De Novo Mutations in the Motor Domain of KIF1A Cause Cognitive Impairment,Spastic Paraparesis,Axonal Neuropathy,and Cerebellar Atrophy

KIF1A is a neuron‐specific motor protein that plays important roles in cargo transport along neurites. Recessive mutations in KIF1A were previously described in families with spastic paraparesis or sensory and autonomic neuropathy type‐2. Here, we report 11 heterozygous de novo missense mutations (p.S58L, p.T99M, p.G102D, p.V144F, p.R167C, p.A202P, p.S215R, p.R216P, p.L249Q, p.E253K, and p.R316W) in KIF1A in 14 individuals, including two monozygotic twins. Two mutations (p.T99M and p.E253K) were recurrent, each being found in unrelated cases. All these de novo mutations are located in the motor domain (MD) of KIF1A. Structural modeling revealed that they alter conserved residues that are critical for the structure and function of the MD. Transfection studies suggested that at least five of these mutations affect the transport of the MD along axons. Individuals with de novo mutations in KIF1A display a phenotype characterized by cognitive impairment and variable presence of cerebellar atrophy, spastic paraparesis, optic nerve atrophy, peripheral neuropathy, and epilepsy. Our findings thus indicate that de novo missense mutations in the MD of KIF1A cause a phenotype that overlaps with, while being more severe, than that associated with recessive mutations in the same gene.     

Addressing climate change through a nursing lens within the framework of the United Nations Sustainable Development Goals

Background

In 2000, the United Nations (UN) introduced the Millennium Development Goals (MDG), described as a global movement with the primary aim of ending world-wide poverty (“Millennium Summit,” 2000). The second phase of the project, known as the post-2015 Sustainable Development Goals (SDG) agenda offers an increased emphasis on lessening the mitigating factors associated with climate change and adapting to the negative effects of climate change. Nurses are in the unique position to address the health-related impacts related to climate change through community health approaches aimed at education and promotion of environmental stewardship.

Characterizing the PK/PD relationship for inhibition of capsaicin-induced dermal vasodilatation by MK-3207, an oral calcitonin gene related peptide receptor antagonist

Aims

Calcitonin gene related peptide (CGRP) receptor antagonists are effective acute migraine treatments. A capsaicin-induced dermal vasodilatation (CIDV) model has been developed to provide target-engagement information in healthy volunteers. In the model, CGRP release is provoked after dermal capsaicin application, by activating transient receptor potential vanilloid-type-1 (TRPV1) receptors at peripheral sensory nerves. Laser Doppler imaging is used to quantify CIDV and subsequent inhibition by CGRP receptor antagonists. We sought to evaluate a CGRP receptor antagonist, MK-3207, in the biomarker model and to assess the predictability of the CIDV response to migraine clinical efficacy.

Methods

An integrated population pharmacokinetic/pharmacodynamic (PK/PD) model was developed to describe the exposure−response relationship for CIDV inhibition by CGRP and TRPV1 receptor antagonists. MK-3207 dose−response predictions were made based on estimated potency from the PK/PD model and mean plasma concentrations observed at the doses investigated.

Results

The results suggested that a 20 mg dose of MK-3207 (EC₅₀ of 1.59 nm) would be required to attain the peripheral CIDV response at a target level that was shown previously to correlate with 2 h clinical efficacy based on phase 3 telcagepant clinical data, and that a plateau of the dose−response would be reached around 40–100 mg. These predictions provided a quantitative rationale for dose selection in a phase 2 clinical trial of MK-3207 and helped with interpretation of the efficacy results from the trial.

Conclusions

The integrated CIDV PK/PD model provides a useful platform for characterization of PK/PD relationships and predictions of dose−response relationships to aid in future development of CGRP and TRPV1 receptor antagonists.     

Individualized dosing guidelines for PEGasparaginase and factors influencing the clearance: a population pharmacokinetic model

Considerable inter- and intra-patient variability exist in serum activity levels of PEGasparaginase, essential for pediatric acute lymphoblastic leukemia (ALL) treatment. A population pharmacokinetic (popPK) model was developed, identifying patient characteristics that explain these variabilities. Patients (n=92) were treated according to the Dutch Childhood Oncology Group (DCOG) ALL-11 protocol, using therapeutic drug monitoring to individualize PEGasparaginase doses. Non-linear mixed effects modeling (NONMEM) was used to analyze popPK evaluating several covariates. The final model was validated using an independent database (n=28). Guidelines for starting doses and dose adjustments were developed. A one-compartment model with timedependent clearance was adequately described in popPK. Normalization of clearance and volume of distribution by body surface area reduced inter-individual variability. Clearance was 0.084 L/day/m² for 12.7 days, increasing by 0.082 L/day/m²/day thereafter. Clearance was 38% higher during an infection, and 11-19% higher during induction treatment than during intensification and maintenance (P<0.001). In order to target an asparaginase activity level of 100 IU/L, a loading dose of 800 IU/m² (induction) and 600 IU/m² (intensification) is advised. In conclusion, variability of PEGasparaginase activity levels can be explained by body surface area, the treatment phase and the occurrence of an infection. With this popPK model, PEGasparaginase treatment can be individualized further, taking into account the covariates and the dosing guidelines provided. (clinicaltrials gov. Identifier [CCMO register]: NL50250.078.14).     

Which ultrasound lesions contribute to dactylitis in psoriatic arthritis and their reliability in a clinical setting

Clinical Rheumatology - To explore the frequency of ultrasound elementary lesions in dactylitis in psoriatic arthritis (PsA), and the reliability of scoring these lesions in a clinical setting. In...     

Upper respiratory tract infections in general practice: diagnosis,antibiotic prescribing,duration of symptoms and use of diagnostic tests

A diagnosis/antibiotic prescribing study was performed in 5 counties in Sweden for 1 week in November 2000. As part of this study, the characteristics and clinical management of patients with upper respiratory tract infections (n = 2899) in primary care were analyzed. Almost half of the patients were aged < 15 y and one-fifth of the patients consulted out of hours. Of all patients seeking primary care for upper respiratory tract infections, 56.0% were prescribed an antibiotic. Almost all patients who were given the diagnoses streptococcal tonsillitis, acute otitis media or acute sinusitis were prescribed antibiotics, compared to 10% of patients with common cold or acute pharyngitis. The most frequently prescribed antibiotic was penicillin V (79.2%) and this was even more pronounced out of hours, when the diagnoses otitis media and streptococcal tonsillitis were more frequently used. In patients with common cold and acute pharyngitis, the percentage who received antibiotics increased with increasing length of symptoms and increasing CRP levels. In patients with acute pharyngitis or streptococcal tonsillitis, antibiotics were prescribed less frequently provided streptococcal tests were performed. The management of patients with upper respiratory tract infections in general practice seems to be in good agreement with current Swedish guidelines. However, the study indicates some areas for improvement. The diagnosis of acute sinusitis seems to have been overestimated and used only to justify antibiotic treatment.