A Systematic Review of Magnesium Sulfate for Perinatal Neuroprotection: What Have We Learnt From the Past Decade?

There is an important unmet need to improve long term outcomes of encephalopathy for preterm and term infants. Meta-analyses of large controlled trials suggest that maternal treatment with magnesium sulfate (MgSO4) is associated with a reduced risk of cerebral palsy and gross motor dysfunction after premature birth. However, to date, follow up to school age has found an apparent lack of long-term clinical benefit. Because of this inconsistency, it remains controversial whether MgSO4 offers sustained neuroprotection. We systematically reviewed preclinical and clinical studies reported from January 1 2010, to January 31 2020 to evaluate the most recent advances and knowledge gaps relating to the efficacy of MgSO4 for the treatment of perinatal brain injury. The outcomes of MgSO4 in preterm and term-equivalent animal models of perinatal encephalopathy were highly inconsistent between studies. None of the perinatal rodent studies that suggested benefit directly controlled body or brain temperature. The majority of the studies did not control for sex, study long term histological and functional outcomes or use pragmatic treatment regimens and many did not report controlling for potential study bias. Finally, most of the recent preterm or term human studies that tested the potential of MgSO4 for perinatal neuroprotection were relatively underpowered, but nevertheless, suggest that any improvements in neurodevelopment were at best modest or absent. On balance, these data suggest that further rigorous testing in translational preclinical models of perinatal encephalopathy is essential to ensure safety and best regimens for optimal preterm neuroprotection, and before further clinical trials of MgSO4 for perinatal encephalopathy at term are undertaken

Heavy metals and radioactivity reduction from acid mine drainage lime neutralized sludge

Abstract: The worldwide known treatment processes of acid mine drainage result into the formation of hydrous ferric oxides that is amorphous, poorly crystalline and into the generation of hazardous voluminous sludge posing threat to the environment. Applicable treatment technologies to treat hazardous solid material and produce useful products are limited and in most cases nonexistence. A chemical treatment process utilizing different reagents was developed to treat hazardous acid mine drainage (AMD) sludge with the objectives to conduct radioactivity assessment of the sludge generated from lime treatment process and determine the reagent that provides the best results. Leaching with 0.5 M citric acid, 0.4 M oxalic acid, 0.5 M sodium carbonate and 0.5 M sodium bicarbonate was investigated. The leaching time applied was 24 hours at 25 oC. The characterization of the raw AMD revealed that the AMD sludge from lime treatment process is radioactive. The sludge was laden with radioactive elements namely, 238U, 214Pb, 226Ra, 232Th, 40K and 214Bi. 0.5 M citric acid provided the best results and the hazardous contaminants were significantly reduced. The constituents in the sludge after treatment revealed that there is a great potential for the sludge to be used for other applications such as building and construction

The effects of temperature and body mass on jump performance of the locust Locusta migratoria

Locusts jump by rapidly releasing energy from cuticular springs built into the hind femur that deform when the femur muscle contracts. This study is the first to examine the effect of temperature on jump energy at each life stage of any orthopteran. Ballistics and high-speed cinematography were used to quantify the energy, distance, and take-off angle of the jump at 15, 25, and 35°C in the locust Locusta migratoria. Allometric analysis across the five juvenile stages at 35°C reveals that jump distance (D; m) scales with body mass (M; g) according to the power equation D = 0.35M0.17±0.08 (95% CI), jump take-off angle (A; degrees) scales as A = 52.5M0.00±0.06, and jump energy (E; mJ per jump) scales as E = 1.91M1.14±0.09. Temperature has no significant effect on the exponent of these relationships, and only a modest effect on the elevation, with an overall Q10 of 1.08 for jump distance and 1.09 for jump energy. On average, adults jump 87% farther and with 74% more energy than predicted based on juvenile scaling data. The positive allometric scaling of jump distance and jump energy across the juvenile life stages is likely facilitated by the concomitant relative increase in the total length (Lf+t; mm) of the femur and tibia of the hind leg, Lf+t = 34.9M0.37±0.02. The weak temperature-dependence of jump performance can be traced to the maximum tension of the hind femur muscle and the energy storage capacity of the femur's cuticular springs. The disproportionately greater jump energy and jump distance of adults is associated with relatively longer (12%) legs and a relatively larger (11%) femur muscle cross-sectional area, which could allow more strain loading into the femur's cuticular springs. Augmented jump performance in volant adult locusts achieves the take-off velocity required to initiate flight.Edward P. Snelling, Christie L. Becker, Roger S. Seymou

High Erk-1 activation and Gadd45a expression as prognostic markers in high risk pediatric haemolymphoproliferative diseases

Studies on activated cell-signaling pathways responsible for neoplastic transformation are numerous in solid tumors and in adult leukemias. Despite of positive results in the evolution of pediatric hematopoietic neoplasias, there are some high-risk subtypes at worse prognosis. The aim of this study was to asses the expression and activation status of crucial proteins involved in cell-signaling pathways in order to identify molecular alterations responsible for the proliferation and/or escape from apoptosis of leukemic blasts. The quantitative and qualitative expression and activation of Erk-1, c-Jun, Caspase8, and Gadd45a was analyzed, by immunocytochemical (ICC) and western blotting methods, in bone marrow blasts of 72 patients affected by acute myeloid leukemia (AML), T-cell acute lymphoblastic leukemia (ALL) and stage IV non-Hodgkin Lymphoma (NHL). We found an upregulation of Erk-1, Caspase8, c-Jun, and Gadd45a proteins with a constitutive activation in 95.8%, 91.7%, 86.2%, 83.4% of analyzed specimens, respectively. It is worth noting that all AML patients showed an upregulation of all proteins studied and the high expression of GADD45a was associated to the lowest DFS median (p = 0.04). On univariate analysis, only Erk-1 phosphorylation status was found to be correlated with a significantly shorter 5-years DFS in all disease subgroups (p = 0.033) and the lowest DFS median in ALL/NHL subgroup (p = 0.04). Moreover, the simultaneous activation of multiple kinases, as we found for c-Jun and Erk-1 (r = 0.26; p = 0.025), might synergistically enhance survival and proliferation potential of leukemic cells. These results demonstrate an involvement of these proteins in survival of blast cells and, consequently, on relapse percentages of the different subgroups of patients

Quantitative Metabolomics by 1H-NMR and LC-MS/MS Confirms Altered Metabolic Pathways in Diabetes

Insulin is as a major postprandial hormone with profound effects on carbohydrate, fat, and protein metabolism. In the absence of exogenous insulin, patients with type 1 diabetes exhibit a variety of metabolic abnormalities including hyperglycemia, glycosurea, accelerated ketogenesis, and muscle wasting due to increased proteolysis. We analyzed plasma from type 1 diabetic (T1D) humans during insulin treatment (I+) and acute insulin deprivation (I-) and non-diabetic participants (ND) by 1H nuclear magnetic resonance spectroscopy and liquid chromatography-tandem mass spectrometry. The aim was to determine if this combination of analytical methods could provide information on metabolic pathways known to be altered by insulin deficiency. Multivariate statistics differentiated proton spectra from I- and I+ based on several derived plasma metabolites that were elevated during insulin deprivation (lactate, acetate, allantoin, ketones). Mass spectrometry revealed significant perturbations in levels of plasma amino acids and amino acid metabolites during insulin deprivation. Further analysis of metabolite levels measured by the two analytical techniques indicates several known metabolic pathways that are perturbed in T1D (I-) (protein synthesis and breakdown, gluconeogenesis, ketogenesis, amino acid oxidation, mitochondrial bioenergetics, and oxidative stress). This work demonstrates the promise of combining multiple analytical methods with advanced statistical methods in quantitative metabolomics research, which we have applied to the clinical situation of acute insulin deprivation in T1D to reflect the numerous metabolic pathways known to be affected by insulin deficiency

Therapeutic hypothermia translates from ancient history in to practice

Acute postasphyxial encephalopathy around the time of birth remains a major cause of death and disability. The possibility that hypothermia may be able to prevent or lessen asphyxial brain injury is a “dream revisited”. In this review, a historical perspective is provided from the first reported use of therapeutic hypothermia for brain injuries in antiquity, to the present day. The first uncontrolled trials of cooling for resuscitation were reported more than 50 y ago. The seminal insight that led to the modern revival of studies of neuroprotection was that after profound asphyxia, many brain cells show initial recovery from the insult during a short “latent” phase, typically lasting ~6 h, only to die hours to days later during a “secondary” deterioration phase characterized by seizures, cytotoxic edema, and progressive failure of cerebral oxidative metabolism. Studies designed around this conceptual framework showed that mild hypothermia initiated as early as possible before the onset of secondary deterioration, and continued for a sufficient duration to allow the secondary deterioration to resolve, is associated with potent, long-lasting neuroprotection. There is now compelling evidence from randomized controlled trials that mild induced hypothermia significantly improves intact survival and neurodevelopmental outcomes to midchildhood

Analysis of 17,576 Potentially Functional SNPs in Three Case–Control Studies of Myocardial Infarction

Myocardial infarction (MI) is a common complex disease with a genetic component. While several single nucleotide polymorphisms (SNPs) have been reported to be associated with risk of MI, they do not fully explain the observed genetic component of MI. We have been investigating the association between MI and SNPs that are located in genes and have the potential to affect gene function or expression. We have previously published studies that tested about 12,000 SNPs for association with risk of MI, early-onset MI, or coronary stenosis. In the current study we tested 17,576 SNPs that could affect gene function or expression. In order to use genotyping resources efficiently, we staged the testing of these SNPs in three case–control studies of MI. In the first study (762 cases, 857 controls) we tested 17,576 SNPs and found 1,949 SNPs that were associated with MI (P<0.05). We tested these 1,949 SNPs in a second study (579 cases and 1159 controls) and found that 24 SNPs were associated with MI (1-sided P<0.05) and had the same risk alleles in the first and second study. Finally, we tested these 24 SNPs in a third study (475 cases and 619 controls) and found that 5 SNPs in 4 genes (ENO1, FXN (2 SNPs), HLA-DPB2, and LPA) were associated with MI in the third study (1-sided P<0.05), and had the same risk alleles in all three studies. The false discovery rate for this group of 5 SNPs was 0.23. Thus, we have identified 5 SNPs that merit further examination for their potential association with MI. One of these SNPs (in LPA), has been previously shown to be associated with risk of cardiovascular disease in other studies

Institutional capacity for health systems research in East and Central African schools of public health: knowledge translation and effective communication

BACKGROUND: Local health systems research (HSR) provides policymakers and practitioners with contextual, evidence-based solutions to health problems. However, producers and users of HSR rarely understand the complexities of the context within which each operates, leading to the “know–do” gap. Universities are well placed to conduct knowledge translation (KT) integrating research production with uptake. The HEALTH Alliance Africa Hub, a consortium of seven schools of public health (SPHs) in East and Central Africa, was formed to build capacity in HSR. This paper presents information on the capacity of the various SPHs to conduct KT activities. METHODS: In 2011, each member of the Africa Hub undertook an institutional HSR capacity assessment using a context-adapted and modified self-assessment tool. KT capacity was measured by several indicators including the presence of a KT strategy, an organizational structure to support KT activities, KT skills, and institutional links with stakeholders and media. Respondents rated their opinions on the various indicators using a 5-point Likert scale. Averages across all respondents for each school were calculated. Thereafter, each school held a results validation workshop. RESULTS: A total of 123 respondents from all seven SPHs participated. Only one school had a clear KT strategy; more commonly, research was disseminated at scientific conferences and workshops. While most respondents perceived their SPH as having strong institutional ties with organizations interested in HSR as well as strong institutional leadership, the organizational structures required to support KT activities were absent. Furthermore, individual researchers indicated that they had little time or skills to conduct KT. Additionally, institutional and individual links with policymakers and media were reported as weak. CONCLUSIONS: Few SPHs in Africa have a clear KT strategy. Strengthening the weak KT capacity of the SPHs requires working with institutional leadership to develop KT strategies designed to guide organizational structure and development of networks with both the media and policymakers to improve research uptake.DFI

A mathematical model of the human metabolic system and metabolic flexibility

In healthy subjects some tissues in the human body display metabolic flexibility, by this we mean the ability for the tissue to switch its fuel source between predominantly carbohydrates in the post prandial state and predominantly fats in the fasted state. Many of the pathways involved with human metabolism are controlled by insulin, and insulin- resistant states such as obesity and type-2 diabetes are characterised by a loss or impairment of metabolic flexibility. In this paper we derive a system of 12 first-order coupled differential equations that describe the transport between and storage in different tissues of the human body. We find steady state solutions to these equations and use these results to nondimensionalise the model. We then solve the model numerically to simulate a healthy balanced meal and a high fat meal and we discuss and compare these results. Our numerical results show good agreement with experimental data where we have data available to us and the results show behaviour that agrees with intuition where we currently have no data with which to compare

Signalling plasticity and energy saving in a tropical bushcricket

Males of the tropical bushcricket Mecopoda elongata synchronize their acoustic advertisement signals (chirps) in interactions with other males. However, synchrony is not perfect and distinct leader and follower roles are often maintained. In entrainment experiments in which conspecific signals were presented at various rates, chirps displayed as follower showed notable signal plasticity. Follower chirps were shortened by reducing the number and duration of syllables, especially those of low and medium amplitude. The degree of shortening depended on the time delay between leader and follower signals and the sound level of the entraining stimulus. The same signal plasticity was evident in male duets, with the effect that the last syllables of highest amplitude overlapped more strongly. Respiratory measurements showed that solo singing males producing higher chirp rates suffered from higher metabolic costs compared to males singing at lower rates. In contrast, respiratory rate was rather constant during a synchronous entrainment to a conspecific signal repeated at various rates. This allowed males to maintain a steady duty cycle, associated with a constant metabolic rate. Results are discussed with respect to the preference for leader signals in females and the possible benefits males may gain by overlapping their follower signals in a chorus