Bi-allelic variants in neuronal cell adhesion molecule cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, neuropathy/spasticity.

Cell adhesion molecules are membrane-bound proteins predominantly expressed in the central nervous system along principal axonal pathways with key roles in nervous system development, neural cell differentiation and migration, axonal growth and guidance, myelination, and synapse formation. Here, we describe ten affected individuals with bi-allelic variants in the neuronal cell adhesion molecule NRCAM that lead to a neurodevelopmental syndrome of varying severity; the individuals are from eight families. This syndrome is characterized by developmental delay/intellectual disability, hypotonia, peripheral neuropathy, and/or spasticity. Computational analyses of NRCAM variants, many of which cluster in the third fibronectin type III (Fn-III) domain, strongly suggest a deleterious effect on NRCAM structure and function, including possible disruption of its interactions with other proteins. These findings are corroborated by previous in vitro studies of murine Nrcam-deficient cells, revealing abnormal neurite outgrowth, synaptogenesis, and formation of nodes of Ranvier on myelinated axons. Our studies on zebrafish nrcamaΔ mutants lacking the third Fn-III domain revealed that mutant larvae displayed significantly altered swimming behavior compared to wild-type larvae (p < 0.03). Moreover, nrcamaΔ mutants displayed a trend toward increased amounts of α-tubulin fibers in the dorsal telencephalon, demonstrating an alteration in white matter tracts and projections. Taken together, our study provides evidence that NRCAM disruption causes a variable form of a neurodevelopmental disorder and broadens the knowledge on the growing role of the cell adhesion molecule family in the nervous system.

Pharmacological and neurosurgical management of cerebral palsy and dystonia: Clinical practice guideline update.

Dystonia, typically characterized by slow repetitive involuntary movements, stiff abnormal postures, and hypertonia, is common among individuals with cerebral palsy (CP). Dystonia can interfere with activities and have considerable impact on motor function, pain/comfort, and ease of caregiving. Although pharmacological and neurosurgical approaches are used clinically in individuals with CP and dystonia that is causing interference, evidence to support these options is limited. This clinical practice guideline update comprises 10 evidence-based recommendations on the use of pharmacological and neurosurgical interventions for individuals with CP and dystonia causing interference, developed by an international expert panel following the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. The recommendations are intended to help inform clinicians in their use of these management options for individuals with CP and dystonia, and to guide a shared decision-making process in selecting a management approach that is aligned with the individual's and the family's values and preferences.

A longitudinal study of endocrinology and foraging ecology of subadult gray whales prior to death based on baleen analysis.

Individual-level assessments of wild animal health, vital rates, and foraging ecology are critical for understanding population-wide impacts of exposure to stressors. Large whales face multiple stressors, including, but not limited to, ocean noise, pollution, and ship strikes. Because baleen is a continuously growing keratinized structure, serial extraction, and quantification of hormones and stable isotopes along the length of baleen provide a historical record of whale physiology and foraging ecology. Furthermore, baleen analysis enables the investigation of dead specimens, even decades later, allowing comparisons between historic and modern populations. Here, we examined baleen of five sub-adult gray whales and observed distinct patterns of oscillations in δ15N values along the length of their baleen plates which enabled estimation of baleen growth rates and differentiation of isotopic niche widths of the whales during wintering and summer foraging. In contrast, no regular patterns were apparent in δ13C values. Prolonged elevation of cortisol in four individuals before death indicates that chronic stress may have impacted their health and survival. Triiodothyronine (T3) increased over months in the whales with unknown causes of death, simultaneous with elevations in cortisol, but both hormones remained stable in the one case of acute death attributed to killer whale predation. This parallel elevation of cortisol and T3 challenges the classic understanding of their interaction and might relate to increased energetic demands during exposure to stressors. Reproductive hormone profiles in subadults did not show cyclical trends, suggesting they had not yet reached sexual maturity. This study highlights the potential of baleen analysis to retrospectively assess gray whales' physiological status, exposure to stressors, reproductive status, and foraging ecology in the months or years leading up to their death, which can be a useful tool for conservation diagnostics to mitigate unusual mortality events.

Validation of Dynamic 3D MRI for Urodynamics Assessment Using an Anatomically Realistic In Vitro Model of the Bladder.

Lowery urinary tract symptoms (LUTS) affect a large majority of the aging population. 3D Dynamic MRI shows promise as a noninvasive diagnostic tool that can assess bladder anatomy and function (urodynamics) while overcoming challenges associated with current urodynamic assessment methods. However, validation of this technique remains an unmet need. In this study, an anatomically realistic, bladder-mimicking in vitro flow model was created and used to systematically benchmark 3D dynamic MRI performance using a highly controllable syringe pump. Time-resolved volumes of the synthetic bladder model were obtained during simulated filling and voiding events and used to calculate volumetric flowrate. During MRI acquisitions, pressure during each event was recorded and used to create PV loops for work assessment. Error between control and MRI-derived volume for voiding and filling events exhibited 3.36% and 4.66% differences, respectively. A slight increase in average error was observed for MRI-derived flowrate when compared to the control flowrate (4.90% and 7.67% for voiding and filling, respectively). Overall, average error in segmented volumes increased with decreasing volume flowrate. Pressure drops were observed during voiding. Pressure increased during filling. Enhanced validation of novel 3D MRI urodynamics is achieved by using high-resolution PIV for visualizing and quantifying velocity inside the bladder model, which is not currently possible with 3D Dynamic MRI.

Motion-robust, blood-suppressed, reduced-distortion diffusion MRI of the liver.

PURPOSE: To evaluate feasibility and reproducibility of liver diffusion-weighted (DW) MRI using cardiac-motion-robust, blood-suppressed, reduced-distortion techniques. METHODS: DW-MRI data were acquired at 3T in an anatomically accurate liver phantom including controlled pulsatile motion, in eight healthy volunteers and four patients with known or suspected liver metastases. Standard monopolar and motion-robust (M1-nulled, and M1-optimized) DW gradient waveforms were each acquired with single-shot echo-planar imaging (ssEPI) and multishot EPI (msEPI). In the motion phantom, apparent diffusion coefficient (ADC) was measured in the motion-affected volume. In healthy volunteers, ADC was measured in the left and right liver lobes separately to evaluate ADC reproducibility between the two lobes. Image distortions were quantified using the normalized cross-correlation coefficient, with an undistorted T2-weighted reference. RESULTS: In the motion phantom, ADC mean and SD in motion-affected volumes substantially increased with increasing motion for monopolar waveforms. ADC remained stable in the presence of increasing motion when using motion-robust waveforms. M1-optimized waveforms suppressed slow flow signal present with M1-nulled waveforms. In healthy volunteers, monopolar waveforms generated significantly different ADC measurements between left and right liver lobes ( p = 0 . 0078 $$ p=0.0078 $$ , reproducibility coefficients (RPC) =  470 × 1 0 - 6 $$ 470\times 1{0}^{-6} $$ mm 2 $$ {}^2 $$ /s for monopolar-msEPI), while M1-optimized waveforms showed more reproducible ADC values ( p = 0 . 29 $$ p=0.29 $$ , RPC = 220 × 1 0 - 6 $$ \mathrm{RPC}=220\times 1{0}^{-6} $$ mm 2 $$ {}^2 $$ /s for M1-optimized-msEPI). In phantom and healthy volunteer studies, motion-robust acquisitions with msEPI showed significantly reduced image distortion ( p < 0 . 001 $$ p<0.001 $$ ) compared to ssEPI. Patient scans showed reduction of wormhole artifacts when combining M1-optimized waveforms with msEPI. CONCLUSION: Synergistic effects of combined M1-optimized diffusion waveforms and msEPI acquisitions enable reproducible liver DWI with motion robustness, blood signal suppression, and reduced distortion.

Function and Mechanism of Myelin Regulation in Alcohol Abuse and Alcoholism.

Excessive alcohol use has adverse effects on the central nervous system (CNS) and can lead to alcohol use disorders (AUDs). Recent studies have suggested that myelin reductions may directly contribute to CNS dysfunctions associated with AUDs. Myelin consists of compact lipid membranes wrapped around axons to provide electrical insulation and trophic support. Regulation of myelin is considered as a new form of neural plasticity due to its profound impacts on the computation of neural networks. In this review, the authors first discuss experimental evidence showing how alcohol exposure causes demyelination in different brain regions, often accompanied by deficits in cognition and emotion. Next, they discuss postulated molecular and cellular mechanisms underlying alcohol's impact on myelin. It is clear that more extensive investigations are needed in this important but underexplored research field in order to gain a better understanding of the myelin-behavior relationship and to develop new treatment strategies for AUDs.

A pilot feasibility study of gabapentin for managing pain in children with dystonic cerebral palsy.

BACKGROUND: Gabapentin is often used to manage pain in children with dystonic cerebral palsy, however the evidence for its effectiveness in this population is limited. The primary objective of this feasibility pilot study was to assess the factors which might impact on a future randomised controlled trial including the ability to recruit and retain participants, assess adherence/compliance to the prescribed intervention, and ability to complete all outcome assessments. The secondary objective was to gather preliminary evidence for the effectiveness of gabapentin at reducing pain, improving comfort and reducing dystonia in children with dystonic cerebral palsy. METHODS: This open label pilot study recruited children aged 5-18 years with dystonic cerebral palsy and accompanying pain affecting daily activities from four centres around Australia. Children were prescribed gabapentin for 12 weeks and were assessed at baseline, 6 weeks and 12 weeks. The primary outcome was feasibility of the protocol. Secondary outcomes were pain behaviour, pain intensity, care and comfort, individualised goal setting and dystonia severity. RESULTS: Thirteen children (mean age 10.4 years (SD 2.4yrs), 9 females) were recruited from 71 screened over 15 months. Two children withdrew while eight children experienced side effects. There were issues with adherence to medication dosage regimens and data collection. Improvements were seen in pain behaviour, comfort and pain related goals at 12 weeks. Dystonia was not significantly changed. CONCLUSIONS: Whilst gabapentin has potential to improve pain and comfort in children with dystonic CP, the feasibility of implementing a definitive randomised controlled trial is low. Alternative trials designs are required to further examine the effectiveness of gabapentin in this heterogeneous population. TRIAL REGISTRATION: The trial was registered with the Australian Clinical Trial Registry ( ACTRN12616000366459 ) on 22/03/2016 and the Therapeutic Goods Administration (CT-2016-CTN-00500-1) on 22/06/2016.

National surveillance of oral medication prescription for children with dystonic cerebral palsy.

AIM: Oral medications are often first-line medical management for children with cerebral palsy who have generalised dystonia; however, evidence for their effectiveness is limited and dosing practices are inconsistent. As a first step to improve consistency, this study aimed to examine current clinical practice of expert doctors for prescribing medications for children with dystonic cerebral palsy including prescribing patterns and combinations of medications used. METHODS: This was a prospective surveillance study of medical doctors working in major Australian centres who manage children with cerebral palsy. Each week over a continuous 6-month period, doctors completed a custom developed online survey for children seen that week with dystonic cerebral palsy for whom they prescribed a new medication to treat dystonia. RESULTS: Twenty-five doctors consented to participate, 16 of whom prescribed new medications for dystonia in children with cerebral palsy over the study period. There were 77 children who were prescribed new medications. Baclofen and gabapentin were prescribed most, followed by levodopa, trihexyphenidyl and diazepam. The most common combinations of medications were baclofen and diazepam or baclofen and gabapentin. Dosage regimens were variable, particularly for trihexyphenidyl and diazepam. CONCLUSION: Inconsistencies in dosing regimens remain for oral medication prescription by Australian doctors when managing dystonia in cerebral palsy. Future studies using the consensus of expert clinicians will be conducted to develop guidelines in an area where the evidence for individual medications is extremely limited.

PR1P Stabilizes VEGF and Upregulates Its Signaling to Reduce Elastase-induced Murine Emphysema.

Emphysema is a progressive and fatal lung disease with no cure that is characterized by thinning, enlargement, and destruction of alveoli, leading to impaired gas exchange. Disease progression is due in part to dysregulation of VEGF (vascular endothelial growth factor) signaling in the lungs and increased lung-cell apoptosis. Here we asked whether PR1P (Prominin-1-derived peptide), a novel short peptide we designed that increases VEGF binding to endothelial cells, could be used to improve outcome in in vitro and in vivo models of emphysema. We used computer simulation and in vitro and in vivo studies to show that PR1P upregulated endogenous VEGF receptor-2 signaling by binding VEGF and preventing its proteolytic degradation. In so doing, PR1P mitigated toxin-induced lung-cell apoptosis, including from cigarette-smoke extract in vitro and from LPS in vivo in mice. Remarkably, inhaled PR1P led to significantly increased VEGF concentrations in murine lungs within 30 minutes that remained greater than twofold above that of control animals 24 hours later. Finally, inhaled PR1P reduced acute lung injury in 4- and 21-day elastase-induced murine emphysema models. Taken together, these results highlight the potential of PR1P as a novel therapeutic agent for the treatment of emphysema or other lung diseases characterized by VEGF signaling dysregulation.

A bounding quantitative cancer risk assessment for occupational exposures to asphalt emissions during road paving operations.

The International Agency for Research on Cancer recently classified straight-run bitumens and associated emissions during road paving as possibly carcinogenic to humans (Group 2B), owing to potential exposures to polycyclic aromatic hydrocarbons. We examine existing chemistry, exposure, epidemiology, and animal toxicity data to explore quantitative cancer risk implications for paving workers exposed to asphalt emissions from the data used in identifying this qualitative hazard. Epidemiology studies show no consistent cancer risk elevation. One skin-painting mouse study of paving asphalt emission condensate found a single tumor at only the highest tested dose, as did one rat inhalation study. These studies were used to develop an upper bound on possible carcinogenic potency of emissions that are inhaled or dermally deposited. Extending earlier work on roofing asphalt, we conducted time-to-tumor modeling using the dose-time-response shape for several dose levels of benzo[a]pyrene (B[a]P) in concurrent bioassay controls to infer presumed parallel dose-time-response curves for paving-asphalt-emission condensate. In addition, we developed a scientific rationale, based on general scaling considerations and on dermal uptake, for the chosen means to scale observed dermal cancer potencies in mice to apply to dermal exposures in humans. The results indicate that paving asphalt emissions have a reduced dermal cancer potency compared to roofing asphalt, consistent with the lower levels of the multi-ringed PAHs implicated in cancer risks. Based on existing occupational exposure studies, cancer risks to pavers from both dermal and inhalation exposure to asphalt emissions is within a range typically acceptable within regulatory frameworks.

Pharmacological and neurosurgical interventions for managing dystonia in cerebral palsy: a systematic review.

AIM: To systematically review evidence for pharmacological/neurosurgical interventions for managing dystonia in individuals with cerebral palsy (CP) to inform a care pathway. METHOD: Searches included studies with a minimum of five participants with dystonia in CP receiving oral baclofen, benzodiazepines (clonazepam, diazepam, lorazepam), clonidine, gabapentin, levodopa, trihexyphenidyl, botulinum toxin, intrathecal baclofen (ITB), or deep brain stimulation (DBS). Evidence was classified according to American Academy of Neurology guidelines. RESULTS: Twenty-eight articles underwent data extraction: one levodopa, five trihexyphenidyl, three botulinum toxin, six ITB, and 13 DBS studies. No articles for oral baclofen, benzodiazepines, clonidine, or gabapentin met the inclusion criteria. Evidence for reducing dystonia was level C (possibly effective) for ITB and DBS; level C (possibly ineffective) for trihexyphenidyl; and level U (inadequate data) for botulinum toxin. INTERPRETATION: For dystonia reduction, ITB and DBS are possibly effective, whereas trihexyphenidyl was possibly ineffective. There is insufficient evidence to support oral medications or botulinum toxin to reduce dystonia. There is insufficient evidence for pharmacological and neurosurgical interventions to improve motor function, decrease pain, and ease caregiving. The majority of the pharmacological and neurosurgical management of dystonia in CP is based on clinical expert opinion. WHAT THIS PAPER ADDS: Intrathecal baclofen and deep brain stimulation are possibly effective in reducing dystonia. Current evidence does not support effectiveness of oral medications or botulinum toxin to reduce dystonia. Evidence is inadequate for pharmacological/neurosurgical interventions impact on improving motor function, pain/comfort, and easing caregiving. The majority of the care pathway rests on expert opinion.

Surface-enhanced Raman scattering for rapid hematopoietic stem cell differentiation analysis.

Raman-spectroscopy-based methods, such as surface-enhanced Raman spectroscopy, are a well-evolved method to molecular fingerprint cell types. Here we demonstrate that surface-enhanced Raman spectroscopy can enable us to distinguish cell development stages of bone marrow hematopoietic stem cells towards red blood cells through the identification of specific surface-enhanced Raman spectroscopy biomarkers. The approach taken here is to allow cells to take in gold nanoparticles as Raman enhancement platforms for kinetic structural observations presented here through the view of the multidimensional parameter contribution, thereby enabling profiling of bone marrow hematopoietic stem cells acquired from proliferation (stage one), differentiation (stage two), and mature red blood cells (stage three).

Identification, classification and assessment of dyskinesia in children with cerebral palsy: A survey of clinicians.

AIM: The aims of this study were to investigate clinicians' knowledge, and barriers they perceive exist, relating to the identification and measurement of dyskinesia (dystonia/choreoathetosis) in children with cerebral palsy (CP) and to explore educational needs regarding improving identification and assessment of dyskinesia. METHODS: This was a cross-sectional online survey of clinicians working with children with CP. Data analysis was descriptive, with qualitative analysis of unstructured questions. RESULTS: In total, 163 completed surveys from Australian clinicians were analysed. Respondents were allied health (n = 140) followed by medical doctors (n = 18) working mainly in tertiary hospitals and not-for-profit organisations. Hypertonia subtypes and movement disorders seen in children with CP appear to be identified by clinicians, although limited knowledge about dyskinesia and access to training were reported as significant barriers to accurate identification. Despite knowledge of available measurement scales, only a small percentage were used clinically and reported to be only somewhat useful or not useful at all. Barriers identified for use of scales included limited training opportunities and knowledge of scales and lack of confidence in their use. CONCLUSION: A lack of confidence in identifying and measuring movement disorders in children with CP was reported by Australian clinicians. It was identified that a greater understanding of dyskinetic CP and the tools available to identify and measure it would be valuable in clinical practice. The results of this survey will inform the development of a 'Toolbox' to help identify, classify and measure dyskinetic CP and its impact on activity and participation using the framework of the International Classification of Functioning, Disability and Health.

Windows of Susceptibility and Consequences of Early Life Exposures to 17ß-estradiol on Medaka (Oryzias latipes) Reproductive Success.

Estrogens and estrogen mimics are commonly found in surface waters and are associated with deleterious effects in fish populations. Impaired fertility and fecundity in fish following chronic exposures to estrogens and estrogen mimics during critical windows in development are well documented. However, information regarding differential reproductive effects of exposure within defined developmental stages remains sparse. In this study, reproductive capacity was assessed in Japanese medaka (Oryzias latipes) after exposure to two concentrations of 17ß-estradiol (E2ß; 2 ng/L and 50 ng/L) during four distinct stages of development: gonad development, gonad differentiation, development of secondary sex characteristics (SSC) and gametogenesis. Exposure to E2ß did not adversely impact survival, hatch success, growth, or genotypic ratios. In contrast, exposure to 50 ng/L E2ß during SSC development altered phenotypic ratios and SSC. Exposure to both E2ß treatments reduced reproductive capacity (fertility, fecundity) by 7.3-57.4% in adult medaka breeding pairs, with hindrance of SSC development resulting in the largest disruption in breeding capacity (51.6-57.4% decrease) in the high concentration. This study documents differential effects among four critical stages of development and provides insight into factors (window of exposure, exposure concentration and duration of exposure period) contributing to reproductive disruption in fish.

Identification and measurement of dystonia in cerebral palsy.

AIM: To establish the prevalence and severity of dystonia in a population of children with cerebral palsy (CP) with hypertonia assessment and measurement tools. METHOD: A cross-sectional study of 151 children (84 males, 67 females) with CP who were assessed with the Hypertonia Assessment Tool (HAT) and Barry-Albright Dystonia scale (BAD) for identification and measurement of severity of dystonia. HAT dystonia items were assessed for construct and convergent validity. RESULTS: Distribution by predominant motor type (PMT) was: 85% spastic, 14% dyskinetic, and 1% ataxic. Spastic and dyskinetic groups showed widespread evidence of dystonia according to HAT profiles and BAD scores. The dyskinetic PMT group had a higher mean BAD score than the spastic group (difference of 13 units, 95% CI 9.1-16.4). Dystonia severity (BAD score) increased linearly across gross motor (p<0.001), manual ability (p<0.001) and communication functional levels (p<0.001). Divergence was noted in how HAT item six identified dystonia compared to items one and two. INTERPRETATION: The HAT provided an estimate of the prevalence of both spasticity and dystonia in a large CP population, beyond predominant motor type. Dystonia is a common finding in the spastic PMT group, and its severity increases as motor function worsens. WHAT THIS PAPER ADDS: Dystonia is readily identified in cerebral palsy (CP) using the Hypertonia Assessment Tool, regardless of the predominant motor type. Spasticity and dystonia frequently coexist in the CP population. Severity of dystonia is inversely related to motor function.

Thermal and aqueous stability improvement of graphene oxide enhanced diphenylalanine nanocomposites.

Nanocomposites of diphenylalanine (FF) and carbon based materials provide an opportunity to overcome drawbacks associated with using FF micro- and nanostructures in nanobiotechnology applications, in particular their poor structural stability in liquid solutions. In this study, FF/graphene oxide (GO) composites were found to self-assemble into layered micro- and nanostructures, which exhibited improved thermal and aqueous stability. Dependent on the FF/GO ratio, the solubility of these structures was reduced to 35.65% after 30 min as compared to 92.4% for pure FF samples. Such functional nanocomposites may extend the use of FF structures to e.g. biosensing, electrochemical, electromechanical or electronic applications.

'Framed': Terminating the Parenting Rights of Parents with Intellectual Disability in Iceland.

BACKGROUND: The aim was to investigate the role of measured intellectual function in framing parents as 'unfit' in child custody deprivation cases. METHOD: Grounded theory was used to analyse a national sample of custody deprivation cases in Iceland 2002-2014. RESULTS: The terminology used to evaluate and describe the intellectual and developmental status of parents in child deprivation custody cases served as a device to define and shape the 'unfit parent'. Intellect itself, whether as low, average or even above average at times acts as a master narrative which informs and explains all manner of perceived parental deficiencies. CONCLUSION: The intellectual and developmental status served as a yardstick of identifying, understanding and interpreting the unfit parent. As a tool to achieve an end, parents were framed in language and culture using underlying belief set to make sense of events and issues.

Metallothionein regulates intracellular zinc signaling during CD4(+) T cell activation.

BACKGROUND: The ultra-low redox potential and zinc binding properties of the intracellular pool of mammalian metallothioneins (MT) suggest a role for MT in the transduction of redox signals into intracellular zinc signals. Increased expression of MT after exposure to heavy metals, oxidative stress, or inflammatory cytokines leads to an increased intracellular redox-mobilizable zinc pool that can affect downstream zinc-sensitive signaling pathways. CD4(+) T helper cells are poised to be influenced by MT transduced zinc signaling because they produce intracellular reactive oxygen species following activation through the T cell receptor and are sensitive to small changes in intracellular [Zn(2+)]. RESULTS: MT expression and intracellular [Zn(2+)] are both increased during primary activation and expansion of naïve CD4(+) T cells into the Tr1 phenotype in vitro. When Tr1 cells from wildtype mice are compared with congenic mice lacking functional Mt1 and Mt2 genes, the expression of intracellular MT is associated with a greater increase in intracellular [Zn(2+)] immediately following exposure to reactive oxygen species or upon restimulation through the T cell receptor. The release of Zn(2+) from MT is associated with a greater increase in p38 MAPK activation following restimulation and decreased p38 MAPK activation in MT knockout Tr1 cells can be rescued by increasing intracellular [Zn(2+)]. Additionally, IL-10 secretion is increased in MT knockout Tr1 cells compared with wildtype controls and this increase is prevented when the intracellular [Zn(2+)] is increased experimentally. CONCLUSIONS: Differences in zinc signaling associated with MT expression appear to be a result of preferential oxidation of MT and concomitant release of Zn(2+). Although zinc is released from many proteins following oxidation, release is greater when the cell contains an intracellular pool of MT. By expressing MT in response to certain environmental conditions, CD4(+) T cells are able to more efficiently release intracellular zinc and regulate signaling pathways following stimulation. The link between MT expression and increased zinc signaling following activation represents an important immunomodulatory mechanism of MT and illuminates the complex role MT plays in shaping immune responses.

A survey of the governance capacity of national public health associations to enhance population health.

BACKGROUND: National public health associations (PHAs) are key partners with governments and communities to improve, protect and promote the public's health. Governance and organizational capacity are among the key determinants of a PHA's effectiveness as an advocate for appropriate public health policies and practice. METHODS: During 2014, the World Federation of Public Health Associations (WFPHA) conducted an on-line survey of its 82 PHA members, to identify the state of organizational governance of national public health associations, as well as the factors that influence optimal organizational governance. The survey consisted of 13 questions and focused on the main elements of organizational governance: cultivating accountability; engaging stakeholders; setting shared direction; stewarding resources; and, continuous governance enhancement. Four questions included a qualitative open-ended response for additional comments. The survey data were analyzed using Microsoft Excel. The qualitative data was analyzed using thematic content analysis RESULTS: Responses were received from 62 PHAs, constituting a 75.6 % response rate. The two most important factors that support governance effectiveness were a high degree of integrity and ethical behavior of the PHA's leaders (77 %) and the competence of people serving on the PHA's governing body (76 %). The lack of financial resources was considered as the most important factor that negatively affected organizational governance effectiveness (73 %). The lack of mentoring for future PHA leaders; ineffective or incompetent leadership; lack of understanding about good governance practices; and lack of accurate information for strategic planning were identified as factors influencing PHA governance effectiveness. Critical elements for PHA sustainability included diversity, gender-responsiveness and inclusive governance practices, and strategies to build the future generation of public health leaders. CONCLUSION: National PHA have a responsibility to put into place the practices and infrastructure that enhance organizational governance. This will enhance their ability to be effective advocates for policies and practices that enhance, protect and promote the public's health. The WFPHA has an important role to play in providing the technical assistance and financial resources to assist PHAs in attaining and sustaining a higher level of governance capacity.