The DSC results indicate that the CLB/polymer interactions are at

The DSC results indicate that the CLB/polymer interactions are at the molecular level. Loading CLB into these polymers results in an evident increase in their glass

transition temperatures, and Delta T(g) depends on the beta-CD content. The controlled-release experiments show that the presence of beta-CD can appropriately slow the release of CLB from HPMA-beta-CDs and adjust the ratio of CLB released in total drug loading.”
“Purpose: To compare the safety and efficacy of removing 5000 centistokes silicone oil between 20-gauge and 25-gauge vitrectomy technique.\n\nMethods: Prospective case series of 34 consecutive patients undergoing 5000 centistokes silicone oil removal Transmembrane Transporters inhibitor using 20-gauge or 25-gauge cannulas. The main outcome measures were the safety and efficacy of silicone oil removal. The safety was evaluated by recording intraoperative and postoperative complication rates, including bleeding, recurrence of retinal detachment, hypotony, choroidal detachment, corneal edema, endophthalmitis, vitreous hemorrhage, conjunctival injection, and subconjunctival hemorrhage. The efficacy was judged by the ability to attain the complete

removal of silicone oil and the total surgical time to complete the procedure.\n\nResults: Sixteen patients underwent 20-gauge vitrectomy for the removal of 5000 centistokes silicone oil between January HDAC inhibitors list 2008 and January 2010, and 18 patients underwent 25-gauge vitrectomy for

the removal of 5000 centistokes silicone oil from January 2010 to August 2012. Silicone oil was successfully removed completely in all cases. Using 25-gauge vitrectomy to remove silicone oil was significantly more time efficient with the mean total surgical time of 25 +/- 6 minutes compared with 42 +/- 10 minutes in 20-gauge vitrectomy group (P click here < 0.05). There were no differences in the intraoperative or postoperative complication rates between the two groups. None of the patients developed postoperative recurrence of retinal detachment, hypotony, choroidal detachment, corneal edema, endophthalmitis, or vitreous hemorrhage.\n\nConclusion: Twenty-five-gauge silicone oil removal is safe and effective. Surgical time is significantly reduced using sutureless 25-gauge sclerotomies. This may translate to cost reduction by decreasing time spent in the operating room.”
“Aims: Gender differences are known to occur in the pharmacokinetics of many drugs. Mechanisms may include differences in body composition, body weight, cardiac output, hormonal status, and use of different co-medications. Recently subtle gender-dependent differences in cytochrome P450 (CYP) 3A-dependent metabolism have been demonstrated. Buprenorphine N-dealkylation to norbuprenorphine is primarily performed by CYP3A. We therefore asked whether gender-dependent differences occur in the pharmacokinetics of buprenorphine.

The Bw4 epitope of HLA-B*5101 and HLA-B*1513 is determined by the

The Bw4 epitope of HLA-B*5101 and HLA-B*1513 is determined by the NIALR sequence motif at positions 77, 80, 81, 82, and 83 in the a, helix. Mutation of these positions to the residues present in the alternative and nonfunctional Bw6 motif showed that the functional this website activity of the Bw4 epitopes of B*5101 and B* 1513 is retained after substitution at positions 77, 80, and 81, but lost after substitution

of position 83. Mutation of leucine to arginine at position 82 led to loss of function for B*5101 but not for B*1513. Further mutagenesis, in which B*1513 residues were replaced by their B*5101 counterparts, showed that polymorphisms in all three extracellular domains contribute to this functional difference. Prominent were positions 67 in the alpha(1) domain, 116 in the alpha(2) domain, and 194 in the alpha(3) domain. Lesser contributions were made by additional

positions in the alpha(2) domain. These positions are not part of the Bw4 epitope and include residues shaping the B and F pockets that determine the sequence JQ-EZ-05 concentration and conformation of the peptides bound by HLA class I molecules. This analysis shows how polymorphism at sites throughout the HLA class I molecule can influence the interaction of the Bw4 epitope with KIR3DL1. This influence is likely mediated by changes in the peptides bound, which alter the conformation of the Bw4 epitope. The Journal of Immunology, 2008, Cilengitide 181: 6293-6300.”
“Dengue viruses cause two severe diseases that alter vascular fluid barrier functions, dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Preexisting antibodies to dengue virus disposes patients to immune-enhanced edema (DSS) or hemorrhagic (DHF) disease following infection by a discrete

dengue virus serotype. Although the endothelium is the primary vascular fluid barrier, direct effects of dengue virus on endothelial cells (ECs) have not been considered primary factors in pathogenesis. Here, we show that dengue virus infection of human ECs elicits immune-enhancing EC responses. Our results suggest that rapid early dengue virus proliferation within ECs is permitted by dengue virus regulation of early, but not late, beta interferon (IFN-beta) responses. The analysis of EC responses following synchronous dengue virus infection revealed the high-level induction and secretion of immune cells (T cells, B cells, and mast cells) as well as activating and recruiting cytokines BAFF (119-fold), IL-6/8 (4- to 7-fold), CXCL9/10/11 (45- to 338-fold), RANTES (724-fold), and interleukin-7 (IL-7; 128-fold). Moreover, we found that properdin factor B, an alternative pathway complement activator that directs chemotactic anaphylatoxin C3a and C5a production, was induced 34-fold. Thus, dengue virus-infected ECs evoke key inflammatory responses observed in dengue virus patients which are linked to DHF and DSS.

Here we describe serotype, multilocus sequence type (ST), and pen

Here we describe serotype, multilocus sequence type (ST), and penicillin susceptibility of thirty pneumococcal invasive disease isolates received by the University of Malaya Medical Centre between February 2000 and January 2007 and relate this to the serotypes included in current pneumococcal conjugate vaccines. A high level of diversity was observed; fourteen serotypes and 26 sequence

types (ST), (11 of which were not previously described) were Y-27632 purchase detected from 30 isolates. Penicillin non-susceptible pneumococci accounted for 33% of isolates. The extent of molecular heterogeneity within carried and disease-causing Malaysian pneumococci remains unknown. Larger surveillance www.selleckchem.com/ferroptosis.html and epidemiological studies are now required in this region to provide robust evidence on which to

base future vaccine policy.”
“This article provides a new model for predicting the surface tension of molten alkali halides, because the subject is worthy of investigation. A relationship exists between the surface tension (gamma) at the melting point (T (m) ), molar volume (V), internuclear distance (D), and radius ratio The basic idea results from the assumption that all of the parameters are constants. The relation depends on the reliability and accuracy of all the constants on which it is based. The formula was examined and showed remarkable agreement between the calculated surface tension and experimental data within a difference of less than 10 pct for most of the salts studied.”
“We present

simulations investigating the effects of solvent quality on the dynamics of flexible (RNA-like) and semi flexible (DNA-like) polymers ejecting from spherical viral capsids. We find that the mean ejection time increases and the ejection time distributions are broadened as the solvent quality decreases. Our results thus suggest that DNA ejection may be very efficiently controlled by tuning the salt concentration in the environment, in agreement with recent experimental findings. We also observe random pauses in the ejection. These become extremely long for semi flexible polymers at lower Selleck 5-Fluoracil solvent quality, and we interpret this as a signature of a low driving force for ejection. We find that, for most polymers, ejection is an all-or-nothing process at the solvent conditions we investigated: polymers normally completely eject once the process is initiated.”
“Nine Daphniphyllum alkaloids, including three new ones, paxiphyllines C-E (1-3, resp.), were isolated from the twigs and the leaves of Daphniphyllum paxianum. Paxiphylline C (1) represents the first example of Daphniphyllum alkaloids with a carbonyldioxy group. Their structures were elucidated on the basis of spectroscopic data.

Our a-priori hypothesis was that

Our a-priori hypothesis was that AICAR clinical trial schizophrenia patients would show an increased prevalence of the nontaster phenotype compared with controls. The genotypes of two nonsynonymous coding single-nucleotide polymorphisms in TAS2R38 were assayed for 176 schizophrenia patients and 229 healthy control individuals, and the two-allele haplotypes were estimated. There was an over-representation of the major PTC nontaster haplotype among patients of European descent, relative to control individuals of similar ancestry.

Patients and controls of African ancestry did not differ. The PTC nontaster haplotype is a genetic marker that may be used to identify subsets of schizophrenia patients who potentially harbor vulnerability genes in this region of chromosome 7q. Psychiatr Genet 22:286-289 (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.”
“Chagas disease is a major endemic disease caused by the protozoan parasite Trypanosoma cruzi. This parasitic disease is widely distributed throughout Latin America, affecting 10 million people. There are also reports of canine infection in the southern part of the United States. Dogs are considered the predominant domestic reservoir for 7: cruzi in many

areas of endemicity. In Mexico, CA4P inhibitor dog infection by this parasite has been poorly studied. In this work 209 dogs from six villages in Jalisco, Mexico, were assessed to detect anti-T cruzi antibodies by ELISA and Western blot. Seventeen (17) seropositive dogs (8.1 %) were detected by both tests, representing a seropositive value similar to that found in some southern states of Mexico where the infection is present. No statistical differences were observed concerning the age and sex of infected and non-infected dogs. The major antigens recognized by positive sera were 26, 32, 66 and 80 kDa. These proteins are candidates to develop a specific diagnostic method for canine Chagas.

No antibodies against HSP16 protein were found in 7: cruzi seropositive sera. This is the first report of canine serology of Chagas disease in this central part of Mexico. This report will contribute to the knowledge of the infection status of domestic reservoirs in Rabusertib in vivo the state of Jalisco, Mexico. (C) 2014 Asociacion Argentina de Microbiologia. Published by Elsevier Espana, S.L. All rights reserved.”
“Background: Slug, a regulator of epithelial mesenchymal transition, was identified to be differentially expressed in esophageal squamous cell carcinoma (ESCC) using cDNA microarrays by our laboratory. This study aimed to determine the clinical significance of Slug overexpression in ESCC and determine its correlation with clinicopathological parameters and disease prognosis for ESCC patients.

Geochemical and other data indicate that, at the time the dinosau

Geochemical and other data indicate that, at the time the dinosaurs first appeared, the atmospheric oxygen concentration was only about half of what it is today, and development of the avian-type respiratory system

may have been key in the dinosaurs’ evolutionary success, enabling them to out-compete the mammals and dominate the land for 150 million years.”
“(Early development of Dimorphandra wilsonii (Fabaceae Caesalpinioideae) in Cerrado under different soil fertility conditions). Dimorphandra wilsonii Rizz. is a critically endangered tree species. It has been described for sites of higher soil fertility in the Cerrado Domain. However, it occurs nowadays in isolated areas of low natural fertility. To study species adaptation to oligotrophic conditions, plants were grown in a greenhouse in soils from oligotrophic sites but with different levels of fertility. After soil fertility analysis, the macronutrients check details (NPK) and lime doses to be used in each treatment were defined, resulting in a combination of two liming levels and three fertilization levels. After 220 days, the treatments that significantly increased seedling growth were the one whose substrate was limed and fertilized with twice the prescribed NPK dosage, and the one with the indicated dosage of NPK but no liming. Liming itself did not EGFR signaling pathway promote growth enhancement, but favored increased growth response to increasing levels of

nutrient availability. Root nodules were found in all the treatments, and the results led to the conclusion that D. wilsonii nutritional requirements are consistent with its original distribution sites in the

Cerrado Domain. It was also possible to highlight nitrogen biological fixation, an unusual feature in Caesalpinioideae, as an adaptive strategy for survival in areas of low nutrient availability.”
“Parodiolyra is a member of Olyreae, a tribe of herbaceous bamboo species within the Poaceae. The genus has five species, four of which were previously regarded as belonging to Olyra L. Parodiolyra has a Neotropical distribution and only two species occur on forests in Eastern Brazil: P. micrantha (Kunth) Zuloaga & Davidse and P. ramosissima (Trin.) Soderstr. & Zuloaga, the first widely distributed in the Neotropics while the second is endemic to the state of Bahia. Leaf anatomy Selleck HDAC inhibitor of the two species was analysed with the aid of an optical microscope. The objective was to describe the microscopic characters and evaluate if they can be useful for the taxonomy of the genus. The observed anatomical structures did not differ from other genera of herbaceous bamboos, however some characters, both from the mesophyll and the epidermis, were useful to delimit the two species.”
“Background: Intensive care unit (ICU)-acquired pneumonia and ventilator-associated pneumonia (VAP) are associated with poor clinical and economic outcomes.

Biopsies were taken irrespective of the clinical features of weal

Biopsies were taken irrespective of the clinical features of weal eruption. Other diseases known to be associated with small-vessel vasculitis had previously been excluded.\n\nResults. Individual weals lasted < 24 h in 57.4% of patients, and pain or tenderness was reported only by 8.6%. Extracutaneous features were present in 81%, hypocomplementaemia in 11% and abnormalities of other laboratory parameters (i.e. raised erythrocyte sedimentation rate, microscopic haematuria) in 76.6%. Hydroxyzine was effective in only one patient. Both oral corticosteroids and cinnarizine were effective in a high percentage of the patients.\n\nConclusion. This diagnostic

this website approach allowed us to identify a large group (47 patients) with UV. Most did not present the clinical (prolonged duration

of weals and bruising) and laboratory features that have previously been described as characteristic of UV. Cinnarizine MAPK Inhibitor Library solubility dmso was found to be a valuable treatment option.”
“The association between ambient temperature and lung function in children with asthma is still uncertain. A panel of 270 children (aged 7-12 years) with asthma was recruited from six Australian cities. They performed three successive forced expiratory manoeuvres twice daily for 4 weeks. The highest peak expiratory flow rate (PEF) and forced expiratory volume in 1 s (FEV1) were stored for each session. During the same period, data were https://www.selleckchem.com/products/Staurosporine.html obtained

daily on ambient temperature, relative humidity and air pollution. Mixed models were used to examine the effects of temperature on lung function, controlling for individual characteristics and environmental factors. Ambient temperature was negatively related to both morning and evening PEF and FEV1 for 0-3 days lag. In general, the effects of temperature were stronger in males than in females for evening PEF, while the effects were stronger in females for evening FEV1. Children with asthma living in southern cities were more sensitive to high temperature than those in the northernmost city. Higher ambient temperature is associated with lower lung function in children with asthma. Preventive health policies will be required to protect children with asthma from increasingly frequent high temperatures.”
“The depth, pattern, timing and duration of unconsciousness, including sleep, vary greatly in inflammatory disease, and are regarded as reliable indicators of disease severity. Similarly, these indicators are applicable to the encephalopathies of sepsis, malaria, and trypanosomiasis, and to viral diseases such as influenza and AIDS. They are also applicable to sterile neuroinflammatory states, including Alzheimer’s disease, Parkinson’s disease, traumatic brain injury, stroke and type-2 diabetes, as well as in iatrogenic brain states following brain irradiation and chemotherapy.

001) However, TH increased phase singularity number (wavebreaks)

001). However, TH increased phase singularity number (wavebreaks) during VF (P<0.05) and Si pacing (P<0.05). TH resulted in earlier onset of APD alternans (P<0.001), which was predominantly SDA (P<0.05), and increased pacing-induced VF episodes (P<0.05). TH also decreased CV, shortened wavelength, and enhanced APD dispersion and the spatial heterogeneity of CV restitution.\n\nConclusions: TH (30 degrees C) increased the vulnerability of pacing-induced VF by (1) facilitating wavebreaks during VF and Si pacing, and (2) enhancing proarrhythmic electrophysiological parameters, including promoting

earlier onset of APD alternans (predominantly SDA) during Mizoribine manufacturer S1 pacing. (Circ J 2009; 73: 2214-2222)”
“Brain metastasis has become an increasing cause of

morbidity NCT-501 solubility dmso and mortality in cancer patients as the treatment of systemic disease has improved. Brain metastases frequently are highly vascularized, a process driven primarily by VEGF. VEGF mediates numerous changes within the vasculature including endothelial cell retraction and increased permeability, vasodilation, and new vessel formation. Here we describe a xenograft brain metastasis model that mimics the critical steps of metastasis including tumor cell dissemination and vascular adhesion, tumor growth and tumor associated angiogenesis. Magnetic resonance (MR) imaging was used to evaluate two aspects of the functional response of brain metastasis to the anti-VEGF receptor therapeutic, AZD2171 (Cediranib, RECENTIN (TM)). MR tracking of individual cells demonstrated that cediranib did not impede tumor

cell extravasation into the brain parenchyma despite evidence that anti-VEGF treatment decreases the permeability of the blood brain barrier. In a second assay, blood volume imaging using ultrasmall superparamagnetic iron oxide revealed that treatment of well-developed brain metastasis with cediranib for 7 days led to a heterogeneous response with respect to individual tumors. Overall, there was a significant average decrease in the tumor vascular bed volume. The majority of large tumors demonstrated substantially reduced central blood volumes relative to normal brain while retaining a rim of elevated blood volume at JQ-EZ-05 chemical structure the tumor brain interface. Small tumors or occasional large tumors displayed a static response. Models and assays such as those described here will be important for designing mechanism-based approaches to the use of anti-angiogenesis therapies for the treatment of brain metastasis.”
“Objective: We describe the short-term results of the patients who underwent transapical treatment of a paravalvular leak (PVL) in our centre. Background: Increasing experience with transapical aortic valve implantation has inspired us to explore this approach for prosthetic paravalvular leak reduction in high risk patients.

Considering the therapeutic

transplantation of OECs, howe

Considering the therapeutic

transplantation of OECs, however, the basic question to date is not ‘how’ to translate but rather ‘what’ Selleckchem Belnacasan to translate into clinical practice. The aim of the present article is to provide a summary of the current literature and to define the open issues relevant for translating basic research on OECs into clinical practice. (C) 2009 Elsevier Ireland Ltd. All rights reserved.”
“Background: Alterations in epigenetic marks, including methylation or acetylation, are common in human cancers. For many epigenetic pathways, however, direct measures of activity are unknown, making their role in various cancers difficult to assess. Gene expression signatures facilitate the examination of patterns of epigenetic pathway activation across and within human cancer types allowing Etomoxir better understanding of the relationships between these pathways.\n\nMethods: We used Bayesian regression to generate gene expression signatures from normal epithelial cells before and after epigenetic pathway activation. Signatures were applied to datasets from TCGA, GEO, CaArray, ArrayExpress, and the cancer cell line encyclopedia. For TCGA data, signature results were correlated with copy number variation and DNA methylation changes. GSEA

was used to identify biologic pathways related to the signatures.\n\nResults: We developed and validated signatures reflecting downstream effects of enhancer of zeste homolog 2 (EZH2), histone deacetylase( HDAC) 1, HDAC4, sirtuin 1(SIRT1), and DNA methyltransferase 2(DNMT2). By applying these

signatures to data from cancer cell lines and tumors in large public repositories, we identify those cancers that have the highest and lowest selleck inhibitor activation of each of these pathways. Highest EZH2 activation is seen in neuroblastoma, hepatocellular carcinoma, small cell lung cancer, and melanoma, while highest HDAC activity is seen in pharyngeal cancer, kidney cancer, and pancreatic cancer. Across all datasets studied, activation of both EZH2 and HDAC4 is significantly underrepresented. Using breast cancer and glioblastoma as examples to examine intrinsic subtypes of particular cancers, EZH2 activation was highest in luminal breast cancers and proneural glioblastomas, while HDAC4 activation was highest in basal breast cancer and mesenchymal glioblastoma. EZH2 and HDAC4 activation are associated with particular chromosome abnormalities: EZH2 activation with aberrations in genes from the TGF and phosphatidylinositol pathways and HDAC4 activation with aberrations in inflammatory and chemokine related genes.\n\nConclusion: Gene expression patterns can reveal the activation level of epigenetic pathways. Epigenetic pathways define biologically relevant subsets of human cancers. EZH2 activation and HDAC4 activation correlate with growth factor signaling and inflammation, respectively, and represent two distinct states for cancer cells.

The predominant SW aspect of the enigmatic dragonblood tree under

The predominant SW aspect of the enigmatic dragonblood tree underlines the importance of fog. Long-term weather observations by Socotri put these short-term meteorological observations into a longer perspective. Socotri informants also described the Selleckchem Prexasertib drought years when livestock populations crashed, after which windows of opportunities for the regeneration of dragonblood and other grazing-sensitive trees may have occurred. (C) 2010 Elsevier Ltd. All rights reserved.”
“In the current health care climate, economic and cultural conditions have created an

optimal opportunity to envision a new direction for nursing as a profession. Nurses find themselves at the formative stages of charting this new direction. The articulation of a professional practice model provides a framework for setting this new direction and thus the achievement of exemplary clinical outcomes. In this article, the authors describe the evolution of the professional

Tariquidar practice model at the Massachusetts General Hospital and how the model continues to be evaluated and modified over time by the nurses within the system.”
“Epilepsy remains a major medical problem for which there is no effective treatment. Oxidative damage plays an important role in epilepsy pathogenesis and may represent a target for treatment of epilepsy. Recent studies have suggested that nuclear factor learn more erythroid 2-related factor 2 (Nrf2) binds to antioxidant response element (ARE) to induce antioxidant and phase II detoxification enzymes under conditions of oxidative stress, which reduces oxidative damage and accumulation of toxic metabolites. This study evaluated the role of Nrf2-ARE signal pathway in protecting the brain from seizure-mediated damage. Wistar rats and Nrf2-deficient or control mice were chronic kindled in the amygdala. Sulforaphane (SF) was used to activate Nrf2-ARE signal pathway. The progression of kindling, the cognitive impairment and oxidative stress parameters were assessed to determine the extent of seizure-mediated

brain damage. Our results indicate that activation Nrf2-ARE signal pathway with SF in hippocampus suppressed the progression of amygdala kindling, and also ameliorated the cognitive impairment and oxidative stress induced by epileptic seizure. These observations suggest that Nrf2-ARE signal pathway may represent a strategic target for epilepsy therapies. Crown Copyright (C) 2013 Published by Elsevier B.V. All rights reserved.”
“Background: Surrogate decision makers (SDMs) face difficult decisions at end of life (EOL) for decisionally incapacitated intensive care unit (ICU) patients. Purpose: To identify and describe the underlying psychological processes of surrogate decision making for adults at EOL in the ICU. Methods: Qualitative case study design using a cognitive task analysis interviewing approach.

Through its Sustainable Immunization Financing Program, launched

Through its Sustainable Immunization Financing Program, launched in 2007, the Sabin Vaccine Institute is working

with fifteen African and Asian countries to establish stable internal funding for their immunization programs. The Sabin program advocates strengthening immunization programs through budget reforms, decentralization, and legislation. Six of the fifteen countries have 3-deazaneplanocin A inhibitor increased their national immunization budgets, and nine are preparing legislation to finance immunization sustainably. Lessons from this work with immunization programs may be applicable in other countries as well as to other health programs.”
“Ginsenoside Rb1 is generally recognized as one of the principal bioactive ingredients in ginseng and shows neuroprotective effects in various neurons. Endoplasmic reticulum (ER) stress is considered to play an important role in numerous neurodegenerative disorders. Recently, glucogen synthase kinase 3 beta (GSK3 beta) was reported to regulate ER stress-induced C/EBP homologous protein (CHOP) in neuronal cells. Therefore, in this study, we investigated the effects of ginsenoside Rb1 on GSK3 beta-mediated ER stress in high glucose-treated hippocampal neurons. Results from the MTT assay showed that treatment with 1 mu M Rb1 for 72 h protected neurons from high glucose-induced cell injury. Using western blot analysis, we found that treatment with Rb1 effectively inhibited

the phosphorylation of the high glucose-induced protein kinase RNA-like ER kinase (PERK) and of GSK3 beta, and reduced the level of the CHOP protein. The levels of these proteins were also decreased by treatment Vorinostat cost with the GSK3 beta inhibitor Licl. Rb1 also significantly decreased the mRNA expression of the gene CHOP, as shown by quantitative RT-PCR analysis. Taken together, the present results suggested that Rb1 may protect neurons from high glucose-induced cell damage by inhibiting GSK3 beta-mediated CHOP induction, providing a potentially new strategy for preventing and treating cognitive

impairment Bcl-2 protein caused by diabetes.”
“Subacute and subchronic toxicity of the herbicide Avalon (R), a mixture of bentazone and dicamba, were tested on rats. Avalon (R) was administered at dose levels of 250, 500 and 1000 mg/kg body weight/day for 28 and 90 days. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) activities were monitored together with biochemistry parameters. The results showed that the mixture caused increases in the activities of ALT, AST and ALP, elevated concentrations of sodium, albumin and albumin/globulin ratio in males. In females, ALT activity, cholesterol and phosphate levels were increased. The changes generally were dose related and, in most cases, females exhibited lower susceptibility than males. The effects of a mixture are, in the most cases, different from the effects of the individual substances.