Assessing Autism in Deaf/Hard-of-Hearing Youths: Interdisciplinary Teams, COVID Considerations, and Future Directions.

Autism spectrum disorders are more prevalent in children who are Deaf or Hard of Hearing (D/HH) than in the general population. This potential for diagnostic overlap underscores the importance of understanding the best approaches for assessing autism spectrum disorder in D/HH youths. Despite the recognition of clinical significance, youths who are D/HH are often identified as autistic later than individuals with normal hearing, which results in delayed access to appropriate early intervention services. Three primary barriers to early identification include behavioral phenotypic overlap, a lack of "gold-standard" screening and diagnostic tools for this population, and limited access to qualified clinicians. In the current article, we seek to address these barriers to prompt an appropriate identification of autism by providing recommendations for autism assessment in children who are D/HH from an interdisciplinary hearing and development clinic, including virtual service delivery during COVID-19. Strengths, gaps, and future directions for implementation are addressed.

IFN-γ secretion of PBMC from non-drug-allergic control persons: Considerations for the validity of a positive lymphocyte transformation test.

BACKGROUND: The lymphocyte transformation test (LTT) is used for the in vitro detection of a drug sensitization in assumed drug allergic patients. It is based on the detection of antigen (drug)-specific activation of T cells indicated by e.g. proliferation or cytokine secretion. However, occasional stimulatory effects of the drug unrelated to specific drug-allergic mechanisms can only be detected if a larger number of non-drug allergic control persons are tested with this specific drug. In this respect, the overall specificity of the LTT with ELISA read-out is summarized in several review articles, but the impact of a specific drug on the specificity has not yet been analyzed in a larger set of control persons. OBJECTIVE: Do amoxicillin, cefuroxime and clindamycin induce an interferon (IFN)-y or interleukin (IL)-5 secretion of PBMC from control persons using the LTT with ELISA read-out? METHODS: We performed LTTs with amoxicillin, cefuroxime and clindamycin and determined drug-specific IFN-γ and IL-5 secretion measured by ELISA read-out. We included PBMC from 60 non-drug allergic control persons, who were unexposed to the tested drug at the time of blood donation. RESULTS: PBMC from 12 out of 23 control persons tested with amoxicillin gave a positive stimulation index (SI > 3.0) for IFN-γ resulting in a specificity of 47.8%. The corresponding specificity was 75% for cefuroxime (5/20 if SI > 3.0) and 58.8% for clindamycin (7/17, if SI > 2.0), respectively. In a next step, we calculated the Δ IFN-γ concentration by subtracting the background IFN-γ concentration in the unstimulated sample from the stimulated sample. After stimulation with amoxicillin, a mean concentration of 21.0 pg/mL IFN-γ was secreted. The less outlier prone median concentration was 7.4 pg/mL and much higher than for cefuroxime (1.7 pg/mL) and clindamycin (1.0 pg/mL). Remarkably, IL-5 concentrations were below the detection limit (< 1 pg/mL) for all drugs in all control persons who responded to TT. CONCLUSION: Consideration of these observations may be helpful since a positive LTT result in a control patient may challenge the validity of a positive LTT result in the same experiment for a patient with assumed drug allergy.

In vivo characterization of connective tissue remodeling using infrared photoacoustic spectra.

Premature cervical remodeling is a critical precursor of spontaneous preterm birth, and the remodeling process is characterized by an increase in tissue hydration. Nevertheless, current clinical measurements of cervical remodeling are subjective and detect only late events, such as cervical effacement and dilation. Here, we present a photoacoustic endoscope that can quantify tissue hydration by measuring near-infrared cervical spectra. We quantify the water contents of tissue-mimicking hydrogel phantoms as an analog of cervical connective tissue. Applying this method to pregnant women in vivo, we observed an increase in the water content of the cervix throughout pregnancy. The application of this technique in maternal healthcare may advance our understanding of cervical remodeling and provide a sensitive method for predicting preterm birth.

Transvaginal fast-scanning optical-resolution photoacoustic endoscopy.

Photoacoustic endoscopy offers in vivo examination of the visceral tissue using endogenous contrast, but its typical B-scan rate is ∼10 Hz, restricted by the speed of the scanning unit and the laser pulse repetition rate. Here, we present a transvaginal fast-scanning optical-resolution photoacoustic endoscope with a 250-Hz B-scan rate over a 3-mm scanning range. Using this modality, we not only illustrated the morphological differences of vasculatures among the human ectocervix, uterine body, and sublingual mucosa but also showed the longitudinal and cross-sectional differences of cervical vasculatures in pregnant women. This technology is promising for screening the visceral pathological changes associated with angiogenesis.

Home-Based Treatment with Immunoglobulins: an Evaluation from the Perspective of Patients and Healthcare Professionals.

PURPOSE: This study aims to evaluate home-based treatment with immunoglobulin (IgG) by assessing and comparing the experiences and perceived value of patients and healthcare professionals, and potential differences in experiences between subcutaneous (SCIg) and intravenous (IVIg) modes of administration. As choices on the location and type of treatment are determined in a shared decision-making process, we evaluated the home-based treatment from the perspectives of both patients and professionals. METHODS: A questionnaire study was conducted among 205 patients, 44 informal caregivers, 43 hospital professionals, and 21 nurses of the Sanquin Home Service (SHS) that provides home treatment with immunoglobulins in the Netherlands. Experiences, perceived benefits, and effects on the patients' quality of life and overall ratings were assessed. RESULTS: Both patients and professionals were predominantly positive about the home treatment, irrespective of the administration mode. The home-based treatment with Ig contributed to the patients' autonomy, participation, and perceived health. Patients and informal caregivers valued the treatment with a global rating of 8.84, and professionals with 8.32 (on a scale from 0 "worst" to 10 "best possible care"). SCIg and IVIg patient groups differed in their experiences regarding the accessibility and communication of the home treatment service. Furthermore, hospital professionals reported lower effects on quality of life than patients themselves. CONCLUSIONS: Home-based treatment with immunoglobulins is highly valued because of its personalized and effective character, meeting the needs and preferences of patients. Nonetheless, patients and professionals do have different perspectives on the value of this type of care.

Drug-induced cutaneous lupus erythematosus after immunoglobulin treatment in chronic inflammatory demyelinating polyneuropathy: a case series.

We describe six patients with cutaneous lupus erythematosus (cLE) during immunoglobulin G (IgG) treatment. Five patients were diagnosed with chronic inflammatory demyelinating polyneuropathy (CIDP) and one patient with possible CIDP. Five patients received intravenous immunoglobulin (IVIg) and one patient received subcutaneous immunoglobulin (SCIg). Skin lesions were systematically assessed by a dermatologist including skin biopsies. Patients showed disseminated erythematous plaques on several parts of the body with pre-dominance of the chest and face. Skin biopsies showed perivascular and perifollicular vacuolar inflammation, consistent with the diagnosis of cLE. There were no signs of systemic lupus erythematosus. Anti-SSA (Ro60) antibodies were found in two patients and anti-Ro52 antibodies were detectable in one patient. Symptoms improved in three patients after switching to another brand of IVIg and after use of topical corticosteroids. However, these measures did not lead to a complete resolution of the skin lesions. To achieve complete remission, IgG treatment was ceased in four patients. This led to remission of the skin lesions in two patients and to marked improvement in the other two patients. IVIg had to be restarted in two patients because of a relapse of CIDP which led to worsening of the skin lesions. In one patient with clear IVIg dependency, treatment was continued with addition of topical steroids. In the patient using SCIg, cLE was photosensitive and showed spontaneous remission. The relation of cLE with IgG treatment suggests an immunoglobulin-induced cLE. Only one report previously described the occurrence of IVIg induced cLE in a patient with common variable immunodeficiency.

Anti-SSA antibodies are present in immunoglobulin preparations.

BACKGROUND: Anti-SSA autoantibodies are among the most frequently detected autoantibodies and have traditionally been associated with Sjögren's syndrome (SjS) and systemic lupus erythematosus. The unexpected finding of anti-SSA antibodies in a patient with common variable immunodeficiency disorder (CVID) treated with intravenous immunoglobulin (IVIG), who developed discoid lupus erythematosus, prompted us to investigate the presence of anti-SSA antibodies in IVIG preparations. Since anti-SSA antibodies may be present in apparently healthy individuals without overt autoimmune features, IVIG preparations may also contain anti-SSA antibodies. STUDY DESIGN AND METHODS: IVIG consists of polyclonal immunoglobulin G isolated from the plasma of more than 1000 blood donors. Several IVIG batches from different suppliers and serum samples of patients receiving these IVIG products were tested for the presence of anti-nuclear antibodies (ANAs) and extractable nuclear antibodies (ENAs). In addition, we tested several plasma pools for the presence of anti-SSA and subsequent serum samples of individual donors. RESULTS: Several CVID-patients receiving IVIG tested positive for ANA and anti-SSA. The IVIG products administered also contained clearly detectable concentrations of these antibodies. The frequency of apparently healthy blood donors with anti-SSA positivity was 0.69% and one of 1894 donors (0.05%) showed a very high titer of anti-SSA of more than 10,000 U/mL. CONCLUSION: Anti-SSA is present in IVIG products and in blood donors without clinical symptoms. IVIG replacement can interfere with ANA and ENA serology by passive transfer of autoantibodies. We hypothesize that such autoantibodies may be causally related to disease manifestations in some recipients.

Drugs for treating urinary schistosomiasis.

BACKGROUND: Urinary schistosomiasis is caused by an intravascular infection with parasitic Schistosoma haematobium worms. The adult worms typically migrate to the venous plexus of the human bladder and excrete eggs which the infected person passes in their urine. Chronic infection can cause substantial morbidity and long-term complications as the eggs become trapped in human tissues causing inflammation and fibrosis. We summarised evidence of drugs active against the infection. This is new edition of a review first published in 1997. OBJECTIVES: To evaluate the efficacy and safety of drugs for treating urinary schistosomiasis. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register, MEDLINE, CENTRAL, EMBASE and LILACS and reference lists of articles up to 23 May 2014. SELECTION CRITERIA: Randomized controlled trials (RCTs) of antischistosomal drugs and drug combinations compared to placebo, no intervention, or each other. DATA COLLECTION AND ANALYSIS: Two researchers independently screened the records, extracted the data and assessed risk of bias. The primary efficacy outcomes were parasitological failure (defined as the continued presence of S. haematobium eggs in the urine at time points greater than one month after treatment), and percent reduction of egg counts from baseline. We presented dichotomous data as risk ratios (RR), and continuous data as mean difference (MD), alongside their 95% confidence intervals (CIs). Where appropriate we combined trials in meta analyses or tables. We assessed the quality of evidence using the GRADE approach. MAIN RESULTS: We included 30 RCTs enrolling 8165 participants in this review. Twenty-four trials were conducted in children in sub-Saharan Africa, and 21 trials were over 20 years old. Many studies were assessed as being at unclear risk of bias due to inadequate descriptions of study methods. PraziquantelOn average, a single 40 mg/kg dose of praziquantel reduced the proportion of people still excreting eggs in their urine by around 60% compared to placebo at one to two months after treatment (treatment failure: RR 0.42, 95% CI 0.29 to 0.59, 864 participants, seven trials, high quality evidence). The proportion of people cured with praziquantel varied substantially between trials, from 22.5% to 83.3%, but was higher than 60% in five of the seven trials. At one to two months following praziquantel treatment at 40 mg/kg, the mean number of schistosome eggs in the urine was reduced by over 95% in five out of six trials (678 participants, six trials, high quality evidence).Splitting praziquantel 40 mg/kg into two doses over 12 hours probably has no benefits over a single dose, and in a single trial of 220 participants the split dose caused more vomiting (RR 0.5, 95% CI 0.29 to 0.86) and dizziness (RR 0.39, 95% CI 0.16 to 0.94). MetrifonateA single dose of metrifonate 10 mg/kg reduced egg excretion (210 participants, one trial, at eight months), but was only marginally better than placebo at achieving cure at one month (RR 0.83, 95% CI 0.74 to 0.94, 142 participants, one trial). In a single trial comparing one, two and three doses, the absolute number of participants cured improved from 47% after one dose to 81% after three doses (93 participants, one trial, low quality evidence).Two small trials compared 40 mg/kg single dose praziquantel with two or three doses of 10 mg/kg metrifonate and found no clear evidence of differences in cure (metrifonate 2 x 10 mg/kg at one month: RR 1.03, 95% CI 0.8 to 1.34, 72 participants, one trial; metrifonate 3 x 10 mg/kg at three months: RR 0.33, 95% CI 0.07 to 1.57, 100 participants, one trial. In one trial both drugs performed badly and in one trial both performed well. Other drugsThree trials have evaluated the antimalarial artesunate; with inconsistent results. Substantial antischistosomal effects were only seen in one of the three trials, which was at unclear risk of bias due to poor reporting of the trial methods. Similarly, another anti-malarial mefloquine has been evaluated in two small trials with inconsistent effects.Adverse events were described as mild for all evaluated drugs, but adverse event monitoring and reporting was generally of low quality. AUTHORS' CONCLUSIONS: Praziquantel 40 mg/kg is the most studied drug for treating urinary schistosomiasis, and has the strongest evidence base.Potential strategies to improve future treatments for schistosomiasis include the combination of praziquantel with metrifonate, or with antimalarial drugs with antischistosomal properties such as artesunate and mefloquine. Evaluation of these combinations requires rigorous, adequately powered trials using standardized outcome measures.

Corticosteroids for dengue infection.

BACKGROUND: Dengue is a common and important mosquito-borne viral infection. In many low- and middle-income countries it is endemic and is an important public health problem. Severe dengue is an important cause of death in children. There is no specific treatment for dengue, but observational studies suggest corticosteroids may have a benefit in dengue-related shock, and some people believe corticosteroids may prevent the progression to severe illness if given early in the course of the illness. OBJECTIVES: To compare treatment of dengue with and without use of corticosteroids or placebo in relation to preventing shock-related death and disease progression in children and adults. SEARCH METHODS: We searched the Cochrane Infectious Disease Group Centralized Register; CENTRAL; MEDLINE; EMBASE; and LILACS, up to 6 January 2014. We screened reference lists and contacted the relevant study authors for additional information where required. SELECTION CRITERIA: Randomized controlled trials or quasi-randomized controlled trials comparing corticosteroids with placebo or no corticosteroids in patients diagnosed with dengue-related shock, or patients in an early symptomatic state of dengue with positive serology. DATA COLLECTION AND ANALYSIS: Two researchers independently screened eligibility of records, extracted data and assessed quality of the studies. We presented findings in meta-analysis and summary of findings tables and evaluated the quality of evidence using GRADE. MAIN RESULTS: We included eight studies enrolling 948 participants in this review. Paitents with dengue-related shock Four studies enrolled children younger than 15 years with dengue-related shock at hospitals in Southeast Asia and evaluated intravenous corticosteroids. The trials did not detect an effect on death (four trials, 284 participants, very low quality evidence), the need for blood transfusion (two trials, 89 participants, very low quality evidence), pulmonary haemorrhage (one trial, 63 participants, very low quality evidence), convulsions (one trial, 63 participants, very low quality evidence), or duration of hospitalization (one trial, 63 participants, very low quality evidence). The body of evidence is too small to confidently prove or exclude clinically important effects. Furthermore, the trials are more than 20 years old with several methodological limitations. Patients with dengue at an early stage Four studies enrolled 664 children and adults with dengue at an early stage of infection (without shock) in Columbia, India, Sri Lanka and Vietnam. In these participants there were no evidence of effects of oral or intravenous corticosteroids on mortality (four trials, 664 participants, low quality evidence), or on the development of complications of severe dengue such as shock (two trials, 286 participants, very low quality evidence), severe bleeding (two trials, 425 participants, very low quality evidence), severe thrombocytopaenia (one trial, 225 participants, very low quality evidence), ascites (one trial, 178 participants, very low quality evidence) and intensive care unit (ICU) admissions (two trials, 286 participants, very low quality evidence). AUTHORS' CONCLUSIONS: The evidence from trials using corticosteroids in dengue is inconclusive and the quality of evidence is low to very low. This applies to both the use of corticosteroids in dengue-related shock and for dengue at an early stage. There is insufficient evidence to evaluate the effects of corticosteroids in the treatment of early stage dengue fever and dengue-related shock outside of the context of a randomized controlled trial.

Artesunate plus pyronaridine for treating uncomplicated Plasmodium falciparum malaria.

BACKGROUND: The World Health Organization (WHO) recommends that people with uncomplicated Plasmodium falciparum malaria are treated using Artemisinin-based Combination Therapy (ACT). ACT combines three-days of a short-acting artemisinin derivative with a longer-acting antimalarial which has a different mode of action. Pyronaridine has been reported as an effective antimalarial over two decades of use in parts of Asia, and is currently being evaluated as a partner drug for artesunate. OBJECTIVES: To evaluate the efficacy and safety of artesunate-pyronaridine compared to alternative ACTs for treating people with uncomplicated P. falciparum malaria. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library; MEDLINE; EMBASE; LILACS; ClinicalTrials.gov; the metaRegister of Controlled Trials (mRCT); and the WHO International Clinical Trials Search Portal up to 16 January 2014. We searched reference lists and conference abstracts, and contacted experts for information about ongoing and unpublished trials. SELECTION CRITERIA: Randomized controlled trials of artesunate-pyronaridine versus other ACTs in adults and children with uncomplicated P. falciparum malaria.For the safety analysis, we also included adverse events data from trials comparing any treatment regimen containing pyronaridine with regimens not containing pyronaridine. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial eligibility and risk of bias, and extracted data. We combined dichotomous data using risk ratios (RR) and continuous data using mean differences (MD), and presented all results with a 95% confidence interval (CI). We used the GRADE approach to assess the quality of evidence. MAIN RESULTS: We included six randomized controlled trials enrolling 3718 children and adults. Artesunate-pyronaridine versus artemether-lumefantrineIn two multicentre trials, enrolling mainly older children and adults from west and south-central Africa, both artesunate-pyronaridine and artemether-lumefantrine had fewer than 5% PCR adjusted treatment failures during 42 days of follow-up, with no differences between groups (two trials, 1472 participants, low quality evidence). There were fewer new infections during the first 28 days in those given artesunate-pyronaridine (PCR-unadjusted treatment failure: RR 0.60, 95% CI 0.40 to 0.90, two trials, 1720 participants, moderate quality evidence), but no difference was detected over the whole 42 day follow-up (two trials, 1691 participants, moderate quality evidence). Artesunate-pyronaridine versus artesunate plus mefloquineIn one multicentre trial, enrolling mainly older children and adults from South East Asia, both artesunate-pyronaridine and artesunate plus mefloquine had fewer than 5% PCR adjusted treatment failures during 28 days follow-up (one trial, 1187 participants, moderate quality evidence). PCR-adjusted treatment failures were 6% by day 42 for these treated with artesunate-pyronaridine, and 4% for those with artesunate-mefloquine (RR 1.64, 95% CI 0.89 to 3.00, one trial, 1116 participants, low quality evidence). Again, there were fewer new infections during the first 28 days in those given artesunate-pyronaridine (PCR-unadjusted treatment failure: RR 0.35, 95% CI 0.17 to 0.73, one trial, 1720 participants, moderate quality evidence), but no differences were detected over the whole 42 days (one trial, 1146 participants, low quality evidence). Adverse effectsSerious adverse events were uncommon in these trials, with no difference detected between artesunate-pyronaridine and comparator ACTs. The analysis of liver function tests showed biochemical elevation were four times more frequent with artesunate-pyronaridine than with the other antimalarials (RR 4.17, 95% CI 1.38 to 12.62, four trials, 3523 participants, moderate quality evidence). AUTHORS' CONCLUSIONS: Artesunate-pyronaridine performed well in these trials compared to artemether-lumefantrine and artesunate plus mefloquine, with PCR-adjusted treatment failure at day 28 below the 5% standard set by the WHO. Further efficacy and safety studies in African and Asian children are required to clarify whether this combination is an option for first-line treatment.

Intravenous immunoglobulin in neonates with rhesus hemolytic disease: a randomized controlled trial.

BACKGROUND: Despite limited data, international guidelines recommend the use of intravenous immunoglobulin (IVIg) in neonates with rhesus hemolytic disease. OBJECTIVE: We tested whether prophylactic use of IVIg reduces the need for exchange transfusions in neonates with rhesus hemolytic disease. DESIGN AND SETTING: We performed a randomized, double-blind, placebo-controlled trial in neonates with rhesus hemolytic disease. After stratification for treatment with intrauterine transfusion, neonates were randomly assigned for IVIg (0.75 g/kg) or placebo (5% glucose). The primary outcome was the rate of exchange transfusions. Secondary outcomes were duration of phototherapy, maximum bilirubin levels, and the need of top-up red-cell transfusions. RESULTS: Eighty infants were included in the study, 53 of whom (66%) were treated with intrauterine transfusion(s). There was no difference in the rate of exchange transfusions between the IVIg and placebo groups (7 of 41 [17%] vs 6 of 39 [15%]; P = .99) and in the number of exchange transfusions per patient (median [range]: 0 [0-2] vs 0 [0-2]; P = .90) or in duration of phototherapy (4.7 [1.8] vs 5.1 [2.1] days; P = .34), maximum bilirubin levels (14.8 [4.7] vs 14.1 [4.9] mg/dL; P = .52), and proportion of neonates who required top-up red-cell transfusions (34 of 41 [83%] vs 34 of 39 [87%]; P = .76). CONCLUSIONS: Prophylactic IVIg does not reduce the need for exchange transfusion or the rates of other adverse neonatal outcomes. Our findings do not support the use of IVIg in neonates with rhesus hemolytic disease.

The efficacy of two modified proprioceptive neuromuscular facilitation stretching techniques in subjects with reduced hamstring muscle length.

Difference scores in knee extension angle and electromyographic (EMG) activity were quantified before and after modified proprioceptive neuromuscular facilitation (PNF) hold-relax (HR) and hold-relax-antagonist contraction (HR-AC) stretching procedures in 35 healthy individuals with reduced hamstring muscle length bilaterally (knee extension angle <160 degrees ). Participants were randomly assigned each PNF procedure to opposite lower extremities. Knee extension values were measured by using a goniometer. EMG data were collected for 10 seconds before and immediately after each PNF stretching technique and normalized to maximum voluntary isometric contraction (% MVIC). A significant time by stretch-type interaction was detected (F(1,34) = 21.1; p < 0.001). Angles of knee extension for HR and HR-AC were not different prior to stretching (p = 0.45). Poststretch knee extension angle was greater in the HR-AC condition than the HR condition (p < 0.007). The proportion of subjects who exceeded the minimal detectable change (MDC(95)) with the HR-AC stretch (97%) did not differ (p = 0.07) from the proportion who exceeded the MDC(95) with the HR stretch (80%). Because EMG activation increased (p < 0.013) after the HR-AC procedure, it is doubtful a relationship exists between range of motion improvement after stretching and inhibition of the hamstrings. On average the 10-second modified HR procedure produced an 11 degrees gain in knee extension angle within a single stretch session.

Peer teaching among physical therapy students during human gross anatomy: perceptions of peer teachers and students.

Despite nearly 200 accredited entry-level physical therapist education programs in the United States that culminate in a doctoral degree, only a paucity of reports have been published regarding the efficacy of peer teaching in gross anatomy. No one has described the usefulness of peer teaching from the viewpoint of the peer teacher. An organized peer teaching method provided by four second-year doctors of physical therapy (DPT) students in a semester course in gross anatomy had a positive impact on the academic performance in gross anatomy of first-year DPT students. The unique feature of the weekly peer teaching sessions was a packet assembled by the second-year peer teachers, which contained diagrams, fill-in-the blank questions, and helpful mnemonic devices. This study surveyed perceptions of first-year DPT students in response to a peer teaching method, using a structured 10-item questionnaire and a five-point Likert scale. Second-year DPT peer teachers provided written reflections about the benefits and challenges of serving as a peer teacher. Results revealed that 13 planned peer-teaching experiences provided by four second-year DPT students were valuable and promoted a firm understanding of anatomical relationships important for the clinical competence of physical therapist students. Moreover, peer teachers acknowledged acquiring clinically desirable teaching, academic, organizational, and time management skills from the experience. As a result, physical therapist educators may wish to consider this model of peer teaching to augment their teaching strategies for a class in gross human anatomy.

Angiotensin II receptor-independent antiinflammatory and antiaggregatory properties of losartan: role of the active metabolite EXP3179.

Angiotensin II (Ang II) type 1 receptor (AT(1)) antagonists such as losartan (LOS) are widely used for the treatment of hypertension and elicit antiinflammatory and antiaggregatory in vitro and in patients, although the underlying mechanism are unclear. Following computer-based molecule similarity, we proposed that on cytochrome-P450 degradation, the LOS metabolite EXP3179 is generated, which shows molecule homology to indomethacin, a cyclooxygenase inhibitor with antiinflammatory and antiaggregatory properties. Subsequently, serum-levels of EXP3179 were determined for 8 hours in patients receiving a single oral dose of 100 mg LOS. High-performance liquid chromatography followed by liquid chromatography-mass spectrometry (GC-MS) [corrected] from serum samples revealed a maximum of 10(-7) mol/L for EXP3179 peaking between 3 to 4 hours. The increase in serum-EXP3179 levels was associated with a significant reduction in platelet aggregation in vivo (-35+/-4%, P<0.001 versus control). EXP3179 generation was investigated in a chemical reaction mimicking the liver cytochrome-P450-dependent LOS-degradation and human endothelial cells were exposed to Ang II or lipopolysaccharides (LPS) in the presence of EXP3179 (10(-7) mol/L). LPS- and Ang II-induced COX-2 transcription was abolished by EXP3179. Moreover, EXP3179 significantly reduced Ang II- and LPS-induced formation of prostaglandin F2alpha as determined by GC-MS [corrected]. Thus, antiinflammatory properties of LOS are mediated via its EXP3179 metabolite by abolishing COX-2 mRNA upregulation and COX-dependent TXA2 and PGF2alpha generation. Serum levels of EXP3179 are detectable in patients in concentrations that exhibit antiinflammatory and antiaggregatory properties in vitro.