The effect of manual therapy on ankle dorsiflexion range of motion: A pilot crossover randomized trial.

INTRODUCTION: Restricted ankle dorsiflexion is common after lower limb injury. The aim of this pilot study was to investigate the effect of passive ankle joint mobilization and calf muscle massage on ankle dorsiflexion range of motion in adults with residual restricted dorsiflexion. The secondary aim was to assess the methodology of the pilot study to inform a larger clinical trial. METHOD: The study design was a randomized crossover trial with assessor blinding. Twenty-five healthy participants with a history of lower limb injury were included in the study. Ankle joint mobilization and calf muscle massage were applied for 5 min in a random order, one to two weeks apart. Ankle dorsiflexion was measured by using the weight-bearing lunge pre- and post-intervention (cm). Paired t-tests were used to analyze the effect of the manual therapy interventions on restricted ankles. A minimal detectable difference 95% (MMD95) was calculated. The pilot study was analyzed for suitability of inclusion criteria, blinding of assessors and the manual therapist, and the washout period. RESULTS: A significant increase in dorsiflexion was demonstrated for ankle joint mobilization (change score = 0.51 ± 0.76, p = 0.003) and calf muscle soft tissue massage (change score = 0.91 ± 1.07, p < 0.001). There was no difference in change scores between manual therapy techniques (mobilization 0.51 ± 0.76, massage 0.91 ± 1.07, p = 0.12). Evaluation of the pilot study revealed limitations to be modified in future studies. CONCLUSION: These preliminary data indicate ankle joint mobilization and calf muscle soft tissue massage had similar effects on increasing ankle dorsiflexion range of motion in ankles with residual dorsiflexion restriction.

Identification and Optimization of RNA-Splicing Modulators as Huntingtin Protein-Lowering Agents for the Treatment of Huntington's Disease.

Huntington's disease (HD) is caused by an expanded CAG trinucleotide repeat in exon 1 of the huntingtin (HTT) gene. We report the design of a series of HTT pre-mRNA splicing modulators that lower huntingtin (HTT) protein, including the toxic mutant huntingtin (mHTT), by promoting insertion of a pseudoexon containing a premature termination codon at the exon 49-50 junction. The resulting transcript undergoes nonsense-mediated decay, leading to a reduction of HTT mRNA transcripts and protein levels. The starting benzamide core was modified to pyrazine amide and further optimized to give a potent, CNS-penetrant, and orally bioavailable HTT-splicing modulator 27. This compound reduced canonical splicing of the HTT RNA exon 49-50 and demonstrated significant HTT-lowering in both human HD stem cells and mouse BACHD models. Compound 27 is a structurally diverse HTT-splicing modulator that may help understand the mechanism of adverse effects such as peripheral neuropathy associated with branaplam.

RNA-based drug discovery for spinal muscular atrophy: a story of small molecules and antisense oligonucleotides.

INTRODUCTION: Spinal Muscular Atrophy (SMA), the second most prevalent autosomal genetic disease affecting infants, is caused by the lack of SMN1, which encodes a neuron functioning vital protein, SMN. Improving exon 7 splicing in the paralogous gene SMN2, also coding for SMN protein, increases protein production efficiency from SMN2 to overcome the genetic deficit in SMN1. Several molecular mechanisms have been investigated to improve SMN2 functional splicing. AREAS COVERED: This manuscript will cover two of the three mechanistically distinct available treatment options for SMA, both targeting the SMN2 splicing mechanism. The first therapeutic, nusinersen (Spinraza®, 2017), is an antisense oligonucleotide (ASO) targeting the splicing inhibitory sequence in the intron downstream of exon 7 from SMN2, thus increasing exon 7 inclusion. The second drug is a small molecule, risdiplam (Evrysdi®, 2021), that enhances the binding of splice factors and also promotes exon 7 inclusion. Both therapies, albeit through different mechanisms, increase full-length SMN protein expression. EXPERT OPINION: Nusinersen and risdiplam have directly helped SMA patients and families, but they also herald a sea change in drug development for genetic diseases. This piece aims to draw parallels between both development histories; this may help chart the course for future targeted agents.

'Make the Connection' parenting skills programme: a controlled trial of associated improvement in maternal attitudes.

OBJECTIVE: Assess the effectiveness of Make the Connection (MTC), an attachment-focused parenting programme, in fostering maternal attitudes thought to underlie sensitive responding. BACKGROUND: Effective parenting programmes are likely to mitigate negative outcomes associated with insecure attachment in infancy. Negative maternal attitudes and cognitions are thought to underlie insensitive parenting behaviour, and thus constitute a promising target for intervention. METHODS: 180 mothers of young infants were assigned to experimental or waitlist control groups based on programme availability. Mothers completed questionnaires assessing parental attitudes at baseline, and again either after participating in MTC or after a 9-week waitlist period. RESULTS: Participants who completed MTC showed significant improvement in overall attitude with a medium effect size relative to the waitlist control group, which showed no change. A small but significant interaction with infant age was noted, such that mothers of younger infants showed slightly more attitude improvement. Relative to the control group, participation in Make the Connection was associated with significant improvement in all attitudes except for self-efficacy as a parent, which improved with time regardless of programme participation. CONCLUSION: Make the Connection is effective in promoting positive parent-to-infant attachment and is a strong candidate for public health initiatives targeting parenting skills.

Selectivity in early prosocial behavior.

Prosocial behavior requires expenditure of personal resources for the benefit of others, a fact that creates a "problem" when considering the evolution of prosociality. Models that address this problem have been developed, with emphasis typically placed on reciprocity. One model considers the advantages of being selective in terms of one's allocation of prosocial behavior so as to improve the chance that one will be benefitted in return. In this review paper, we first summarize this "partner choice" model and then focus on prosocial development in the preschool years, where we make the case for selective partner choice in early instances of human prosocial behavior.

Two case reports of oral ulcers with lamotrigine several weeks after oxcarbazepine withdrawal.

OBJECTIVE: To report two cases of mouth ulcers in lamotrigine patients after oxcarbazepine withdrawal. PATIENTS AND METHODS: The first patient was a 35-year-old woman with bipolar disorder II (BD II) started on lamotrigine and tapered off oxcarbazepine while an inpatient. The second patient was a 36-year-old man with BD II. He was discharged on lamotrigine and oxcarbazepine with the recommendation of a slow withdrawal of oxcarbazepine. RESULTS: Many weeks after hospital discharge and after a stable lamotrigine dose had been established, both patients developed painful mouth ulcers that were diagnosed during outpatient visits. The first patient developed ulcers 39 days after oxcarbazepine was stopped and the ulcers resolved 4 days after lamotrigine discontinuation. The second patient was taking 1200 mg/day of oxcarbazepine and after leaving hospital decreased this to 600 mg/day. Twenty-two days after the oxcarbazepine decrease, he developed oral ulcers that resolved with oxcarbazepine and lamotrigine discontinuation. CONCLUSIONS: Lamotrigine is mainly metabolized by glucuronidation, specifically by the uridine 5'-diphosphate glucuronosyltransferases 1A4 (UGT1A4). Carbamazepine is a UGT1A4 inducer. These two cases suggest that oxcarbazepine may also induce lamotrigine metabolism. The discontinuation or dosage decrease of carbamazepine or oxcarbazepine may be associated with a slow increase of lamotrigine levels over several weeks and thus increase risk of lamotrigine toxicity that may manifest as oral ulcers. Hospital psychiatrists need to be aware that discontinuation of inducers may take several weeks to manifest as side effects.