Measurement in saliva from neurotypical adults of biomarkers pertinent to autism spectrum disorders.

AIM: Measure biomarkers pertinent to autism in saliva from humans. MATERIALS & METHODS: At 7:30 PM (reading instructions) and 8:30 PM (hearing instructions), neurotypical adults (6 M, 6 F) each spat into tubes containing protease inhibitors. Cells were counted, samples aliquoted, frozen and thawed. Rationale was given for choice of biomarkers. ELISA: CD26, IL-12, carnitine, C4B, GSH, GSSG, MT-2, testosterone, IFN-γ. Mass spectrometry: cystine, glutamine, glutamic acid, GABA, serotonin. Electrochemiluminescentimmunoassay: cortisol. Radioimmunoassay: melatonin. RESULTS: Cells averaged 2.16 × 106/ml. M > F: CD-26, C4B, MT-2. Testosterone, cortisol. Glutamine, glutamic acid, IFN-γ, melatonin and GSSG were measurable. Remaining biomarkers were measured in <50% of samples. Concentrations were equal at both times. CONCLUSION: Saliva can be collected by literate individuals without added instruction. Ten biomarkers were measurable.

Drug-induced hypersensitivity: role in drug development.

Drug-induced hypersensitivity is an adverse reaction, characterised by damaging immune-mediated responses, initiated by medicine given at therapeutic doses for prevention, diagnosis or treatment. Immune-mediated drug hypersensitivity accounts for 6-10% of the adverse drug reactions, which rank between the fourth and sixth leading causes of death in the US. With <10% of all adverse drug reactions reported, the magnitude of the problem is significant, with estimates of costs >$US30 billion annually in the US (1995 value). In addition, the costs of not determining the potential of a drug to produce hypersensitivity in the pre-clinical phase of drug development can be substantial. It has been estimated that the pre-clinical phase and clinical phase I, phase II and phase III costs are approximately $US6 million, $US12 million, $US12 million and $US100 million per drug, respectively (1999 values). It is important that investigational drugs with the potential to produce hypersensitivity reactions be identified as early in the development process as possible. Some adverse reactions to drugs can be avoided if drug-drug interactions are known or if there is a structure-activity relationship established. However, these methods are inadequate. Appropriate animal models of drug-induced hypersensitivity are needed, especially because hypersensitivity has been cited as the leading reason for taking drugs off the market. It is of critical importance to be able to predict hypersensitivity reactions to drugs. Most anaphylactic reactions occur in atopic individuals. Similarly, patients who have experienced other hypersensitivity reactions are more likely to have recurrent reactions. Therefore, animal models should be considered that predispose the animal to the reaction, such as the use of appropriate adjuvants and species. Using known positive controls of varying strengths, the investigator can rank the reaction against the positive controls as standards. This approach might yield greater results in a shorter period of time than using novel models. For the greatest safety, use of well understood models that have been thoroughly validated is imperative.

Theoretical aspects of autism: causes--a review.

Autism, a member of the pervasive developmental disorders (PDDs), has been increasing dramatically since its description by Leo Kanner in 1943. First estimated to occur in 4 to 5 per 10,000 children, the incidence of autism is now 1 per 110 in the United States, and 1 per 64 in the United Kingdom, with similar incidences throughout the world. Searching information from 1943 to the present in PubMed and Ovid Medline databases, this review summarizes results that correlate the timing of changes in incidence with environmental changes. Autism could result from more than one cause, with different manifestations in different individuals that share common symptoms. Documented causes of autism include genetic mutations and/or deletions, viral infections, and encephalitis following vaccination. Therefore, autism is the result of genetic defects and/or inflammation of the brain. The inflammation could be caused by a defective placenta, immature blood-brain barrier, the immune response of the mother to infection while pregnant, a premature birth, encephalitis in the child after birth, or a toxic environment.

Theoretical aspects of autism: biomarkers--a review.

Autism is dramatically increasing in incidence and is now considered an epidemic. There are no objective means to diagnose the disorder. Diagnosis is made subjectively, based on the perceived behavior of the subject. This review presents an approach toward development of an objective measure of autism. Covering the literature from 1943 to the present in the PubMed and Ovid Medline databases, this review summarizes evidence of hormones, metabolites, amino acids, and other biomarkers present in significantly different quantities in autistic subjects compared to age- and sex-matched controls. These differences can be measured in the gastrointestinal, immunologic, neurologic, and toxicologic systems of the body, with some biomarkers showing ubiquitous application. In addition, there are unifying concepts, i.e., increased vulnerability to oxidative stress, immune glutamatergic dysfunction, and pineal gland malfunction. The variances of the biomarkers from the norm present the opportunity to create biomarker arrays that when properly developed and analyzed could result in an objective diagnosis with a ranking of the severity of autism for each subject. The contribution of each biomarker to the overall diagnosis could be calculated, thus providing a profile pattern unique to the individual. This profile could consequently provide information for therapeutic interventions on an individual basis.

Mechanisms and biomarkers of cardiovascular injury induced by phosphodiesterase inhibitor III SK&F 95654 in the spontaneously hypertensive rat.

The cardiovascular injury of the type III selective PDE inhibitor SK&F 95654 was investigated in SHR. Twenty-four hours after a single sc injection of 100 or 200 mg/kg of the drug, rats exhibited cardiomyocyte necrosis and apoptosis, interstitial inflammation, hemorrhage and edema, as well as mesenteric arterial hemorrhage and necrosis, periarteritis, EC and VSMC apoptosis, EC activation, and MC activation and degranulation. Elevated serum levels of cTnT and decreased cTnT immunoperoxidase staining on cardiomyocytes were detected in the drug-treated rats. Serum levels of alpha2-macroglobulin and IL-6 were significantly elevated following drug treatment. NMR spectral patterns of urine samples are significantly different between the drug-treated and control rats. These results indicate that measurement of serum cTnT, acute phase proteins, and cytokines as well as metabonomic urine profiles may serve as potential biomarkers for drug-induced cardiovascular injury in rats. Increased expression of CD63 on MC (tissue biomarker of MC), of nitrotyrosine on MC and EC (an indirect indicator of NO in vivo), and of iNOS on MC and EC (source of NO) suggest that NO produced by activated and degranulated MC as well as activated EC play an important role in SK&F 95654-induced mesenteric vascular injury.