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.     

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.     

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.

A Model of Shared Mycobacteriology Testing Services: Lessons Learned

Objective

The need for public health laboratories (PHLs) to prioritize resources has led to increased interest in sharing diagnostic services. To address this concept for tuberculosis (TB) testing, the New York State Department of Health Wadsworth Center and the Rhode Island State Health Laboratories assessed the feasibility of shared services for the detection and characterization of Mycobacterium tuberculosis complex (MTBC).

Methods

We assessed multiple aspects of shared services including shipping, testing, reporting, and cost. Rhode Island State Health Laboratories shipped MTBC-positive specimens and isolates to Wadsworth Center. Average turnaround times were calculated and cost analysis was performed.

Results

Testing turnaround times were similar at both PHLs; however, the availability of conventional drug susceptibility testing (DST) results for Rhode Island primary specimens and isolates were extended by approximately four days of shipping time. An extended molecular testing panel was performed on every specimen submitted from Rhode Island State Health Laboratories to Wadsworth Center, and the total cost per specimen at Wadsworth Center was $177.12 less than at Rhode Island State Health Laboratories, plus shipping. Following a mid-study review, Wadsworth Center provided testing turnaround times for detection (same day), species determination of MTBC (same day), and molecular DST (2.5 days).

Conclusion

The collaboration between Wadsworth Center and Rhode Island State Health Laboratories to assess shared services of TB testing highlighted a successful model that may serve as a guideline for other PHLs. The provision of additional rapid testing at a lower cost demonstrated in this study could potentially improve patient management and result in significant cost and resource savings if used in similar models across the country.Public health laboratories (PHLs) are essential for disease prevention and control. They serve as a first line of defense by rapidly recognizing and averting the spread of communicable diseases. In addition, they play a critical role in providing specialized tests for low-incidence, high-risk diseases, such as tuberculosis (TB), rabies, and botulism.¹ Due to recent economic constraints, many PHLs have suffered financial pressures, including budget and staffing cuts. In some cases, PHLs have reduced or eliminated certain tests, creating a potential risk to the public''s health. As an alternative to the discontinuation of services, one suggested approach was the investigation of shared services with other PHLs in different jurisdictions through testing directories and pilot projects with assistance and support from the Centers for Disease Control and Prevention (CDC) and the Association of Public Health Laboratories (APHL).^2,3TB, which is caused by the bacteria Mycobacterium tuberculosis, is a disease for which PHLs play an important role by providing diagnostics that contribute to prevention. Despite an overall decline in cases, TB continues to be a significant burden on social, public health, and economic systems in the United States.⁴ Maintaining a comprehensive and efficient laboratory system is critical to the continued decline of TB rates and overall prevention and control of TB in the United States. However, providing comprehensive TB testing services is becoming increasingly expensive per case identified. Additionally, retaining technical proficiency remains a challenge, especially as many experienced personnel are lost to retirement and are difficult to replace.⁵In 2013, a total of 9,582 new TB cases were reported in the United States, with an incidence rate of 3.0 cases per 100,000 population. Only four states reported more than 500 cases of TB: California, Texas, New York, and Florida, accounting for half of all TB cases in the United States. The TB incidence rate in New York State (NYS) is 4.4 per 100,000 population.⁴ The overall number of TB cases in NYS has decreased slightly over time, while the number of drug-resistant TB (DR TB) cases has remained steady during the past five years. Additionally, the percentage of multidrug-resistant TB (MDR TB) cases in NYS has increased from 1.3% to 3.6% during the past five years.⁶ In contrast, the TB incidence rate in Rhode Island is 2.6 per 100,000 population, and the overall number of TB cases has remained constant; DR TB and MDR TB cases in Rhode Island are rare.^4,7 Given the low number of TB-positive specimens received each year in Rhode Island State Health Laboratories, developing an extensive, increasingly molecular-based, testing program for TB may not be cost effective. In contrast, a high proportion of specimens received each year by the NYS Department of Health Wadsworth Center are Mycobacterium tuberculosis complex (MTBC) positive, including DR TB and MDR TB cases, and an extensive testing program has been implemented.We assessed the feasibility of shared services for the detection and characterization of MTBC between Wadsworth Center and Rhode Island State Health Laboratories during a 10-month time period. Multiple aspects critical to the implementation of shared services were examined, including shipping, testing, reporting, and cost. During this project, Wadsworth Center provided services to Rhode Island State Health Laboratories for rapid detection of MTBC, MTBC species identification, rapid detection of mutations associated with rifampin and isoniazid resistance, and conventional drug susceptibility testing (DST). Importantly, this partnership allowed Wadsworth Center to assess its ability to share its extended testing capabilities with another PHL, determine if the additional services provided were beneficial to patient treatment and outcomes, and identify any potential issues with this testing approach.     

Alcohol policy impact on young risky drinkers and their support for proposed measures

Objective: To explore the impacts of existing policies on young Australian risky drinkers' access to alcohol and to gauge their support for proposed alcohol measures. Methods: The 16–19 year old participants were recruited from three Australian states using non‐random convenience sampling, for either a face‐to‐face or online quantitative survey (N=958). The sample was deliberately selected to represent drinkers whose consumption placed them in the riskiest drinking 20–25% of their age bracket. Results: Half (49%) the sample who were younger than the Australian legal purchase age reported it was ‘easy’ to buy alcohol from bottle stores, and 75% of those who had tried to purchase alcohol, said it was ‘easy’ the last time they tried. Half of those under 18, who had attempted to enter a licensed venue, reported they did not have their identification checked last time they gained access. Ninety per cent of all respondents drank within a private location at their last risky drinking session. Sixty‐five per cent supported ‘increasing the price of [alcohol by 20¢] a standard drink if the extra 20¢ was used to support prevention and treatment of alcohol problems'. Conclusions: Age‐ or intoxication‐based restrictions to alcohol were commonly bypassed. Implications: Point‐of‐sale alcohol controls require improvement to prevent under age access. Given that a significant proportion of drinking occasions for those under 18 were in private premises, prevention strategies need to target these locations. There were diverse levels of support for strategies to reduce harm, including potential community backing for an evidence‐based proposed price policy.