Common data elements for clinical research in Friedreich's ataxia

To reduce study start‐up time, increase data sharing, and assist investigators conducting clinical studies, the National Institute of Neurological Disorders and Stroke embarked on an initiative to create common data elements for neuroscience clinical research. The Common Data Element Team developed general common data elements, which are commonly collected in clinical studies regardless of therapeutic area, such as demographics. In the present project, we applied such approaches to data collection in Friedreich's ataxia (FRDA), a neurological disorder that involves multiple organ systems. To develop FRDA common data elements, FRDA experts formed a working group and subgroups to define elements in the following: ataxia and performance measures; biomarkers; cardiac and other clinical outcomes; and demographics, laboratory tests, and medical history. The basic development process included identification of international experts in FRDA clinical research, meeting by teleconference to develop a draft of standardized common data elements recommendations, vetting of recommendations across the subgroups, and dissemination of recommendations to the research community for public comment. The full recommendations were published online in September 2011 at http://www.commondataelements.ninds.nih.gov/FA.aspx . The subgroups′ recommendations are classified as core, supplemental, or exploratory. Template case report forms were created for many of the core tests. The present set of data elements should ideally lead to decreased initiation time for clinical research studies and greater ability to compare and analyze data across studies. Their incorporation into new, ongoing studies will be assessed in an ongoing fashion to define their utility in FRDA. © 2012 Movement Disorder Society     

The reliability of lymphoma diagnosis in small tissue samples is heavily influenced by lymphoma subtype

A specific pathologic diagnosis is important in malignant lymphoma because the diverse disease subtypes require tailored approaches to clinical management. Reliance on small samples obtained with cutting needles has been advocated as a less invasive alternative to using larger, excised samples. Although published studies have demonstrated the safety and apparent sufficiency of this approach in informing clinical care, none have systematically determined the accuracy of pathologic lymphoma subtyping based on very small samples. We used a tissue microarray representing 67 cases of malignant lymphoma and 17 samples of nonneoplastic lymphoid tissue to model lymphoma diagnosis in small samples. Overall, 73.8% of the cases were diagnosed with a level of confidence deemed sufficient for directing clinical management; 85.9% of these diagnoses were accurate. Small cell lymphomas with highly distinctive immunophenotypes, including small lymphocytic, mantle cell, and T-lymphoblastic lymphoma, were recognized most consistently and accurately in the small samples. In contrast, follicular lymphoma and marginal zone lymphoma were especially difficult. Our results indicate that the reliability of lymphoma diagnoses based on small samples is heavily influenced by lymphoma subtype.     

Competencies and skills for remote and rural maternity care: a review of the literature

AIM: This paper reports a review of the literature on skills, competencies and continuing professional development necessary for sustainable remote and rural maternity care. BACKGROUND: There is a general sense that maternity care providers in rural areas need specific skills and competencies. However, how these differ from generic skills and competencies is often unclear. METHODS: Approaches used to access the research studies included a comprehensive search in relevant electronic databases using relevant keywords (e.g. 'remote', 'midwifery', 'obstetrics', 'nurse-midwives', education', 'hospitals', 'skills', 'competencies', etc.). Experts were approached for (un-)published literature, and books and journals known to the authors were also used. Key journals were hand searched and references were followed up. The original search was conducted in 2004 and updated in 2006. FINDINGS: Little published literature exists on professional education, training or continuous professional development in maternity care in remote and rural settings. Although we found a large literature on competency, little was specific to competencies for rural practice or for maternity care. 'Hands-on' skills courses such as Advanced Life Support in Obstetrics and the Neonatal Resuscitation Programme increase confidence in practice, but no published evidence of effectiveness of such courses exists. CONCLUSION: Educators need to be aware of the barriers facing rural practitioners, and there is potential for increasing distant learning facilitated by videoconferencing or Internet access. They should also consider other assessment methods than portfolios. More research is needed on the levels of skills and competencies required for maternity care professionals practising in remote and rural areas.     

Dissipative particle dynamics simulation of multicompartment micelle nanoreactor with channel for reactants

The structural variation of multicompartment micelles is investigated using a dissipative particle dynamics simulation method for nano-reactor application. It turns out that well-defined multicompartment micelles with channel structures can be generated through the self-assembly of triblock copolymers consisting of a hydrophilic (A), a lipophilic (B), and a fluorophobic (C) block arranged in a B–A–C sequence: The corona and core are formed by the hydrophilic A block and the fluorophilic C block, respectively while the channel between the aqueous phase and core is formed by the lipophilic B block and the core. By performing a set of simulations, it is confirmed that channel size can be controlled as a function of the block length ratios between blocks A and B. Furthermore, it is also confirmed that the reactants pass through such channels to reach the micelle core by analyzing the pair correlation functions. By monitoring the change of the number of reactants in the multicompartment micelle, it is revealed that the diffusion of reactants into the core is slowed down as the concentration gradient is decreased. This work provides mesoscopic insight for the formation of multicompartment micelles and transport of reactants for use in the design of micelles as nanoreactors.

The structural variation of multicompartment micelles is investigated using a dissipative particle dynamics simulation method for nano-reactor application.     

High frequency of Fredrickson's phenotypes IV and IIb in Brazilians infected by human immunodeficiency virus

Background  

Human immunodeficiency virus (HIV) infection is very prevalent in Brazil. HIV therapy has been recently associated with coronary heart disease (CHD). Dyslipidemia is a major risk factor for CHD that is frequently described in HIV positive patients, but very few studies have been conducted in Brazilian patients evaluating their lipid profiles.     

Etoposide causes illegitimate V(D)J recombination in human lymphoid leukemic cells

Etoposide is one of the most widely used antineoplastics. Unfortunately, the same treatment schedules associated with impressive efficacy are associated with an increased risk of secondary acute myeloid leukemia (AML), which has prompted its withdrawal from some treatment regimens, thereby potentially compromising efficacy against the original tumor. Because etoposide-associated AML is characterized by site-specific illegitimate DNA recombination, we studied whether etoposide could directly cause site-specific deletions of exons 2 and 3 in the hprt gene. Human lymphoid CCRF-CEM cells were treated with etoposide for 4 hours, and DNA was isolated after subculturing. The deletion of exons 2 and 3 from hprt was assayed by a quantitative polymerase chain reaction (PCR) method. In the absence of etoposide treatment, the frequency of deletions of exons 2 and 3 was very low (5.05 x 10(-8)). After exposure to 10 mumol/ L etoposide, the frequency of the exon 2 + 3 deletion was increased immediately after and at 24 hours after etoposide treatment (65 to 89 x 10(-8)) and increased to higher levels (128 to 173 x 10(-8)) after 2 and 6 days of subculture (P < .001 overall). The frequency of the exon 2 + 3 deletion assessed at 6 days of subculture after 4 hours of 0, 0.25, 1, 2.5, 5, and 10 mumol/L etoposide treatment increased with etoposide concentration, ie, 5.05 x 10(-8), 89.2 x 10(-8), 108 x 10(-8), 142 x 10(-8), 163 x 10(-8), and 173 x 10(-8), respectively (P < .0001). Sequencing of a subset of amplified products confirmed the presence of DNA sequences at the breakpoints consistent with V(D)J recombination. By contrast, exon 2 + 3 deletions after etoposide treatment in the myeloid cell lines KG-1A and K562 showed no evidence of V(D)J recombinase in their genesis. We conclude that etoposide can induce the illegitimate site-specific action of V(D)J recombinase on an unnatural DNA substrate after a single treatment in human lymphoid cells.     

The contribution of black carbon to global ice nucleating particle concentrations relevant to mixed-phase clouds

Black carbon (BC) aerosol plays an important role in the Earth’s climate system because it absorbs solar radiation and therefore potentially warms the climate; however, BC can also act as a seed for cloud particles, which may offset much of its warming potential. If BC acts as an ice nucleating particle (INP), BC could affect the lifetime, albedo, and radiative properties of clouds containing both supercooled liquid water droplets and ice particles (mixed-phase clouds). Over 40% of global BC emissions are from biomass burning; however, the ability of biomass burning BC to act as an INP in mixed-phase cloud conditions is almost entirely unconstrained. To provide these observational constraints, we measured the contribution of BC to INP concentrations ([INP]) in real-world prescribed burns and wildfires. We found that BC contributes, at most, 10% to [INP] during these burns. From this, we developed a parameterization for biomass burning BC and combined it with a BC parameterization previously used for fossil fuel emissions. Applying these parameterizations to global model output, we find that the contribution of BC to potential [INP] relevant to mixed-phase clouds is ∼5% on a global average.

Black carbon (BC) is the primary light-absorbing aerosol in the atmosphere. Its short lifetime (days to weeks) relative to CO2 and methane makes it an intriguing target for near-term climate mitigation (1). Errors associated with BC climate forcing, however, obfuscate its efficacy as a climate mitigator. The largest contributions to BC’s forcing uncertainties are often attributed to its effects on clouds, in particular mixed-phase clouds [i.e., clouds containing supercooled cloud droplets and ice particles, (2)]. Efforts to reduce these uncertainties are hindered by the complexity of aerosol–cloud interactions (3). Particularly vexing is quantifying the abundance and identity of ice nucleating particles (INPs). INPs provide the only pathway for primary ice formation in mixed-phase clouds; however, they are rare [e.g., ∼1 in 106 particles are INPs at −20 °C (4)]. Despite their rarity, INPs influence mixed-phase cloud ice concentrations and precipitation and therefore alter cloud albedo and lifetime (5). Furthermore, the INP properties of aerosols, such as BC, will affect their own lifetime, vertical structure, and transport to climate-sensitive regions such as the Arctic (6). Despite its importance to the Earth’s climate and near-term climate mitigation strategies, the INP efficiency of BC relevant to mixed-phase clouds remains almost entirely unconstrained from direct observations, encumbering attempts to estimate BC’s impact on mixed-phase clouds in modeling studies (7).BC’s efficacy as an immersion-freezing INP (henceforth, INP will refer only to freezing by particles encapsulated within supercooled cloud droplets, termed immersion freezing and pertinent to mixed-phase cloud conditions) has been studied in the laboratory for decades, with starkly conflicting results. Early laboratory studies showed that acetylene and kerosene flame-generated soot can nucleate ice below −20 °C. (8, 9); after normalizing for surface area, these studies indicated that BC may be more ice active than the well-known INP mineral dust (10). Results from later laboratory studies were contradictory, suggesting that BC was not active as an INP above instrument limits of detection. These included soot aerosols from miniCAST soot generators, graphite spark generator soot, hydrocarbon flame-generated soot, and fullerene soot, as well as various lamp blacks and carbon blacks (11–15).Unfortunately, field study measurements of the contribution of BC to INP concentrations ([INP]) have also been inconclusive. For example, in-cloud measurements from the high-altitude observatory at Jungfraujoch, Switzerland saw that BC is enriched in ice-particle residuals and therefore may efficiently nucleate ice (16); later measurements at the same site, however, saw that BC is depleted in the ice phase, which suggests that BC does not play a significant role in mixed-phase cloud ice nucleation (17, 18).These contradictions in laboratory and field studies suggest that fuel type and combustion conditions determine the ice nucleation properties of BC. Such conditions prescribe BC’s physical and morphological properties as well as its coemitted and coagulated species. Major BC fuel types include fossil fuels and flammable biomass, and major combustion sources include diesel exhaust, residential fuel burning, prescribed burns, and wildfires (2). BC particles from fossil fuel combustion and anthropogenic pollution are not significant sources of INPs. For example, studies on diesel exhaust have shown that less than 1 in 109 BC particles are ice nucleation active at −30 °C (19). Furthermore, ambient [INP] in Beijing, China were relatively constant over several weeks despite BC concentrations varying by a factor of 30 and reaching values as high as 17.26 μg⋅m−3 (20).Elevated [INP] have been observed in biomass-burning smoke during laboratory and field studies (21–23); however, it is unclear from these studies if the INPs are actually BC. Some studies have shown that BC may be the dominant INP type in select biomass burning conditions. For example, soot particles were found to contribute up to 64% of the INPs in prescribed burns within a predominantly wiregrass understory (24). Furthermore, BC contributed up to 70% to [INP] in controlled laboratory burns of grasses (25). As biomass burning represents ∼40% of global BC emissions (2), BC from biomass burning could be a significant source of INP globally. In both of these studies, however, the overall ice-active fractions may be too low to influence [INP], even on the regional level (21). Thus, it remains unclear whether BC contributes to [INP] outside of thick plumes and on a global scale (26).Regional- and global-scale estimates of BC [INP] rely on models that can implement theory-based or empirical ice nucleation parameterizations. Using parameterizations based on BC INP activity from the acetylene and kerosene-burner soot studies, models have found that BC contributes ∼50% to [INP] in springtime low-level Arctic mixed-phase clouds (27), and 23 to 61% to global [INP] depending on dust loadings (28). Taking into account the aforementioned negative results, these modeling studies highlight that BC’s contribution to [INP] is poorly constrained and is estimated to vary from no contribution to being the most abundant INP globally.To assess the role of BC from biomass burning as an INP, we determined the contribution of refractory BC (rBC)-containing particles to [INP] from field measurements of both prescribed burns and wildfires using the single-particle soot photometer coupled to a continuous-flow diffusion chamber (SP2-CFDC) (29, 30). The SP2-CFDC selectively removes rBC from an aerosol stream and quantifies that effect on [INP]. From these burns, we found that rBC-containing particles contributed ≤10% to [INP]. From these results, we developed a surface-area normalized parameterization for BC INPs from biomass burning. The parameterization aligns well with other surface-area normalized parameterizations derived from laboratory proxies of BC and diesel exhaust BC (15, 19, 31). These parameterizations are over four orders of magnitude lower than the parameterization derived from acetylene and kerosene-burner soot studies and used in the aforementioned modeling studies. Assuming the INP characteristics of BC from the burns in this study can be extended to different biomass-burning fuel types and combustion conditions, this study strongly suggests that BC is not an efficient INP. Under this assumption, we assessed the global importance of BC as an INP by applying our parameterization to simulated biomass-burning aerosol from a global chemical transport model. A similar parameterization for diesel exhaust (19) was applied to simulated fossil fuel BC. From these treatments, we estimate that BC’s contribution to simulated, potential [INP] is only ∼5% on a global average.     

In utero repair of myelomeningocele with autologous amniotic membrane in the fetal lamb model

Background

Despite advances in prenatal repair, myelomeningocele (MMC) still produces devastating neurologic deficits. The amniotic membranes (AM) are a biologically active tissue that has been used anecdotally for human fetal MMC repair. This study evaluated the use of autologous AM compared to skin closure in an established fetal MMC model.

Methods

Seven fetal lambs underwent surgical creation of MMC at gestational age of 75 days followed by in utero repair at gestational age of 100 days. Lambs were repaired with an autologous AM patch followed by skin closure (n = 4) or skin closure alone (n = 3). Gross necropsy and histopathology of the spinal cords were performed at term to assess neuronal preservation at the lesion.

Results

An increase in preserved motor neurons and a larger area of spinal cord tissue were seen in AM-repaired lambs, as was decreased wound healing of the overlying skin. Loss of nearly all spinal cord tissue with limited motor neuron preservation was seen in skin only-repaired lambs.

Conclusions

AM-repaired lambs showed increased protection of spinal cord tissue compared to skin only-repaired lambs, but the overlying skin failed to close in AM-repaired lambs. These results suggest a potential role for AM in fetal MMC repair that warrants further study.     

New insight into the evolution of the vertebrate respiratory system and the discovery of unidirectional airflow in iguana lungs

The generally accepted framework for the evolution of a key feature of the avian respiratory system, unidirectional airflow, is that it is an adaptation for efficiency of gas exchange and expanded aerobic capacities, and therefore it has historically been viewed as important to the ability of birds to fly and to maintain an endothermic metabolism. This pattern of flow has been presumed to arise from specific features of the respiratory system, such as an enclosed intrapulmonary bronchus and parabronchi. Here we show unidirectional airflow in the green iguana, a lizard with a strikingly different natural history from that of birds and lacking these anatomical features. This discovery indicates a paradigm shift is needed. The selective drivers of the trait, its date of origin, and the fundamental aerodynamic mechanisms by which unidirectional flow arises must be reassessed to be congruent with the natural history of this lineage. Unidirectional flow may serve functions other than expanded aerobic capacity; it may have been present in the ancestral diapsid; and it can occur in structurally simple lungs.Energetically demanding forms of locomotion, such as powered flight, require a great capacity for gas exchange and selection for aerobic stamina may underlie many unique features of the avian respiratory system (1, 2). The avian respiratory system consists of highly vascularized lungs and avascular air sacs, which are membranous structures that effect ventilation and, in some species, extend between the muscles and even enter the bones (3). The topography of the conducting airways is complex; they form a circular system of tubes, analogous to the loop formed by the blood circulatory system in which arteries connect to veins through numerous small diameter vessels, the capillaries. Likewise, the avian conducting airways connect to each other through numerous tubules, the parabronchi, to form a circular path for respiratory gases (3). Gases flow through most of the parabronchi in the same direction during both inhalation and exhalation (unidirectional flow). This is due to the presence of aerodynamic valves (4–10). In contrast, the mammalian conducting airways arborize with the branch tips ending in blind sacs, there are no valves, and gases travel in the opposite direction along the conducting airways during expiration from the direction followed during inspiration (tidal flow). The presence of aerodynamic valves and unidirectional flow has generally been thought to be a highly derived feature found, among extant animals, only in birds and having evolved either in the crown group with flight or somewhere along the saurischian lineage leading to birds (11), perhaps as a mechanism to meet the high energetic demands of endothermy.The discovery of unidirectional flow in the lungs of alligators (12, 13) and the savannah monitor lizard (14) indicates that we do not understand the distribution of this phenomenon among different lineages of vertebrates and raises questions about its underlying value. It is possible that unidirectional flow evolved convergently in crocodilians and monitor lizards and serves to expand aerobic capacity. Although monitor lizards are ectotherms, their lifestyles are largely convergent with small predatory mammals (15) and they have high aerobic capacities compared with other lizards (16). In contrast, extant alligators have limited aerobic stamina (17) but their common ancestor with birds may have had a great aerobic capacity (18) or may have been endothermic (19, 20). Crocodilians and monitor lizards also share a suite of features of their pulmonary and cardiac anatomy that have been purported to give rise to, or coevolve with, birdlike patterns of flow. These features are: (i) a bronchus that has grown deep into the lung as a mesobronchium, (ii) partitioning of the respiratory system into a mechanical part that functions in ventilation and a gas-exchanging region, (iii) intercameral perforations, and (iv) separation of the heart into right and left sides (1, 21). Crocodilians and monitors are also derived in having evolved mechanisms to supplement costal ventilation while exercising (18, 22, 23). Thus, unidirectional flow in these lineages may be one of many derived traits underpinning exceptionally high rates of oxygen consumption during activity.It is also possible, however, that this pattern of flow evolved before the split of Diapsida into the Lepidosauromorpha (tuatara, lizards, snakes) and Archosauromorpha (crocodilians and birds) in an ectothermic ancestor lacking expanded aerobic capacities and living as long ago as the Permian Period. Unidirectional flow has been purported to serve ectotherms by harnessing the heart as a pump for air during periods of breath-holding (apnea) (12). Light can be shed on this pattern of evolution with observations of more squamates (snakes, lizards), which are the most diverse and largest (∼9,000 species) group of living reptiles (24).To test the hypothesis that unidirectional flow is present in squamates other than varanid lizards; to better understand anatomical features that give rise to these patterns of flow; and to gain insight into the underlying value of this pattern of flow, green iguanas (Iguana iguana) were studied. Green iguanas differ from monitors because they are herbivores and because they have structurally simple lungs that lack an enclosed intrapulmonary bronchus. Iguanas lack septation of the cardiac ventricle and have poor locomotor stamina. The poor stamina is due in part from an impairment during running in their blood and air circulatory systems (19, 25, 26).