Multiple drug intolerance syndrome and multiple drug allergy syndrome: Epidemiology and associations with anxiety and depression.

BACKGROUND: The epidemiology of multiple drug intolerance syndrome (MDIS) and multiple drug allergy syndrome (MDAS) is poorly characterized. We used electronic health record (EHR) data to describe prevalences of MDIS and MDAS and to examine associations with anxiety and depression. METHODS: Patients with ≥3 outpatient encounters at Partners HealthCare System from 2008 to 2015 were included. Patients with MDIS had intolerances to ≥3 drug classes, and patients with MDAS had hypersensitivities to ≥2 drug classes. Psychiatric conditions and comorbidities were defined from the EHR and used in multivariable logistic regression models to assess the relation between anxiety/depression and MDIS/MDAS. RESULTS: Of 746 888 patients, 47 634 (6.4%) had MDIS and 8615 (1.2%) had MDAS; 3171 (0.4%) had both. Anxiety (adjusted odds ratio [aOR] 1.72 [1.65, 1.80]), depression (aOR 1.46 [1.41, 1.52]), and both anxiety and depression (aOR 1.97 [1.86, 2.08]) were associated with increased odds of MDIS. Depression was associated with increased odds of MDAS (aOR 1.41 [1.28, 1.56]), but there were no clear associations with anxiety (aOR 1.13 [0.99, 1.30]) nor both depression and anxiety (aOR 1.13 [0.92, 1.38]). CONCLUSION: While 6% of patients had MDIS, only 1% had MDAS. MDIS was associated with both anxiety and depression; patients with both anxiety and depression had an almost twofold increased odds of MDIS. MDAS was associated with a 40% increased odds of depression, but there was no significant association with anxiety. Psychological assessments may be useful in the evaluation and treatment of patients with MDIS and MDAS; physiologic causes for MDAS warrant further investigation.

Evaluation of avoralstat, an oral kallikrein inhibitor, in a Phase 3 hereditary angioedema prophylaxis trial: The OPuS-2 study.

BACKGROUND: Effective inhibition of plasma kallikrein may have significant benefits for patients with hereditary angioedema due to deficiency of C1 inhibitor (C1-INH-HAE) by reducing the frequency of angioedema attacks. Avoralstat is a small molecule inhibitor of plasma kallikrein. This study (OPuS-2) evaluated the efficacy and safety of prophylactic avoralstat 300 or 500 mg compared with placebo. METHODS: OPuS-2 was a Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Subjects were administered avoralstat 300 mg, avoralstat 500 mg, or placebo orally 3 times per day for 12 weeks. The primary efficacy endpoint was the angioedema attack rate based on adjudicator-confirmed attacks. RESULTS: A total of 110 subjects were randomized and dosed. The least squares (LS) mean attack rates per week were 0.589, 0.675, and 0.593 for subjects receiving avoralstat 500 mg, avoralstat 300 mg, and placebo, respectively. Overall, 1 subject in each of the avoralstat groups and no subjects in the placebo group were attack-free during the 84-day treatment period. The LS mean duration of all confirmed attacks was 25.4, 29.4, and 31.4 hours for the avoralstat 500 mg, avoralstat 300 mg, and placebo groups, respectively. Using the Angioedema Quality of Life Questionnaire (AE-QoL), improved QoL was observed for the avoralstat 500 mg group compared with placebo. Avoralstat was generally safe and well tolerated. CONCLUSIONS: Although this study did not demonstrate efficacy of avoralstat in preventing angioedema attacks in C1-INH-HAE, it provided evidence of shortened angioedema episodes and improved QoL in the avoralstat 500 mg treatment group compared with placebo.

Impregnation of catheters with anacardic acid from cashew nut shell prevents Staphylococcus aureus biofilm development.

AIM: The effect of anacardic acid impregnation on catheter surfaces for the prevention of Staphylococcus aureus attachments and biofilm formations were evaluated. METHODS AND RESULTS: Silicon catheter tubes were impregnated using different concentrations of anacardic acids (0·002-0·25%). Anacardic acids are antibacterial phenolic lipids from cashew nut (Anacardium occidentale) shell oil. Anacardic acid-impregnated silicon catheters revealed no significant haemolytic activity and were cytocompatible against fibroblast cell line (L929). Sustained release of anacardic acids was observed for 4 days. Anacardic acid-impregnated silicon catheters efficiently inhibited S. aureus colonization and the biofilm formation on its surface. The in vivo antibiofilm activity of anacardic acid-impregnated catheters was tested in an intraperitoneal catheter-associated medaka fish infection model. Significant reduction in S. aureus colonization on anacardic acid-impregnated catheter tubes was observed. CONCLUSIONS: Our data suggest that anacardic acid-impregnated silicon catheters may help in preventing catheter-related staphylococcal infections. SIGNIFICANCE AND IMPACT OF THE STUDY: This study opens new directions for designing antimicrobial phytochemical-coated surfaces with ideal antibiofilm properties and could be of great interest for biomedical research scientists.

Oligomerization of FVFLM peptides and their ability to inhibit beta amyloid peptides aggregation: consideration as a possible model.

Preeclampsia, a pregnancy-specific disorder, shares typical pathophysiological features with protein misfolding disorders including Alzheimer's disease. Characteristic for preeclampsia is the involvement of multiple proteins of which fragments of SERPINA1 and ß-amyloid co-aggregate in urine and placenta of preeclamptic women. To explore the biophysical basis of this interaction, we investigated the multidimensional efficacy of the FVFLM sequence in SERPINA1, as a model inhibitory agent of ß-amyloid aggregation. After studying the oligomerization of FVFLM peptides using all-atom molecular dynamics simulations with the GROMOS43a1 force field and explicit water, we report that FVFLM can aggregate and its aggregation is spontaneous with a remarkably faster rate than that recorded for KLVFF (aggregation "hot-spot" from ß-amyloid). The fast kinetics of FVFLM aggregation was found to be driven primarily by core-like aromatic interactions originating from the anti-parallel orientation of complementarily uncharged strands. The conspicuously stable aggregation mechanism observed for FVFLM peptides is found not to conform to the popular 'dock-lock' scheme. We also found high propensity of FVFLM for KLVFF binding. When present, FVFLM disrupts the ß-amyloid aggregation pathway and we propose that FVFLM-like peptides might be used to prevent the assembly of full-length Aß or other pro-amyloidogenic peptides into amyloid fibrils.

Repeat treatment of acute hereditary angioedema attacks with open-label icatibant in the FAST-1 trial.

Hereditary angioedema (HAE) is characterized by potentially life-threatening recurrent episodes of oedema. The open-label extension (OLE) phase of the For Angioedema Subcutaneous Treatment (FAST)-1 trial (NCT00097695) evaluated the efficacy and safety of repeated icatibant exposure in adults with multiple HAE attacks. Following completion of the randomized, controlled phase, patients could receive open-label icatibant (30 mg subcutaneously) for subsequent attacks. The primary end-point was time to onset of primary symptom relief, as assessed by visual analogue scale (VAS). Descriptive statistics were reported for cutaneous/abdominal attacks 1-10 treated in the OLE phase and individual laryngeal attacks. Post-hoc analyses were conducted in patients with ≥ 5 attacks across the controlled and OLE phases. Safety was evaluated throughout. During the OLE phase, 72 patients received icatibant for 340 attacks. For cutaneous/abdominal attacks 1-10, the median time to onset of primary symptom relief was 1·0-2·0 h. For laryngeal attacks 1-12, patient-assessed median time to initial symptom improvement was 0·3-1·2 h. Post-hoc analyses showed the time to onset of symptom relief based on composite VAS was consistent across repeated treatments with icatibant. One injection of icatibant was sufficient to treat 88·2% of attacks; rescue medication was required in 5·3% of attacks. No icatibant-related serious adverse events were reported. Icatibant provided consistent efficacy and was well tolerated for repeated treatment of HAE attacks.

Classification, diagnosis, and approach to treatment for angioedema: consensus report from the Hereditary Angioedema International Working Group.

Angioedema is defined as localized and self-limiting edema of the subcutaneous and submucosal tissue, due to a temporary increase in vascular permeability caused by the release of vasoactive mediator(s). When angioedema recurs without significant wheals, the patient should be diagnosed to have angioedema as a distinct disease. In the absence of accepted classification, different types of angioedema are not uniquely identified. For this reason, the European Academy of Allergy and Clinical Immunology gave its patronage to a consensus conference aimed at classifying angioedema. Four types of acquired and three types of hereditary angioedema were identified as separate forms from the analysis of the literature and were presented in detail at the meeting. Here, we summarize the analysis of the data and the resulting classification of angioedema.

Synthesis and antioxygenic activities of seabuckthorn flavone-3-ols and analogs.

A practical synthesis of polyhydroxy- and regiospecifically methylated flavone-3-ols which are components of commercial 'seabuckthorn flavone' has been achieved by modified Algar-Flynn-Oyamada method. Antioxidant activities of seabuckthorn extracts, isolated products and a number of flavone-3-ols have been determined. Structure-activity relationships have been discussed. Amongst the compounds tested, gallic acid, which is also present in seabuckthorn, was found to be the most effective antioxidant and radioprotectant.

Isolation and characterization of larvicidal principle of garlic.

The larvicidal principles of garlic, Allium sativum L.,have been isolated and identified as diallyl disulfide and diallyl trisulfide. Both natural and synthetic samples of these larvicides are fatal at 5 parts per million to Culex pipiens quinquefasciatus Say.

Evaluating putative ecological drivers of microcystin spatiotemporal dynamics using metabarcoding and environmental data.

Microcystin is a cyanobacterial hepatotoxin of global concern. Understanding the environmental factors that cause high concentrations of microcystin is crucial to the development of lake management strategies that minimize harmful exposures. While the literature is replete with studies linking cyanobacterial production of microcystin to changes in various nutrients, abiotic stressors, grazers, and competitors, no single biotic or abiotic factor has been shown to be reliably predictive of microcystin concentrations in complex ecosystems. We performed random forest regression analyses with 16S and 18S rRNA gene sequencing data and environmental data to determine which putative ecological drivers best explained spatiotemporal variation in total microcystin and several individual congeners in a eutrophic freshwater reservoir. Model performance was best for predicting concentrations of the congener MC-LR, with ca. 88% of spatiotemporal variance explained. Most of the variance was associated with changes in the relative abundance of the cyanobacterial genus Microcystis. Follow-up RF regression analyses revealed that factors that were the most important in predicting MC-LR were also the most important in predicting Microcystis population dynamics. We discuss how these results relate to prevailing ecological hypotheses regarding the function of microcystin.

New synthetic precocenoids as potential insect control agents.

Ageratochromes or precocenes are known for their insect growth regulating (IGR) activity. The present investigation was taken up with an objective to look for the lead structure in these compounds which can be elaborated synthetically to obtain useful growth regulators for practical purposes. With this in mind, some variants of precocenes were synthesized in the laboratory and tested for their toxicity and growth regulating activity using red cotton bug Dysdercus koenigii as the test insect. Most of the precocenoids showed toxicity of various degree and metamorphic derangements to different extents. Adults emerging from treated nymphs could not complete the normal life span. Among the compounds tested 8-acetyl-7-hydroxy-5-methoxy-dimethylchromene (alloevodinol) was more toxic and also showed developmental defects at very low dose such as 0.5 mg l(-1)/nymph. Precocene II (6, 7-dimethoxy-2, 2-dimethylchromene) was used as the standard compound. It was the least toxic and showed effects at 30 mg l(-1)/nymph.

Percutaneous Closure of Perimembranous Ventricular Septal Defect with Amplatzer Device.

BACKGROUND: The Amplatzer perimembranous ventricular septal occluder is an innovative device for percutaneous closure of perimembranous ventricular septal defects (PMVSD). In appropriately selected cases this procedure is safe and effective. METHODS: Fourteen patients with the mean age 10.53 years (range 18 months to 55 years) and mean body weight 20.64 kg (range 6 to 52 kg) underwent PMVSD closure. RESULT: The PMVSD mean diameter was 5.28 mm (range from 4 to 9 mm). Implantation was successful in 92% of the cases and all patients had complete occlusion of the shunt within three months. CONCLUSION: Device orientation was excellent in all cases. Device-related aortic insufficiency, tricuspid insufficiency or left ventricular dysfunction was not observed. One patient had embolisation of the device and another had complete heart block which required a permanent pacemaker implantation. The excellent short term results need to be confirmed over long-term follow-up.

Spatial and temporal dynamics of a freshwater eukaryotic plankton community revealed via 18S rRNA gene metabarcoding.

DNA metabarcoding is a sophisticated molecular tool that can enhance biological surveys of freshwater plankton communities by providing broader taxonomic coverage and, for certain groups, higher taxonomic resolution compared to morphological methods. We conducted 18S rRNA gene metabarcoding analyses on 214 water samples collected over a four-month period from multiple sites within a freshwater reservoir. We detected 1,314 unique operational taxonomic units that included various metazoans, protists, chlorophytes, and fungi. Alpha diversity differed among sites, suggesting local habitat variation linked to differing species responses. Strong temporal variation was detected at both daily and monthly scales. Diversity and relative abundance patterns for several protist groups (including dinoflagellates, ciliates, and cryptophytes) differed from arthropods (e.g., cladocerans and copepods), a traditional focus of plankton surveys. This suggests that the protists respond to different environmental dimensions and may therefore provide additional information regarding ecosystem status. Comparison of the sequence-based population survey data to conventional-based data revealed similar trends for taxa that were ranked among the most abundant in both approaches, although some groups were missing in each data set. These results highlight the potential benefit of supplementing conventional biological survey approaches with metabarcoding to obtain a more comprehensive understanding of freshwater plankton community structure and dynamics.

Is third-time heart retransplantation justifiable?

Since repeat heart transplantation traditionally carries higher risk than primary engraftment, we tested the hypothesis that third-time cardiac allograft transplantation is associated with prohibitive mortality and morbidity. The cohort of all third-time cardiac retransplants performed at our institution (n=3) and reported to UNOS from 1987 to 2002 (n=10) was reviewed. The primary endpoints were early and late mortality. Extending the study frame through 2003 captures a total of 5 and 15 third-time heart transplant recipients in UCLA and UNOS databases, respectively. Of the 15 patients undergoing third-time retransplants, preoperatively one was ventricular assist device-dependent, four were on intravenous inotropes, and two had creatinine levels greater than 2.5. Additionally, four were male recipients of female donor hearts and the mean donor ischemic time was 2.6 hours. One patient was diagnosed with acute allograft rejection, 13 with coronary artery vasculopathy/chronic rejection, and one with primary graft failure. At our institution, five patients underwent a third heart transplant. There was no early or hospital mortality. One patient died late from transplant coronary artery disease and another following a fourth allograft. The mortality rate for third-time heart allograft recipients is acceptable. These results are influenced by small sample size, younger age, case selection, and operations at select, high-volume institutions with significant experience.

On the involvement of intramolecular protein disulfide in the irreversible inactivation of 3-hydroxy-3-methylglutaryl-CoA reductase by diallyl disulfide.

Treatment with diallyl disulfide, a constituent of garlic oil, irreversibly inactivated microsomal and a soluble 50 kDa form of HMG-CoA reductase. No radioactivity was found to be protein-bound on treating the soluble enzyme with [35S]diallyl disulfide, indicating the absence of the mixed disulfide of the type allyl-S-S-protein. SDS-PAGE and Western blot analyses of the diallyl-disulfide-treated protein showed no traces of the dimer of the type protein-S-S-protein, but clearly indicated BME-reversible increased mobility, as expected of an intramolecular protein disulfide. The sulfhydryl groups, as measured by alkylation with iodo[2-14C]acetic acid, were found to decrease in the diallyl-disulfide-treated enzyme protein. Tryptic peptide analysis also gave support for the possible presence of disulfide-containing peptides in such a protein. It appears that diallyl disulfide inactivated HMG-CoA reductase by forming an internal protein disulfide that became inaccessible for reduction by DTT, and thereby retaining the inactive state of the enzyme.

The nature of inhibition of 3-hydroxy-3-methylglutaryl CoA reductase by garlic-derived diallyl disulfide.

A concentration dependent inhibition of 3-hydroxy-3-methylglutaryl CoA (HMG CoA) reductase was found on preincubation of microsomal preparations with diallyl disulfide, a component of garlic oil. This inhibited state was only partially reversed even with high concentrations of DTT. Glutathione, a naturally occurring reducing thiol agent, was ineffective. The substrate, HMG CoA, but not NADPH, was able to give partial protection for the DTT-dependent, but not glutathione-dependent activity. The garlic-derived diallyl disulfide is the most effective among the sulfides tested for inhibition of HMG CoA reductase. Formation of protein internal disulfides, inaccessible for reduction by thiol agents, but not of protein dimer, is likely to be the cause of this inactivation.