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.     

Improvisations in classic and modified techniques of flap surgery to improve the success rate for pressure ulcer healing in patients with spinal cord injury

The recurrence of pressure ulcers (PrUs) and dehiscence of reconstructive flap have always been a problem. The present study aimed to evaluate the results of reconstructive flap surgeries in patients with spinal cord injury (SCI) having PrUs, using classic and modified flaps with improvisations to decrease wound dehiscence, flap necrosis and tension in flap. This is a prospective clinical study. The setting was a tertiary care centre in northern India. Thirty‐five patients with SCI having 37 stage III and IV PrUs. PrUs were treated using classic and modified flaps with improvisations. The outcome was evaluated using criteria of wound dehiscence, flap necrosis and recurrence. The results of flap surgery were excellent in 32 (86·48%) patients, good in 4 (10·81%) patients and poor in 1 (2·7%) patient. Partial flap necrosis (2·7%), low incidence of PrU recurrence rate at flap site (5·4%) and overall PrU recurrence (11·4%) were the complications observed. Improvisation of classic and modified techniques of flap surgeries along with reinforcement of general care principles of paraplegia can be effective in minimising complications often associated with PrU reconstructive surgery thus improving the ultimate outcome.     

Enhancing the Reliability in the Noninvasive Measurement of the His Bundle Magnetic Field Using a Novel Signal Averaging Methodology

Background: Extraction of the weak electrical activity of the “His Bundle” (HB) by noninvasive methods has not been very successful in the past. The study reassesses the use of signal averaged magnetocardiography (SAMCG), overcoming some of the limitations in earlier studies including in the signal averaging methodology. Methods: SAMCG on healthy subjects (14 male and 1 female) were performed using R‐peak as the fiducial point in all cases and also using QRS‐onset as the fiducial point in select cases. Results: A conspicuous feature (H) with a magnitude up to 200 femto Tesla (fT) attributed to the HB activity was observed in the PR segment at several spatial positions on the thorax, with onset at 35–50 ms before the QRS‐onset (V) in 15 out of 18 trials constituting 83% of cases studied. The QRS‐onset as the fiducial point resolved the feature better compared to the conventionally used R‐peak, especially in trials exhibiting spread in heart rate (HR). This is attributed to the fluctuations in Q_onRD (the time interval between QRS‐onset and R‐peak) compared to the temporal stability of the H‐V duration. Conclusions: SAMCG reveals a well‐resolved H feature. The double hump morphology of the feature extended at least up to a frequency of 150 Hz. The importance of the choice of QRS‐onset as the fiducial point is unequivocally demonstrated, illustrated by measurements on subjects exhibiting considerable heart rate variability. The latter has a general validity and should be applicable to SAECG as well.     

Double Recombinant Mycobacterium bovis BCG Strain for Screening of Primary and Rationale-Based Antimycobacterial Compounds

Conventional antimycobacterial screening involves CFU analysis, which poses a great challenge due to slow growth of mycobacteria. Recombinant strains carrying reporter genes under the influence of constitutive promoters allow rapid and wide screening of compounds but without revealing their modes of action. Reporter strains using pathway-specific promoters provide a better alternative but allow a limited screening of compounds interfering with only a particular metabolic pathway. This reduces these strains to merely a second-line screening system, as they fail to identify even the more potent compounds if they are not inhibiting the pathway of interest. In this study, we have generated a double recombinant Mycobacterium bovis BCG strain carrying firefly and Renilla luciferase genes as two reporters under the control of a constitutive and an inducible mycobacterial promoter. The presence of dual reporters allows simultaneous expression and analysis of two reporter enzymes within a single system. The expression profile of the firefly luciferase gene, rendered by a constitutive mycobacterial promoter, coincides with the decline in bacterial growth in response to a wide range of antimycobacterial drugs, while the enhanced expression of Renilla luciferase mirrors the selective induction of the reporter gene expression as a result of pathway-specific inhibition. Thus, the double recombinant strain allows the screening of both primary and rationally synthesized antimycobacterial compounds in a single assay. The inhibiting response of drugs was monitored with a dual-luciferase reporter assay which can be easily adapted in high-throughput mode.