Langerhans Cell Histiocytosis of the Head and Neck: Experience at a Rural Tertiary Referral Center.

OBJECTIVES: Retrospectively analyze head and neck Langerhans Cell Histiocytosis at a rural tertiary referral center and compare results with previously published data. METHODS: Electronic health record review was performed from 2003 to 2019. Patients with biopsy proven LCH with primary head and neck involvement were included. Demographics, presentation, imaging characteristics, treatment modality, delay in diagnosis (DD, ≥60 days), and outcomes were analyzed and reported. RESULTS: Twenty-four patients were included. The most common presenting symptoms were otorrhea (n = 6) and scalp pain or swelling (n = 6). All patients had bony involvement. The most common site was facial or skull lesions (n = 20). Most skull lesions (75%) demonstrated CNS risk. Six patients were treated with primary surgery, 15 with primary chemotherapy, and 3 with surgery plus adjuvant chemotherapy. Nine patients experienced relapse of disease with median time to documented relapse of 11.4 months; all were treated with salvage chemotherapy to achieve complete remission (median follow-up: 72 months). Patients most likely to relapse were those with multisystem disease (5/7, 71.4%), temporal bone lesions (4/7, 57.1%), and DD (7/12, 58.3%). Of the 9 total patients who experienced relapse, 78% had a delay in diagnosis. CONCLUSIONS: LCH is a complex disease process in which diagnosis can be delayed if not considered in the differential. Within the head and neck, the skull, including isolated temporal bone involvement, is the most common site of involvement. Treatment modality does not appear to have an influence on relapse rates. Relapse was more likely to occur in the first year after treatment and close monitoring is required.

Assessment of the effects of sex, age, and rearing condition on ultrasonic vocalizations elicited by pups during the maternal potentiation paradigm in C57BL/6J mice.

Isolation-induced ultrasonic vocalizations (USVs) are important to elicit parental retrieval. This behavior is critical for the animal's survival and can be altered in models of developmental disorders. The potentiation of vocalizations in response to reunion with the dam, also called maternal potentiation, has been extensively studied in rats. However, the assessment of this paradigm in mice is scarce. In rats, the potentiation of vocalizations is dependent on rearing conditions. Since mice are the main species used for genetic models of diseases, we aimed to investigate how different factors such as age, sex, and rearing conditions can affect the potentiation of vocalizations in the maternal potentiation paradigm in mice. We carried out experiments using biparental (dam and sire) or uniparental rearing (dam). Pups were tested on postnatal days (PD) 9 or 12. Pups showed increased potentiation in both sexes at PD9 with uniparental rearing. Both rearing conditions and ages changed the repertoire from the first to the second isolation. Spectral parameters were affected by sex, rearing condition and reunion at PD9. At PD12, only duration was altered by reunion. We conclude that the performance of the pups in the maternal potentiation paradigm is dependent on age, sex, and rearing condition.

Locally delivered GLP-1 analogues liraglutide and exenatide enhance microvascular perfusion in individuals with and without type 2 diabetes.

AIMS/HYPOTHESIS: Glucagon-like peptide-1 (GLP-1) analogues reduce the risk of macrovascular disease in diabetes; however, little is known about their microvascular effects. This research examined the microvascular actions of the GLP-1 analogues liraglutide and exenatide in individuals with and without type 2 diabetes (study 1). It also explored the involvement of the GLP-1 receptor (study 2) and the nitric oxide pathway in mediating the microvascular effects of the analogues. METHODS: Trial design: Studies 1 and 2 had a randomised, controlled, double-blind study design. Study 1 participants, intervention and methods: three participant groups were recruited: individuals with well-controlled type 2 diabetes, and obese and lean individuals without diabetes (21 participants per group). Liraglutide (0.06 mg), exenatide (0.5 µg) and saline (154 mmol/l NaCl; 0.9%) control were microinjected into separate sites in the dermis (forearm) in a randomised order, blinded to operator and participant. Skin microvascular perfusion was assessed by laser Doppler perfusion imaging. Outcomes were stabilised response (mean skin perfusion between 7.5 and 10 min post microinjection) and total response (AUC, normalised for baseline perfusion). Perfusion response to GLP-1 analogues was compared with saline within each group as well as between groups. Study 2 participants, intervention and methods: in healthy individuals (N = 16), liraglutide (0.06 mg) and saline microinjected sites were pretreated with saline or the GLP-1 receptor blocker, exendin-(9,39), in a randomised order, blinded to participant and operator. Outcomes were as above (stabilised response and total perfusion response). Perfusion response to liraglutide was compared between the saline and the exendin-(9,39) pretreated sites. In vitro study: the effects of liraglutide and exenatide on nitrate levels and endothelial nitric oxide synthase phosphorylation (activation) were examined using human microvascular endothelial cells. RESULTS: Study 1 results: both analogues increased skin perfusion (stabilised response and total response) in all groups (n = 21 per group, p < 0.001), with the microvascular responses similar across groups (p ≥ 0.389). Study 2 results: liraglutide response (stabilised response and total response) was not influenced by pretreatment with exendin-(9,39) (70 nmol/l) (N = 15, one dataset excluded) (p ≥ 0.609). Liraglutide and exenatide increased nitrate production and endothelial nitric oxide synthase (eNOS) phosphorylation (p ≤ 0.020). CONCLUSIONS/INTERPRETATION: Liraglutide and exenatide increased skin microvascular perfusion in individuals with and without well-controlled diabetes, potentially mediated, at least in part, by NO. TRIAL REGISTRATION: ClinicalTrials.gov NCT01677104. FUNDING: This work was supported by Diabetes UK (grant numbers: 09/0003955 and 12/0004600 [RW and JM Collins Legacy, Funded Studentship]).

Aerosols in the Pre-industrial Atmosphere.

PURPOSE OF REVIEW: We assess the current understanding of the state and behaviour of aerosols under pre-industrial conditions and the importance for climate. RECENT FINDINGS: Studies show that the magnitude of anthropogenic aerosol radiative forcing over the industrial period calculated by climate models is strongly affected by the abundance and properties of aerosols in the pre-industrial atmosphere. The low concentration of aerosol particles under relatively pristine conditions means that global mean cloud albedo may have been twice as sensitive to changes in natural aerosol emissions under pre-industrial conditions compared to present-day conditions. Consequently, the discovery of new aerosol formation processes and revisions to aerosol emissions have large effects on simulated historical aerosol radiative forcing. SUMMARY: We review what is known about the microphysical, chemical, and radiative properties of aerosols in the pre-industrial atmosphere and the processes that control them. Aerosol properties were controlled by a combination of natural emissions, modification of the natural emissions by human activities such as land-use change, and anthropogenic emissions from biofuel combustion and early industrial processes. Although aerosol concentrations were lower in the pre-industrial atmosphere than today, model simulations show that relatively high aerosol concentrations could have been maintained over continental regions due to biogenically controlled new particle formation and wildfires. Despite the importance of pre-industrial aerosols for historical climate change, the relevant processes and emissions are given relatively little consideration in climate models, and there have been very few attempts to evaluate them. Consequently, we have very low confidence in the ability of models to simulate the aerosol conditions that form the baseline for historical climate simulations. Nevertheless, it is clear that the 1850s should be regarded as an early industrial reference period, and the aerosol forcing calculated from this period is smaller than the forcing since 1750. Improvements in historical reconstructions of natural and early anthropogenic emissions, exploitation of new Earth system models, and a deeper understanding and evaluation of the controlling processes are key aspects to reducing uncertainties in future.

The coevolution of toxin and antitoxin genes drives the dynamics of bacterial addiction complexes and intragenomic conflict.

Bacterial genomes commonly contain 'addiction' gene complexes that code for both a toxin and a corresponding antitoxin. As long as both genes are expressed, cells carrying the complex can remain healthy. However, loss of the complex (including segregational loss in daughter cells) can entail death of the cell. We develop a theoretical model to explore a number of evolutionary puzzles posed by toxin-antitoxin (TA) population biology. We first extend earlier results demonstrating that TA complexes can spread on plasmids, as an adaptation to plasmid competition in spatially structured environments, and highlight the role of kin selection. We then considered the emergence of TA complexes on plasmids from previously unlinked toxin and antitoxin genes. We find that one of these traits must offer at least initially a direct advantage in some but not all environments encountered by the evolving plasmid population. Finally, our study predicts non-transitive 'rock-paper-scissors' dynamics to be a feature of intragenomic conflict mediated by TA complexes. Intragenomic conflict could be sufficient to select deleterious genes on chromosomes and helps to explain the previously perplexing observation that many TA genes are found on bacterial chromosomes.

Psychosocial factors associated with use of continuous glucose monitoring.

AIMS: To identify psychosocial factors associated with the use of continuous glucose monitoring by adults with Type 1 diabetes. METHODS: Twenty adult patients (aged 45 +/- 15 years, diabetes duration 25 +/- 19 years, 50% female) followed at our site in the multi-centre Juvenile Diabetes Research Foundation continuous glucose monitoring trial were divided into three groups: Glycated haemoglobin (HbA(1c)) Responders who demonstrated an improvement in glycaemic control with continuous glucose monitoring (baseline HbA(1c)> or = 7.0%, HbA(1c) reduction greater than or equal to 0.5%), Hypoglycaemia Responders (baseline HbA(1c) < 7.0%) who demonstrated decreased time < 3.9 mmol/l while remaining within target HbA(1c), and HbA(1c) Non-Responders (baseline HbA(1c)> or = 7.0%, HbA(1c) reduction less than 0.5%). Subjects participated in semi-structured interviews focusing on their psychosocial experiences with continuous glucose monitoring. RESULTS: Three major themes were identified that differentiated Responders (including both the HbA(1c) and Hypoglycaemia groups) from Non-Responders: (i) coping with frustrations-Responders used self-controlled rather than emotions-based coping when faced with continuous glucose monitoring frustrations; (ii) use of information-Responders used retrospective pattern analysis, not just minute-by-minute data analysis, in glycaemic management; (iii) 'significant other'/spousal involvement-Responders endorsed interest, encouragement and participation by their loved ones. Both Responders and Non-Responders expressed body image concerns when wearing continuous glucose monitoring devices. CONCLUSIONS: This qualitative study points to the importance of coping skills, retrospective review of data, and 'significant other' involvement in the effective use of continuous glucose monitoring. These findings will inform clinical initiatives to improve patient selection and training in the use of this new technology and have served as the basis for development of quantitative surveys to be used in clinical practice.

Anxiety: its role in the history of psychiatric epidemiology.

BACKGROUND: The role played by anxiety in the history of psychiatric epidemiology has not been well recognized. Such lack of understanding retarded the incremental growth of psychiatric research in general populations. It seems useful to look back on this history while deliberations are being carried out about how anxiety will be presented in DSM-V. METHOD: Drawing on the literature and our own research, we examined work that was carried out during and after the Second World War by a Research Branch of the United States War Department, by the Stirling County Study, and by the Midtown Manhattan Study. The differential influences of Meyerian psychobiology and Freudian psychoanalysis are noted. RESULTS: The instruments developed in the early epidemiologic endeavors used questions about nervousness, palpitations, sweating, trembling, shortness of breath, upset stomach, etc. These symptoms are important features of what the clinical literature called 'manifest', 'free-floating' or 'chronic anxiety'. A useful descriptive name is 'autonomic anxiety'. CONCLUSIONS: Although not focusing on specific circumstances as in Panic and Phobic disorders, a non-specific form of autonomic anxiety is a common, disabling and usually chronic disorder that received empirical verification in studies of several community populations. It is suggested that two types of general anxiety may need to be recognized, one dominated by excessive worry and feelings of stress, as in the current DSM-IV definition of Generalized Anxiety Disorder (GAD), and another emphasizing frequent unexplainable autonomic fearfulness, as in the early epidemiologic studies.

Physical and biological development of a newly breached managed realignment site, Humber estuary, UK.

As part of the Humber flood defence upgrade works (Urgent works) undertaken by the Environment Agency, the Paull Holme Strays site was identified as one of twelve potential managed realignment sites within the Humber catchment. The site was breached in September 2003, creating 80 hectares of new intertidal habitat. Initial accretion monitoring commenced in December 2003 with annual surveys of invertebrate colonisation commencing in October 2004. The present study gives details of the physical development of the newly created mudflat within the site, together with invertebrate colonisation and benthic community change over time. Comparisons between the newly created habitat and the existing mudflat outside the old sea wall are made. The macrofaunal communities found within the area as a whole are considered to be characteristic of the area with low species diversity, high abundance and small body size. The community within the managed realignment site is still in an early successional stage with low abundance and diversity in comparison with other sites within this part of the Humber. However the community biomass increased considerably between 2004 and 2005. Colonisation within the managed realignment site is still primarily concentrated in the areas around the two breach sites and is thought to be restricted in other areas due to infrequent tidal inundation.

Role of arginine 138 in the catalysis and regulation of Escherichia coli dihydrodipicolinate synthase.

In plants and bacteria, the branch point of (S)-lysine biosynthesis is the condensation of (S)-aspartate-beta-semialdehyde [(S)-ASA] and pyruvate, a reaction catalyzed by dihydrodipicolinate synthase (DHDPS, EC 4.2.1.52). It has been proposed that Arg138, a residue situated at the entrance to the active site of DHDPS, is responsible for binding the carboxyl of (S)-ASA and may additionally be involved in the mechanism of (S)-lysine inhibition. This study tests these assertions by mutation of Arg138 to both histidine and alanine. Following purification, DHDPS-R138H and DHDPS-R138A each showed severely compromised activity (approximately 0.1% that of the wild type), and the apparent Michaelis-Menten constant for (S)-ASA in each mutant, calculated using a pseudo-single substrate analysis, was significantly higher than that of the wild type. This provides good evidence that Arg138 is indeed essential for catalysis and plays a key role in substrate binding. To test whether structural changes could account for the change in kinetic behavior, the solution structure was probed via far-UV circular dichroism, confirming that the mutations at position 138 did not modify secondary structure. The crystal structures of both mutant enzymes were determined, confirming the presence of the mutations and suggesting that Arg138 plays an important role in catalysis: the stabilization of the catalytic triad residues, a motif we have previously demonstrated to be essential for activity. In addition, the role of Arg138 in (S)-lysine inhibition was examined. Both mutant enzymes showed the same IC(50) values as the wild type but different partial inhibition patterns, from which it is concluded that arginine 138 is not essential for (S)-lysine inhibition.

Anxiety and depression: a 40-year perspective on relationships regarding prevalence, distribution, and comorbidity.

OBJECTIVE: Building on a report about the prevalence of depression over time, this paper examines historical trends regarding anxiety in terms of its prevalence, its distribution by age and gender, and its comorbidity with depression. Methods for conducting such time trend analysis are reviewed. METHOD: Representative samples of adults were selected and interviewed in 1952, 1970, and 1992. Logistic regressions were used for statistical analysis. RESULTS: Although twice as common as depression, the prevalence of anxiety was equally stable. Anxiety was consistently and significantly more characteristic of women than men. A re-distribution of rates in 1992 indicated that depression but not anxiety had significantly increased among younger women (P = 0.03). Throughout the study, approximately half of the cases of anxiety also suffered depression. CONCLUSION: The relationships between anxiety and depression remained similar over time with the exception that depression came to resemble anxiety as a disorder to which women were significantly more vulnerable than men. Social and historical factors should be investigated to assess their relevance to this change.

Assessment of the safety of recombinant tissue factor pathway inhibitor in patients with severe sepsis: a multicenter, randomized, placebo-controlled, single-blind, dose escalation study.

OBJECTIVE: To identify a safe and potentially effective recombinant tissue factor pathway inhibitor (rTFPI) dose for further clinical evaluation in patients with severe sepsis. DESIGN: Prospective, randomized, single-blind, placebo-controlled, dose escalation, multicenter, multinational phase II clinical trial. SETTING: Thirty-eight intensive care units in the United States and Europe. PATIENTS: Two hundred and ten subjects with severe sepsis who received standard supportive care and antimicrobial therapy. INTERVENTIONS: Subjects received a continuous intravenous infusion of placebo or rTFPI at 0.025 or 0.05 mg/kg/hr for 4 days (96 hrs). MEASUREMENTS AND MAIN RESULTS: There were no significant imbalances in demographics, severity of illness, or source of infection in patients randomized to placebo or either dose of rTFPI. A 20% relative reduction in 28-day all-cause mortality was observed when all rTFPI-treated patients were compared with all placebo patients. An improvement in pulmonary organ dysfunction score and in a composite intensive care unit score (pulmonary, cardiovascular, and coagulation) were also noted in the rTFPI-treated patients. Logistic regression modeling indicated a substantial treatment by baseline laboratory international normalized ratio (INR) interaction effect when only treatment and INR were in the model (p =.037) and when baseline Acute Physiology and Chronic Health Evaluation (APACHE II) and log10 interleukin 6 were adjusted for (p =.026). This interaction effect indicates that higher baseline INR is associated with a more pronounced beneficial rTFPI effect. There was no increase in mortality in subjects treated with either dose of rTFPI compared with placebo. Biological activity, as detected by a statistically significant reduction in thrombin-antithrombin complexes (TATc), was noted in the all rTFPI-treated patients compared with those receiving placebo. There were no major imbalances across all treatment groups with respect to safety. The frequency of adverse events (AEs) and severe adverse events (SAEs) was similar among the treatment groups, with a slight increase in SAEs and SAEs involving bleeding in the 0.05 mg/kg/hr rTFPI group. The overall incidence of AEs involving bleeding was 28% of patients in the all placebo group and 23% of patients in the all rTFPI-treated group; a slight but statistically insignificant increase in incidence of SAEs involving bleeding was observed in the all rTFPI group (9%) as compared with the all placebo group (6%; p =.39). CONCLUSIONS: Although the trial was not powered to show efficacy, a trend toward reduction in 28-day all-cause mortality was observed in the all rTFPI group compared with all placebo. This study demonstrates that rTFPI doses of 0.025 and 0.05 mg/kg/hr could be safely administered to severe sepsis patients. Additionally, rTFPI demonstrated bioactivity, as shown by reduction in TATc complexes and interleukin-6 levels. These findings warrant further evaluation of rTFPI in an adequately powered, placebo controlled, randomized trial for the treatment of severe sepsis.

Multiple informants: mortality associated with psychiatric disorders in the Stirling County Study.

This paper applies new statistical procedures for analyzing multiple-source information about the relation of psychiatric diagnoses to mortality. The data come from the Stirling County Study, a longitudinal community investigation of adults, that collected multiple-source reports (self-report and physician-report) about psychiatric disorders. These reports are used as predictors of mortality risk over a 16-year follow-up period (1952-1968). Despite extensive efforts, one or both of these reports were sometimes missing. Missingness of self-report was related to demographic characteristics as well as to physician-reports of psychiatric diagnosis. The statistical procedures used here draw together into a single frame of reference both informant reports for the initial Stirling survey and relate these to mortality risk using weighted generalized estimating equation regression models for time to event data. This unified method has two advantages over traditional approaches: 1) the relative predictiveness of each informant can be assessed and 2) all subjects contribute to the analysis. The methods are applicable to other areas of epidemiology where multiple informant reports are used. The results for self-reports and physician-reports of disorders were comparable: Psychiatric diagnosis was associated with higher mortality, particularly among younger subjects.

Lenercept (p55 tumor necrosis factor receptor fusion protein) in severe sepsis and early septic shock: a randomized, double-blind, placebo-controlled, multicenter phase III trial with 1,342 patients.

OBJECTIVE: Phase III study to confirm a trend observed in a previous phase II study showing that a single dose of lenercept, human recombinant p55 tumor necrosis factor receptor-immunoglobulin G1 (TNFR55-IgG1) fusion protein, decreased mortality in patients with severe sepsis or early septic shock. DESIGN: Multicenter, double-blind, phase III, placebo-controlled, randomized study. SETTING: A total of 108 community and university-affiliated hospitals in the United States (60), Canada (6) and Europe (42). PATIENTS: A total of 1,342 patients were recruited who fulfilled the entry criteria within the 12-hr period preceding the study drug administration. INTERVENTION: After randomization, an intravenous dose of 0.125 mg/kg lenercept or placebo was given. The patient was monitored for up to 28 days, during which standard diagnostic, supportive, and therapeutic care was provided. MEASUREMENTS AND MAIN RESULTS: The primary outcome measure was 28-day all-cause mortality. Baseline characteristics were as follows: a total of 1,342 patients were randomized; 662 received lenercept and 680 received placebo. The mean age was 60.5 yrs (range, 17-96 yrs); 39% were female; 65% had medical admissions, 8% had scheduled surgical admissions, and 27% had unscheduled surgical admissions; 73% had severe sepsis without shock, and 27% had severe sepsis with early septic shock. Lenercept and placebo groups were similar at baseline with respect to demographic characteristics, simplified acute physiology score II-predicted mortality, profiles of clinical site of infection and microbiological documentation, number of dysfunctioning organs, and interleukin-6 (IL-6) plasma concentration. Lenercept pharmacokinetics were similar in severe sepsis and early septic shock patients. Tumor necrosis factor was bound in a stable manner to lenercept as reflected by the accumulation of total serum tumor necrosis factor alpha concentrations. There were 369 deaths, 177 on lenercept (27% mortality) and 192 on placebo (28% mortality). A one-sided Cochran-Armitage test, stratified by geographic region and baseline, predicted 28-day all-cause mortality (simplified acute physiology score II), gave a p value of .141 (one-sided). Lenercept treatment had no effect on incidence or resolution of organ dysfunctions. There was no evidence that lenercept was detrimental in the overall population. CONCLUSION: Lenercept had no significant effect on mortality in the study population.

Incidence of depression in the Stirling County Study: historical and comparative perspectives.

BACKGROUND: The Stirling County Study provides a 40-year perspective on the epidemiology of psychiatric disorders in an adult population in Atlantic Canada. Across samples selected in 1952, 1970 and 1992 current prevalence of depression was stable. This paper concerns time trends in annual incidence as assessed through cohorts selected from the first two samples. METHODS: Consistent interview data were analysed by a computerized diagnostic algorithm. The cohorts consisted of subjects at risk for a first depression: Cohort-1 (N = 575) was followed 1952-1970; Cohort-2 (N = 639) was followed 1970-1992. Life-table methods were used to calculate incidence rates and proportional hazards procedures were used for statistical assessment. RESULTS: Average annual incidence of depression was 4.5 per 1000 for Cohort-1 and 3.7 for Cohort-2. Differences by gender, age and time were not statistically significant. The stability of incidence and the similarity of distribution by gender and age in these two cohorts corresponds to findings about the two early samples. In contrast, current prevalence in the recent sample was distributed differently and showed an increase among women under 45 years. CONCLUSIONS: The stability of the incidence of depression emphasizes the distinctive characteristics of current prevalence in the recent sample and suggests that the dominance of women in rates of depression may have occurred among those born after the Second World War. The results offer partial support for the interpretation of an increase in depression based on retrospective data in other recent studies but they indicate that the increase is specific to women.

A 40-year perspective on the prevalence of depression: the Stirling County Study.

BACKGROUND: According to epidemiologic studies that use recall of lifetime episodes, the prevalence of depression is increasing. This report from the Stirling County Study compares rates of current depression among representative samples of adults from a population in Atlantic Canada. METHODS: Sample sizes were 1003, 1201, and 1396 in 1952, 1970, and 1992, respectively. The depression component of the study's method, the DPAX (DP for depression and AX for anxiety), was employed. The original procedure (DPAX-1) was applied in all years. A revision (DPAX-2) was used in 1970 and 1992. The Diagnostic Interview Schedule (DIS) was also used in 1992. RESULTS: With the DPAX-1, the overall prevalence of current depression was steady at 5% over the 2 early samples but declined in 1992 because of vernacular changes referring to dysphoria. The DPAX-2 gave a stable overall prevalence of 5% in the 2 recent samples, but indicated that women and younger people were at greater risk in 1992 than in 1970. The DIS, like the DPAX-2, found a current 1992 rate of 5% for major depressive episodes combined with dysthymia. Recalled lifetime rates using the DIS showed the same profile interpreted in other studies as suggesting an increase in depression over time. CONCLUSIONS: Three samples over a 40-year period showed a stable current prevalence of depression using the DPAX methods that was comparable in 1992 with the current rates using the DIS. This casts doubt on the interpretation that depression is generally increasing. Within the overall steady rate observed in this study, historical change was a matter of redistribution by sex and age, with a higher rate among younger women being of recent origin.

A comparison of diagnostic interviews for depression in the Stirling County study: challenges for psychiatric epidemiology.

BACKGROUND: High prevalence rates in psychiatric epidemiologic studies raise questions about whether data-gathering procedures identify transient responses rather than clinical disorders. This issue is explored relevant to depression using data from the Stirling County Study. METHODS: The study's customary method, the DPAX (DP for depression and AX for anxiety) was compared with the Diagnostic Interview Schedule (DIS), both of which were administered to a sample of 1396 subjects selected in 1992. Reasons for discordance were analyzed, and demographic correlates of responses to questions about dysphoria were examined. These lay-administered interviews were then compared with clinician-administered interviews that used the Structured Clinical Interview for DSM-III-R (SCID) with 139 subjects. The kappa statistic and logistic regression were used for statistical assessment. RESULTS: For the level of agreement between the DPAX and the DIS for current and lifetime depression, kappa = 0.40 and kappa = 0.33, respectively. Subjects diagnosed only by the DPAX tended to have less education than those diagnosed only by the DIS. Some idioms for dysphoria seemed to work better than others. Using SCID interviews as a clinical standard, the DPAX had 15% sensitivity and 96% specificity and the DIS had 25% sensitivity and 98% specificity. CONCLUSIONS: Comprehension of an interview can be improved by using multiple questions for dysphoria and a simpler mode of inquiry. Clinician-administered interviews tend to corroborate disorders identified in lay-administered interviews but suggest that survey methods underestimate prevalence. Further research is needed to evaluate the validity of both types of interviews, but evidence from a 16-year follow-up evaluation indicates that depression diagnosed by the DPAX is a serious disorder in terms of morbidity and mortality.

Impact of immunomodulating therapy on morbidity in patients with severe sepsis.

We assessed the impact, over a 28-d period, of therapy with the tumor necrosis factor (TNF) neutralizing receptor fusion protein (p55-IgG) on the incidence of end-organ failures in patients with severe sepsis or early septic shock in a subgroup of 165 patients recruited into a randomized, multicenter clinical trial to receive placebo (n = 78) or a single infusion of p55-IgG, 0.083 mg/kg (n = 87). At study entry, distribution of organ dysfunctions and other baseline characteristics were similar for the two study groups. Treatment with p55-IgG was associated with a trend toward reduced 28-d mortality (p = 0.07), a decreased incidence of new organ dysfunctions (relative risk [RR], 0.57; 95% confidence interval [95% CI] 0.29 to 1.10, p = 0.10), and a decreased overall incidence-density of organ failures (RR 0.65; 95% CI 0.60 to 0.71, p = 0.0001). Patients treated with p55-IgG had more organ failure-free days after study entry than those who received placebo. Average intensive care unit (ICU) stay was 2.6 d shorter (95% CI 0.2 to 5.0) for patients who received p55-IgG than for those who received placebo. For those patients who survived, this difference was 4.1 d (95% CI 1.6 to 6.6). Duration of ventilatory support was 3.2 d shorter (95% CI 0.1 to 6.3) among 28-d survivors who received p55-IgG, compared with placebo. In conclusion, in the population of septic patients studied, treatment with p55-IgG was associated with a trend toward shorter need for mechanical ventilatory support, a decreased length of stay (LOS), and a decreased incidence and duration of organ failure.

Nature of pathology: the character of danger implicit in functional impairment.

OBJECTIVE: To facilitate clinical and scientific consensus in definitions of psychiatric disorders and with regard to the nature and meaning of pathology more generally. METHOD: An essay based on a review of definitional problems encountered by psychiatric epidemiologists, with examples taken from selected studies of historic importance. A remedy is suggested and illustrated by experiences with its use in the Stirling County Study. RESULTS: A concept of pathology, termed for reference as "impairment-risk," is defined as the danger that functional impairment carries for subsequent health adversities. The concept is based on the classical notions of Rudolf Virchow, the empirical orientations of Adolf Meyer's psychobiology, the functional concepts of physiology, and the dynamics implied by evolutionary biology. The ideas embedded in "impairment-risk" are beginning to be represented in official classifications of mental disorders. CONCLUSIONS: Impairment-risk has potential in the further development of psychiatric epidemiology because of the connections made possible among neuroscience, genetics, general medicine, psychology, and the more empirical of the social and behavioural sciences.

p55 Tumor necrosis factor receptor fusion protein in the treatment of patients with severe sepsis and septic shock. A randomized controlled multicenter trial. Ro 45-2081 Study Group.

OBJECTIVE: To evaluate the safety and efficacy of p55 tumor necrosis factor receptor fusion protein, a recombinant chimeric protein of human p55 (type I) tumor necrosis factor receptor (CD120a) extracellular domain and IgG1 sequences (referred to as p55-IgG), in the treatment of patients with severe sepsis or septic shock. DESIGN: Randomized, prospective, multicenter, double-blind, placebo-controlled clinical trial. SETTING: Forty-four community and university-affiliated hospitals in the United States and Europe. PATIENTS: There were 498 patients enrolled in this clinical trial. INTERVENTION: Patients prospectively stratified within each site into refractory shock or severe sepsis groups were randomized to receive a single infusion of p55-IgG, 0.083 mg/kg, 0.042 mg/kg, or 0.008 mg/kg, or placebo. Patients received standard aggressive medical/surgical care during the 28-day postinfusion period. OUTCOME MEASURE: Twenty-eight-day all-cause mortality. RESULTS: The distribution of variables describing demographics, organ system dysfunction or failure, infecting microorganisms, predicted mortality, plasma interleukin 6 levels, and plasma tumor necrosis factor alpha (TNF-alpha) levels were similar among patients in the p55-IgG and placebo treatment arms. A planned interim analysis was performed after 201 patients were enrolled. Because a statistically nonsignificant trend toward increased mortality was present in patients who had received 0.008 mg/kg, this treatment arm was discontinued, and the study continued with 3 arms. Among all infused patients, there was a statistically nonsignificant trend toward reduced 28-day all-cause mortality in those who received p55-IgG compared with placebo-treated patients (5% reduction, 0.042 mg/kg vs placebo; 15% reduction, 0.083 mg/kg vs placebo; P=.30). However, in patients with severe sepsis and early septic shock (n=247), therapy with p55-IgG, 0.083 mg/kg, was associated with a 36% reduction in 28-day all-cause mortality compared with placebo (P=.07): 20 (23%) of 87 patients died among those treated with p55-IgG, 0.083 mg/kg; 30 (37%) of 82 among those treated with p55-IgG, 0.042 mg/kg; and 28 (36%) of 78 in the placebo group. A prospectively planned logistic regression analysis to assess treatment effect on 28-day all-cause mortality by means of predicted mortality and serum interleukin 6 levels as continuous covariates demonstrated a significant improvement in outcome for the patients with severe sepsis treated with p55-IgG, 0.083 mg/kg, compared with placebo (P=.01). Serious adverse events, including death and the development of new organ system dysfunction, were reported in 65% of patients infused with placebo, with no increased frequency (56%) present in the 2 p55-IgG treatment arms. There were no reports of immediate hypersensitivity reactions caused by p55-IgG. CONCLUSIONS: In this dose-finding study, there was no decrease in mortality between placebo and p55-IgG in all infused patients. In the prospectively defined population of patients with severe sepsis who received p55-IgG, 0.083 mg/kg, there was a trend toward reduced mortality at day 28 that became significant when predicted mortality and plasma interleukin 6 levels were included in a logistic regression analysis.

Surveillance of wild animal diseases in Europe.

A study of the methods and personnel involved in general surveillance of wild animal diseases in Europe was conducted by correspondence and personal interview in 1993-1994. Twenty-seven of the thirty-six countries contacted participated in the study. A great range was observed in the intensity of surveillance programmes and the details of their organisation. Programmes of comprehensive general surveillance were present in four countries, while eleven countries had general surveillance programmes which were limited to certain geographical regions and/or wild animal species. Twelve countries had no programmes of general wildlife disease surveillance, but had surveillance programmes for one or more specific diseases which included wild animals. Significant information on the occurrence of diseases in wild animals was available in each participating country. Factors found to be important in the structure and function of surveillance programmes were as follows: historical occurrences of rabies, hog cholera (classical swine fever), viral haemorrhagic disease of rabbits and the European brown hare syndrome; approaches to wildlife management and relationships between wildlife-oriented field personnel and the surveillance programme; whether or not fees were charged for diagnosis of diseases in wild animal specimens; training and equipment of diagnostic personnel; organisation of wild animal disease data.