Strategies for the Activation and Release of the Membranolytic Peptide Melittin from Liposomes Using Endosomal pH as a Trigger.

Endosomolytic peptides are often coupled to drug delivery systems to enhance endosomal escape, which is crucial for the delivery of macromolecular drugs that are vulnerable to degradation in the endolysosomal pathway. Melittin is a 26 amino acid peptide derived from bee venom that has a very high membranolytic activity. However, such lytic peptides also impose a significant safety risk when applied in vivo as they often have similar activity against red blood cells and other nontarget cell membranes. Our aim is to control the membrane-disrupting capacity of these peptides in time and space by physically constraining them to a nanocarrier surface in such a way that they only become activated when delivered inside acidic endosomes. To this end, a variety of chemical approaches for the coupling of lytic peptides to liposomes via functionalized PEG-lipids were explored, including maleimide-thiol chemistry, click-chemistry, and aldehyde-hydrazide chemistry. The latter enables reversible conjugation via a hydrazone bond, allowing for release of the peptide under endosomal conditions. By carefully choosing the conjugation site and by using a pH activated analog of the melittin peptide, lytic activity toward a model membrane is completely inhibited at physiological pH. At endosomal pH the activity is restored by hydrolysis of the acid-labile hydrazone bond, releasing the peptide in its most active, free form. Furthermore, using an analogue containing a nonhydrolyzable bond as a control, it was shown that the activity observed can be completely attributed to release of the peptide, validating dynamic covalent conjugation as a suitable strategy to maintain safety during circulation.

Computational modeling of flow and gas exchange in models of the human maxillary sinus.

The present study uses numerical modeling to increase the understanding of sinus gas exchange, which is thought to be a factor in sinus disease. Order-of-magnitude estimates and computational fluid dynamics simulations were used to investigate convective and diffusive transport between the nose and the sinus in a range of simplified geometries. The interaction between mucociliary transport and gas exchange was modeled and found to be negligible. Diffusion was the dominant transport mechanism for small ostia and large concentration differences between the sinus and the nose, whereas convection was important for larger ostia or smaller concentration differences. The presence of one or more accessory ostia can increase the sinus ventilation rate by several orders of magnitude, because it allows a net flow through the sinus. Estimates of nitric oxide (NO) transport through the ostium based on measured sinus and nasal NO concentrations suggest that the sinuses cannot supply all the NO in nasally exhaled air.

Obstructive sleep apnoea adenotonsillectomy in children: when to refer to a centre with a paediatric intensive care unit?

OBJECTIVE: To identify regional surgical referral patterns for adenotonsillectomy in children with obstructive sleep apnoea to our tertiary centre with paediatric intensive care unit facilities and to establish guidelines for elective paediatric intensive care unit referral and admission. METHODS: Two methods were used. A questionnaire was sent to ENT consultants in five surrounding hospitals with no in-house paediatric intensive care facilities. The second was a prospective observational study undertaken in our tertiary centre for a sub-set of patients undergoing obstructive sleep apnoea adenotonsillectomy between January 2002 and February 2005. These children were considered high risk as judged clinically by an ENT surgeon. Most had obstructive sleep apnoea and a co-morbidity. Otherwise healthy children with simple obstructive sleep apnoea were excluded. RESULTS: 15 out of 20 consultants responded to the questionnaire. Four referred on the grounds of clinical history, five referred based on pulse oximetry, nine referred syndromal children and four did not refer electively. Of the 49 high risk patients operated on, only 12 required paediatric intensive care admission with no emergency paediatric intensive care admissions. No otherwise healthy children with uncomplicated obstructive sleep apnoea symptoms required paediatric intensive care admission during the study period. CONCLUSION: There was no regional consensus regarding paediatric intensive care unit referral for obstructive sleep apnoea adenotonsillectomy. Clinical judgement without complex sleep studies by those experienced in this area was sufficient to detect complicated cases of obstructive sleep apnoea with co-morbidity requiring paediatric intensive care.

Squamous cell carcinoma of the larynx in HIV-positive patients: difficulties in diagnosis and management.

Patients who are infected with human immunodeficiency virus (HIV) are at increased risk of developing laryngeal squamous cell carcinoma. This malignancy on average appears in a younger age group at a more advanced stage and has a more aggressive course in HIV patients. These patients have difficult management challenges, diagnostically, in staging, and particularly in determining the optimal treatment for each individual patient because their underlying HIV infection can markedly increase morbidity associated with active treatments. They frequently have problems associated with swallowing both before and after treatment. We present two cases that highlight difficulties in the diagnosis and management of these patients as well as post-treatment complications, with particular emphasis on swallowing problems.

Endonasal bilateral simultaneous orbital decompression.

OBJECTIVE: To study the morbidity of the operation, to investigate it's safety and effectiveness in order to establish if it is reasonable to offer it as treatment to patients in one sitting instead of a staged procedure. Finally, to indentify the patient's long term satisfaction and to establish best practice. DESIGN: Retrospective case series study and prospective telephone interview. SETTING: Teaching General Hospital, Scotland, UK. SUBJECTS: 14 patients with dysthyroid orbitopathy who underwent the operation over a 4 year period. RESULTS: Proptosis improved in all but one of the cases. There was a relatively small morbidity and short inpatient stay. A significant amount of patients reported satisfaction with the results. All patients expressed strong preference for the simultaneous procedure instead of a staged one. CONCLUSIONS: The study shows that for the management of orbitopathy , bilateral simultaneous orbital decompression with endoscopic approach is a safe and effective operation, with small morbidity and significant patient satisfaction. Therefore, it is reasonable to offer it to patients instead of a staged procedure.

Laryngeal inflammatory pseudotumour: an unusual cause of airway obstruction.

We report a rare case of a laryngeal pseudotumour in a child presenting with stridor, which was treated by endoscopic laryngeal resection, without the need for a tracheostomy. A short review of the literature is also presented. Although rare, laryngeal pseudotumour should be considered as part of the differential diagnosis of stridor and upper airway obstruction in children.

Surgery-induced thyroiditis following laryngectomy.

A 77-year-old euthyroid man developed atrial fibrillation on the fourth post-operative day following a total laryngectomy and right radical neck dissection including a hemi-thyroidectomy for a squamous cell carcinoma of the larynx with nodal metastases. The episode of atrial fibrillation coincided with an elevated serum free thyroxine of 3.36 ng/dl (43.3 pmol/L) (reference values: 0.71-1.85 ng/dl or 9.1-23.8 pmol/L), normal total triiodothyronine of 104 ng/dl (1.6 nmol/L) (reference values: 46-137 ng/dl or 0.7-2.1 nmol/L) and a suppressed thyroid-stimulating hormone (TSH) of 0.05 mIU/L (reference values: 0.35-5.0 mIU/L). These values, in relation to those prior and subsequent, suggested a surgery-induced thyroiditis. The limited literature about this controversial entity is reviewed.