Structural Characterisation Reveals Mechanism of IL-13-Neutralising Monoclonal Antibody Tralokinumab as Inhibition of Binding to IL-13Rα1 and IL-13Rα2.

Interleukin (IL)-13 is a pleiotropic T helper type 2 cytokine frequently associated with asthma and atopic dermatitis. IL-13-mediated signalling is initiated by binding to IL-13Rα1, which then recruits IL-4Rα to form a heterodimeric receptor complex. IL-13 also binds to IL-13Rα2, considered as either a decoy or a key mediator of fibrosis. IL-13-neutralising antibodies act by preventing IL-13 binding to IL-13Rα1, IL-4Rα and/or IL-13Rα2. Tralokinumab (CAT-354) is an IL-13-neutralising human IgG4 monoclonal antibody that has shown clinical benefit in patients with asthma. To decipher how tralokinumab inhibits the effects of IL-13, we determined the structure of tralokinumab Fab in complex with human IL-13 to 2 Å resolution. The structure analysis reveals that tralokinumab prevents IL-13 from binding to both IL-13Rα1 and IL-13Rα2. This is supported by biochemical ligand-receptor interaction assay data. The tralokinumab epitope is mainly composed of residues in helices D and A of IL-13. It is mostly light chain complementarity-determining regions that are driving paratope interactions; the variable light complementarity-determining region 2 plays a key role by providing residue contacts for a network of hydrogen bonds and a salt bridge in the core of binding. The key residues within the paratope contributing to binding were identified as Asp50, Asp51, Ser30 and Lys31. This study demonstrates that tralokinumab prevents the IL-13 pharmacodynamic effect by binding to IL-13 helices A and D, thus preventing IL-13 from interacting with IL-13Rα1 and IL-13Rα2.

Ultrasound evaluation of traumatic patient in a tertiary level hospital.

This study was designed to assess the use of ultrasonography in evaluation of trauma patients to see any intraperitoneal collection, collection in pleural cavity, any vital organ injury or any localized collection in blunt trauma to abdomen. This cross sectional study was performed in patient having history of trauma who attended the Centre for Nuclear Medicine & Ultrasound (CNM&U), Mymensingh for ultrasonic evaluation. Ultrasonography scanning was done to see any intraperitoneal collection, pleural collection or vital organ injury. Vulnerable age, causes of trauma, types of organ injury and relation between ages & types of organ involved were also evaluated. Fifty patients were evaluated among those 44(88%) were male & 6(12%) were female. Ultrasonographic examination detected 26(52%) patients with intraperitoneal collection, 13(26%) patients with intraabdominal organ injury, 5(10%) patients with pleural collection. Liver (30%) is the mostly affected organ. It was also found that the most vulnerable age having trauma to abdomen was 11 to 30 (54%) years. The most common cause of trauma was road traffic accident (46%). Younger people were more vulnerable to liver and pancreatic injury, older people to splenic injury and middle aged to renal injury. Ultrasonography is a useful primary tool for evaluating traumatic patient specially to detect intraperitoneal collection and organ injury in country like Bangladesh where accidental injury is very common.

An unusual presentation of epilepsy.

OBJECTIVE: To report a case of fluctuating hearing due to auditory aura, as an unusual presentation of temporal lobe epilepsy. METHODS: Case report and review of English language literature on temporal lobe epilepsy and auditory aura. RESULTS: A 31-year-old man presented with intermittent symptoms of bilateral fullness in the ears associated with deafness. He was subsequently diagnosed with temporal lobe epilepsy. Further enquiry revealed a family history of epilepsy. CONCLUSION: Auditory aura as a presentation of temporal lobe epilepsy is rarely encountered in otolaryngological practice. This case highlights the importance of obtaining detailed information on epilepsy, including any family history of epilepsy, as a routine part of history-taking in patients presenting with fluctuating hearing loss.

Novel method of intralesional cidofovir injection into laryngotracheal papillomata.

Laryngeal papillomatosis is characterised by multiple papillomata affecting the upper respiratory tract. This condition is difficult to treat due to its recurrent nature. Treatment often involves surgical debulking. A number of non-surgical treatments have been reported. Intralesional cidofovir, a cytosine nucleoside analogue with antiviral activity, has been used in an attempt to manage the condition. We present a novel technique of administering cidofovir in a case of recurrent laryngotracheal papillomata.

Non-classical presentation of congenital cholesteatoma.

Congenital cholesteatoma is a rare entity. It arises from aberrant epithelial remnants left at the time of closure of the neural groove, between the 3rd and 5th week of embryonic life. Otoscopy typically shows a pearly white mass, medial to the intact tympanic membrane, primarily in the anterosuperior quadrant, without a preceding history of otorrhoea, tympanic membrane perforation or surgery. It can present at any age from birth to early adulthood. The most common presenting symptom is hearing loss or facial nerve palsy. We present a non-classical presentation of congenital cholesteatoma with loss of taste sensation and numbness on the anterior two-thirds of the tongue associated with a bulging posterosuperior quadrant of the ipsilateral tympanic membrane in a 52-year-old male. After investigation, the patient underwent surgical management resulting in improvement of his symptoms.

Angiopoietins in malignancy.

BACKGROUND: Tumour growth is dependant upon the development of an adequate blood supply. This, in turn, is thought to depend upon a switch by the tumour, from a dormant to angiogenic state. Recent data suggest that this switch may occur when the balance of pro- and anti-angiogenic agents alters to promote angiogenesis. Angiopoietins may be involved in this balance. METHODS: An electronic literature search was performed with respect to angiopoietins from 1996 to the present. Published data from in-vitro and in-vivo studies were critically analysed. A specific focus was made of studies relating to tumour growth and vasculature. RESULTS: Since angiopoietin-1 was first described in 1996, three more angiopoietins have been described. All family members bind to the Tie-2 receptor. There is now a considerable accumulation of data that suggests they play a pivotal role in the development and stabilisation of tumour vasculature. angiopoietin-2 appears to be pro-angiogenic whilst angiopoietin-1 appears to be a stabilising factor. CONCLUSIONS: Recent trials of anti-angiogenic agents show promise in the treatment of solid human cancers. The angiopoietins are a new family of proteins that appear to be influential in the development of the tumour vasculature. Manipulation of the angiopoietin balance may provide a potential therapeutic target in human cancer.

Three-dimensional computer-aided endoscopic sinus surgery.

Three-dimensional computer-aided surgery adds a 'third-dimension' to endoscopic sinus surgery. The images it provides have the potential to provide the surgeon with further information that might result in safer and more effective surgery with less surgical morbidity. The gold test, as yet untested, will be whether the technique leads to fewer revision procedures and complications as a result of more complete and safe initial surgery. Its greatest asset lies in reinforcing the surgeons' estimate of an instrument's position in a difficult anatomical area. It can augment the learning curve and enhance teaching and training in endoscopic sinus surgery but it is not a substitute for a thorough knowledge of paranasal sinus anatomy.

Kinetics of bromination of safranine by peroxydisulphate ion in presence of bromide ion.

Kinetics of bromination safranine by peroxydisulphate ion in presence of bromide ion has been investigated at various temperatures and ionic strengths. The rate followed first order kinetics in peroxy disulphate and bromide ion each, and zero order kinetics in safranine. A linear relation was obtained for the variation of logarithm of rate constant (log k) with the square root of ionic strength of the media (mu). The rate constants for the rate controlling step were evaluated and interpreted as a function of ionic strengths and temperatures. The values of activation parameters were also computed.

Influence of monovalent cations on the rates of dibromosuccinate and hydroxide ions.

The rate constants for the reaction between dibromosuccinate and hydroxide ions have been determined in the presence of lithium and sodium chloride. Effects of temperatures and added electrolytes on this reaction have also been examined. It has been found that smaller radii have less accelerating effects on the rate of reaction. The activation parameters such as apparent energy of activation (Ea), change in enthalpy of activation (DeltaH#), change in entropy of activation (DeltaS#) and change in free energy of activation (DeltaG#) have been calculated in the absence and presence of lithium and sodium chloride for the reaction and discussed.

Kinetics of reaction between phenothiazine dye/methylene green and peroxydisulphate ion in presence of bromide ion.

The rate of nuclear bromination was observed when the methylene green reacts with peroxydisulphate ion in presence of bromide ion. The reaction obeys zero order kinetics in the dye whereas first order kinetics in peroxodisulphate and bromide ion. The reaction was studied at various ionic strengths and temperatures to find out the effect of ionic strength on rate of nuclear brominating and energy of activation. The kinetics pertains to the rate determining stage of peroxydisulphate-bromide reaction. The study in different concentration of bromide and peroxydisulphate has shown that the rate constant increases by increasing the ionic strength and temperature of the system. The effect of ionic strength on the activation parameters was also studied.

Lipid profile and its relation to fasting insulin level in non-insulin dependent diabetes mellitus (NIDDM).

Atherosclerotic cardiovascular disease is the major cause of morbidity and mortality in NIDDM patients. But the exact pathophysiology of accelerated atherosclerosis seen in NIDDM is not completely understood. Hyperinsulinemia and hyperlipidemia frequently coexist in these subjects. Present study was undertaken to demonstrate relationship of serum insulin with atherogenic lipids in 92 (male = 62, female = 30) newly diagnosed, middle-aged, nonsmoking, uncomplicated and untreated NIDDM patients with normal body mass index (BMI). Fourty (male = 20, female = 20) non-diabetic healthy subjects with a negative family history of diabetes served as control. After an overnight fasting, venous blood was collected for plasma glucose, serum insulin and lipid profile. ECG and oral glucose tolerance test (OGTT) were done in all subjects. Diabetes mellitus was diagnosed by WHO criteria. Total cholesterol, LDL-c, LDL/HDL ratio, TG (p always < 0.001) and fasting serum insulin (p = 0.033) were significantly higher and HDL-c was significantly lower (p = 0.001) in NIDDM than control subjects. Fasting serum insulin was inversely related to the degree of hyperglycemia in NIDDM subjects (r = -0.1867; p = 0.037). NIDDM with hyperinsulinemia (n = 18) had a strong negative correlation (r = -0.449, p = 0.031) with HDL-c. Neither total cholesterol nor LDL-c had any significant correlation with insulin. The results indicate that diabetic state itself is associated with atherogenic lipid disorder.