Methylphenidate for attention-deficit/hyperactivity disorder in patients with Smith-Magenis syndrome: protocol for a series of N-of-1 trials.

BACKGROUND: Smith-Magenis syndrome (SMS) is a rare genetic neurodevelopmental disorder characterized by intellectual disability and severe behavioural and sleep disturbances. Often, patients with SMS are diagnosed with attention-deficit/hyperactivity disorder (ADHD). However, the effectiveness of methylphenidate (MPH), the first-line pharmacological treatment for ADHD, in patients with SMS is unclear. Our objective is to examine the effectiveness of MPH for ADHD symptoms in individuals with SMS, proposing an alternative trial design as traditional randomized controlled trials are complex in these rare and heterogeneous patient populations. METHODS AND ANALYSIS: We will initiate an N-of-1 series of double-blind randomized and placebo-controlled multiple crossover trials in six patients aged ≥ 6 years with a genetically confirmed SMS diagnosis and a multidisciplinary established ADHD diagnosis, according to a power analysis based on a summary measures analysis of the treatment effect. Each N-of-1 trial consists of a baseline period, dose titration phase, three cycles each including randomized intervention, placebo and washout periods, and follow-up. The intervention includes twice daily MPH (doses based on age and body weight). The primary outcome measure will be the subscale hyperactivity/inattention of the Strengths and Difficulties Questionnaire (SDQ), rated daily. Secondary outcome measures are the shortened version of the Emotion Dysregulation Inventory (EDI) reactivity index, Goal Attainment Scaling (GAS), and the personal questionnaire (PQ). Statistical analysis will include a mixed model analysis. All subjects will receive an assessment of their individual treatment effect and data will be aggregated to investigate the effectiveness of MPH for ADHD in SMS at a population level. CONCLUSIONS: This study will provide information on the effectiveness of MPH for ADHD in SMS, incorporating personalized outcome measures. This protocol presents the first properly powered N-of-1 study in a rare genetic neurodevelopmental disorder, providing a much-needed bridge between science and practice to optimize evidence-based and personalized care. TRIAL REGISTRATION: This study is registered in the Netherlands Trial Register (NTR9125).

Sensitization to triglycidylisocyanurate (TGIC) with cutaneous and respiratory manifestations.

The case is presented of a man with allergic contact dermatitis and occupational asthma due to triglycidylisocyanurate (TGIC), which is used as a hardener in thermosetting powder paint. The contact dermatitis was confirmed by patch testing (TGIC 0.5% and 5% in petrolatum), and the occupational asthma was confirmed by bronchial provocation testing: two challenges to an aerosol of lactose containing TGIC (0.05% and 0.1%, w/w, each for 0.5+1+2+4 min) led to a maximal decrease in FEV1 of 22% and 31% after 6 and 4 h, respectively. Skin prick tests with unconjugated TGIC were possibly positive. This case confirms that exposure to TGIC in powder paints may cause not only contact dermatitis, but also occupational asthma.

The alpha 6 beta 1 (VLA-6) and alpha 6 beta 4 protein complexes: tissue distribution and biochemical properties.

A member of the integrin family, the alpha 6 beta 4 complex was previously identified on human and mouse carcinoma cell lines by using a rat monoclonal antibody to alpha 6. Here we describe two monoclonal antibodies that recognize epitopes on the beta 4 subunit of the human and mouse alpha 6 beta 4 complexes. The monoclonal antibodies against beta 4 were able to preclear alpha 6 beta 4, but not alpha 6 beta 1 from cell line extracts. A substantial fraction of the total beta 4 subunits present on the cell surface was not associated with alpha 6, as it could not be removed by anti-alpha 6 antibodies, but remained precipitable with anti-beta 4 antibodies. There was no evidence for novel alpha subunits associated with beta 4. The alpha 6 subunit consists of disulfide-linked heavy and light chains. The variability in size of these two chains from different cell types is largely due to differences in modifications of N-linked glycans. Additional heterogeneity may be caused by differential proteolytic cleavage of the alpha 6 precursor. Immunoperoxidase staining of tissue sections of neonatal and adult mice revealed that beta 4 expression is limited to epithelial tissues and peripheral nerves. The alpha 6 subunit has a wider distribution that includes all tissues and cells stained by antibodies against beta 4. Cells and tissue that are positive for alpha 6, but negative for beta 4, may express the alpha 6 beta 1 complex.

Integrin recognition of different cell-binding fragments of laminin (P1, E3, E8) and evidence that alpha 6 beta 1 but not alpha 6 beta 4 functions as a major receptor for fragment E8.

The involvement of integrins in mediating interaction of cells to well-characterized proteolytic fragments (P1, E3, and E8) of laminin was assessed by antibody blocking studies. Cell adhesion to fragment P1 was affected by mAbs against the integrin beta 1 and beta 3 subunits and furthermore could be prevented completely by a synthetic peptide containing the Arg-Gly-Asp sequence. Because the beta 3 antibody-sensitive cell lines expressed the vitronectin receptor (alpha v beta 3) at high levels, the involvement of this receptor in cell adhesion to P1 is strongly suggested. Integrin-mediated cell adhesion to E3 is of low affinity and was inhibited by antibodies against the integrin beta 1 subunit. In contrast, adhesion of some cell types to E3 was not or only partially sensitive to inhibition by anti-integrin subunit antibodies. Cell adhesion to E8 was blocked completed by integrin alpha 6 or beta 1 antibodies. The alpha 6-specific antibody did not inhibit cell adhesion to E3 or P1. Furthermore, the antibody only blocked adhesion to laminin of those cells that adhered exclusively to the E8 fragment. In addition, expression of alpha 6 beta 1 was closely correlated with the ability of cells to bind to the E8 fragment of laminin. These results indicate that the alpha 6 beta 1 integrin is a specific receptor for the E8 fragment of laminin. Many cell types expressed, instead of or in addition to alpha 6 beta 1 the recently described integrin alpha 6 beta 4. Although the ligand of alpha 6 beta 4 was not identified, it must be different from that of alpha 6 beta 1, because cells that express alpha 6 beta 4, but not alpha 6 beta 1, do not adhere to E8, and cell adhesion to E8 was specifically blocked by beta 1 specific antibodies. In conclusion, the data indicate that distinct integrin receptors belonging to the beta 1 or beta 3 subfamily are involved in adhesion of cells to the various laminin fragments. Adhesion to E3 may also be brought about by other receptor molecules, possibly proteoglycans, not belonging to the integrin family.

A comparison of glassy-carbon and carbon-polymer composite electrodes incorporated into electrochemical detection systems for high-performance liquid chromatography.

A comparison has been made of the performance of a novel composite carbon-polymer electrode and a glassy-carbon electrode for use as working electrodes in an electrochemical detector for HPLC. The composite electrode was found to be comparable to the glassy-carbon electrode in terms of current response, superior in terms of cost, machinability, noise levels, stabilization time and accessible potential range, and inferior in terms of the potentials required for the oxidation of certain model compounds such as epinephrine and norepinephrine.