Exosome-inspired targeting of cancer cells with enhanced affinity.

One of the major challenges in the area of novel drug delivery systems (NDDSs) is finding distinguished ligands for specific receptors represented by many cancer cells in order to enhance their cancer homing efficacy. Exosomes, the so-called natural nanocarriers or "Trojan horses," are secreted by the majority of cancer cells. These carriers exchange biomolecular information (e.g. proteins, siRNA, enzymes) between cancer cells and their stromal compartments in order to adjust a variety of cellular behaviours, including metastasis, apoptosis in T cells and angiogenesis. By exhibiting exosomal smart functions and biomimetic traits, exosome-mimicking nanocarriers will be one step ahead of the conventional targeted DDSs for the efficient delivery of antitumor drugs. In the present study, we tried to describe an engineering route to make some surface-functionalized nanoparticles that can mimic the targeting mechanism recruited by tumor-derived exosomes. The ligand-receptor interactions were investigated by molecular dynamics (MD) simulations. In addition, the selected ligand was experimentally studied to verify its improved targeting efficacy. The present study describes a novel targeting method that forces the mucin-domain-containing molecule-4 (TIM4)-embellished nanoparticles (NPs) to swarm towards the cancerous cells. These NPs can interact with the phosphatidylserine (PS) receptor on the surface of several kinds of cancer cells, such as U-87 MG (glioblastoma cell line). The molecular affinity between TIM4 as a homing device and PS, the target receptor, was investigated using MD simulations and surface plasmon resonance (SPR). According to the calculated free energies and the cellular uptake of TIM4-functionalized NPs, it seems that the TIM4/PS complex releases enough free energy to induce endocytosis. Our results emphasize on the potential of the proposed ligand as a good candidate for many targeted drug delivery applications. In this report, we present our proof-of-concept results in order to spotlight the importance of using computer-based simulating methods at the molecular level for the next-generation nanomedicine.

Isolated finger flexion: a novel form of focal neuromyotonia.

Two almost identical elderly women are described who presented with gradually progressive painless involuntary flexion of the ring and middle fingers over 12 months, leading eventually to contractures. The flexion deformity persisted during sleep and was the sole neurological abnormality. Both patients had advanced chronic obstructive pulmonary disease and were on long term salbutamol and oxygen. Neurophysiological studies indicated that this was due to neuromyotonia mainly involving flexor digitorum superficialis muscles without evidence of underlying peripheral neuropathy, proximal conduction block, or generalised neuromyotonia. Voltage gated potassium channel antibodies were negative. The clinical and neurophysiological picture remained static over a 2 year follow up period. It is suggested that this is a novel form of acquired focal neuromyotonia and speculate both on its cause and distribution.

Median nerve injury: an underrecognised complication of brachial artery cardiac catheterisation?

OBJECTIVE: To describe the local neurological complications associated with cardiac catheterisation via the right brachial artery. METHODS: A follow up study to determine the mechanism of injury and outcome of patients who sustained a high median nerve palsy after this procedure. Five right handed patients were identified in a 24 month period. Each was assessed clinically and electrophysiologically at presentation. All were followed up initially (range six to 22 months) clinically, electrophysiologically, and using components from the Chessington occupational therapy neurological assessment battery (COTNAB) functional hand assessment. RESULTS: The incidence of this complication was between 0.2 and 1.4%. Three mechanisms of injury were identified. These included direct nerve compression due to formation of antecubital fossa haematoma, direct nerve trauma, and ischaemia secondary to brachial artery occlusion. The initial neurological and nerve conduction deficits improved with time. However, all cases had persistent disability in hand function as documented clinically and on the dexterity and stereognosis subcomponent of the COTNAB test. CONCLUSION: This is an uncommon, but probably underrecognised complication. Those performing cardiac catheterisation via the right brachial artery should be aware of the potential risks of damage to the median nerve. They should evaluate hand function after the procedure and take prompt action if median nerve dysfunction is noted. Damage to the median nerve results in appreciable long term disability, which may have medicolegal relevance.

Reduction in heart rate variability in patients with systemic lupus erythematosus.

OBJECTIVE: To determine whether heart rate variability and cardiovascular reflex tests are abnormal in patients with systemic lupus erythematosus (SLE). METHODS: We measured heart rate variability (24 h ambulatory recordings), and used baroreflex sensitivity testing and cardiovascular reflex tests in a cross sectional, case-control study. Those taking drugs with cardiovascular activity were excluded. RESULTS: Determination of heart rate variability was simple to perform, well tolerated, and found to be reduced in the patients with lupus, but not strongly related to disease activity or duration. CONCLUSION: This may reflect underlying autonomic dysfunction; longitudinal studies will determine full clinical relevance.