Approaches for CNS delivery of drugs – nose to brain targeting of antiretroviral agents as a potential attempt for complete elimination of major reservoir site of HIV to aid AIDS treatment

Introduction: Human immune-deficiency virus (HIV) infection causing acquired immune-deficiency syndrome (AIDS) is one of the most life-threatening infections. The central nervous system (CNS) is reported to be the most important HIV reservoir site where the antiretroviral drugs are unable to reach.

Areas covered: This article includes the review about HIV infections, its pathogenesis, HIV infections in CNS, its consequences, current therapies, challenges associated with the existing therapies, approaches to overcome them, CNS delivery of drugs – barriers, transport routes, approaches for transporting drugs across the blood–brain barrier, nasal route of drug delivery, and nose to brain targeting of antiretroviral agents as a potential approach for complete cure of AIDS.

Expert opinion: Various approaches are exploited to enhance the drug delivery to the brain for various categories of drugs. However, very few have investigated on the delivery of antiretrovirals to the brain. Targeting antiretrovirals to CNS through oral/nasal routes along with oral/parenteral delivery of drug to the plasma can be a promising approach for an attempt to completely eradicate HIV reservoir and cure AIDS, after clinical trials. Further research is required to identify the exact location of the HIV reservoir in CNS and developing good animal models for evaluation of different newly developed formulations.     

Oscillating gradient diffusion kurtosis imaging of normal and injured mouse brains

Recent advances in diffusion MRI employ multiple diffusion encoding schemes with varying diffusion direction, weighting, and diffusion time to investigate specific microstructural properties in biological tissues. In this study, we examined time‐dependent diffusion kurtosis contrast in adult mouse brains and in neonatal mouse brains after hypoxic–ischemic (HI) injury. In vivo diffusion kurtosis maps were acquired with a short diffusion time using an oscillating gradient spin echo (OGSE) sequence at 100 Hz and with a relatively long diffusion time (20 ms) using a pulsed gradient spin echo (PGSE) sequence. In the adult mouse brain, we found that the cortex and hippocampus showed larger differences between OGSE kurtosis and PGSE kurtosis than major white matter tracts. In neonatal mouse brains with unilateral HI injury, the OGSE kurtosis map overall provided stronger edema contrast than the PGSE kurtosis map, and the differences between OGSE and PGSE kurtosis measurements in the edema region reflected heterogeneity of injury. This is the first in vivo study that has demonstrated multi‐direction OGSE kurtosis contrasts in the mouse brain. Comparing PGSE and OGSE kurtosis measures may provide additional information on microstructural changes after ischemic stroke.     

Hypoxic–ischaemic brain injury following cardiac arrest

Hypoxic–ischaemic brain injury (HIBI) has become an increasingly common cause of admission to intensive care units and prolonged or permanent neurological disability. It is essential to provide an accurate prognosis to guide management. Clinical assessment is often difficult and ancillary investigation is necessary. Outcome depends on the severity of the initial insult, the effectiveness of immediate resuscitation and transfer, and the post-resuscitation management on the intensive care unit. Some patients remain profoundly impaired and others may develop complications including myoclonic epilepsy, cognitive impairment, border-zone infarction and movement disorders. The management of patients with HIBI presents considerable clinical, ethical and legal difficulties.     

Methods for identifying subject‐specific abnormalities in neuroimaging data

Algorithms that are capable of capturing subject‐specific abnormalities (SSA) in neuroimaging data have long been an area of focus for diverse neuropsychiatric conditions such as multiple sclerosis, schizophrenia, and traumatic brain injury. Several algorithms have been proposed that define SSA in patients (i.e., comparison group) relative to image intensity levels derived from healthy controls (HC) (i.e., reference group) based on extreme values. However, the assumptions underlying these approaches have not always been fully validated, and may be dependent on the statistical distributions of the transformed data. The current study evaluated variations of two commonly used techniques (“pothole” method and standardization with an independent reference group) for identifying SSA using simulated data (derived from normal, t and chi‐square distributions) and fractional anisotropy maps derived from 50 HC. Results indicated substantial group‐wise bias in the estimation of extreme data points using the pothole method, with the degree of bias being inversely related to sample size. Statistical theory was utilized to develop a distribution‐corrected z‐score (DisCo‐Z) threshold, with additional simulations demonstrating elimination of the bias and a more consistent estimation of extremes based on expected distributional properties. Data from previously published studies examining SSA in mild traumatic brain injury were then re‐analyzed using the DisCo‐Z method, with results confirming the evidence of group‐wise bias. We conclude that the benefits of identifying SSA in neuropsychiatric research are substantial, but that proposed SSA approaches require careful implementation under the different distributional properties that characterize neuroimaging data. Hum Brain Mapp 35:5457–5470, 2014. © 2014 Wiley Periodicals, Inc.     

颅脑超声诊断新生儿脑损伤的临床价值

目的探讨颅脑超声诊断新生儿脑损伤的临床价值。方法应用颅脑超声对1 387例住院新生儿进行早期检查及随访,分析声像图表现。结果颅脑超声检查1 387例,其中正常声像图594例,异常声像图793例。结论颅脑超声对新生儿脑损伤诊断率高,并能连续监测新生儿病情变化,故可成为新生儿脑损伤早期诊断、判断其严重程度及随访的有效手段。     

Frizzled fissure to improve central nervous system drug delivery?

Delivery of therapeutics to the brain is challenging because of efflux pumps located in the vascular endothelium. A detailed analysis of Wnt signaling in a human brain endothelial cell line indicates that expression and function of P-glycoprotein, a major efflux transporter, is controlled by non-canonical Wnt signaling. Inhibition of this pathway leads to downregulation of P-glycoprotein and increased transcellular drug transport and reveals a potential strategy for improving drug delivery for treatment of neurologic diseases.     

Social work‐generated evidence in traumatic brain injury from 1975 to 2014: A systematic scoping review

The International Network for Social Workers in Acquired Brain Injury (INSWABI) commissioned a systematic scoping review to ascertain the social work‐generated evidence base on people with traumatic brain injury (TBI) of working age. The review aimed to identify the output, impact and quality of publications authored by social workers on this topic. Study quality was evaluated through assessment frameworks drawn from the United Kingdom National Service Framework for Long‐Term Conditions. In the 40‐year period from 1975 to 2014, 115 items were published that met the search criteria (intervention studies, n = 10; observational studies, n = 52; literature reviews, n = 6; expert opinion or policy analysis, n = 39; and others, n = 8). The publications could be grouped into five major fields of practice: families, social inclusion, military, inequalities and psychological adjustment. There was a significant increase in the number of publications over each decade. Impact was demonstrated in that the great majority of publications had been cited at least once (80.6%, 103/115). Articles published in rehabilitation journals were cited significantly more often than articles published in social work journals. A significant improvement in publication quality was observed across the four decades, with the majority of studies in the last decade rated as high quality.     

Application of diffusional kurtosis imaging to detect occult brain damage in multiple sclerosis and neuromyelitis optica

Multiple sclerosis (MS) and neuromyelitis optica (NMO) are two common types of inflammatory demyelinating disease of the central nervous system. Early distinction of NMO from MS is crucial but quite challenging. In this study, 13 NMO spectrum disorder patients (Expanded Disability Status Scale (EDSS) of 3.0 ± 1.7, ranging from 2 to 6.5; disease duration of 5.3 ± 4.7 years), 17 relapsing–remitting MS patients (EDSS of 2.6 ± 1.4, ranging from 1 to 5.5; disease duration of 7.9 ± 7.8 years) and 18 healthy volunteers were recruited. Diffusional kurtosis imaging was employed to discriminate NMO and MS patients at the early or stable stage from each other, and from healthy volunteers. The presence of alterations in diffusion and diffusional kurtosis metrics in normal‐appearing white matter (NAWM) and diffusely increased mean diffusivity (MD) in the cortical normal‐appearing gray matter (NAGM) favors the diagnosis of MS rather than NMO. Meanwhile, normal diffusivities and kurtosis metrics in all NAWM as well as increases in MD in the frontal and temporal NAGM suggest NMO. Our results suggest that diffusion and diffusional kurtosis metrics may well aid in discriminating the two diseases.