A phase 4, randomized, head-to-head trial comparing the efficacy of subcutaneous injections of brodalumab to oral administrations of fumaric acid esters in adults with moderate-to-severe plaque psoriasis (CHANGE).

BACKGROUND: Brodalumab is a fully human monoclonal immunoglobulin IgG2 antibody that binds to the human IL-17 receptor subunit A and by that inhibits the biologic action of IL-17A, IL-17F, IL-17C and IL-17E. Therapy with fumaric acid esters (FAE) is a well established and widely used first-line systemic treatment for subjects with moderate-to-severe plaque psoriasis. OBJECTIVES: To compare brodalumab to FAE in terms of clinical efficacy, patient-reported outcomes and safety in subjects with moderate-to-severe plaque psoriasis who were naïve to systemic treatment. METHODS: Eligible subjects were randomized 1 : 1 to 210 mg brodalumab injections or oral FAE according to product label in this 24-week, open-label, assessor-blinded, multi-centre, head-to-head phase 4 trial. The primary endpoints were having PASI75 and having sPGA score of 0 or 1 (sPGA 0/1). Subjects with missing values for the primary endpoints were considered non-responders. RESULTS: A total of 210 subjects were randomized. 91/105 subjects completed brodalumab treatment and 58/105 subjects completed FAE treatment. At Week 24, significantly more subjects in the brodalumab group compared to the FAE group had PASI75 (81.0% vs. 38.1%, P < 0.001) and sPGA 0/1 (64.8% vs. 20.0%, P < 0.001). In the brodalumab group, the median time to both PASI75 and to PASI90 was significantly shorter than in the FAE group (4.1 weeks vs. 16.4 weeks, and 7.4 weeks vs. 24.4 weeks, respectively, P < 0.0001 for both). The rate of adverse events was lower in subjects treated with brodalumab compared to subjects treated with FAE (616.4 vs. 1195.8 events per 100 exposure years). No new safety signals were detected for brodalumab. CONCLUSIONS: Brodalumab was associated with rapid and significant improvements in signs and symptoms of moderate-to-severe plaque psoriasis, with a superior efficacy profile to what was observed with FAE in systemic-naïve subjects over 24 weeks.

The gut microbiome and inflammation in obsessive-compulsive disorder patients compared to age- and sex-matched controls: a pilot study.

OBJECTIVE: To compare the gut microbiome profile (by way of taxon analysis and indices of ß- and α-diversity) and inflammatory markers (C-reactive protein [CRP], interleukin-6[IL-6] and tumour necrosis factor-α [TNF-α]) of obsessive-compulsive disorder (OCD) outpatients and non-psychiatric community controls. METHODS: We collected morning stool and blood samples from 21 non-depressed, medication-free OCD patients and 22 age- and sex-matched non-psychiatric community controls. Microbiota analysis was performed using Illumina sequencing of the V3 region of 16S rRNA; serum CRP samples were analysed using immunoturbidimetry and plasma IL-6/TNF-α were examined by high-sensitivity ELISA. Multiple comparisons were corrected for using the false discovery rate (α = 0.05). RESULTS: Compared to controls, the OCD group presented lower species richness/evenness (α-diversity, Inverse Simpson) and lower relative abundance of three butyrate producing genera (Oscillospira, Odoribacter and Anaerostipes). Compared to controls, mean CRP, but not IL-6 and TNF-α, was elevated OCD patients. CRP revealed moderate to strong associations with psychiatric symptomatology. CONCLUSION: To our knowledge, this is the first investigation of the gut microbiome in OCD. In addition, our findings lend further support for the potential association of inflammation and OCD. These results suggest the gut microbiome may be a potential pathway of interest for future OCD research.

You'll feel better in the morning: slow wave activity and overnight mood regulation in interepisode bipolar disorder.

BACKGROUND: Sleep disturbances are prominent correlates of acute mood episodes and inadequate recovery in bipolar disorder (BD), yet the mechanistic relationship between sleep physiology and mood remains poorly understood. Using a series of pre-sleep mood inductions and overnight sleep recording, this study examined the relationship between overnight mood regulation and a marker of sleep intensity (non-rapid eye movement sleep slow wave activity; NREM SWA) during the interepisode phase of BD. METHODS: Adults with interepisode BD type 1 (BD; n = 20) and healthy adult controls (CTL; n = 23) slept in the laboratory for a screening night, a neutral mood induction night (baseline), a happy mood induction night, and a sad mood induction night. NREM SWA (0.75-4.75 Hz) was derived from overnight sleep EEG recordings. Overnight mood regulation was evaluated using an affect grid pleasantness rating post-mood induction (pre-sleep) and the next morning. RESULTS: Overnight mood regulation did not differ between groups following the sad or happy inductions. SWA did not significantly change for either group on the sad induction night compared with baseline. In BD only, SWA on the sad night was related to impaired overnight negative mood regulation. On the happy induction night, SWA increased relative to baseline in both groups, though SWA was not related to overnight mood regulation for either group. CONCLUSIONS: These findings indicate that SWA disruption may play a role in sustaining negative mood state from the previous night in interepisode BD. However, positive mood state could enhance SWA in bipolar patients and healthy adults.

Healthcare avoidance by people who inject drugs in Bangkok, Thailand.

BACKGROUND: Although people who inject drugs (IDU) often contend with various health-related harms, timely access to health care among this population remains low. We sought to identify specific individual, social and structural factors constraining healthcare access among IDU in Bangkok, Thailand. METHODS: Data were derived from a community-recruited sample of IDU participating in the Mitsampan Community Research Project between July and October 2011. We assessed the prevalence and correlates of healthcare avoidance due to one's drug use using multivariate logistic regression. RESULTS: Among 437 participants, 112 (25.6%) reported avoiding health care because they were IDU. In multivariate analyses, factors independently associated with avoiding health care included having ever been drug tested by police [adjusted odds ratio (AOR) = 1.80], experienced verbal abuse (AOR = 3.15), been discouraged from engaging in usual family activities (AOR = 3.27), been refused medical care (AOR = 10.90), experienced any barriers to health care (AOR = 4.87) and received healthcare information and support at a drop-in centre (AOR = 1.92) (all P < 0.05). CONCLUSIONS: These findings highlight the need to address the broader policy environment, which perpetuates the criminalization and stigmatization of IDU, and to expand peer-based interventions to facilitate access to health care for IDU in this setting.

Hypersomnia subtypes, sleep and relapse in bipolar disorder.

BACKGROUND: Though poorly defined, hypersomnia is associated with negative health outcomes and new-onset and recurrence of psychiatric illness. Lack of definition impedes generalizability across studies. The present research clarifies hypersomnia diagnoses in bipolar disorder by exploring possible subgroups and their relationship to prospective sleep data and relapse into mood episodes. METHOD: A community sample of 159 adults (aged 18-70 years) with bipolar spectrum diagnoses, euthymic at study entry, was included. Self-report inventories and clinician-administered interviews determined features of hypersomnia. Participants completed sleep diaries and wore wrist actigraphs at home to obtain prospective sleep data. Approximately 7 months later, psychiatric status was reassessed. Factor analysis and latent profile analysis explored empirical groupings within hypersomnia diagnoses. RESULTS: Factor analyses confirmed two separate subtypes of hypersomnia ('long sleep' and 'excessive sleepiness') that were uncorrelated. Latent profile analyses suggested a four-class solution, with 'long sleep' and 'excessive sleepiness' again representing two separate classes. Prospective sleep data suggested that the sleep of 'long sleepers' is characterized by a long time in bed, not long sleep duration. Longitudinal assessment suggested that 'excessive sleepiness' at baseline predicted mania/hypomania relapse. CONCLUSIONS: This study is the largest of hypersomnia to include objective sleep measurement, and refines our understanding of classification, characterization and associated morbidity. Hypersomnia appears to be comprised of two separate subgroups: long sleep and excessive sleepiness. Long sleep is characterized primarily by long bedrest duration. Excessive sleepiness is not associated with longer sleep or bedrest, but predicts relapse to mania/hypomania. Understanding these entities has important research and treatment implications.

Low rates of hepatitis C testing among people who inject drugs in Thailand: implications for peer-based interventions.

BACKGROUND: Regular testing for hepatitis C virus (HCV) provides an opportunity for HCV prevention and treatment efforts. In Thailand, the barriers and facilitators of HCV testing among people who inject drugs (IDU) are not known. METHODS: Using data derived from the Mitsampan Community Research Project between July and October 2011, we assessed the prevalence and factors associated with ever having been tested for HCV antibodies using bivariate statistics and multivariate logistic regression. RESULTS: Among 427 participants, 141 (33.0%) reported a history of HCV antibody testing. In multivariate analyses, factors positively associated with receiving an HCV antibody test included higher than secondary education [adjusted odds ratio (AOR) = 2.20; 95% confidence interval (CI): 1.35-3.64], binge drug use (AOR = 1.81; 95% CI: 1.12-2.93), methadone treatment enrollment (AOR = 3.47; 95% CI: 1.85-6.95) and having received peer-based education on HCV (AOR = 4.22; 95% CI: 2.66-6.77). CONCLUSIONS: We found one-third of Thai IDU in our sample reporting a history of HCV testing. The finding that IDU who received peer-based HCV education were more likely to access HCV testing provides evidence for the value of peer-based interventions for this population.

Does laparoscopic-guided transversus abdominis plane block have an effect on postoperative pain and recovery after sleeve gastrectomy?

OBJECTIVE: Postoperative pain management is thought to have an effect on patient comfort, morbidity, and mortality after bariatric surgery. Local anesthetic agents are frequently used for this purpose. Local anesthetics can be used in many different ways. In this study, we aimed to investigate the effect of transversus abdominis plane (TAP) block on postoperative pain by laparoscopic method. PATIENTS AND METHODS: A prospective randomized clinical trial was performed. While TAP block was applied to one group with bupivacaine, no action was taken for the other group. Postoperative analgesia was given to both patient groups with the "patient-controlled analgesia (PCA)" device. Demographic, operational, and postoperative clinical and pain data of the patients were recorded. RESULTS: TAP block and non-TAP block groups consisted of 30 patients each. Visual analog scale (VAS) scores of the patients at 6, 12, and 24 hours were lower in the TAP group compared to the non-TAP group (p=0.015, 0.018, 0.04, respectively). According to the PCA device data, the analgesic requirement was lower in the TAP group at 6, 12, and 24 hours (p <0.001). Rescue analgesia was required more in the non-TAP group (p=0.04). There was no statistically significant difference between the two groups in terms of gas discharge time (p=0.102), stool discharge occurred earlier in the TAP group (p=0.02). Oral intake times (p=0.554) and length of stay hospital (p=0.551) were similar. CONCLUSIONS: Laparoscopic TAP block using bupivacaine can be safely administered in morbidly obese patients and reduces postoperative analgesic requirements. Thus, side effects that may develop secondary to the use of analgesics are avoided.

A role for the Adenomatous Polyposis Coli protein in chromosome segregation.

Mutations in the Adenomatous Polyposis Coli (APC) gene are responsible for familial colon cancer and also occur in the early stages of sporadic colon cancer. APC functions in the Wnt signalling pathway to regulate the degradation of beta-catenin (reviewed in refs 1-3). APC also binds to and stabilizes microtubules in vivo and in vitro, localizes to clusters at the ends of microtubules near the plasma membrane of interphase cells, and is an important regulator of cytoskeletal function. Here we show that cells carrying a truncated APC gene (Min) are defective in chromosome segregation. Moreover, during mitosis, APC localizes to the ends of microtubules embedded in kinetochores and forms a complex with the checkpoint proteins Bub1 and Bub3. In vitro, APC is a high-affinity substrate for Bub kinases. Our data are consistent with a role for APC in kinetochore-microtubule attachment and suggest that truncations in APC that eliminate microtubule binding may contribute to chromosomal instability in cancer cells.

Probing the architecture of a simple kinetochore using DNA-protein crosslinking.

In budding yeast, accurate chromosome segregation requires that one and only one kinetochore assemble per chromosome. In this paper, we report the use of DNA-protein crosslinking and nondenaturing gel analysis to study the structure of CBF3, a four-protein complex that binds to the essential CDEIII region of Saccharomyces cerevisiae centromeres. We find that three subunits of CBF3 are in direct contact with CDEIII over a region of DNA that spans 80 bp. A highly asymmetric core complex containing p58(CTF13) p64(CEP3) and p110(NDC10) in direct contact with DNA forms at the genetically defined center of CDEIII. This core complex spans approximately 56 bp of CEN3. An extended complex comprising the core complex and additional DNA-bound p110(NDC10) also forms. It spans approximately 80 bp of DNA. CBF3 makes sequence-specific and -nonspecific contacts with DNA. Both contribute significantly to the energy of CBF3-DNA interaction. Moreover, important sequence-specific contacts are made with bases that are not conserved among yeast centromeres. These findings provide a foundation for understanding the organization of the CBF3-centromere complex, a structure that appears to initiate the formation of microtubule attachment sites at yeast kinetochores. These results also have implications for understanding centromere-binding proteins in higher cells.

Association of p60c-src with endosomal membranes in mammalian fibroblasts.

We have examined the subcellular localization of p60c-src in mammalian fibroblasts. Analysis of indirect immunofluorescence by three-dimensional optical sectioning microscopy revealed a granular cytoplasmic staining that co-localized with the microtubule organizing center. Immunofluorescence experiments with antibodies against a number of membrane markers demonstrated a striking co-localization between p60c-src and the cation-dependent mannose-6-phosphate receptor (CI-MPR), a marker that identifies endosomes. Both p60c-src and the CI-MPR were found to cluster at the spindle poles throughout mitosis. In addition, treatment of interphase and mitotic cells with brefeldin A resulted in a clustering of p60c-src and CI-MPR at a peri-centriolar position. Biochemical fractionation of cellular membranes showed that a major proportion of p60c-src co-enriched with endocytic membranes. Treatment of membranes containing HRP to alter their apparent density also altered the density of p60c-src-containing membranes. Similar density shift experiments with total cellular membranes revealed that the majority of membrane-associated p60c-src in the cell is associated with endosomes, while very little is associated with plasma membranes. These results support a role for p60c-src in the regulation of endosomal membranes and protein trafficking.

Analysis of spermatogenesis in non-obstructive azoospermic and virtually azoospermic men with known testicular pathology.

It is widely thought that human testicles affected by unilateral pathology will have greater impairment of spermatogenesis than the otherwise unaffected testis. This study reviewed records of non-obstructive azoospermic (NOA) and virtually azoospermic (NOVA) men with associated testicular pathology who underwent testicular fine needle aspiration (FNA) mapping. Concentration of spermatozoa found in each testis was analysed to discern sperm-lateralization patterns in affected and unaffected testes. A total of 1098 FNA sites from 56 men (32 varicocele, 16 cryptorchidism, three epididymo-orchitis, two mumps orchitis, three torsion) were analysed. Overall, 38 patients (68%) had spermatozoa detected in at least one testis. Most men (68%) had equal proportions of FNA sites showing spermatozoa from both testes, 29% had more spermatozoa from the unaffected testis and 3% had more spermatozoa from the affected testis. Significantly fewer sperm-positive sites were observed on the affected (272 out of 752) than unaffected side (164 out of 346) (P < 0.0001, chi-squared test). When assessed by FNA mapping, most NOA and NOVA men with known unilateral testis pathology will have equal proportions of spermatozoa in both testes. However, when sperm production differs between sides, the unaffected side is much more likely to have spermatozoa. This information may be used to refine sperm-retrieval strategies in selected patients.

Fibrinopeptide A cleavage and platelet release in whole blood in vitro. Effects of stimuli, inhibitors, and agitation.

The relationship between platelet release and fibrinopeptide A cleavage from fibrinogen to form fibrin I in vitro was examined in blood allowed to clot undisturbed or with gentle agitation. In undisturbed or agitated blood platelet release and fibrin I formation occurred simultaneously. When hirudin was added to undisturbed blood it prevented platelet release as well as fibrin I formation. In contrast, hirudin added to agitated blood had little effect on platelet release despite complete inhibition of fibrin I formation. Collagen added to either undisturbed or agitated blood increased platelet release and then fibrin I formation, and ADP added to undisturbed blood caused an initial burst of platelet release followed by slight acceleration of fibrinopeptide A cleavage. Prostaglandin E1 and theophylline prevented platelet release in both undisturbed and agitated blood, but did not affect fibrin I formation. The results with inhibitors in agitated blood suggest that fibrin I formation and platelet release can occur independently in the presence of the increased interactions induced by agitation. Addition of thrombin or tissue thromboplastin to undisturbed blood accelerated fibrin I formation with little effect on platelet release. Finally, initial thrombin formation in undisturbed blood appeared to be associated with the platelet surface. These relationships suggest that thrombin formation via the intrinsic system leads to thrombin generation on the platelet surface and simultaneous platelet release and fibrin I formation, while thrombin generated via tissue thromboplastin leads to thrombin formation in the plasma and fibrin I formation preceding platelet release. Activation by interaction of blood with collagen causes initial acceleration of platelet release and later acceleration of fibrin I formation.

Sequence of fibrinogen proteolysis and platelet release after intrauterine infusion of hypertonic saline.

Plasma fibrinopeptide B (Bbeta1-14 or FPB) immunoreactivity was studied by radioimmunoassay in patients who received intrauterine infusion of hypertonic saline to terminate pregnancy. FPB immunoreactivity increased with thrombin treatment (TIFPB) suggesting the presence of a larger FPB-containing peptide, since purified FPB is not altered by thrombin, whereas thrombin increases the immunoreactivity of Bbeta1-42 (which includes FPB) 10-fold. TIFPB immunoreactivity in plasma, drawn 4 h after hypertonic saline infusion eluted from Sephadex G-50 similarly to isolated Bbeta1-42. Streptokinase, incubated with normal plasma progressively generated TIFPB immunoreactivity, which showed a major component which eluted from Sephadex G-50 similarly to Bbeta1-42. Streptokinase generated TIFPB much more rapidly in reptilase-treated plasma that contains fibrin I, (which still includes FPB), indicating that fibrin I is preferred over fibrinogen as a substrate for plasmin cleavage of arginine (Bbeta42)-alanine (Bbeta43). Serial studies were then made in 10 patients receiving intrauterine hypertonic saline. Fibrinopeptide A (FPA) levels rose immediately, reached a peak between 1 and 2 h, were declining at 4 h, and were normal at 24 and 48 h. TIFPB levels rose slightly in the 1st h, reached a peak at 4 h, and had returned to base-line values at 24 h. Serum fibrinogen degradation product levels were unchanged at 1 h, reached their highest level at 4 h, and were still markedly elevated at 24 and 48 h. Fibrinogen levels dropped slightly being lowest at 4 and 24 h. Platelet counts declined in parallel with the fibrinogen levels over the first 4 h, but continued to decrease through 48 h. Beta thromboglobulin (betaTG) levels generally paralleled FPA levels whereas platelet factor 4 (PF4) levels showed only slight changes. The data indicate that immediately after intrauterine hypertonic saline infusion thrombin is formed that cleaves FPA from fibrinogen to produce fibrin I and releases betaTG and PF4 from platelets. Later plasmin cleaves Bbeta1-42 from fibrin I to produce fragment X, which is further degraded to form serum fibrinogen degradation products. This sequence of proteolysis indicates that plasmin action on fibrin I serves as a mechanism that regulates fibrin II formation by removing the Bbeta chain cleavage site, which is required for thrombin action in converting fibrin I to fibrin II.

The generation of fibrinopeptide A in clinical blood samples: evidence for thrombin activity.

Plasma fibrinopeptide A (FPA) concentrations were measured in clinical blood samples incubated in the collecting syringe for different time periods before addition to heparin and Trasylol, and the rate of in vitro generation of FPA was calculated as the mean increment in FPA concentration per minute over the linear portion of the generation curve. 36 normal individuals had a mean plasma FPA level of 0.64 +/- 0.56 pmol/ml and an FPA generation rate of less than 0.5 pmol/ml per min. Clinical samples with elevated plasma FPA levels manifested slow (less than 1 pmol/ml per min) (28 patients) or rapid FPA generation (greater than 1 pmol/ml per min) (33 patients). Slow FPA generation was found in 10/10 patients with venous thrombosis, in 4/4 with aortic aneurysm, and in several patients with acquired hypofibrinogenemia. In one such patient, addition of fibrinogen resulted in rapid FPA generation whereas thrombin addition was without effect. Rapid FPA generation was generally linear, was usually associated with slower fibrinopeptide B generation and was inhibited by parenteral or in vitro heparin. It is thought to reflect increased thrombin activity and was seen in patients with pulmonary embolism, active systemic lupus erythematosus, renal transplant rejection, and after infusion of prothrombin concentrates. The initial rate of FPA cleavage by thrombin at fibrinogen concentrations from 0.05 to 4 mg/ml showed little change between 2 and 4 mg/ml with a Km of 2.99 muM. At a fibrinogen concentration of 2.5 mg/ml the FPA cleavage rate was 49.2 +/- 1.6 nmol/ml per min per U of thrombin. Exogenous thrombin added to normal blood generated 21.7 nmol/ml per U of thrombin FPA in the first minute with a nonlinear pattern reflecting inactivation of thrombin and the presence of alternative substrates. Hence, the thrombin concentration in the blood cannot be calculated from the FPA generation rate. The FPA generation rates in clinical samples with rapid generation (1-28 pmol/ml per min) could be produced by 2 X 10(-5) to 5.6 X 10(-4) thrombin U/ml acting on purified fibrinogen at physiological conditions of pH, ionic strength, and temperature.

Exercise-induced myocardial ischemia in patients with coronary artery disease: lack of evidence for platelet activation or fibrin formation in peripheral venous blood.

The hypothesis that exercise-induced myocardial ischemia is associated with abnormal platelet activation and fibrin formation or dissolution was tested in patients with coronary artery disease undergoing upright bicycle stress testing. In vivo platelet activation was assessed by radioimmunoassay of platelet factor 4, beta-thrombo-globulin and thromboxane B2. In vivo fibrin formation was assessed by radioimmunoassay of fibrinopeptide A, and fibrinolysis was assessed by radioimmunoassay of thrombin-increasable fibrinopeptide B which reflects plasmin cleavage of fibrin I. Peripheral venous concentrations of these substances were measured in 10 normal subjects and 13 patients with coronary artery disease at rest and during symptom-limited peak exercise. Platelet factor 4, beta-thromboglobulin and thromboxane B2 concentrations were correlated with rest and exercise catecholamine concentrations to determine if exercise-induced elevation of norepinephrine and epinephrine enhances platelet activation. Left ventricular end-diastolic and end-systolic volumes, ejection fraction and segmental wall motion were measured at rest and during peak exercise by first pass radionuclide angiography. All patients with coronary artery disease had documented exercise-induced myocardial ischemia manifested by angina pectoris, ischemic electrocardiographic changes, left ventricular segmental dyssynergy and a reduction in ejection fraction. Rest and peak exercise plasma concentrations were not significantly different for platelet factor 4, beta-thromboglobulin, thromboxane B2, fibrinopeptide A and thrombin-increasable fibrinopeptide B. Peripheral venous concentrations of norepinephrine and epinephrine increased significantly (p less than 0.001) in both groups of patients. The elevated catecholamine levels did not lead to detectable platelet activation. This study demonstrates that enhanced platelet activation, thromboxane release and fibrin formation or dissolution are not detectable in peripheral venous blood of patients with coronary disease during exercise-induced myocardial ischemia.

Prophylactic anticoagulation following acute myocardial infarction.

Although several large trials have failed to demonstrate unequivocally that anticoagulation decreases mortality following myocardial infarction (MI), anticoagulation has been advocated to prevent embolic cerebrovascular accidents (CVAs). Since CVAs occur during hospitalization in only 1.5% to 3% of MIs, it is not justifiable to anticoagulate all patients after MI because the risk of anticoagulation exceeds the potential benefit. However, a group of patients who are at high risk of developing left ventricular thrombi (LVT) and CVA following MI can be identified. Thirty percent to 40% of patients with transmural anterior MI develop LVT, and early anticoagulation with heparin sodium prevents LVT formation and CVAs in this group. A two-dimensional echocardiogram before hospital discharge allows the identification of patients at risk for later embolization and helps determine the need for anticoagulation with warfarin sodium following hospitalization.

Identification of patients at risk for anaphylaxis due to streptokinase.

To identify patients at risk for immediate-type allergic reactions to streptokinase, we performed streptokinase skin tests on patients immediately before planned administration of intravenous streptokinase for treatment of acute myocardial infarction. Forty-five patients had negative skin tests and received streptokinase without allergic reaction. One patient had a positive skin test and was given urokinase instead, without incident. Positive skin tests were also present in a patient who had recently had an anaphylactic reaction to streptokinase, and in two physician volunteers who had been sensitized to streptokinase during initial determination of the optimal skin testing dose. Immunoassays for IgE to streptokinase were performed on serum samples from skin-tested patients and volunteers, and on 16 other patients who had not been skin tested but had previously received streptokinase without allergic reactions. The skin test was a sensitive and specific indicator of elevated levels of IgE to streptokinase. We propose that skin testing immediately before streptokinase administration is a practical approach for identifying patients at risk for immediate-type allergic reactions to streptokinase, and its use may possibly prevent anaphylaxis and death.

Scintigraphic detection of occult hemorrhage using RBCs labeled in vitro with technetium Tc 99m sodium pertechnetate.

Scintigraphy with RBCs labeled with technetium Tc 99m sodium pertechnetate effectively located the source of hemorrhage in a patient receiving long-term anticoagulant therapy. (The patient was initially seen with a large hematoma on the flank.) More important, the procedure was used to monitor activity in this otherwise-occult bleeding site. Scintigraphic studies may be useful in the management of these difficult clinical problems.

Heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia with or without thrombosis has been recognized increasingly as a serious complication of heparin use. This article reviews type II heparin-induced thrombocytopenia, which is mediated by an antibody that in most cases has specificity for a complex between heparin and platelet factor 4, a secreted platelet alpha-granule protein. The antibody-heparin-platelet factor 4 complex can activate platelets and endothelial cells, thereby initiating thrombosis. Clinical thrombosis in this syndrome may be arterial or venous. Treatment of the syndrome requires discontinuation of heparin and institution of an alternative anticoagulant.

The effect of clonidine on the cessation of cigarette smoking.

The effect of clonidine on smoking cessation was studied by randomly assigning 186 smokers in a double-blind fashion to either placebo or clonidine. Abstinence from smoking was reported more frequently by subjects receiving clonidine, but the difference was statistically significant only at the end of the first week (34.4% vs 21.5%; p less than 0.05). Bothersome side effects were common and resulted in the early discontinuation of the study medication by 23 of the subjects taking clonidine and eight taking placebo (p less than 0.05). Although this study did not demonstrate a significant effect of clonidine on smoking cessation, a beneficial trend was detected and therefore further trials with transcutaneous delivery of this agent in combination with behavior modification techniques are warranted.