Rapid infrared mapping for highly accurate automated histology in Barrett's oesophagus.

Barrett's oesophagus (BE) is a premalignant condition that can progress to oesophageal adenocarcinoma. Endoscopic surveillance aims to identify potential progression at an early, treatable stage, but generates large numbers of tissue biopsies. Fourier transform infrared (FTIR) mapping was used to develop an automated histology tool for detection of BE and Barrett's neoplasia in tissue biopsies. 22 oesophageal tissue samples were collected from 19 patients. Contiguous frozen tissue sections were taken for pathology review and FTIR imaging. 45 mid-IR images were measured on an Agilent 620 FTIR microscope with an Agilent 670 spectrometer. Each image covering a 140 µm × 140 µm region was measured in 5 minutes, using a 1.1 µm2 pixel size and 64 scans per pixel. Principal component fed linear discriminant analysis was used to build classification models based on spectral differences, which were then tested using leave-one-sample-out cross validation. Key biochemical differences were identified by their spectral signatures: high glycogen content was seen in normal squamous (NSQ) tissue, high glycoprotein content was observed in glandular BE tissue, and high DNA content in dysplasia/adenocarcinoma samples. Classification of normal squamous samples versus 'abnormal' samples (any stage of Barrett's) was performed with 100% sensitivity and specificity. Neoplastic Barrett's (dysplasia or adenocarcinoma) was identified with 95.6% sensitivity and 86.4% specificity. Highly accurate pathology classification can be achieved with FTIR measurement of frozen tissue sections in a clinically applicable timeframe.

Multi-centre Raman spectral mapping of oesophageal cancer tissues: a study to assess system transferability.

The potential for Raman spectroscopy to provide early and improved diagnosis on a wide range of tissue and biopsy samples in situ is well documented. The standard histopathology diagnostic methods of reviewing H&E and/or immunohistochemical (IHC) stained tissue sections provides valuable clinical information, but requires both logistics (review, analysis and interpretation by an expert) and costly processing and reagents. Vibrational spectroscopy offers a complimentary diagnostic tool providing specific and multiplexed information relating to molecular structure and composition, but is not yet used to a significant extent in a clinical setting. One of the challenges for clinical implementation is that each Raman spectrometer system will have different characteristics and therefore spectra are not readily compatible between systems. This is essential for clinical implementation where classification models are used to compare measured biochemical or tissue spectra against a library training dataset. In this study, we demonstrate the development and validation of a classification model to discriminate between adenocarcinoma (AC) and non-cancerous intraepithelial metaplasia (IM) oesophageal tissue samples, measured on three different Raman instruments across three different locations. Spectra were corrected using system transfer spectral correction algorithms including wavenumber shift (offset) correction, instrument response correction and baseline removal. The results from this study indicate that the combined correction methods do minimize the instrument and sample quality variations within and between the instrument sites. However, more tissue samples of varying pathology states and greater tissue area coverage (per sample) are needed to properly assess the ability of Raman spectroscopy and system transferability algorithms over multiple instrument sites.

Staging Early Esophageal Cancer.

Staging esophageal cancer provides a standardized measure of the extent of disease that can be used to inform decisions about therapy and guide prognosis. For esophageal cancer, the treatment pathways vary greatly depending on stage of disease, and accurate staging is therefore crucial in ensuring the optimal therapy for each patient. For early esophageal cancer (T1 lesions), endoscopic resection can be curative and simultaneously gives accurate staging of depth of invasion. For tumors invading the submucosa or more advanced disease, comprehensive investigation is required to accurately stage the tumor and assess suitability for curative resection. A combined imaging approach of computed tomography (CT), positron emission tomography (PET), and endoscopic ultrasound (EUS) offers complementary diagnostic information and gives the greatest chance of accurate staging. Staging laparoscopy can identify peritoneal disease and small superficial liver lesions that could be missed on CT or PET, and alters management in up to 20 % of patients. Optical diagnostic techniques offer the prospect of further extending the possibilities of endoscopic staging in real time. Optical coherence tomography can image superficial lesions and could provide information on depth of invasion for these lesions. Real-time lymph node analysis using optical diagnostics such as Raman spectroscopy could be used to support immediate endoscopic therapy without waiting for results of cytology or further investigations.

Improvement over time in outcomes for patients undergoing endoscopic therapy for Barrett's oesophagus-related neoplasia: 6-year experience from the first 500 patients treated in the UK patient registry.

BACKGROUND: Barrett's oesophagus (BE) is a pre-malignant condition leading to oesophageal adenocarcinoma (OAC). Treatment of neoplasia at an early stage is desirable. Combined endoscopic mucosal resection (EMR) followed by radiofrequency ablation (RFA) is an alternative to surgery for patients with BE-related neoplasia. METHODS: We examined prospective data from the UK registry of patients undergoing RFA/EMR for BE-related neoplasia from 2008 to 2013. Before RFA, visible lesions were removed by EMR. Thereafter, patients had RFA 3-monthly until all BE was ablated or cancer developed (endpoints). End of treatment biopsies were recommended at around 12 months from first RFA treatment or when endpoints were reached. Outcomes for clearance of dysplasia (CR-D) and BE (CR-IM) at end of treatment were assessed over two time periods (2008-2010 and 2011-2013). Durability of successful treatment and progression to OAC were also evaluated. RESULTS: 508 patients have completed treatment. CR-D and CR-IM improved significantly between the former and later time periods, from 77% and 56% to 92% and 83%, respectively (p<0.0001). EMR for visible lesions prior to RFA increased from 48% to 60% (p=0.013). Rescue EMR after RFA decreased from 13% to 2% (p<0.0001). Progression to OAC at 12 months is not significantly different (3.6% vs 2.1%, p=0.51). CONCLUSIONS: Clinical outcomes for BE neoplasia have improved significantly over the past 6 years with improved lesion recognition and aggressive resection of visible lesions before RFA. Despite advances in technique, the rate of cancer progression remains 2-4% at 1 year in these high-risk patients. TRIAL REGISTRATION NUMBER: ISRCTN93069556.

Meta-analysis of endoscopic therapy for low-grade dysplasia in Barrett's oesophagus.

BACKGROUND: The optimal management of patients with Barrett's-associated low-grade dysplasia (LGD) is unclear. The objective of this study was to identify systematically all reports of endoscopic treatment of LGD, and to assess outcomes in terms of disease progression, eradication of dysplasia and intestinal metaplasia, and complication rates. METHODS: A systematic review of articles reporting endoscopic treatment of LGD was conducted in accordance with PRISMA guidelines. MEDLINE and Embase databases were searched to identify the relevant literature. Rates of complete eradication of intestinal metaplasia (CE-IM) and dysplasia (CE-D) were reported. The pooled incidence of progression to cancer was calculated following endoscopic therapy. RESULTS: Thirty-seven studies met the inclusion criteria, reporting outcomes of endoscopic therapy for 521 patients with LGD. The pooled incidence of progression to cancer was 3·90 (95 per cent confidence interval (c.i.) 1·27 to 9·10) per 1000 patient-years. CE-IM and CE-D were achieved in 67·8 (95 per cent c.i. 50·2 to 81·5) and 88·9 (83·9 to 92·5) per cent of patients respectively. The commonest adverse event was stricture formation. CONCLUSION: Reports of endoscopic therapy were heterogeneous and follow-up periods were short. There is a high likelihood of historical overdiagnosis of LGD. Endoscopic therapy, particularly radiofrequency ablation, appears safe and effective at eradicating LGD, but does not eliminate the risk of progression to cancer.

Examining evidence for a relationship between human-animal interactions and common mental disorders during the COVID-19 pandemic: a systematic literature review.

Introduction: COVID-19 lockdowns, shelter in place, closures of transportation and mental health services, and dearth of mental health providers created new barriers to obtaining support for mental health needs at a time of increased rates of anxiety and depression. During the pandemic, a record number of households owned and adopted pets, opening a potential avenue to investigate the relationship between pets and mental health. This systematic literature review examined the question: What is the evidence for a relationship between human-animal interaction and/or animal ownership and common mental disorders among adults who interacted with pets compared to adults who did not during the COVID-19 pandemic? Methods: To address this question, four databases were searched: Medline, PsycINFO, Web of Science, and SCOPUS for peer-reviewed literature published between 2020 and July 2023. Of the 1,746 articles identified by the searches, 21 studies were included in this review. Results: Results suggest that there exists a relationship between animal ownership and strong pet attachment and pet interaction, though the directionality of the relationship was not investigated by the included studies. There was an association between having a stronger relationship with a pet and lower feelings of depression and other mental health symptoms. There was also evidence of an association between anxiety and higher levels of animal attachment. Conclusion: Understanding the association between human-animal interaction and common mental disorders may be helpful to clinicians assessing the mental health of clients. Clinicians may glean additional insight about stressors, risk factors, social supports, and lifestyle of clients based on the client's status as a pet owner. Future research could further explore the direction of the causal relationship of human-animal interaction and/or animal ownership on common mental disorders; this could further inform how the HAI relationship can be used to support clients with mental health struggles.

Editorial: Defining a bad Barrett's segment: is it dependent on goblet cells?

The identification of patients with "bad Barrett's" who are at risk of neoplastic progression is a vital and pressing task. The view that specialized intestinal metaplasia with goblet cells is the predominant preneoplastic phenotype has had wide, but by no means universal, acceptance. An important caveat is presented in the thoughtful paper by Liu et al. in this issue. Of 68 patients with columnar metaplasia, 22 patients had no goblet cells identified and 46 had goblet cells in their biopsies. In both groups there were chromosomal and DNA content abnormalities and genetic instability. However, there were no significant differences between these cellular DNA abnormalities in the two groups. Both were significantly different from gastric controls. Thus, all metaplasia in the columnar-lined esophagus may already be on the path to cancer.

Interprofessional education: effects on professional practice and health care outcomes.

BACKGROUND: Patient care is a complex activity which demands that health and social care professionals work together in an effective manner. The evidence suggests, however, that these professionals do not collaborate well together. Interprofessional education (IPE) offers a possible way to improve collaboration and patient care. OBJECTIVES: To assess the effectiveness of IPE interventions compared to education interventions in which the same health and social care professionals learn separately from one another; and to assess the effectiveness of IPE interventions compared to no education intervention. SEARCH STRATEGY: We searched the Cochrane Effective Practice and Organisation of Care Group specialised register, MEDLINE and CINAHL, for the years 1999 to 2006. We also handsearched the Journal of Interprofessional Care (1999 to 2006), reference lists of the six included studies and leading IPE books, IPE conference proceedings, and websites of IPE organisations. SELECTION CRITERIA: Randomised controlled trials (RCTs), controlled before and after (CBA) studies and interrupted time series (ITS) studies of IPE interventions that reported objectively measured or self reported (validated instrument) patient/client and/or healthcare process outcomes. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed the eligibility of potentially relevant studies, and extracted data from, and assessed study quality of, included studies. A meta-analysis of study outcomes was not possible given the small number of included studies and the heterogeneity in methodological designs and outcome measures. Consequently, the results are presented in a narrative format. MAIN RESULTS: We included six studies (four RCTs and two CBA studies). Four of these studies indicated that IPE produced positive outcomes in the following areas: emergency department culture and patient satisfaction; collaborative team behaviour and reduction of clinical error rates for emergency department teams; management of care delivered to domestic violence victims; and mental health practitioner competencies related to the delivery of patient care. In addition, two of the six studies reported mixed outcomes (positive and neutral) and two studies reported that the IPE interventions had no impact on either professional practice or patient care. AUTHORS' CONCLUSIONS: This updated review found six studies that met the inclusion criteria, in contrast to our first review that found no eligible studies. Although these studies reported some positive outcomes, due to the small number of studies, the heterogeneity of interventions, and the methodological limitations, it is not possible to draw generalisable inferences about the key elements of IPE and its effectiveness. More rigorous IPE studies (i.e. those employing RCTs, CBA or ITS designs with rigorous randomisation procedures, better allocation concealment, larger sample sizes, and more appropriate control groups) are needed to provide better evidence of the impact of IPE on professional practice and healthcare outcomes. These studies should also include data collection strategies that provide insight into how IPE affects changes in health care processes and patient outcomes.

Ethical planning for an influenza pandemic.

A U.K. Pandemic Influenza Contingency Plan was developed in 2006 but little research has since been carried out as to how ethically acceptable it will be to society. A survey containing two hypothetical scenarios was distributed to 1,018 hospital staff. The survey considered their attitudes to the professional and ethical responsibilities of healthcare workers, and to resource allocation on the intensive care unit (ICU). Of those distributed, 406 (40%) surveys were returned. During a pandemic, 320 (79%) healthcare professionals would continue to work and 339 (83%) felt it would be unprofessional for doctors to leave work. Only 218 (54%) chose the same patient for the last ICU bed. Most staff surveyed felt they should (professionally) and would (voluntarily) work during a pandemic despite high personal risk. A wide diversity of opinion existed regarding resource allocation of ICU beds. These ethical issues require open debate to ensure U.K. pandemic plans are ethically acceptable and practically applicable.

A best evidence systematic review of interprofessional education: BEME Guide no. 9.

BACKGROUND AND REVIEW CONTEXT: Evidence to support the proposition that learning together will help practitioners and agencies work better together remains limited and thinly spread. This review identified, collated, analysed and synthesised the best available contemporary evidence from 21 of the strongest evaluations of IPE to inform the above proposition. In this way we sought to help shape future interprofessional education and maximize the potential for interprofessional learning to contribute to collaborative practice and better care. OBJECTIVES OF THE REVIEW: To identify and review the strongest evaluations of IPE. To classify the outcomes of IPE and note the influence of context on particular outcomes. To develop a narrative about the mechanisms that underpin and inform positive and negative outcomes of IPE. SEARCH STRATEGY: Bibliographic database searches as follows: Medline 1966-2003, CINAHL 1982-2001, BEI 1964-2001, ASSIA 1990-2003 which produced 10,495 abstracts. Subsequently, 884 full papers were obtained and scrutinized. In addition, hand searching (2003-5 issues) of 21 journals known to have published two or more higher quality studies from a previous review. TOPIC DEFINITION AND INCLUSION CRITERIA: Peer-reviewed papers and reports included in the review had to be formal educational initiatives attended by at least two of the many professional groups from health and social care, with the objective of improving care; and learning with, from and about each other. DATA COLLECTION, ANALYSIS AND SYNTHESIS: Standard systematic review procedures were applied for sifting abstracts, scrutinizing full papers and abstracting data. Two members of the team checked each abstract to decide whether the full paper should be read. A third member was consulted over any discrepancies. Similarly, each full paper was read by at least two members of the team and agreement sought before passing it to one member of the team (SR) for data abstraction. Other members of the team checked 10% of the abstraction records. Coding into a Statistical Package for Social Scientists (SPSS) data base led to collection of different outcome measures used in the primary studies via the common metric of an adapted Kirkpatrick's four-level model of educational outcomes. Additionally, a narrative synthesis was built after analysis of primary data with the 3-P model (presage-process-product) of education development and delivery. HEADLINE RESULTS: Government calls for enhanced collaboration amongst practitioners frequently leads to IPE that is then developed and delivered by educators, practitioners or service managers. Staff development is a key influence on the effectiveness of IPE for learners who all have unique values about themselves and others. Authenticity and customization of IPE are important mechanisms for positive outcomes of IPE. Interprofessional education is generally well received, enabling knowledge and skills necessary for collaborative working to be learnt; it is less able to positively influence attitudes and perceptions towards others in the service delivery team. In the context of quality improvement initiatives interprofessional education is frequently used as a mechanism to enhance the development of practice and improvement of services.

sTREM-1 is elevated in cystic fibrosis and correlates with proteases.

BACKGROUND: sTREM-1 (soluble triggering receptor expressed on myeloid cells-1) is a novel inflammatory marker that may be of clinical use in cystic fibrosis (CF). Dysregulation of the TREM pathway has been demonstrated in other inflammatory diseases and modulation in animal models has therapeutic benefit. We hypothesised that sTREM-1 could act as a biomarker of disease in cystic fibrosis. METHODS: Plasma from 17 patients with CF (stable and pre and post pulmonary exacerbation) and eight healthy volunteers was analyzed for sTREM-1 and proteases (matrix metalloproteinase-8 (MMP-8), MMP-9, and human neutrophil elastase HNE). RESULTS: sTREM-1 Levels were elevated in stable CF subjects compared to controls (148 pg/ml (130-160) [median(IQR)] vs. 87 (55-118) (P < 0.01)) but were not further increased during pulmonary exacerbation nor decreased after antibiotic treatment in CF. Protease levels were increased in CF plasma compared to controls: MMP-8 = 3.1 ng/ml (1.5-7.6) vs. 0.3 (0.18-0.53) (P < 0.01) (Wilcoxon); MMP-9 = 170 ng/ml (124-282) vs. 49 (39-90) (P < 0.01); HNE = 30.2 ng/ml (22.7-30.9) vs. 17.5 (11.2-22.2) (P < 0.05). sTREM-1 correlated positively with protease levels lnMMP-8 r2 = 0.55 (P = 0.08), lnMMP-9 r2 = 0.61(P < 0.05), lnHNE r2 = 0.35 (P < 0.05). CONCLUSIONS: sTREM-1 is constitutively elevated in CF and positively correlates with protease levels. Modulation of this pathway may be of therapeutic benefit to patients with CF. Pediatr Pulmonol. 2017;52:467-471. © 2017 Wiley Periodicals, Inc.

Barrett's oesophagus: how should we manage it?

Endoscopic surveillance remains the core management of non-dysplastic Barrett's oesophagus, although questions regarding its efficacy in reducing mortality from oesophageal adenocarcinoma have yet to be definitively answered, and randomised trial data are awaited. One of the main goals of current research is to achieve risk stratification, identifying those at high risk of progression. The recent British Society of Gastroenterology (BSG) guidelines on surveillance have taken a step in this direction with interval stratification on clinicopathological grounds. The majority of Barrett's oesophagus remains undiagnosed, and this has led to investigation of methods of screening for Barrett's oesophagus, ideally non-endoscopic methods capable of reliably identifying dysplasia. Chemoprevention to prevent progression is currently under investigation, and may become a key component of future treatment. The availability of effective endotherapy means that accurate identification of dysplasia is more important than ever. There is now evidence to support intervention with radiofrequency ablation (RFA) for low-grade dysplasia (LGD), but recent data have emphasised the need for consensus pathology for LGD. Ablative treatment has become well established for high-grade dysplasia, and should be employed for flat lesions where there is no visible abnormality. Of the ablative modalities, RFA has the strongest evidence base. Endoscopic resection should be performed for all visible lesions, and is now the treatment of choice for T1a tumours. Targeting those with high-risk disease will, hopefully, lead to efficacious and cost-effective surveillance, and the trend towards earlier intervention to halt progression gives cause for optimism that this will ultimately result in fewer deaths from oesophageal adenocarcinoma.

Long-term prognosis and the effect of carotid endarterectomy in patients with recurrent ipsilateral ischemic events. North American Symptomatic Carotid Endarterectomy Trial Group.

BACKGROUND AND PURPOSE: The present study examines how the prognosis of patients who present with an ischemic event (TIA or nondisabling stroke) referable to a 70 to 99% carotid artery stenosis is modified by the pattern of their ischemic history. We also examined the benefits of performing carotid endarterectomy on the recently symptomatic artery. METHODS: A total of 608 patients was divided into two groups. The recent group (N = 444) consisted of patients who became newly symptomatic within the previous 6 months of their presenting event. Prior to this, they were asymptomatic. The recurrent group (N = 164) consisted of patients who had one or more ischemic events within the previous 6 months of their presenting event, as well as one or more within the previous 7 to 12 months. All events were ipsilateral to the presenting event. RESULTS: Kaplan-Meier risk estimates of ipsilateral stroke at 2 years for medically treated patients were 18.6 +/- 3.3% in the recent group and 41.2 +/- 6.9% in the recurrent group (p = 0.0002, logrank test). For patients who underwent carotid endarterectomy, the risks were 7.8 +/- 2.0% and 10.8 +/- 3.4% (p = 0.36, logrank test). Multivariate analyses did not identify any baseline patients characteristics as confounders nor any statistical interactions. CONCLUSIONS: There is a need for urgency in considering carotid endarterectomy for patients with 70 to 99% carotid artery stenosis who have had recurrent ipsilateral ischemic events extending back more than 6 months. These patients are at more than twice the risk of stroke as those who are newly symptomatic.

The histopathology of treated Barrett's esophagus: squamous reepithelialization after acid suppression and laser and photodynamic therapy.

Columnar metaplasia of the lower esophageal epithelium (Barrett's esophagus) occurs in response to acid reflux, and its most important long-term complication is malignancy. In view of this, techniques are being explored for the eradication of Barrett's esophagus, and histopathologists will increasingly be required to assess response to these therapies in esophageal biopsy samples. The histopathologic features before and after treatment were studied in biopsy samples from 16 patients receiving omeprazole only, 10 treated by KTP laser photoablation, and five who underwent photodynamic therapy. All the treatment modalities resulted in histologic changes with at least partial squamous reepithelialization of the metaplastic columnar epithelium. The histologic findings suggest three main mechanisms for this: encroachment of adjacent squamous epithelium at the squamocolumnar junction, extension of epithelium from the submucosal gland duct to form squamous islands, and squamous metaplasia within the Barrett's columnar mucosa itself. The latter mechanism implies the existence of pluripotential stem cells within Barrett's mucosa. A relatively common finding was residual glandular mucosa, nonneoplastic and dysplastic, beneath squamous epithelium indicating the requirement for histologic confirmation of endoscopically suspected complete squamous reepithelialization with sufficiently deep biopsies.

Infant size at 8 months of age: relationship to maternal use of alcohol, nicotine, and caffeine during pregnancy.

To examine the relationship of maternal alcohol consumption, caffeine use, and smoking to infant size at 8 months of age, a follow-up cohort of 453 infants was examined at birth and again at their 8-month birthday. Even after adjustment for other relevant variables, maternal alcohol use during early pregnancy (average ounces of absolute alcohol by self-report) was significantly related to infant weight and length at 8 months of age but not as strongly related to head circumference. Maternal smoking and caffeine use during pregnancy were not significantly related to infant size at 8 months, although nicotine use had been highly related to the birth size in this sample. Maternal use of marijuana was significantly and negatively related to infant length at 8 months of age, but not to weight or head circumference. The magnitude of the growth retardation is smaller at 8 months than at birth in this sample of infants whose mothers are primarily white, married, and well-educated, and who report a variety of alcohol use patterns. Significance was tested using multiple regression analyses that adjusted for the effects of nicotine use, caffeine use, birth order, maternal height, and gestational age as well as sex and age of infant at examination.

Independent dysmorphology evaluations at birth and 4 years of age for children exposed to varying amounts of alcohol in utero.

Two groups of 4-year-old children were examined by a dysmorphologist without knowledge of previous examination results or prenatal exposure and categorized as to whether or not they showed fetal alcohol effects. A priori classification of children into the two groups was on the basis of their mothers' self-report of drinking when interviewed during pregnancy. Children born to 108 mothers in a "heavier" drinking group (absolute alcohol concentration greater than or equal to 30 mL/d [1.0 oz/d]) were compared with a matched group of children born to 97 mothers whose average absolute alcohol concentration was less than 0.3 mL/d (0.01 oz/d). The percentage of children with fetal alcohol effects in the heavier drinking v the comparison group was 20.4% v 9.3%. When fetal alcohol effects were studied in relation to only the absolute alcohol concentration scores, there was a significantly greater chance of a child being classified as having fetal alcohol effects with increasing levels of alcohol exposure prior to recognition of pregnancy (P = .013). A logistic regression, run on the absolute alcohol concentration scores and other primary exposures, indicated that fetal alcohol effects classification was not significantly related to nicotine, caffeine, or marijuana but was significantly related to absolute alcohol concentration scores even after statistically adjusting for these other exposures (P = .002). Classification of fetal alcohol effects at 4 years of age was compared to a fetal alcohol effects classification obtained at birth by an independent dysmorphologist in a sample of 75 subjects examined at both ages, and 80% of the infants classified as having fetal alcohol effects at birth were classified as having fetal alcohol effects at 4 years of age.(ABSTRACT TRUNCATED AT 250 WORDS)

Control of alveolar surfactant in rats at rest and during prolonged hyperpnoea: pharmacological evidence for two tissue pools of surfactant.

1. Propranolol, atropine and indomethacin (i.p.) affect neither the amount (PLalv), nor the specific activity (PLalvsp.act.) of alveolar surfactant-type phospholipids lavaged from the lungs of unanaesthetized rats, either at rest or made hyperpnoeic for 24 h with 5%CO2/13%O2/82%N2. 2. Whereas salbutamol (280 micrograms kg-1 body weight, i.p.) consistently increased PLalv and PLalvsp.act., pilocarpine (1.5, 3, 10 and 50 mg kg-1, i.p.) and labetalol (1 and 5 mg kg-1, i.p.) had no effect. The dose of pilocarpine reported by others to release surfactant (150 mg kg-1) induced marked salivation, diarrhoea, chromodacryorrhoea and a three-fold increase in tidal volume. 3. In the isolated perfused lung of the rat, salbutamol (1.5 microM) consistently increased PLalvsp.act, whereas pilocarpine (0.1 and 1 microM) had no effect on these variables. 4. In the isolated perfused lung, the maximum amount of surfactant that could be released by salbutamol (0.5 mM) was smaller than that which could be released in response to an increase in tidal volume (peak inflation pressure 28 cmH2O). 5. When the concentration of salbutamol in the isolated perfused lung was adjusted to produce the same increase in PLalv as did a single simulated deep breath, the PLalvsp.act was significantly increased by salbutamol, but not by the simulated deep breath. 6. We conclude, that neither the autonomic nervous system nor the prostaglandin system is essential for the release of surfactant at rest or during hyperpnoea. Furthermore, we suggest that two pools of surfactant, with different release mechanisms, exist in lung tissue.

On categorizations in analyses of alcohol teratogenesis.

In biomedical scientific investigations, expositions of findings are conceptually simplest when they comprise comparisons of discrete groups of individuals or involve discrete features or characteristics of individuals. But the descriptive benefits of categorization become outweighed by their limitations in studies involving dose-response relationships, as in many teratogenic and environmental exposure studies. This article addresses a pair of categorization issues concerning the effects of prenatal alcohol exposure that have important public health consequences: the labeling of individuals as fetal alcohol syndrome (FAS) versus fetal alcohol effects (FAE) or alcohol-related neurodevelopmental disorder (ARND), and the categorization of prenatal exposure dose by thresholds. We present data showing that patients with FAS and others with FAE do not have meaningfully different behavioral performance, standardized scores of IQ, arithmetic and adaptive behavior, or secondary disabilities. Similarly overlapping distributions on measures of executive functioning offer a basis for identifying alcohol-affected individuals in a manner that does not simply reflect IQ deficits. At the other end of the teratological continuum, we turn to the reporting of threshold effects in dose-response relationships. Here we illustrate the importance of multivariate analyses using data from the Seattle, Washington, longitudinal prospective study on alcohol and pregnancy. Relationships between many neurobehavioral outcomes and measures of prenatal alcohol exposure are monotone without threshold down to the lowest nonzero levels of exposure, a finding consistent with reports from animal studies. In sum, alcohol effects on the developing human brain appear to be a continuum without threshold when dose and behavioral effects are quantified appropriately.

Facial effects of fetal alcohol exposure: assessment by photographs and morphometric analysis.

This study was designed to assess the limits of alcohol-related facial dysmorphogenesis. Standard full face and lateral facial photographs were obtained on 21 7-year-old children who had been exposed gestationally to known, heavy quantities of ethanol. Only two of these children had been previously considered to have definite fetal alcohol syndrome (FAS). Similar photographs of 21 other 7-year-old children with negligible gestational ethanol exposure were obtained for control purposes. Copies of the 42 photographs were given to each of seven expert clinicians who were asked to select any child with an FAS-related facial appearance. Six of seven judges were accurate in identifying children with high levels of alcohol exposure as having a fetal alcohol-affected face. A set of homologous points on the photographs were then digitized and analyzed by newly developed morphometric methods to determine the facial shape characteristics that distinguish the selected photographs of highly exposed children. The analysis confirmed that the judges specifically identified children with facial changes consistent with those previously published as defining the face of the FAS: short palpebral fissures, a relatively long and flat midface, and a retrusive mandible. This methodology may be useful in more accurately delineating the facial phenotype in other conditions diagnosed primarily on the basis of subjective clinical criteria.