Prevention of measles virus infection by intranasal delivery of fusion inhibitor peptides.

UNLABELLED: Measles virus (MV) infection is undergoing resurgence and remains one of the leading causes of death among young children worldwide despite the availability of an effective measles vaccine. MV infects its target cells by coordinated action of the MV H and the fusion (F) envelope glycoprotein; upon receptor engagement by H, the prefusion F undergoes a structural transition, extending and inserting into the target cell membrane and then refolding into a postfusion structure that fuses the viral and cell membranes. By interfering with this structural transition of F, peptides derived from the heptad-repeat (HR) regions of F can potently inhibit MV infection at the entry stage. We show here that specific features of H's interaction with its receptors modulate the susceptibility of MV F to peptide fusion inhibitors. A higher concentration of inhibitory peptides is required to inhibit F-mediated fusion when H is engaged to its nectin-4 receptor than when H is engaged to its CD150 receptor. Peptide inhibition of F may be subverted by continued engagement of receptor by H, a finding that highlights the ongoing role of H-receptor interaction after F has been activated and that helps guide the design of more potent inhibitory peptides. Intranasal administration of these peptides results in peptide accumulation in the airway epithelium with minimal systemic levels of peptide and efficiently prevents MV infection in vivo in animal models. The results suggest an antiviral strategy for prophylaxis in vulnerable and/or immunocompromised hosts. IMPORTANCE: Measles virus (MV) infection causes an acute illness that may be associated with infection of the central nervous system (CNS) and severe neurological disease. No specific treatment is available. We have shown that parenterally delivered fusion-inhibitory peptides protect mice from lethal CNS MV disease. Here we show, using established small-animal models of MV infection, that fusion-inhibitory peptides delivered intranasally provide effective prophylaxis against MV infection. Since the fusion inhibitors are stable at room temperature, this intranasal strategy is feasible even outside health care settings, could be used to protect individuals and communities in case of MV outbreaks, and could complement global efforts to control measles.

Breathing pattern and workload during automatic tube compensation, pressure support and T-piece trials in weaning patients.

BACKGROUND AND OBJECTIVE: Automatic tube compensation has been designed as a new ventilatory mode to compensate for the non-linear resistance of the endotracheal tube. The study investigated the effects of automatic tube compensation compared with breathing through a T-piece or pressure support during a trial of spontaneous breathing used for weaning patients from mechanical ventilation of the lungs. METHODS: Twelve patients were studied who were ready for weaning after prolonged mechanical ventilation (10.2 +/- 8.4 days) due to acute respiratory failure. Patients with chronic obstructive pulmonary disease were excluded. Thirty minutes of automatic tube compensation were compared with 30 min periods of 7 cmH2O pressure support and T-piece breathing. Breathing patterns and workload indices were measured at the end of each study period. RESULTS: During T-piece breathing, the peak inspiratory flow rate (0.65 +/- 0.20 L s(-1)) and minute ventilation (8.9 +/- 2.7L min(-1)) were lower than during either pressure support (peak inspiratory flow rate 0.81 +/- 0.25 L s(-1) minute ventilation 10.2 +/- 2.3 L min(-1), respectively) or automatic tube compensation (peak inspiratory flow rate 0.75 +/- 0.26L s(-1); minute ventilation 10.8 +/- 2.7 L min(-1)). The pressure-time product as well as patients' work of breathing were comparable during automatic tube compensation (pressure-time product 214.5 +/- 104.6 cmH2O s(-1) min(-1), patient work of breathing 1.1 +/- 0.4 J L(-1)) and T-piece breathing (pressure-time product 208.3 +/- 121.6 cmH2O s(-1) min(-1), patient work of breathing 1.1 +/- 0.4 J L(-1)), whereas pressure support resulted in a significant decrease in workload indices (pressure-time product 121.2 +/- 64.1 cmH2O s(-1) min(-1), patient work of breathing 0.7 +/- 0.4 J L(-1)). CONCLUSIONS: In weaning from mechanical lung ventilation, patients' work of breathing during spontaneous breathing trials is clearly reduced by the application of pressure support 7 cmH2O, whereas the workload during automatic tube compensation corresponded closely to the values during trials of breathing through a T-piece.

Clinical significance of intracranial developmental venous anomalies.

OBJECTIVES: Venous angiomas, or developmental venous anomalies (DVAs), represent the most often occurring cerebral vascular malformation. The clinical significance of a DVA is, however, at present unclear. METHODS: A retrospective analysis was carried out on two series of consecutive cranial MRIs performed between January 1990 and August 1996 in a university department of neuroradiology and in a large radiological private practice. The medical records of all patients in whom a DVA was diagnosed were screened to identify the specific complaint which necessitated the imaging procedure. RESULTS: A total of 67 patients with DVA could be identified. In 12 patients an associated cavernoma was found. The main reason for performing the MRI was the evaluation of seizures or of headaches. In all patients with DVA in whom an intracerebral haemorrhage was diagnosed an associated cavernoma was present at the site of the haemorrhage. None of the 67 patients showed an association between the complaints that led to the MRI and the location of the DVA. CONCLUSIONS: DVAs do not seem to be associated with a specific clinical presentation. In a significant percentage of cases, however, coexisting cavernomas are found which have a defined bleeding potential and should be treated independently of the DVA. This study supports the hypothesis that DVAs are a congenital abnormality of venous drainage without clinical significance.

Stimulus-induced gamma oscillations: harmonics of alpha activity?

Event-related changes of spectral power of the EEG were studied for each integer frequency between 5 and 100 Hz in three subjects during memory storage and retrieval. Spectra were calculated for successive, overlapping time epochs in seven channels. In one subject a stimulus-locked increase of power was observed at 12 Hz, while in the other two alpha power decreased at the individual peak frequencies of 9 and 11 Hz, respectively. In all subjects corresponding changes of power appeared at frequencies which were integer multiples of the individual dominant alpha frequencies. An analysis of the cross covariance of the alpha, beta and gamma activity revealed high coefficients for harmonic frequencies only while all other covariances were negligibly small. It is argued that event-related gamma activity may be an epiphenomenon of event-related changes within the alpha band.

Case 11, Part 2. Angiokeratoma corporis diffusum (Fabry's disease).

A case of Fabry's disease is reported. The patient had multiple supernumerary, impacted, and unerupted teeth and other developmental abnormalities of the facial skeleton. The patient tolerated surgical removal of impacted and unerupted teeth without complications. However, this did not relieve the facial pain. The expected prognosis of this patient will be a continued vascular and renal degeneration with death probable before the age of 50 years if the disease is untreated. Currently, the patient is being considered as a possible candidate for renal transplantation.