Thiazolidinediones under preclinical and early clinical development for the treatment of Parkinson’s disease

Introduction: Current treatment of Parkinson’s disease (PD) is limited to symptomatic dopaminergic therapy, while no interventions have been shown to slow down disease progression.

Areas covered: The following article highlights a group of PPAR-γ agonists called thiazolidinediones (TZDs), which are currently being tested for a putative disease-modifying benefit in PD, using pioglitazone as a prototypic compound. PPAR-γ is highly expressed in neurons of the substantia nigra and CNS immune cells. Preclinical data in rodent and primate support an effect of TZDs in preventing and/or arresting neurodegeneration and development of motor symptoms. Although no data on the neuroprotective effect of TZDs is currently available, a clinical trial is ongoing where the primary objective is to assess pioglitazone’s impact on the progression of PD. The trial is also evaluating the drug’s safety concerns.

Expert opinion: The efficacy data from clinical trials must be carefully weighed against the safety concerns. However, given the solid preclinical data, and since the safety data are not yet fully conclusive and limited to the diabetic population, PPAR-γ research in PD can continue with caution. Ideally, drug discovery and development efforts will lead to the identification of new compounds with reduced risk of peripheral side effects.     

Prognostic importance of atrial natriuretic peptide in patients with chronic heart failure

Several circulating neurohormones have been shown to have prognostic significance in patients with chronic heart failure, but the relation between plasma levels of atrial natriuretic peptide and mortality in this disorder remains unknown. Plasma levels of immunoreactive atrial natriuretic peptide were measured in 102 patients in whom left ventricular ejection fraction, ventricular arrhythmias on ambulatory electrocardiographic recording and plasma levels of norepinephrine, renin activity, aldosterone and arginine vasopressin were also measured. Compared with patients with atrial natriuretic peptide concentrations below the median value of 125 pg/ml, patients with higher levels of the peptide had a higher plasma renin activity (8.9 +/- 1.8 versus 2.6 +/- 0.4 ng/ml per h) and plasma norepinephrine (858 +/- 116 versus 538 +/- 45 pg/ml), more frequent premature ventricular depolarizations (4,485 +/- 715 versus 2,004 +/- 495/day) and more advanced hemodynamic abnormalities (all p less than 0.05). During the subsequent 13 to 25 months of follow-up, patients with high levels of atrial natriuretic peptide had a significantly lower rate of survival than did those whose initial circulating peptide concentrations were normal or mildly increased (p = 0.01). These data indicate that, in patients with chronic heart failure, plasma atrial natriuretic peptide provides important prognostic information. This may relate to the ability of the hormone to reflect the interplay of several pathophysiologic factors that contribute to mortality in this disease.     

Perceptions of the characteristics of the Alberta Nutrition Guidelines for Children and Youth by child care providers may influence early adoption of nutrition guidelines in child care centres

In 2008, the Alberta government released the Alberta Nutrition Guidelines for Children and Youth (ANGCY) as a resource for child care facilities to translate nutrition recommendations into practical food choices. Using a multiple case study method, early adoption of the guidelines was examined in two child care centres in Alberta, Canada. Key constructs from the Diffusion of Innovations framework were used to develop an interview protocol based on the perceived characteristics of the guidelines (relative advantage, compatibility, complexity, trialability and observability) by child care providers. Analysis of the ANGCY was conducted by a trained qualitative researcher and validated by an external qualitative researcher. This entailed reviewing guideline content, layout, organisation, presentation, format, comprehensiveness and dissemination to understand whether characteristics of the guidelines affect the adoption process. Data were collected through direct observation, key informant interviews and documentation of field notes. Qualitative data were analysed using content analysis. Overall, the guidelines were perceived positively by child care providers. Child care providers found the guidelines to have a high relative advantage, be compatible with current practice, have a low level of complexity, easy to try and easy to observe changes. It is valuable to understand how child care providers perceive characteristics of guidelines as this is the first step in identifying the needs of child care providers with respect to early adoption and identifying potential educational strategies important for dissemination.     

Outcome and prognostic factors for children with supratentorial primitive neuroectodermal tumors treated with carboplatin during radiotherapy: A report from the Children's Oncology Group

Background

Supratentorial PNETs (sPNET) are uncommon embryonal malignancies of the central nervous system whose prognosis has historically been poor. We evaluated the outcome and prognostic factors of children with sPNET treated prospectively on a Children's Oncology Group trial.

Procedure

Following surgery, patients received craniospinal radiotherapy with concurrent carboplatin followed by six months of maintenance chemotherapy with cyclophosphamide and vincristine.

Results

Five‐year overall survival (OS) and progression‐free survival (PFS) for all patients was 58 ± 7% and 48 ± 7%. For patients with pineoblastoma (n = 23), five‐year OS and PFS was 81 ± 9% and 62 ± 11%. Extent of resection but not M‐stage was prognostic. Five‐year OS and PFS for 37 patients with non‐pineal tumors (NPsPNET) was 44 ± 8% and 39 ± 8%, significantly worse than for PB (P = 0.055 and 0.009 respectively). Extent of resection and major radiotherapy deviations were prognostic. Five year OS was 59 +/? 11.4% for those undergoing complete resection versus 10.4 +/? 7% for those who did not (P = 0.017). Central pathologic review called 14 (38%) “classic” sPNET, 8 (22%) “undifferentiated” and 13 (35%) “malignant gliomas.” There was no significant difference between the subgroups, although survival distributions approached significance when the combined “classic” and “undifferentiated” group was compared to the “malignant gliomas.”

Conclusions

Carboplatin during RT followed by 6 months of non‐intensive chemotherapy is a feasible treatment strategy for patients with sPNET. Aggressive surgical resection should be attempted if feasible. The classification of supratentorial small cell malignancies can be difficult. Pediatr Blood Cancer 2015;62:776–783. © 2015 Wiley Periodicals, Inc.

     

Mosaicism for Dominant Collagen 6 Mutations as a Cause for Intrafamilial Phenotypic Variability

Collagen 6‐related dystrophies and myopathies (COL6‐RD) are a group of disorders that form a wide phenotypic spectrum, ranging from severe Ullrich congenital muscular dystrophy, intermediate phenotypes, to the milder Bethlem myopathy. Both inter‐ and intrafamilial variable expressivity are commonly observed. We present clinical, immunohistochemical, and genetic data on four COL6‐RD families with marked intergenerational phenotypic heterogeneity. This variable expression seemingly masquerades as anticipation is due to parental mosaicism for a dominant mutation, with subsequent full inheritance and penetrance of the mutation in the heterozygous offspring. We also present an additional fifth simplex patient identified as a mosaic carrier. Parental mosaicism was confirmed in the four families through quantitative analysis of the ratio of mutant versus wild‐type allele (COL6A1, COL6A2, and COL6A3) in genomic DNA from various tissues, including blood, dermal fibroblasts, and saliva. Consistent with somatic mosaicism, parental samples had lower ratios of mutant versus wild‐type allele compared with the fully heterozygote offspring. However, there was notable variability of the mutant allele levels between tissues tested, ranging from 16% (saliva) to 43% (fibroblasts) in one mosaic father. This is the first report demonstrating mosaicism as a cause of intrafamilial/intergenerational variability of COL6‐RD, and suggests that sporadic and parental mosaicism may be more common than previously suspected.     

Acromiohumeral Distance During Neuromuscular Electrical Stimulation of the Lower Trapezius and Serratus Anterior Muscles in Healthy Participants

Context

Compromise to the acromiohumeral distance has been reported in participants with subacromial impingement syndrome compared with healthy participants. In clinical practice, patients with subacromial shoulder impingement are given strengthening programs targeting the lower trapezius (LT) and serratus anterior (SA) muscles to increase scapular posterior tilt and upward rotation. We are the first to use neuromuscular electrical stimulation to stimulate these muscle groups and evaluate how the muscle contraction affects the acromiohumeral distance.

Objective

To investigate if electrical muscle stimulation of the LT and SA muscles, both separately and simultaneously, increases the acromiohumeral distance and to identify which muscle-group contraction or combination most influences the acromiohumeral distance.

Design

Controlled laboratory study.

Setting

Human performance laboratory.

Patients or Other Participants

Twenty participants (10 men and 10 women, age = 26.9 ± 8.0 years, body mass index = 23.8) were screened.

Intervention(s)

Neuromuscular electrical stimulation of the LT and SA.

Main Outcome Measure(s)

Ultrasound measurement of the acromiohumeral distance.

Results

Acromiohumeral distance increased during contraction via neuromuscular electrical stimulation of the LT muscle (t₁₉ = −3.89, P = .004), SA muscle (t₁₉ = −7.67, P = .001), and combined LT and SA muscles (t₁₉ = −5.09, P = .001). We observed no differences in the increased acromiohumeral distance among the 3 procedures (F_2,57 = 3.109, P = .08).

Conclusions

Our results supported the hypothesis that the muscle force couple around the scapula is important in rehabilitation and scapular control and influences acromiohumeral distance.Key Words: subacromial impingement syndrome, real-time ultrasound, rehabilitation

Key Points

• Acromiohumeral distance increased during neuromuscular electrical stimulation of the lower trapezius muscle, serratus anterior muscle, and combined lower trapezius and serratus anterior muscles.
• The increase in acromiohumeral distance was not different among the 3 neuromuscular electrical-stimulation procedures.
• The muscle force couple around the scapula is important in rehabilitation and scapular control and influences acromiohumeral distance.

Optimal upper limb function depends on the ability to statically and dynamically position the shoulder girdle in an optimal coordinated fashion.^1,2 Suboptimal motor control is considered a risk factor for developing shoulder subacromial impingement syndrome.^3–14 Alterations in scapular motion have been linked to a decrease in serratus anterior (SA) muscle activity, an increase in upper trapezius muscle activity, and an imbalance of forces between the upper and lower parts of the trapezius muscle.¹⁵ This may adversely affect scapular positioning, resulting in reduced scapular upward rotation, increased anterior scapular tilt, and scapular winging.^4,9,16 In turn, scapular upward rotation and posterior tilt are considered vital for elevating the acromion and, hence, widening the subacromial space, thereby preventing impingement of the subacromial tissues.^17,18 Atalar et al¹⁹ suggested that reduced scapular mobility led to a decrease in acromiohumeral distance (AHD) during upper extremity abduction. Therefore, when developing rehabilitation strategies for patients with subacromial impingement syndrome, correcting neuromuscular control of the SA and trapezius muscles is important.^20,21Overall, researchers^22,23 have supported the theory that altered activity in the scapular rotator muscles is present in patients with subacromial impingement syndrome and have highlighted the role of scapular rotator muscle training as an essential component of shoulder rehabilitation. A clinical practice strategy, supported by research data, recommends that patients who have subacromial shoulder impingement and present with primary movement dysfunction of the scapula should be given strengthening programs targeting the lower trapezius (LT) and SA muscles.^24,25 The LT muscle is reported to increase posterior scapular tilt, and the SA muscle is believed to increase upward rotation of the scapula.² In turn, posterior scapular tilt and upward scapular rotation are associated with increased AHD.^17,18Authors^9,23,26–29 of electromyographic (EMG) studies have tested muscle activity in participants with subacromial impingement syndrome and in healthy persons. In patients with subacromial impingement syndrome, when the upper extremity was at rest and during flexion and abduction, the EMG signal amplitude of the upper trapezius muscle increased, whereas the EMG signal amplitude of the LT and SA muscles decreased.^30,31 These researchers have considered the immediate changes in the surface EMG activity of the scapular rotator muscles. However, to our knowledge, we are the first to use neuromuscular electrical stimulation (NMES) to stimulate the muscle groups of the LT and SA and evaluate the effect of muscle contraction in these muscles on the AHD. Neuromuscular electrical stimulation is used for various medical applications and is a common intervention during rehabilitation to improve function and motor control,³² prevent and treat shoulder pain,³³ increase range of motion,³⁴ and facilitate changes in muscle action and performance.³⁵ Therefore, the purpose of our study was to investigate whether stimulation of the LT and the SA muscles (separately and simultaneously) with NMES would increase the AHD and to investigate which muscle-group contraction or combination most influenced the AHD.     

Use of Mental Health Services by Adolescents After Traumatic Brain Injury: A Secondary Analysis of a Randomized Controlled Trial

Background

Mental health problems are common after pediatric traumatic brain injury (TBI). Many patients in need of mental health services do not receive them, but studies have not consistently used prospective and objective methods or followed samples for more than 1 year.