Pharmacotherapeutic targeting of cation-chloride cotransporters in neonatal seizures

Seizures are a common manifestation of acute neurologic insults in neonates and are often resistant to the standard antiepileptic drugs that are efficacious in children and adults. The paucity of evidence-based treatment guidelines, coupled with a rudimentary understanding of disease pathogenesis, has made the current treatment of neonatal seizures empiric and often ineffective, highlighting the need for novel therapies. Key developmental differences in γ-aminobutyric acid (GABA)ergic neurotransmission between the immature and mature brain, and trauma-induced alterations in the function of the cation-chloride cotransporters (CCCs) NKCC1 and KCC2, probably contribute to the poor efficacy of standard antiepileptic drugs used in the treatment of neonatal seizures. Although CCCs are attractive drug targets, bumetanide and other existing CCC inhibitors are suboptimal because of pharmacokinetic constraints and lack of target specificity. Newer approaches including isoform-specific NKCC1 inhibitors with increased central nervous system penetration, and direct and indirect strategies to enhance KCC2-mediated neuronal chloride extrusion, might allow therapeutic modulation of the GABAergic system for neonatal seizure treatment.Peer reviewe

Reorganization of surviving mammal communities after the end-Pleistocene megafaunal extinction

Large mammals are at high risk of extinction globally. To understand the consequences of their demise for community assembly, we tracked community structure through the end- Pleistocene megafaunal extinction in North America.We decomposed the effects of biotic and abiotic factors by analyzing co-occurrence within the mutual ranges of species pairs. Although shifting climate drove an increase in niche overlap, co-occurrence decreased, signaling shifts in biotic interactions. Furthermore, the effect of abiotic factors on cooccurrence remained constant over time while the effect of biotic factors decreased. Biotic factors apparently played a key role in continental-scale community assembly before the extinctions. Specifically, large mammals likely promoted co-occurrence in the Pleistocene, and their loss contributed to the modern assembly pattern in which co-occurrence frequently falls below random expectations. Includes supplementary materials

Reorganization of surviving mammal communities after the end-Pleistocene megafaunal extinction

Large mammals are at high risk of extinction globally. To understand the consequences of their demise for community assembly, we tracked community structure through the end-Pleistocene megafaunal extinction in North America. We decomposed the effects of biotic and abiotic factors by analyzing co-occurrence within the mutual ranges of species pairs. Although shifting climate drove an increase in niche overlap, co-occurrence decreased, signaling shifts in biotic interactions. Furthermore, the effect of abiotic factors on co-occurrence remained constant over time while the effect of biotic factors decreased. Biotic factors apparently played a key role in continental-scale community assembly before the extinctions. Specifically, large mammals likely promoted co-occurrence in the Pleistocene, and their loss contributed to the modern assembly pattern in which co-occurrence frequently falls below random expectations.Peer reviewe

Investigating Biotic Interactions in Deep Time

Recent renewed interest in using fossil data to understand how biotic interactions have shaped the evolution of life is challenging the widely held assumption that long-term climate changes are the primary drivers of biodiversity change. New approaches go beyond traditional richness and co-occurrence studies to explicitly model biotic interactions using data on fossil and modern biodiversity. Important developments in three primary areas of research include analysis of (i) macroevolutionary rates, (ii) the impacts of and recovery from extinction events, and (iii) how humans (Homo sapiens) affected interactions among non-human species. We present multiple lines of evidence for an important and measurable role of biotic interactions in shaping the evolution of communities and lineages on long timescales.Peer reviewe

Late quaternary biotic homogenization of North American mammalian faunas

Biotic homogenization-increasing similarity of species composition among ecological communities-has been linked to anthropogenic processes operating over the last century. Fossil evidence, however, suggests that humans have had impacts on ecosystems for millennia. We quantify biotic homogenization of North American mammalian assemblages during the late Pleistocene through Holocene (similar to 30,000 ybp to recent), a timespan encompassing increased evidence of humans on the landscape (similar to 20,000-14,000 ybp). From similar to 10,000 ybp to recent, assemblages became significantly more homogenous (>100% increase in Jaccard similarity), a pattern that cannot be explained by changes in fossil record sampling. Homogenization was most pronounced among mammals larger than 1 kg and occurred in two phases. The first followed the megafaunal extinction at similar to 10,000 ybp. The second, more rapid phase began during human population growth and early agricultural intensification (similar to 2,000-1,000 ybp). We show that North American ecosystems were homogenizing for millennia, extending human impacts back similar to 10,000 years.Peer reviewe

Late quaternary biotic homogenization of North American mammalian faunas

Biotic homogenization-increasing similarity of species composition among ecological communities-has been linked to anthropogenic processes operating over the last century. Fossil evidence, however, suggests that humans have had impacts on ecosystems for millennia. We quantify biotic homogenization of North American mammalian assemblages during the late Pleistocene through Holocene (similar to 30,000 ybp to recent), a timespan encompassing increased evidence of humans on the landscape (similar to 20,000-14,000 ybp). From similar to 10,000 ybp to recent, assemblages became significantly more homogenous (>100% increase in Jaccard similarity), a pattern that cannot be explained by changes in fossil record sampling. Homogenization was most pronounced among mammals larger than 1 kg and occurred in two phases. The first followed the megafaunal extinction at similar to 10,000 ybp. The second, more rapid phase began during human population growth and early agricultural intensification (similar to 2,000-1,000 ybp). We show that North American ecosystems were homogenizing for millennia, extending human impacts back similar to 10,000 years.Peer reviewe

Problematising Local Indigenous Community Research

This book deliberates on developments related to Knowledge Pathing: Multi-, Inter- and Trans-Disciplining in Social Sciences. The book explores the value of this vexed concept in advancing the course for multi-, inter- and trans-disciplinary perspectives, methodologies, theories and epistemologies of knowledge pathing. The discourse on knowledge pathing remains critical in advancing debates and dialogues in the humanities and social sciences spaces of research and studies. This book makes a significant contribution to the scholarly understanding of indigenous knowledge research by focusing on problematising local indigenous community research from Afro-sensed perspectives. The field of indigenous knowledge research and higher education in Africa is complex. Yet, across the continent, higher education has been the sector to least embrace Indigenous Knowledge Systems (IKS) or regard indigenous science as a legitimate source of inspiration for the development of youth and local communities. Higher education institutions and local indigenous communities should thus generate knowledge and power through research. On the other hand, higher education researchers should use their research processes and skills for cross-beneficiation when engaging local indigenous communities. This book embodies the current discourse on decolonisation and the use of indigenous knowledge in research and is intended for research specialists in the field of indigenous knowledge systems

Early cranial ultrasound findings among infants with neonatal encephalopathy in Uganda: an observational study.

BACKGROUND: In sub-Saharan Africa, the timing and nature of brain injury and their relation to mortality in neonatal encephalopathy (NE) are unknown. We evaluated cranial ultrasound (cUS) scans from term Ugandan infants with and without NE for evidence of brain injury. METHODS: Infants were recruited from a national referral hospital in Kampala. Cases (184) had NE and controls (100) were systematically selected unaffected term infants. All had cUS scans <36 h reported blind to NE status. RESULTS: Scans were performed at median age 11.5 (interquartile range (IQR): 5.2-20.2) and 8.4 (IQR: 3.6-13.5) hours, in cases and controls respectively. None had established antepartum injury. Major evolving injury was reported in 21.2% of the cases vs. 1.0% controls (P < 0.001). White matter injury was not significantly associated with bacteremia in encephalopathic infants (odds ratios (OR): 3.06 (95% confidence interval (CI): 0.98-9.60). Major cUS abnormality significantly increased the risk of neonatal death (case fatality 53.9% with brain injury vs. 25.9% without; OR: 3.34 (95% CI: 1.61-6.95)). CONCLUSION: In this low-resource setting, there was no evidence of established antepartum insult, but a high proportion of encephalopathic infants had evidence of major recent and evolving brain injury on early cUS imaging, suggesting prolonged or severe acute exposure to hypoxia-ischemia (HI). Early abnormalities were a significant predictor of death

Problematising Local Indigenous Community Research

This book deliberates on developments related to Knowledge Pathing: Multi-, Inter- and Trans-Disciplining in Social Sciences. The book explores the value of this vexed concept in advancing the course for multi-, inter- and trans-disciplinary perspectives, methodologies, theories and epistemologies of knowledge pathing. The discourse on knowledge pathing remains critical in advancing debates and dialogues in the humanities and social sciences spaces of research and studies. This book makes a significant contribution to the scholarly understanding of indigenous knowledge research by focusing on problematising local indigenous community research from Afro-sensed perspectives. The field of indigenous knowledge research and higher education in Africa is complex. Yet, across the continent, higher education has been the sector to least embrace Indigenous Knowledge Systems (IKS) or regard indigenous science as a legitimate source of inspiration for the development of youth and local communities. Higher education institutions and local indigenous communities should thus generate knowledge and power through research. On the other hand, higher education researchers should use their research processes and skills for cross-beneficiation when engaging local indigenous communities. This book embodies the current discourse on decolonisation and the use of indigenous knowledge in research and is intended for research specialists in the field of indigenous knowledge systems

Valacyclovir in the treatment of acute retinal necrosis

Background: To report the outcome of oral valacyclovir as the sole antiviral therapy for patients with acute retinal necrosis (ARN). Methods: This study reports a retrospective, interventional case series of nine consecutive patients with ten eyes with newly diagnosed ARN treated with oral valacyclovir as the sole antiviral agent. Eight patients received oral valacyclovir 2 g tid (Valtrex, GlaxoSmithKline) and one patient with impaired renal function received oral 1 g tid. The main outcome measures were response to treatment, time to initial response to treatment, time to complete resolution of retinitis, best corrected visual acuity (BCVA) at final follow-up, retinal detachment and development of recurrent or second eye disease. Results: Retinitis resolved in ten of ten (100%) affected eyes. The median time to initial detectable response was seven days and the median time to complete resolution was 21 days. A final BCVA of 20/40 or better was achieved in 6/10 (60%) of eyes. 3/10 eyes (30%) developed a retinal detachment. No patients developed either disease reactivation or second eye involvement over the course of the study (mean follow up 31 weeks, range 7 to 104 weeks). Conclusions: Treatment with oral valacyclovir as the sole antiviral therapy resulted in complete resolution of retinitis. Final BCVA and retinal detachment rate were comparable with previously reported outcomes for intravenous acyclovi