Performance of laboratory tests used to measure blood phenylalanine for the monitoring of patients with phenylketonuria

Analysis of blood phenylalanine is central to the monitoring of patients with phenylketonuria (PKU) and age‐related phenylalanine target treatment‐ranges (0‐12 years; 120‐360 μmol/L, and >12 years; 120‐600 μmol/L) are recommended in order to prevent adverse neurological outcomes. These target treatment‐ranges are based upon plasma phenylalanine concentrations. However, patients are routinely monitored using dried bloodspot (DBS) specimens due to the convenience of collection. Significant differences exist between phenylalanine concentrations in plasma and DBS, with phenylalanine concentrations in DBS specimens analyzed by flow‐injection analysis tandem mass spectrometry reported to be 18% to 28% lower than paired plasma concentrations analyzed using ion‐exchange chromatography. DBS specimens with phenylalanine concentrations of 360 and 600 μmol/L, at the critical upper‐target treatment‐range thresholds would be plasma equivalents of 461 and 768 μmol/L, respectively, when a reported difference of 28% is taken into account. Furthermore, analytical test imprecision and bias in conjunction with pre‐analytical factors such as volume and quality of blood applied to filter paper collection devices to produce DBS specimens affect the final test results. Reporting of inaccurate patient results when comparing DBS results to target treatment‐ranges based on plasma concentrations, together with inter‐laboratory imprecision could have a significant impact on patient management resulting in inappropriate dietary change and potentially adverse patient outcomes. This review is intended to provide perspective on the issues related to the measurement of phenylalanine in blood specimens and to provide direction for the future needs of PKU patients to ensure reliable monitoring of metabolic control using the target treatment‐ranges

A putative relay circuit providing low-threshold mechanoreceptive input to lamina I projection neurons via vertical cells in lamina II of the rat dorsal horn

Background: Lamina I projection neurons respond to painful stimuli, and some are also activated by touch or hair movement. Neuropathic pain resulting from peripheral nerve damage is often associated with tactile allodynia (touch-evoked pain), and this may result from increased responsiveness of lamina I projection neurons to non-noxious mechanical stimuli. It is thought that polysynaptic pathways involving excitatory interneurons can transmit tactile inputs to lamina I projection neurons, but that these are normally suppressed by inhibitory interneurons. Vertical cells in lamina II provide a potential route through which tactile stimuli can activate lamina I projection neurons, since their dendrites extend into the region where tactile afferents terminate, while their axons can innervate the projection cells. The aim of this study was to determine whether vertical cell dendrites were contacted by the central terminals of low-threshold mechanoreceptive primary afferents. Results: We initially demonstrated contacts between dendritic spines of vertical cells that had been recorded in spinal cord slices and axonal boutons containing the vesicular glutamate transporter 1 (VGLUT1), which is expressed by myelinated low-threshold mechanoreceptive afferents. To confirm that the VGLUT1 boutons included primary afferents, we then examined vertical cells recorded in rats that had received injections of cholera toxin B subunit (CTb) into the sciatic nerve. We found that over half of the VGLUT1 boutons contacting the vertical cells were CTb-immunoreactive, indicating that they were of primary afferent origin. Conclusions: These results show that vertical cell dendritic spines are frequently contacted by the central terminals of myelinated low-threshold mechanoreceptive afferents. Since dendritic spines are associated with excitatory synapses, it is likely that most of these contacts were synaptic. Vertical cells in lamina II are therefore a potential route through which tactile afferents can activate lamina I projection neurons, and this pathway could play a role in tactile allodynia

Stretching Interventions in Children With Cerebral Palsy: Why Are They Ineffective in Improving Muscle Function and How Can We Better Their Outcome?

Hyper-resistance at the joint is one of the most common symptoms in children with cerebral palsy (CP). Alterations to the structure and mechanical properties of the musculoskeletal system, such as a decreased muscle length and an increased joint stiffness are typically managed conservatively, by means of physiotherapy involving stretching exercises. However, the effectiveness of stretching-based interventions for improving function is poor. This may be due to the behavior of a spastic muscle during stretch, which is poorly understood. The main aim of this paper is to provide a mechanistic explanation as to why the effectiveness of stretching is limited in children with CP and consider clinically relevant means by which this shortcoming can be tackled. To do this, we review the current literature regarding muscle and tendon plasticity in response to stretching in children with CP. First, we discuss how muscle and tendon interact based on their morphology and mechanical properties to provide a certain range of motion at the joint. We then consider the effect of traditional stretching exercises on these muscle and tendon properties. Finally, we examine possible strategies to increase the effectiveness of stretching therapies and we highlight areas of further research that have the potential to improve the outcome of non-invasive interventions in children with cerebral palsy

Half a Century of Wilson & Jungner: Reflections on the Governance of Population Screening.

Background: In their landmark report on the "Principles and Practice of Screening for Disease" (1968), Wilson and Jungner noted that the practice of screening is just as important for securing beneficial outcomes and avoiding harms as the formulation of principles. Many jurisdictions have since established various kinds of "screening governance organizations" to provide oversight of screening practice. Yet to date there has been relatively little reflection on the nature and organization of screening governance itself, or on how different governance arrangements affect the way screening is implemented and perceived and the balance of benefits and harms it delivers. Methods: An international expert policy workshop convened by Sturdy, Miller and Hogarth. Results: While effective governance is essential to promote beneficial screening practices and avoid attendant harms, screening governance organizations face enduring challenges. These challenges are social and ethical as much as technical. Evidence-based adjudication of the benefits and harms of population screening must take account of factors that inform the production and interpretation of evidence, including the divergent professional, financial and personal commitments of stakeholders. Similarly, when planning and overseeing organized screening programs, screening governance organizations must persuade or compel multiple stakeholders to work together to a common end. Screening governance organizations in different jurisdictions vary widely in how they are constituted, how they relate to other interested organizations and actors, and what powers and authority they wield. Yet we know little about how these differences affect the way screening is implemented, and with what consequences. Conclusions: Systematic research into how screening governance is organized in different jurisdictions would facilitate policy learning to address enduring challenges. Even without such research, informal exchange and sharing of experiences between screening governance organizations can deliver invaluable insights into the social as well as the technical aspects of governance

Neuronal circuitry for pain processing in the dorsal horn

Neurons in the spinal dorsal horn process sensory information, which is then transmitted to several brain regions, including those responsible for pain perception. The dorsal horn provides numerous potential targets for the development of novel analgesics and is thought to undergo changes that contribute to the exaggerated pain felt after nerve injury and inflammation. Despite its obvious importance, we still know little about the neuronal circuits that process sensory information, mainly because of the heterogeneity of the various neuronal components that make up these circuits. Recent studies have begun to shed light on the neuronal organization and circuitry of this complex region

Chronic disease risk among adults with cerebral palsy: the role of premature sarcopoenia, obesity and sedentary behaviour

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/96337/1/obr1052.pd

Muscle and tendon lengthening behaviour of the medial gastrocnemius during ankle joint rotation in children with cerebral palsy.

NEW FINDINGS: What is the central question of this study? Which structures of the medial gastrocnemius muscle-tendon unit contribute to its lengthening during joint rotation and thus receive the stretching stimulus? What is the main finding and its importance? We show, for the first time, that muscle and tendon lengthen in a different manner in children with cerebral palsy compared with typically developing children during a similar amount of muscle-tendon unit lengthening or joint rotation. This indicates possible differences in mechanical muscle and tendon properties attributable to cerebral palsy, which are not evident by assessment of muscle function at the level of a joint. ABSTRACT: Children with cerebral palsy (CP) commonly present with reduced ankle range of motion (ROM) attributable, in part, to changes in mechanical properties of the muscle-tendon unit (MTU). Detailed information about how muscle and tendon interact to contribute to joint rotation is currently lacking but might provide essential information to explain the limited effectiveness of stretching interventions in children with CP. The purpose of this study was to quantify which structures contribute to MTU lengthening and thus receive the stretch during passive ankle joint rotation. Fifteen children with CP (age, in mean ± SD, 11.4 ± 3 years) and 16 typically developing (TD) children (age, in mean ± SD, 10.2 ± 3 years) participated. Ultrasound was combined with motion tracking, joint torque and EMG to record fascicle, muscle and tendon lengthening of the medial gastrocnemius during passive ankle joint rotations over the full ROM and a common ROM. In children with CP, relative to MTU lengthening, muscle and fascicles lengthened less (CP, 50.4% of MTU lengthening; TD, 63% of MTU lengthening; P < 0.04) and tendon lengthened more (CP, 49.6% of MTU lengthening; TD, 37% of MTU lengthening; P < 0.01) regardless of the ROM studied. Differences between groups in the amount of lengthening of the underlying structures during a similar amount of joint rotation and MTU displacement indicate possible differences in tissue mechanical properties attributable to CP, which are not evident by assessment at the level of a joint. These factors should be considered when assessing and treating muscle function in children with CP, for example during stretching exercises, because the muscle might not receive much of the applied lengthening stimulus

Understanding skeletal muscle in cerebral palsy: a path to personalized medicine?

Until recently, there has been little interest in understanding the intrinsic features associated with the pathomorphology of skeletal muscle in cerebral palsy (CP). Coupled with emerging evidence that challenges the role of spasticity as a determinant of gross motor function and in the development of fixed muscle contractures, it has become increasingly important to further elucidate the underlying mechanisms responsible for muscle alterations in CP. This knowledge can help clinicians to understand and apply treatment modalities that take these aspects into account. Thus, the inherent heterogeneity of the CP phenotype allows for the potential of personalized medicine through the understanding of muscle pathomorphology on an individual basis and tailoring treatment approaches accordingly. This review aims to summarize recent developments in the understanding of CP muscle and their relationship to musculoskeletal manifestations, in addition to proposing a treatment paradigm that incorporates this new knowledge

The evolution and outcome of cavitating periventricular leukomalacia in infancy. A study of 46 cases

Peer Reviewe