Direct analysis of volatile organic compounds in foods by headspace extraction atmospheric pressure chemical ionisation mass spectrometry.

RATIONALE: The rapid screening of volatile organic compounds (VOCs) by direct analysis has potential applications in the areas of food and flavour science. Currently, the technique of choice for VOC analysis is gas chromatography/mass spectrometry (GC/MS). However, the long chromatographic run times and elaborate sample preparation associated with this technique have led a movement towards direct analysis techniques, such as selected ion flow tube mass spectrometry (SIFT-MS), proton transfer reaction mass spectrometry (PTR-MS) and electronic noses. The work presented here describes the design and construction of a Venturi jet-pump-based modification for a compact mass spectrometer which enables the direct introduction of volatiles for qualitative and quantitative analysis. METHODS: Volatile organic compounds were extracted from the headspace of heated vials into the atmospheric pressure chemical ionization source of a quadrupole mass spectrometer using a Venturi pump. Samples were analysed directly with no prior sample preparation. Principal component analysis (PCA) was used to differentiate between different classes of samples. RESULTS: The interface is shown to be able to routinely detect problem analytes such as fatty acids and biogenic amines without the requirement of a derivatisation step, and is shown to be able to discriminate between four different varieties of cheese with good intra and inter-day reproducibility using an unsupervised PCA model. Quantitative analysis is demonstrated using indole standards with limits of detection and quantification of 0.395 µg/mL and 1.316 µg/mL, respectively. CONCLUSIONS: The described methodology can routinely detect highly reactive analytes such as volatile fatty acids and diamines without the need for a derivatisation step or lengthy chromatographic separations. The capability of the system was demonstrated by discriminating between different varieties of cheese and monitoring the spoilage of meats.

Antinuclear antibodies associate with loss of response to antitumour necrosis factor-alpha therapy in psoriasis: a retrospective, observational study.

BACKGROUND: An increasing number of patients with severe psoriasis are failing to respond to antitumour necrosis factor (TNF)-alpha therapy (etanercept, infliximab and adalimumab). OBJECTIVES: We observed that many of these patients developed antinuclear antibodies (ANA) and antidouble-stranded DNA (anti-dsDNA) antibodies while on treatment prompting us to investigate whether their development is associated with anti-TNF treatment failure. METHODS: All patients with psoriasis who had received anti-TNF therapies were identified and their blood results and treatment histories were obtained from electronic patient records and case notes. RESULTS: A total of 97 patients had been treated with anti-TNF agents (60 were on their first agent, 22 had been on and stopped one agent, nine had been on and stopped two agents and six had been on and stopped all three agents). ANA developed in 17% of patients on their first treatment, 54% of patients who had failed one treatment, 78% of patients who had failed two treatments and 83% of patients who had failed all three treatments. Anti-dsDNA antibodies developed in 2%, 27%, 33% and 83% of patients from the same respective groups. Significantly, the antibodies developed before treatment had failed with all three agents and their development was not related to the total time that patients had been on anti-TNF therapy. CONCLUSIONS: This study suggests that the development of ANA and anti-dsDNA antibodies on anti-TNF treatment may act as a marker of forthcoming treatment failure. Large-scale prospective studies are required to assess the importance of this observation.

Percent absent end-diastolic velocity in the umbilical artery waveform as a predictor of intrauterine fetal demise of the donor twin after selective laser photocoagulation of communicating vessels in twin-twin transfusion syndrome.

OBJECTIVE: Absent end-diastolic velocity (AEDV) in the umbilical artery of the donor twin is a known risk factor for intrauterine fetal demise (IUFD) of this fetus after selective laser photocoagulation of communicating vessels (SLPCV) for twin-twin transfusion syndrome (TTTS). The aim of this study was to assess the proportion of time, expressed as a percentage, of the cardiac cycle spent in AEDV (%AEDV) as a predictor of IUFD of the donor. METHODS: All patients referred for possible SLPCV underwent complete preoperative staging evaluation including Doppler assessment of the umbilical artery. %AEDV was calculated retrospectively as 100 x (time of the cycle spent in AEDV divided by duration of total cardiac cycle). Patients without AEDV were considered to have a %AEDV of 0. Follow-up Doppler studies were performed 16-24 h after SLPCV. IUFD of the donor was recorded if the donor twin died any time prior to delivery. RESULTS: Of 401 patients undergoing SLPCV, 127 had AEDV. Preoperative AEDV of the donor twin was associated with an increased risk of IUFD of the donor (40.9% vs. 14.2%, P < 0.0001). %AEDV was measured in 72/127 (56.7%) donors with AEDV for whom digital images were available. Within these 72 patients, the mean %AEDV was significantly higher in patients with IUFD of the donor (36.5% vs. 29.6%, P = 0.01). IUFD of the donor was similar in patients with AEDV, regardless of whether %AEDV was measured (36% vs. 47%, P = 0.2). A %AEDV > 30 was associated with a 4.3-fold increase in the risk of IUFD of the donor (95% CI, 1.4-12.7), a sensitivity of 77% and a negative predictive value of 81.3%. Logistic regression showed that %AEDV, but not number of anastomoses, placental location, presence of artery-to-artery anastomoses or the presence or absence of EDV was associated significantly with IUFD of the donor. CONCLUSION: %AEDV is a novel Doppler parameter in the assessment of patients with TTTS. %AEDV, rather than AEDV alone, is a significant risk factor for IUFD of the donor twin and %AEDV > 30 is associated with an increased risk of IUFD of the donor in TTTS patients treated with SLPCV. Assessment of %AEDV should be considered part of the preoperative evaluation of TTTS patients.

Azapirones for generalized anxiety disorder.

BACKGROUND: Azapirones are a group of drugs that work at the 5-HT1A receptor and are used to treat patients suffering from generalized anxiety disorder (GAD). However, several studies have shown conflicting results. Whether azapirones are useful as first line treatment in general anxiety disorders still needs to be answered. OBJECTIVES: To assess the efficacy and the acceptability of azapirones for the treatment of GAD. SEARCH STRATEGY: Initially the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR) and The Cochrane Central Register of Controlled Trials (CENTRAL) were searched, incorporating results of group searches of MEDLINE (1966 to June 2005), EMBASE (1980 to June 2005), CINAHL (1982 to June 2005), PsycLIT (1974 to June 2005), PSYNDEX (1977 to June 2005), and LILACS (1982 to June 2005). Subsequently the revised Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Registers (CCDANCTR-Studies and CCDANCTR-References) were searched on 21-10-2005. Reference lists of relevant papers and major text books of anxiety disorder were examined. Authors, other experts in the field and pharmaceutical companies were contacted for knowledge of suitable trials, published or unpublished. Specialist journals concerning azapirones were handsearched. SELECTION CRITERIA: Randomized controlled trials of azapirones, including buspirone versus placebo and/or other medication and/or psychological treatment, were included. Participants were males and females of all ages with a diagnosis of generalized anxiety disorder. DATA COLLECTION AND ANALYSIS: Data were extracted from the original reports independently by CC, MA and MT. The main outcomes studied were related to the objectives stated above. Data were analysed for generalized anxiety disorder versus placebo, versus other medication and versus psychological treatment separately. Data were analysed using Review Manager Version 4.2.7. MAIN RESULTS: Thirty six trials were included in the review, reporting on 5908 participants randomly allocated to azapirones and/or placebo, benzodiazepines, antidepressants, psychotherapy or kava kava. Azapirones, including buspirone, were superior to placebo in treating GAD. The calculated number needed to treat for azapirones using the Clinical Global Impression scale was 4.4 (95% confidence interval (CI) 2.16 to 15.4). Azapirones may be less effective than benzodiazepines and we were unable to conclude if azapirones were superior to antidepressants, kava kava or psychotherapy. Azapirones appeared to be well tolerated. Fewer participants stopped taking benzodiazepines compared to azapirones. The length of studies ranged from four to nine weeks, with one study lasting 14 weeks. AUTHORS' CONCLUSIONS: Azapirones appeared to be useful in the treatment of GAD, particularly for those participants who had not been on a benzodiazepine. Azapirones may not be superior to benzodiazepines and do not appear as acceptable as benzodiazepines. Side effects appeared mild and non serious in the azapirone treated group. Longer term studies are needed to show that azapirones are effective in treating GAD, which is a chronic long-term illness.

Apolipoprotein E gene polymorphisms are associated with psoriasis but do not determine disease response to acitretin.

BACKGROUND: Psoriasis is associated with abnormal plasma lipid metabolism and a high frequency of cardiovascular events. Increased lipid levels are also seen in patients with psoriasis treated with acitretin. Apolipoprotein E (ApoE) variants have been linked to hypertriglyceridaemia and hypercholesterolaemia in normal individuals. Two coding single nucleotide polymorphisms at +3937 and +4075 define the three common ApoE alleles e2, e3 and e4. OBJECTIVES: To test the hypothesis that particular ApoE polymorphism(s) are associated with psoriasis and that specific ApoE allelic variant(s) may be a marker for predicting disease response to acitretin. METHODS: DNA was genotyped for ApoE polymorphisms using a radioactive hybridization technique in cohorts of patients with psoriasis, including patients with chronic plaque psoriasis (CPP, n = 212), guttate psoriasis (GP, n = 94), palmoplantar pustulosis (PPP, n = 101), controls (n = 137), acitretin responders (n =106) and acitretin nonresponders (n = 84). RESULTS: The frequency of the e4 allele (+3937C/+4075C) was significantly higher in patients with CPP and GP than in controls (P = 0.008 and P = 0.02, respectively). There was no significant difference in allele frequencies between patients with PPP and controls. Allelic distribution was similar in acitretin responders and nonresponders. CONCLUSIONS: These data demonstrate an association between the Apo e4 allele and CPP and GP, suggesting a possible pathogenic role for ApoE in psoriasis. Our results do not support a link between disease response to acitretin and the e2, e3 or e4 allelic variants of ApoE.

Corneodesmosin (CDSN) gene association with psoriasis vulgaris in Caucasian but not in Japanese populations.

PSORS1 on chromosome 6p21.3, which contains the MHC, is a major susceptibility locus for psoriasis vulgaris. This region is characterized by strong linkage disequilibrium and contains the corneodesmosin (CSDN) gene, an attractive candidate for psoriasis susceptibility based on its putative biological function in keratinocyte adhesion, and HLA-Cw6, an established marker for psoriasis susceptibility. We compared two genetically independent populations in order to define the major psoriasis susceptibility gene, a British Caucasian population comprising parent-offspring trios analysed by the transmission disequilibrium test (TDT) and a Japanese case-control population. All individuals were investigated for CDSN polymorphism (+619, +1236, +1240 and +1243) and HLA-C association. Our data confirms strong association with HLA-Cw6 and CDSN allele 5 (+619T, +1240G, +1243C) in the Caucasian cohort (TDT, P = 5.4 x 10(-6)) and in addition defines this region further by identifying a high-risk CDSN haplotype (allele 5 and +1236T, P = 8.5 x 10(-8)). In contrast no association was observed in the Japanese cohort for any HLA-C or CDSN alleles. This data supports a role for the CDSN gene in Caucasian populations with psoriasis. However the lack of association with HLA-Cw6 and CDSN alleles in Japanese psoriasis patients may be because Japanese patients exhibit a form of psoriasis similar to late onset or Type II psoriasis vulgaris in contrast to early onset or Type I disease characterizing our Caucasian population.

Haloperidol plus promethazine for psychosis induced aggression.

BACKGROUND: Health services often manage agitated or violent people and for emergency psychiatric services such behaviour is particularly prevalent (10%). The drugs used in this situation should ensure that the person swiftly and safely becomes calm. OBJECTIVES: To examine whether haloperidol plus promethazine is an effective treatment for psychosis induced agitation/aggression. SEARCH STRATEGY: We searched the Cochrane Schizophrenia Group's Register (July 2004). SELECTION CRITERIA: We included all randomised clinical trials involving aggressive people with psychosis for which haloperidol plus promethazine was being used. DATA COLLECTION AND ANALYSIS: We reliably selected, quality assessed and extracted data from all relevant studies. For binary outcomes we calculated standard estimations of risk ratio (RR) and their 95% confidence intervals (CI). Where possible we estimated weighted number needed to treat or harm (NNT/H). MAIN RESULTS: We identified two relevant high quality studies. One compared the haloperidol plus promethazine mix with midazolam (n=301) and one with lorazepam (n=200). The combined results were largely heterogeneous. In Brazil, haloperidol plus promethazine was an effective means of tranquillisation with over two thirds of people being tranquil or sedated by 30 minutes, but midazolam was more swift (n=301, RR 2.9 CI 1.75 to 4.80, NNH 5 CI 3 to 12). In India, however, 95% of people were tranquil or sedated by 30 minutes if allocated to the combination treatment (vs lorazepam, n=200, RR 0.26 CI 0.10 to 0.68, NNT 8 CI 6 to 17). Over the next few hours of treatment reported differences are negligible. One person given midazolam had respiratory depression (reversed by flumazenil), one given lorazepam had respiratory difficulty. A single person given haloperidol plus promethazine had an epileptic fit. Once the initial tranquillisation was administered, few needed additional medications for continued agitation (n=501, 2 RCTs, RR needing additional tranquillising drugs by four hours 1.67 CI 0.62 to 4.54, 4% vs 2%, I squared 50%) and there were no differences in the low levels of use of restraints. About 28% of people in Brazil in both groups had another episode of aggression in the first day after the initial injection (n=301, RR 0.89 CI 0.62 to 1.29). About half of all people in the Indian study were discharged by four hours (n=200, RR 1.13 CI 0.85 to 1.50) and a similar proportion in Brazil by 15 days (n=301, RR 1.05 CI 0.84 to 1.29). Both studies attained 99% follow up for their primary outcomes. Even by two weeks only 4% of people could not be accounted for (n=501, 2 RCTs, RR 0.91 CI 0.38 to 2.17). AUTHORS' CONCLUSIONS: This review suggests that both benzodiazepines work, but that midazolam has a faster onset and thereby reduces the risk of exposure to violence. Both benzodiazepines have the potential to cause respiratory depression, probably midazolam more so than lorazepam, and we would question the use of this group of drugs outside of those services fully confident of observing for and managing the consequences of respiratory distress. Most evidence, however, exists for the haloperidol plus promethazine mix, with currently more than 400 people randomised to the combination. The onset of action is swift and faster than lorazepam. The combination also seems safe with no clear longer term consequences. We would expect policy makers recommending other drug managements to have equally compelling evidence to support their guidance and hope that this would not be founded in conjecture or consensus, which may be more difficult to defend than evidence from high quality studies.

A Crohn's disease-associated insertion polymorphism (3020insC) in the NOD2 gene is not associated with psoriasis vulgaris, palmo-plantar pustular psoriasis or guttate psoriasis.

A C-insertion polymorphism in the NOD2 gene (3020insC) on chromosome 16 is a rare mutation associated with Crohn's disease. Crohn's disease and psoriasis are more commonly observed together than expected by chance. Furthermore a susceptibility locus for psoriasis has been identified on chromosome 16q which overlaps the recently identified susceptibility locus for Crohn's disease. Thus, NOD2 may potentially be important as a candidate susceptibility gene for psoriasis. We tested this hypothesis by genotyping psoriasis patients for the C-insertion polymorphism using the Taqman ABI 7700 sequencing system. No statistically significant differences were observed between psoriasis vulgaris (n = 216), palmo-plantar pustular psoriasis (PPP) (n = 100), guttate psoriasis (n = 118) and the control group (n = 283). In both patient and control groups, no mutant homozygotes were observed and approximately 4% were heterozygotes. This particular insertion mutation in the NOD2 gene does not appear to contribute to the genetic susceptibility of psoriasis vulgaris, PPP or guttate psoriasis. However, other mutations exist in the NOD2 gene, which may potentially have a role in psoriasis susceptibility.

In vivo endoscopic assessment of arterioarterial anastomoses: insight into their hemodynamic function.

OBJECTIVE: To assess endoscopically the hemodynamic function of arterioarterial (AA) anastomoses in twin-twin transfusion syndrome (TTTS) and monochorionic selective intrauterine growth restriction (IUGR). MATERIALS AND METHODS: The videotapes of TTTS and IUGR patients undergoing laser surgery between July 1997 and December 2001 were reviewed for the presence of AA anastomoses. The hemodynamic equator was defined as the site within the AA anastomosis with color flashing. AA anastomoses were classified as having unidirectional flow, having bi-directional flow, or being non-functional, depending on whether the hemodynamic equator reached a returning vein to one, both, or neither twin, respectively. TTTS was classified in stages as previously described. RESULTS: AA anastomoses were present in 35/183 (19.1%) of TTTS and in 12/24 (50%) IUGR patients. Of these, the hemodynamic equator was visible in 8/35 (22.8%) TTTS patients (all in stage III, and mostly in atypical stage III) and in 6/12 (50%) IUGR patients (overall 14/47, 29.8%). Of the 14 patients with a visible hemodynamic equator, 13 (92.8%) AA anastomoses showed unidirectional (9/13, 69.2% from the smaller to the larger twin) flow, and only 1/14 (7.1%) showed bi-directional flow. CONCLUSION: The hemodynamic equator is visible in approximately 30% of patients with AA anastomoses. Within this group, most AA anastomoses behave as functional arteriovenous anastomoses, and the direction of flow can be from the smaller to the larger twin or vice versa. The data suggest a correlation between sonographic findings and placental vascular design, also implying possible interfetal oxygenation differences. Further assessment of the functional behavior of AA anastomoses is warranted to understand the pathophysiology of TTTS and selective IUGR.

Twin-twin transfusion syndrome with only superficial placental anastomoses: endoscopic and pathological evidence.

Deep arteriovenous placental anastomoses in monochorionic placentas have been considered an essential etiological factor in twin-twin transfusion syndrome (TTTS). Moreover, some investigators have suggested that superficial anastomoses have a protective role. We report on confirmed cases of TTTS with only superficial anastomoses.

Operative fetoscopy via telesurgery.

We describe a case in which telesurgical consultation from Tampa, Florida, USA was used to accomplish operative fetoscopy in Santiago, Chile for the treatment of a twin pregnancy involving an acardiac twin. The procedure was successful and a healthy infant was delivered at 37.5 weeks. Operative fetoscopy, a surgical approach to correct birth defects in utero via combined ultrasound and endoscopy, is only available in a handful of centers worldwide. Telesurgery makes use of telecommunication to allow a surgeon at a primary operating site to consult with another experienced surgeon for complex surgical cases. This case illustrates the potential for ultrasound and telesurgery to expand the horizons of operative fetoscopy.

Anti-E-selectin is ineffective in the treatment of psoriasis: a randomized trial.

BACKGROUND: Skin-homing, memory T lymphocytes play an important role in the pathogenesis of psoriasis by interacting with the vascular addressin, E-selectin and trafficking into lesional skin. Thus an attractive option for targeted therapy of the disease would be blockade of skin-homing T cells with an antibody directed at E-selectin. OBJECTIVE: We performed a multicentre, randomized, placebo-controlled trial to investigate the clinical efficacy and side-effect profile of a humanized monoclonal antibody to E-selectin, CDP850, in the treatment of moderate to severe chronic plaque psoriasis. METHODS: Patients with moderate/severe chronic plaque psoriasis were selected for study. Nine male subjects (mean age 37 years, range 25-47) were given 20 mg kg-1 CDP850 intravenously as a single dose and four subjects (three males, one female; mean age 40 years, range 23-50) received placebo infusion. Clinical response to treatment was assessed using the psoriasis area and severity index (PASI). Skin biopsies were taken for immunohistochemical analysis at the baseline, pretreatment, visit and also at day 2 and weeks 1 and 4 postinfusion. RESULTS: The treatment was well-tolerated with a minimal side-effect profile. Plasma E-selectin levels were significantly decreased in those subjects who received CDP850 compared with those who had placebo for the entire study period. At the end of study (8 weeks postinfusion), there was no significant reduction in PASI from baseline for either the CDP850 or placebo-treated groups. Immunohistochemical analysis of biopsies taken from lesional psoriatic skin showed that 2 days after dosing with CDP850, staining for E-selectin was decreased, although not absent, on dermal vascular endothelial cells when compared with baseline (P < 0.01). This decrease in E-selectin expression was maintained 4 weeks after infusion (P < 0.05). It was not, however, accompanied by a significant reduction in numbers of neutrophils or lymphocytes in the dermis. There was a statistically significant increase in CD1a-positive epidermal Langerhans cells compared with pre-dose levels at week 1 (P < 0.05). CONCLUSIONS: This clinicopathological study shows that anti-E-selectin (CDP850), although a well-tolerated, logical and safe therapy, does not appear to possess a therapeutic role in the treatment of chronic plaque psoriasis.

Contrasting patterns of streptococcal superantigen-induced T-cell proliferation in guttate vs. chronic plaque psoriasis.

BACKGROUND: Streptococcal infection is strongly associated with guttate psoriasis (GP) and may also exacerbate chronic plaque psoriasis (CPP), possibly through the release of superantigenic toxins. OBJECTIVES: To investigate superantigen-induced generation of cutaneous lymphocyte associated antigen (CLA) -positive lymphocytes in GP compared with CPP. METHODS: Peripheral blood lymphocyte (PBL) expression of CLA and T-cell receptor Vbeta chain was assessed in patients with CPP and with active and resolved GP. Expression of superantigen-reactive Vbeta families was compared with in vitro superantigen-induced peripheral blood mononuclear cell (PBMC) proliferation. RESULTS: Peripheral blood mononuclear cells from patients with active GP showed a twofold increased proliferation after stimulation with streptococcal pyogenic toxins A and streptococcal pyogenic toxins C compared with controls (P < 0.01), whereas the response to the staphylococcal toxins and mitogenic stimulation was the same in all groups. Peripheral blood lymphocytes (PBL) from patients with active GP showed increased use of the superantigen-reactive families Vbeta2 (P < 0.01) and Vbeta17 (P < 0.05), which was not evident in the other patient groups or controls. This pattern of Vbeta expression was only observed in CLA-positive T cells. Furthermore, there was a positive correlation between Vbeta2 expression and enhanced proliferation after stimulation with SPEA (r = 0.82, P < 0.01) and SPEC (r = 0.74, P < 0.05) in active GP. CONCLUSIONS: This study supports the concept that streptococcal infection precipitates acute GP at least in part through superantigen driven generation of Vbeta-restricted CLA-positive skin homing lymphocytes, whereas we could find no evidence for a similar mechanism occurring in the maintenance of stable CPP.

Selective photocoagulation of communicating vessels in the treatment of monochorionic twins with selective growth retardation.

OBJECTIVE: Current treatment of patients with selective intrauterine growth retardation in monochorionic twins includes expectant management, termination of pregnancy, or umbilical-cord occlusion. The purpose of this study was to assess the outcome of monochorionic twins with selective intrauterine growth retardation who were treated with selective laser photocoagulation of the communicating vessels. STUDY DESIGN: Monochorionic twin pregnancies with selective intrauterine growth retardation at less than 26 weeks were eligible for the study. Selective intrauterine growth retardation was defined as <10th percentile for gestational age. Absent or reverse end-diastolic velocity in the umbilical artery of the twin with selective intrauterine growth retardation was required for eligibility after January 2000. RESULTS: Thirty patients met the criteria for the study: 17 patients were treated expectantly (group I); 2 patients underwent umbilical-cord ligation of the twin with selective intrauterine growth retardation, and 11 patients underwent selective laser photocoagulation of the communicating vessels (group II). Survival rates for at least 1 fetus were no different between groups I and II (14/17 [82.3%] vs 8/11 [72.3%]; P = .4). However, concomitant demise of the co-twin occurred in 4 of 7 patients, and iatrogenic premature delivery for deterioration of the twin with selective intrauterine growth retardation was necessary in 2 patients in group I, which resulted in significant neonatal morbidity. Of the live-born babies, neurologic handicap was present in 3 of 22 babies (13.6%) versus 0 of 12 in groups I and II, respectively (P < .0001). CONCLUSION: Selective intrauterine growth retardation in monochorionic twins can be effectively treated with selective laser photocoagulation of the communicating vessels. By unlinking the circulations between the fetuses, the pregnancy is rendered "functionally" dichorionic, which improves pregnancy treatment and results in decreased neonatal morbidity. This approach constitutes a new valuable alternative in the treatment of monochorionic twin pregnancies with selective intrauterine growth retardation. A randomized clinical trial of expectant treatment versus selective laser photocoagulation of the communicating vessels for monochorionic selective intrauterine growth retardation can be considered.

The Expert Consensus Guideline Series. Treatment of behavioral emergencies.

OBJECTIVES: Behavioral emergencies are a common and serious problem for consumers, their communities, and the healthcare settings on which they rely to contain, assess, and ultimately help the individual in a behavioral crisis. Partly because of the inherent dangers of this situation, there is little research to guide provider responses to this challenge. Key constructs such as agitation have not been adequately operationalized so that the criteria defining a behavioral emergency are vague. The significant progress that has been made for some disease states with better treatments and higher consumer acceptance has not penetrated this area of practice. A significant number of deaths of patients in restraint has focused government and regulators on these issues, but a consensus about key elements in the management of behavioral emergencies has not yet been articulated by the provider community. The authors assembled a panel of 50 experts to define the following elements: the threshold for emergency interventions, the scope of assessment for varying levels of urgency and cooperation, guiding principles in selecting interventions, and appropriate physical and medication strategies at different levels of diagnostic confidence and for a variety of etiologies and complicating conditions. METHOD: In order to identify issues in this area on which there is consensus, a written survey with 808 decision points was developed. The survey was mailed to a panel of 52 experts, 50 of whom completed it. A modified version of the RAND Corporation 9-point scale for rating appropriateness of medical decisions was used to score options. Consensus on each option was defined as a non-random distribution of scores by chi-square "goodness-of-fit" test. We assigned a categorical rank (first line/preferred choice, second line/alternate choice, third line/usually inappropriate) to each option based on the 95% confidence interval around the mean rating. Guideline tables were constructed describing the preferred strategies in key clinical situations. RESULTS: The expert panel reached consensus on 83% of the options. The relative appropriateness of emergency interventions was ascertained for a continuum of behaviors. When asked about the frequency with which emergency interventions (parenteral medication, restraints, seclusion) were required in their services, 47% of the experts reported that such interventions were necessary for 1%-5% of patients seen in their services and 32% for 6%-20%. In general, the consensus of this panel lends support to many elements of recent Health Care Financing Administration regulations, including the timing of clinician assessment and reassessment and the intensity of nursing care. However, the panel did not endorse the concept of "chemical restraint," instead favoring the idea that medications are treatments for target behaviors in behavioral emergencies even when the causes of these behaviors are not well understood. Control of aggressive behavior emerged as the highest priority during the emergency; however, preserving the physician-patient relationship was rated a close second and became the top priority in the long term. Oral medications, particularly concentrates, were clearly preferred if it is possible to use them. Benzodiazepines alone were top rated in 6 of 12 situations. High-potency conventional antipsychotics used alone never received higher ratings than benzodiazepines used alone. A combination of a benzodiazepine and an antipsychotic was preferred for patients with suspected schizophrenia, mania, or psychotic depression. There was equal support for high-potency conventional or atypical antipsychotics (particularly liquids) in oral combinations with benzodiazepines. Droperidol emerged in fourth place in some situations requiring an injection. CONCLUSIONS: To evaluate many of the treatment options in this survey, the experts had to extrapolate beyond controlled data in comparing modalities with each other or in combination. Within the limits of expert opinion and with the expectation that future research data will take precedence, these guidelines provide some direction for addressing common clinical dilemmas in the management of psychiatric emergencies and can be used to inform clinicians in acute care settings regarding the relative merits of various strategies.

Early migration of cutaneous lymphocyte-associated antigen (CLA) positive T cells into evolving psoriatic plaques.

The majority of T cells in lesional psoriatic skin express the skin homing receptor, cutaneous lymphocyte-associated antigen (CLA). We investigated whether this reflects the selective migration of CLA positive cells into evolving psoriatic plaques, consistent with an important role in disease onset, or whether this occurs in the context of an established cutaneous inflammatory response. We identified the advancing edge of plaques in 16 patients with chronic plaque psoriasis using scanning laser Doppler fluxmetry, and performed immunohistochemical analysis of i) lesional psoriatic skin, ii) clinically normal skin immediately in front of the advancing plaque edge, and iii) uninvolved skin distant from the plaque edge. The T-cell infiltrate was characterized using monoclonal antibodies to CD3, CLA and the integrin alphaEbeta7, which is associated with the retention of lymphocytes at mucosal sites. Epithelial proliferation was assessed using a monoclonal antibody to the nuclear proliferation marker Ki67. There was enrichment of CLA positive T cells in evolving psoriatic skin compared to distant, uninvolved skin (mean CLA positive 75.9% vs 47.8%; P<0.003). This accumulation of CLA positive cells occurred before epidermal hyperproliferation was evident, suggesting that this population of cells plays an important, early role in disease pathogenesis. Established lesional psoriatic skin contained a mixed infiltrate of CLA positive (mean 53.2%) and alphaEbeta7 positive (mean 18.2%) cells, suggesting less tissue-specific T-cell infiltration, although an additional, specific role for alphaEbeta7 in cutaneous inflammation cannot be excluded. Furthermore, this study has highlighted scanning laser Doppler fluxmetry as a useful investigative tool, permitting analysis of the earliest and therefore potentially most important changes in psoriatic plaque formation.

Immunohistochemical evaluation of psoriatic plaques following selective photothermolysis of the superficial capillaries.

BACKGROUND: Elongated and tortuous capillary loops are distinctive features of psoriasis. The significance of these microvascular changes in the pathogenesis of plaques, however, remains unclear. OBJECTIVES: To determine what part the expanded superficial capillary bed plays in the pathogenesis of clinical lesions by selectively thermolysing psoriatic capillaries with a pulsed dye laser (PDL). METHODS: Cutaneous lesions were biopsied before and after treatment and sections assessed by standard immunohistochemical techniques for changes in known indicators of angiogenesis, including endothelial surface area, endothelial cell proliferation and endothelial cell expression of adhesion molecules. We also measured lymphocytic infiltration and epidermal thickness, and quantified the presence of a marker of keratinocyte proliferation before and after treatment. RESULTS: The effect of the PDL was limited to the superficial capillary bed, with no changes in the microvessels (including venules and arterioles) of the upper reticular dermis. Although there was significant clinical improvement in plaques after treatment (P = 0.02), complete clearance of lesions was not achieved. Thermolysis of psoriatic capillaries caused a reduction in both endothelial surface area (P < 0.01) and endothelial cell proliferation in the superficial dermis (P = 0.04). Endothelial expression of surface adhesion molecules (integrins and E-selectin) important in angiogenesis was not, however, altered by treatment. The CD4+ and CD8+ T-cell infiltrate was significantly reduced in the superficial papillary dermis (P = 0.02 and P = 0.04, respectively), but not in the epidermis or upper reticular dermis. Laser treatment significantly reduced epidermal thickness (P = 0.001), but did not alter epidermal keratinocyte proliferation (P = 0.2). CONCLUSIONS: The results demonstrate that dermal capillary changes alone are unlikely to be causal in psoriasis. They indicate that the expanded psoriatic capillaries may be important in facilitating the access of activated T cells to the skin and in maintaining the psoriatic plaque. These results do not refute the consensus view that plaque formation may be mediated by the release of growth factors/cytokines from activated epidermal T cells/keratinocytes.

Selective laser photocoagulation of communicating vessels in severe twin-twin transfusion syndrome in women with an anterior placenta.

BACKGROUND: We describe two techniques for the laser treatment of twin-twin transfusion syndrome in women with anterior placentas. TECHNIQUE: In the first technique, anastomoses were photocoagulated using a flexible endoscope through a single port. The second technique used a side-firing laser fiber with a rigid angled-view endoscope (two ports). EXPERIENCE: Seventy-two women had surgery between July 1997 and December 1999, 35 (48.6%) of whom had anterior placentas. Survival was similar for fetuses with anterior (80%) and posterior (75.6%) placentas, but operating time was significantly longer for those with anterior placentas (81.1 compared with 64.4 minutes for the anterior and posterior placentas, respectively; P = .02, Student t test). At least one fetus survived in 76% (16 of 21) of women treated with flexible endoscopes and 86% (12 of 14) of those treated with the side-firing lasers. Six of 72 women (8.3%) had patent vascular anastomoses on placental examination, and five of them had anterior placentas (P = .08, Fisher exact test). CONCLUSION: Although anterior placentas are surgically more challenging than posterior placentas, both techniques allow an effective percutaneous approach to the laser treatment of twin-twin transfusion syndrome.