Translational development of splice-modifying antisense oligomers.

INTRODUCTION: Antisense nucleic acid analogues can interact with pre-mRNA motifs and influence exon or splice site selection and thereby alter gene expression. Design of antisense molecules to target specific motifs can result in either exon exclusion or exon inclusion during splicing. Novel drugs exploiting the antisense concept are targeting rare, life-limiting diseases; however, the potential exists to treat a wide range of conditions by antisense-mediated splice intervention. Areas covered: In this review, the authors discuss the clinical translation of novel molecular therapeutics to address the fatal neuromuscular disorders Duchenne muscular dystrophy and spinal muscular atrophy. The review also highlights difficulties posed by issues pertaining to restricted participant numbers, variable phenotype and disease progression, and the identification and validation of study endpoints. Expert opinion: Translation of novel therapeutics for Duchenne muscular dystrophy and spinal muscular atrophy has been greatly advanced by multidisciplinary research, academic-industry partnerships and in particular, the engagement and support of the patient community. Sponsors, supporters and regulators are cooperating to deliver new drugs and identify and define meaningful outcome measures. Non-conventional and adaptive trial design could be particularly suited to clinical evaluation of novel therapeutics and strategies to treat serious, rare diseases that may be problematic to study using more conventional clinical trial structures.

Holistic assessment of women with hyperemesis gravidarum: A randomised controlled trial.

BACKGROUND: Hyperemesis gravidarum or severe nausea and vomiting of pregnancy affects women's physical, social and psychological wellbeing and often requires frequent hospital admissions. Current standard care may be too medically focussed to meet all of women's complex needs. AIM: The aim of this study is to test where using a validated questionnaire, the Hyperemesis Impact of Symptoms tool, delivered by a nurse to assess the overall effect of hyperemesis on an individual woman's life and to provide advice tailored to her specific needs, will help her cope better with her symptoms and reduce admissions to hospital. DESIGN: This study was a two arm randomised controlled trial in which women with hyperemesis from four hospitals were randomly allocated to one of two groups: (1) usual care and (2) usual care plus assessment with the Hyperemesis Impact of Symptoms questionnaire and a care plan tailored to their responses. PARTICIPANTS AND METHODS: Recruitment was from women who were admitted with hyperemesis gravidarum; diabetic women or those over 14 weeks gestation were excluded. Those who consented completed questionnaires to assess their quality of life and the severity of symptoms at baseline and at three time points over the following 6 weeks. RESULTS: Women's average social functioning, Hyperemesis Impact of Symptom scores and average number of admissions were not significantly different between either group. The average number of days in hospital for the questionnaire and tailored plan group was significantly lower, 4.97, compared with 6.14 in the usual care group. Using the questionnaire to plan individualised care was not associated with significant reduction in health care costs. CONCLUSION: Using the Hyperemesis Impact of Symptoms questionnaire to tailor a care plan to address women's individual needs was not associated with any significant improvements in the quality of life. The cost effectiveness analysis did not indicate that the questionnaire is cost saving. The Hyperemesis Impact of Symptoms questionnaire is a practical tool for nurses and midwives to assess the overall impact of hyperemesis gravidarum on the individual and could be useful for assessing symptoms and evaluating physical, social and psychological changes following treatment in either clinical or research settings.

Dietary supplementation with different vitamin C doses: no effect on oxidative DNA damage in healthy people.

BACKGROUND: Antioxidants are believed to prevent many types of disease. Some previous studies suggest that dietary supplementation with vitamin C results in a decrease in the level of one of the markers of oxidative damage-8-oxoguanine in the DNA of peripheral blood mononuclear cells (PBMC). AIM OF TRIAL: To investigate the effect of different dose levels of dietary supplementation with vitamin C on oxidative DNA damage. METHODS: A randomised double-blind placebo-controlled trial was carried out using three different levels (80, 200 and 400 mg) of dietary vitamin C supplementation in a healthy population of 160 volunteers; supplementation was for a period of 15 weeks followed by a 10 week washout period. Peripheral blood samples were obtained every 5 weeks from baseline to 25 weeks. RESULTS: An increase in PBMC vitamin C levels was not observed following supplementation in healthy volunteers. There was no effect found on 8-oxoguanine measured using HPLC with electrochemical detection for any of the three supplemented groups compared to placebo. 8-oxoadenine levels were below the limit of detection of the HPLC system used here. CONCLUSIONS: Supplementation with vitamin C had little effect on cellular levels in this group of healthy individuals, suggesting their diets were replete in vitamin C. The dose range of vitamin C used did not affect oxidative damage in PBMC DNA.

Extracorporeal whole body hyperthermia treatment of HIV patients, a feasibility study.

The literature supports that the retrovirus, Human Immunodeficiency Virus (HIV), which is thought to cause Acquired Immunodeficiency Syndrome (AIDS), is heat sensitive at temperatures which can be achieved in man. Invasive or non-invasive induction of whole body hyperthermia (WBH) has been used to treat an array of illnesses, primarily in the field of oncology, until recently. Non-invasive methods have proven to be less toxic than invasive means. However, new technology and refined patient management have shown a dramatic decrease in the side effects with extracorporeal whole body hyperthermia (EWBH). The Food and Drug Administration granted a prospective trial for six HIV positive/AIDS patients to undergo a single treatment of EWBH, with patients randomized to a core temperature of either 41 or 42 degrees C. All patients had failed antiretrovirals and experienced at least one episode of an opportunistic infection. Organetics, Ltd., PS-1 extracorporeal, centrifugal pump device was used to induce EWBH. Results of this feasibility study demonstrated the ability of this equipment and technique to induce EWBH with acceptable toxicity. It was not possible to assess efficacy in this small study.

Comparing abilities of children with profound hearing impairments to learn consonants using electropalatography or traditional aural-oral techniques.

Two groups of nine children with profound hearing impairments and low intelligibility were taught to produce the consonants /t,d,k,g,s,z,S/ using either electropalatographic (palatometry) or traditional aural-oral techniques. Testing was completed pre-, immediately post-, and 6 months post-treatment by examining productions of CV syllables (V = /i,a/) using electropalatography-determined linguapalatal contacts and listener identifications. Intelligibility was also measured using the CID Picture Speech Intelligibility Evaluation (SPINE) test. Both groups improved their consonant productions as a result of 26 50-minute sessions. Sessions were given twice daily over 3- to 4-week training periods. Immediately post-treatment, the electropalatography-trained subjects produced better consonants as measured by linguapalatal contact patterns and listener identifications. The linguapalatal-contact patterns learned by the electropalatography-trained group better matched normal speaker productions than did those of the traditionally trained group. Both groups showed equal improvement for both post-treatment conditions when tested with the CID SPINE test. Although further research is needed, the results of this study suggest that electropalatographic techniques are, at least, equal alternatives to traditional aural-oral speech training techniques for speakers with profound hearing impairments.

In vitro and in vivo inhibition of inositol monophosphatase by the bisphosphonate L-690,330.

We have previously described the synthesis of bisphosphonate-containing inhibitors of inositol monophosphatase. In the present study, a more detailed examination of the in vitro and in vivo properties of one of these compounds, L-690,330, is described. L-690,330 is a competitive inhibitor of inositol monophosphatase with a Ki, depending on the source of IMPase, of between 0.2 and 2 microM. Although approximately 1,000-fold more potent in vitro than lithium, in muscarinic ml receptor-transfected Chinese hamster ovary cells prelabelled with [3H]inositol, L-690,330 only produced 40% of the accumulation of [3H]inositol monophosphates achieved by lithium at the same concentration (10 mM), suggesting that the ability of L-690,330 to cross the cell membrane is limited. Nevertheless, under conditions of cholinergic stimulation (100 mg/kg of pilocarpine s.c.), high doses of L-690,330 were able to increase brain inositol(l)phosphate levels in vivo to three- to fourfold control levels. This effect was dose dependent (ED50 = 0.3 mmol/kg s.c.) and was maximal after 1 h. In peripheral tissues, the effects of L-690,330 on inositol(l)phosphate levels mimicked those of lithium both qualitatively and quantitatively. However, in the brain, the effects of L-690,330 were much less than seen with lithium, consistent with the blood-brain barrier restricting access of the polar L-690,330 into the CNS, thereby further limiting entry of compound into cells in the brain. In the future, it may be possible to develop prodrugs of this compound, which circumvent many of the cell permeability problems inherent in bisphosphonate compounds.

Visual feedback and lip-positioning skills of children with and without impaired hearing.

Interplay between visual feedback and lip-positioning skill was studied in 10 5- to 14-year-old children with normal hearing and 10 with severe to profound hearing impairment. With visual feedback, the subjects in both groups had similar response times and accuracy in matching six visually specified lip separation "targets." Special skill in processing visual information by the hearing-impaired subjects was suggested by higher velocities of lip movement toward the targets and shorter latencies in reaching the goal positions. In the responses of the hearing children, lip-closing movements were executed more accurately than opening movements both with and without visual feedback. In general, the findings showed that, given visually displayed lip-position targets and feedback from positioning actions, children can achieve the targets with high accuracy regardless of hearing status or prior speaking experience.