The Sheep as a Large Animal Model for the Investigation and Treatment of Human Disorders.

An essential aim of biomedical research is to translate basic science information obtained from preclinical research using small and large animal models into clinical practice for the benefit of humans. Research on rodent models has enhanced our understanding of complex pathophysiology, thus providing potential translational pathways. However, the success of translating drugs from pre-clinical to clinical therapy has been poor, partly due to the choice of experimental model. The sheep model, in particular, is being increasingly applied to the field of biomedical research and is arguably one of the most influential models of human organ systems. It has provided essential tools and insights into cardiovascular disorder, orthopaedic examination, reproduction, gene therapy, and new insights into neurodegenerative research. Unlike the widely adopted rodent model, the use of the sheep model has an advantage over improving neuroscientific translation, in particular due to its large body size, gyrencephalic brain, long lifespan, more extended gestation period, and similarities in neuroanatomical structures to humans. This review aims to summarise the current status of sheep to model various human diseases and enable researchers to make informed decisions when considering sheep as a human biomedical model.

Mapping sheep to human brain: The need for a sheep brain atlas.

A brain atlas is essential for understanding the anatomical relationship between neuroanatomical structures. Standard stereotaxic coordinates and reference systems have been developed for humans, non-human primates and small laboratory animals to contribute to translational neuroscience research. Despite similar neuroanatomical and neurofunctional features between the sheep and human brain, little is known of the sheep brain stereotaxy, and a detailed sheep atlas is scarce. Here, we briefly discuss the value of using sheep in neurological research and the paucity of literature concerning the coordinates system during neurosurgical approaches. Recent advancements such as computerized tomography, positron emission tomography, magnetic resonance imaging, functional magnetic resonance imaging and diffusion tensor imaging are used for targeting and localizing the coordinates and brain areas in humans. Still, their application in sheep is rare due to the lack of a 3D stereotaxic sheep atlas by which to map sheep brain structures to its human counterparts. More recently, a T1- and T2-weighted high-resolution MRI 3D stereotaxic atlas of the sheep brain has been generated, however, the journey to create a sheep brain atlas by which to map directly to the human brain is still uncharted. Therefore, developing a detailed sheep brain atlas is valuable for the future to facilitate the use of sheep as a large animal experimental non-primate model for translational neurological research.

Dynamic interaction between hippocampus, orbitofrontal cortex, and subthalamic nucleus during goal conflict in the stop signal task in rats.

Action stopping depends on at least two (fast, slow) frontal circuits depending on the urgency of execution of the 'go' response. Human EEG suggests a third (even slower, limbic) circuit that activates frontal areas at frequencies typical of 'hippocampal theta'. Here we test in male rats whether stop-go conflict engages the hippocampus and so may send theta-modulated information via the frontal cortex to the subthalamic nucleus. We recorded from multi-electrode arrays in the hippocampus, orbitofrontal cortex, and subthalamus in 5 male Long Evans rats performing a stop signal task and, as in previous human experiments, assessed stop-signal specific power for effects of goal conflict. Conflict increased 11-12 Hz theta power modestly in all three structures but with the largest increase in power being at 5 Hz in the frontal cortex but not the hippocampus. There was increased conflict-related coherence in all circuits in the range 5-8 Hz and particularly at 5-6 Hz. Increased coherence coupled with an increase in conflict-induced low frequency power in the frontal cortex may reflect communication with the hippocampus. The data are consistent with a third limbic circuit that can generate stopping when go responses are particularly slow (as, e.g., in a go/no go task). [199 words; 200 max].

Ultrasound-Mediated Blood-Brain Barrier Disruption for Drug Delivery: A Systematic Review of Protocols, Efficacy, and Safety Outcomes from Preclinical and Clinical Studies.

Ultrasound-mediated blood-brain barrier (BBB) disruption has garnered focus as a method of delivering normally impenetrable drugs into the brain. Numerous studies have investigated this approach, and a diverse set of ultrasound parameters appear to influence the efficacy and safety of this approach. An understanding of these findings is essential for safe and reproducible BBB disruption, as well as in identifying the limitations and gaps for further advancement of this drug delivery approach. We aimed to collate and summarise protocols and parameters for achieving ultrasound-mediated BBB disruption in animal and clinical studies, as well as the efficacy and safety methods and outcomes associated with each. A systematic search of electronic databases helped in identifying relevant, included studies. Reference lists of included studies were further screened to identify supplemental studies for inclusion. In total, 107 articles were included in this review, and the following parameters were identified as influencing efficacy and safety outcomes: microbubbles, transducer frequency, peak-negative pressure, pulse characteristics, and the dosing of ultrasound applications. Current protocols and parameters achieving ultrasound-mediated BBB disruption, as well as their associated efficacy and safety outcomes, are identified and summarised. Greater standardisation of protocols and parameters in future preclinical and clinical studies is required to inform robust clinical translation.

Correction: Gandhi et al. Ultrasound-Mediated Blood-Brain Barrier Disruption for Drug Delivery: A Systematic Review of Protocols, Efficacy, and Safety Outcomes from Preclinical and Clinical Studies. Pharmaceutics 2022, 14, 833.

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Construction of simple, customised, brain-spanning, multi-channel, linear microelectrode arrays.

BACKGROUND: The construction of multichannel micro-electrode arrays (MEA) generally requires complex and expensive procedures. Here we describe a simple, cheap, flexible method of linear MEA construction. NEW METHOD: Our method allows manufacture of linear MEA (cross section ∼ 375 × 250 µm with 12 electrodes) of any desired length, with customized spacing of the electrode tips (down to a minimum spacing of 200 µm or less) to suit different needs and experiments. We describe the following steps: (1) set-up for MEA construction; (2) building of a construction jig; (3) building the reference, ground and optional electrical stimulation electrodes; (4) treatment of the main recording microwires; (5) soldering of the microwires to the main connector plug and arrangement of the microwires in a customizable array; and (6) testing of the MEA resistance and correct connections. Finally, we describe methods for quick surgical implantation of multiple MEAs and bipolar micro-stimulation electrodes for in vivo experiments in free-moving rats. RESULTS: We provide examples of multi-site local field potentials from prolonged recordings in awake and free-moving rodents, with recordings viable for months, as well as samples of electrical stimulation effects on cortical and hippocampal recordings. Hippocampal recordings showed clear phase reversal and amplitude changes across its layers. CONCLUSIONS: We briefly discuss how the arrays can support other forms of stimulation such as optogenetic probes.

The Availability of Emergency Obstetric Care in Birthing Centres in Rural Nepal: A Cross-sectional Survey.

OBJECTIVE: The purpose of this health system's study is to assess the availability of Emergency Obstetric Care (EmOC) services in birthing centres in Taplejung District of eastern Nepal. METHODS: A cross-sectional survey was conducted in 2018 in all 16 public health facilities providing delivery services in the district. Data collection comprised: (1) quantitative data collected from health workers; (2) observation of key items; and (3) record data extracted from the health facility register. Descriptive statistics were used to calculate readiness scores using unweighted averages. RESULTS: Although key health personnel were available, EmOC services at the health facilities assessed were below the minimum coverage level recommended by the World Health Organisation. Only the district hospital provided the nine signal functions of Comprehensive EmOC. The other fifteen had only partially functioning Basic EmOC facilities, as they did not provide all of the seven signal functions. The essential equipment for performing certain EmOC functions was either missing or not functional in these health facilities. CONCLUSIONS FOR PRACTICE: The Ministry of Health and Population and the federal government need to ensure that the full range of signal functions are available for safe deliveries in partially functioning EmOC health facilities by addressing the issues related to training, equipment, medicine, commodities and policy.

The epidemiology of hospitalization for pneumonia in children under five in the rural western region of Nepal: a descriptive study.

Pneumonia is one of the major public health problems in children under five years of age. The aim of this study was to analyze the time, place, and characteristics of the distribution of pneumonia in hospitalized children under five years of age at the Dhaulagiri Zonal Hospital (DZH) in Nepal. A descriptive cross-sectional study was carried out at DZH from July 16, 2008 to August 17, 2011 for hospitalized children under five years of age and diagnosed with pneumonia. The main bacterial cause of pneumonia was Streptococcus pneumoniae and the main viral cause was Respiratory Syntical Virus (RSV). The majority of children admitted for treatment of pneumonia were males (60%), from upper class ethnic groups, and common among those aged 29 days to one year (49.1% of overall pneumonia cases). Data from this study show that pneumonia episodes in DZH occurred throughout the year with a sharp increase in the occurrence at the end of August to September. More cases were recorded during the rainy seasons and winter months in all three study years. The cases were from households most concentrated in Baglung municipality where the hospital is located. Pneumonia was found in higher proportions among hospitalized male children, those aged 29 days to one year, and in upper ethnic groups, during the rainy seasons and in winter months, and among local populations near the hospital in the rural western region of Nepal. Strengthening community-based case management, prevention strategies, and health care delivery system would help reduce pneumonia cases and the overall burden associated with it.