNA sequence comparison of human and mouse retinitis pigmentosa GTPase regulator (RPGR) identifies tissue-specific exons and putative regulatory elements.

Retinitis pigmentosa 3 (RP3) is a progressive retinal degeneration due to mutations in the X-linked RPGR gene. Transcription studies in human and mouse tissues have revealed ubiquitously expressed transcripts and also an exceptional high number of tissue-specific alternative splice variants. However, regulation of tissue-specific expression and splicing is unclear, but this is of particular interest as mutations in this ubiquitously expressed gene lead to severe retinal degeneration, while other tissues are unaffected. To elucidate the conservation pattern of RPGR and to identify additional tissue-specific exons and putative regulatory elements we performed comparative genomic sequencing of the human and mouse RPGR gene. Each of the genes spans a region of nearly 59 kb, and all previously identified exons are conserved between the two species. DNA sequence comparison identified 28 conserved sequence elements (CSEs) in introns, upstream of exon 1, within the promotor region, and downstream of the most 3' exon. Some of the intronic CSEs flank tissue-specific exons and therefore may represent important regulatory elements for alternative splicing. Comparative northern blot hybridization of ubiquitous and tissue-specific RPGR probes identified high molecular weight transcripts with similar expression patterns in both human and mouse. These transcripts range from 6 to 15 kb in size and suggest the presence of additional transcribed sequences within RPGR. Our cross-species sequence comparison enables us to define candidate regions that may explain these large transcripts and will therefore contribute to the understanding of RPGR expression and splicing.

The positive inotropic effects of milrinone but not of digoxin are attenuated at short cycle lengths.

The effects of inotropically active agents on the left ventricular force-interval relation are a potential determinant of their clinical utility and safety. However, little information is available concerning the effects of noncatecholamine positive inotropic agents on this relation. Therefore this study compared the short-term effects of digoxin and milrinone on resting hemodynamics, frequency potentiation (FP), and mechanical restitution (MR) in patients undergoing nonemergency cardiac catheterization. Both digoxin and milrinone produced similar increases in LV + dP/dt at rest (12.2 +/- 1.3%, p < 0.000001 and 11.4 +/- 3.2%, p < 0.01, respectively). The positive inotropic effects of digoxin were marginally attenuated during FP (by 8.5 +/- 4.2% and 4.6 +/- 2.9% at 10 and 60 s, respectively, both p = NS compared with baseline). Similarly, on MRC analysis, the parameter c (a measure of sensitivity of contractile performance to reductions in cycle length) increased by 3.6 +/- 3.7% (p = NS). Whereas the positive inotropic effects of milrinone were not significantly attenuated during FP, they were abolished and possibly reversed at short cycle lengths on MR curve construction (6.8 +/- 5.9% negative inotropic effect at 60% of resting cycle length; p = NS; p < 0.05 vs. resting cycle length). In conclusion, in patients with well-preserved left ventricular systolic function, the positive inotropic effects of milrinone but not of digoxin are markedly dependent on heart rate. These properties may influence both relative safety and efficacy of both agents.

Nitrate therapy is an alternative to furosemide/morphine therapy in the management of acute cardiogenic pulmonary edema.

BACKGROUND: Nitrates are superior to furosemide in the management of acute pulmonary edema associated with myocardial infarction; however, their role in the absence of infarction is unclear. METHODS AND RESULTS: A randomized comparison was undertaken of the relative effectiveness of primary therapy with either intravenous morphine/furosemide (men/women; n = 32) or nitroglycerin/N-acetylcysteine (NTG/NAC; n = 37) in consecutive patients with acute pulmonary edema. The primary end point was change in PaO2/FIO2 over the first 60 minutes of therapy. Secondary end points were needed for mechanical respiratory assistance (ie, continuous positive airway pressure via mask or intubation and ventilation) and changes in other gas exchange parameters. Both treatment groups showed improvement in oxygenation after 60 minutes of therapy; however, this reached statistical significance only with NTG/NAC therapy. There was no significant difference between groups in the assessed parameters (95% CI for differences in Pao2/FIO2: furosemide/morphine -12 to 23 and NTG/NAC 4 to 44), a finding also confirmed in 32 patients presenting with respiratory failure. Only 11% of the study group required mechanical ventilatory assistance (continuous positive airway pressure in 4 patients and intubation and ventilation in 3 patients). CONCLUSIONS: NTG/NAC therapy is as effective as furosemide/morphine in the initial management of acute pulmonary edema, regardless of the presence or absence of respiratory failure. The necessity for mechanical ventilatory assistance is infrequent in these patients, regardless of the initial medical treatment regimen.