An ethical analysis of divergent clinical approaches to the application of genetic testing for autism and schizophrenia.

Genetic testing to identify genetic syndromes and copy number variants (CNVs) via whole genome platforms such as chromosome microarray (CMA) or exome sequencing (ES) is routinely performed clinically, and is considered by a variety of organizations and societies to be a "first-tier" test for individuals with developmental delay (DD), intellectual disability (ID), or autism spectrum disorder (ASD). However, in the context of schizophrenia, though CNVs can have a large effect on risk, genetic testing is not typically a part of routine clinical care, and no clinical practice guidelines recommend testing. This raises the question of whether CNV testing should be similarly performed for individuals with schizophrenia. Here we consider this proposition in light of the history of genetic testing for ID/DD and ASD, and through the application of an ethical analysis designed to enable robust, accountable and justifiable decision-making. Using a systematic framework and application of relevant bioethical principles (beneficence, non-maleficence, autonomy, and justice), our examination highlights that while CNV testing for the indication of ID has considerable benefits, there is currently insufficient evidence to suggest that overall, the potential harms are outweighed by the potential benefits of CNV testing for the sole indications of schizophrenia or ASD. However, although the application of CNV tests for children with ASD or schizophrenia without ID/DD is, strictly speaking, off-label use, there may be clinical utility and benefits substantive enough to outweigh the harms. Research is needed to clarify the harms and benefits of testing in pediatric and adult contexts. Given that genetic counseling has demonstrated benefits for schizophrenia, and has the potential to mitigate many of the potential harms from genetic testing, any decisions to implement genetic testing for schizophrenia should involve high-quality evidence-based genetic counseling.

Soy Isoflavone Supplementation Increases Long Interspersed Nucleotide Element-1 (LINE-1) Methylation in Head and Neck Squamous Cell Carcinoma.

AIM: Soy isoflavones have been suggested as epigenetic modulating agents with effects that could be important in carcinogenesis. Hypomethylation of LINE-1 has been associated with head and neck squamous cell carcinoma (HNSCC) development from oral premalignant lesions and with poor prognosis. To determine if neoadjuvant soy isoflavone supplementation could modulate LINE-1 methylation in HNSCC, we undertook a clinical trial. METHODS: Thirty-nine patients received 2-3 weeks of soy isoflavone supplements (300 mg/day) orally prior to surgery. Methylation of LINE-1, and 6 other genes was measured by pyrosequencing in biopsy, resection, and whole blood (WB) specimens. Changes in methylation were tested using paired t tests and ANOVA. Median follow up was 45 months. RESULTS: LINE-1 methylation increased significantly after soy isoflavone (P < 0.005). Amount of change correlated positively with days of isoflavone taken (P = 0.04). Similar changes were not seen in corresponding WB samples. No significant changes in tumor or blood methylation levels were seen in the other candidate genes. CONCLUSION: This is the first demonstration of in vivo increases in tissue-specific global methylation associated with soy isoflavone intake in patients with HNSCC. Prior associations of LINE-1 hypomethylation with genetic instability, carcinogenesis, and prognosis suggest that soy isoflavones maybe potential chemopreventive agents in HNSCC.

Clinical enamel surface changes following an intra-oral acidic challenge.

OBJECTIVES: Investigation of early enamel erosion using replica impressions to compare changes in enamel surface topography in vivo prior to and over a 24 h period following acid challenge. METHOD: A single treatment, blinded, enamel replica clinical study was undertaken in 20 healthy subjects. Replica tooth impressions were taken at baseline, following acid challenge and 2, 4, 7 and 24 h post challenge. Subjects consumed 500 ml of acidic soft drink over 30 min. Scanning electron microscopy of surface tomography was characterised with a descriptive 5 point scale by four judges. Duplicate impressions were taken to assess reproducibility. RESULTS: 18 subjects had scorable sequences. Descriptive analyses showed erosive changes following acid consumption and reparative changes in the subsequent 24 h period. Comparing baseline replica to the 24 h replica, there were no significant differences (p=0.26) in tooth surface characteristics. Comparing the replica taken immediately following acidic challenge with the subsequent replicas at 2, 4, 7 and 24 h, showed clear reduction of erosive effects on the enamel surface at 2 h (p=0.02) and a highly significant reduction at 4, 7 and 24 h (p<0.001). CONCLUSION: This methodology demonstrated the ability to follow the progression and recovery of early erosive enamel lesions over 24 h being accurate and reproducible. This study suggests enamel repair commences within 2 h following a substantial acidic challenge and is completed 4-24 h later. After 24 h, the tooth surface appeared visibly indistinguishable from the original tooth surface, suggestive of a recovery process occurring. CLINICAL SIGNIFICANCE: Healthy erosive lifestyles often culminate in tooth wear. The time taken for enamel remineralisation following acidic challenge is unknown however, this study suggests the repair process is relatively slow following a substantial acidic challenge, and at least 4-24 h should elapse prior to further acidic consumption to allow for recovery.

Drug interactions in human neuropathic pain pharmacotherapy.

Current practice predicates the use of multiple drug combinations in the treatment of neuropathic pain. These combinations may be required because of multiple pain symptoms directly arising from neuropathic pathology, other symptoms attributable to the chronicity and severity of the patient's pain or conditions unrelated to their pain. A fear exists that combination drug use or the addition of a new drug to a therapeutic regimen may lead to increased drug toxicity or decreased efficacy. Many of the drug interactions of significance to neuropathic pain physicians involve the cytochromes P450 2D6 and 3A3/4 isoenzymes. Drug interactions should be more predictable based on the knowledge of which compounds induce, inhibit or are metabolized by specific cytochrome P450 enzymes. Mechanisms of induction or inhibition of biotransformation via the P450 hepatic enzyme system are discussed and various inducers, inhibitors and substrates relating to neuropathic pain pharmacotherapy are listed.

Steroid-sparing action of flurbiprofen: use of an additional parameter of joint scans with 99m technetium.

A double-blind placebo controlled trial was carried out in 14 steroid-dependent patients with rheumatoid arthritis to assess the effectiveness and steroid-sparing action of flurbiprofen over a 4-week period. During the first week, the patients' steroid dosage was stabilized at the minimum necessary to control symptoms. They were then treated with either 100 mg flurbiprofen or placebo 3-times daily for 3 weeks. Steroid dosage was initially reduced to 50% of the stabilized dose and reduced further if practicable, depending on therapeutic response. Clinical assessments were made, at weekly intervals, of pain, swelling, tenderness, erythema, range of movement, grip strength, walking time, and duration of morning stiffness. Joint scanning of 99mTc uptake was also measured before and after treatment in 11 patients. The results showed that whereas 3 out of 6 patients on placebo has distinct inflammatory flare-up, this did not occur in any of the 8 patients on flurbiprofen. Moreover, 3 of the flurbiprofen group showed improvement and a further reduction in steriod dosage was possible in 3 patients. Improvements in joint scans correlated well with the clinical findings in 6 of 11 patients.

Dipyrone versus paracetamol: a double-blind study in typhoid fever.

In a double-blind study in patients with typhoid fever 25 patients received 500 mg dipyrone and 28 received 500 mg paracetamol. Rectal temperature and pulse records were monitored every 30 min. The onset of anti-pyresis in patients given dipyrone (30 min) was significantly different from those given paracetamol (1 h). The area under the time-temperature curves was significantly greater for patients given dipyrone. The sum of the reduction in temperature at all times significantly favoured patients who had been given dipyrone. Both treatments were well tolerated.