Oral delivery of proteins: progress and prognostication

The delivery of proteins has gained momentum with the development of biotechnology sector that provided large-scale availability of therapeutic proteins. The availability is mostly due to the advances in recombinant DNA technology. The low oral bioavailability, however, continues to be a problem for several proteins because of their large molecular size, low permeation through biological membranes, and susceptibility to molecular changes in both biological and physical environments. The demand for effective delivery of proteins by the oral route has brought a tremendous thrust in recent years both in the scope and complexity of drug delivery technology. The important therapeutic proteins and peptides being explored for oral delivery include insulin, calcitonin, interferons, human growth hormone, glucagons, gonadotropin-releasing hormones, enkephalins, vaccines, enzymes, hormone analogs, and enzyme inhibitors. This article reviews the progress in oral delivery of these proteins, provides comments on the strategies to improve their oral bioavailability, and highlights their current market trends.     

Improving the use of mixing factors for dilution ventilation design

In specifying dilution ventilation flow rate, a safety factor, K, is often used to provide a margin of safety and to compensate for uncertainties and health impact severity. In current practice, the selection of K is very subjective. Here the component of K accounting for imperfect mixing, Km, was studied to develop more effective and efficient design procedures. Air flow and contaminant distribution in a 10 m x 3 m x 7 m room with a single contaminant source on a 1-m high table were simulated for steady, isothermal conditions using computational fluid dynamics. A series of 10 simulations explored factorial combinations of air exchange rates (1, 2,4, 8, 16 ACH) and inlet types (a high wall jet and a ceiling diffuser). Nine additional simulations explored exhaust opening location effects and 13 other simulations investigated source location effects. Km was calculated at each of 25,600 grid locations within the room by linear regression of emission rate/flow rate (G/Q) on concentration (C). The linear relationship between C and G/Q at each of the points was nearly perfect (R2 > 0.97). For the simulations with varying dilution flow rate, Km ranged from 0.19 to 2.86 for the wall jet and from 0.94 to 4.34 for the ceiling diffuser. Holding G/Q at 100 ppm and varying source and exhaust location produced room average concentrations from 55.7 to 173 ppm. Unlike orthodox design approaches, this work suggests that air monitoring data often can be used to calculate dilution flow rate requirements. Also, dilution flow rate requirements may be reduced by enhancing room mixing with fans or altering air inlet configuration. However, mixing should not be increased if the altered room air currents could transport contaminant to an occupant's breathing zone or interfere with other control methods that depend on segregation of incoming air and contaminant.     

Redistributive effects of the Swedish social insurance system

BACKGROUND: Four principles are used to distribute payments via the Swedish social-insurance system in cases of temporary or permanent illness and death. This paper studies the redistributive effects on income of these four principles. METHODS: The analysis is based on aggregate social-insurance data from the 25 municipalities that comprise Stockholm County in Sweden. For nine different types of social-insurance payments based on the four principles, the degree of income redistribution is measured according to concentration indexes and differences between Gini coefficients with social-insurance payments excluded and included. RESULTS: The concentration indexes for payments from the nine social-insurance schemes in total is -0.0469. The Gini coefficient falls from 0.0437 excluding insurance payments (i.e. for income only from gainful work, IGW) to 0.0379 when including insurance payments with income from gainful work (IGW + TP). That is, the Gini coefficient is 15% lower when insurance payments are included. Decomposition by payment shows that the largest redistribution effect on income inequality is made by disability pension. CONCLUSION: Municipalities with low average income are favoured by the Swedish social-insurance system. Payment principles can be ranked according to their redistributive capacity: mix of compensating-lost-income and flat-rate, compensating-lost-income, means-testing, flat-rate, and need-based respectively. The nine social-insurance schemes contribute very differently to income redistribution. Disability pension and sickness allowance contribute most to income redistribution and reducing income inequality.     

Formal,structured teaching in postgraduate training: a learner-centred educational programme

Medical education focuses on a learner-centred approach, but postgraduate training programmes have struggled to embrace this practice. In the West Midlands Deanery, a 2-year rolling postgraduate educational programme in obstetrics and gynaecology has been developed to equip trainees with the knowledge, skills and attitudes necessary to promote self-directed learning, via independent learning, interactive large-group presentations and small-group, peer-led activities.     

Migrating foreign body in the tracheobronchial tree: an unusual case of firework penetrating neck injury

Firework injuries can manifest themselves in many different ways; usually as an explosive or burn injury. This case describes an unusual presentation of a firework penetrating injury resulting in a sharp coiled metal foreign body travelling through a small entry wound in the neck and subsequently lodging itself in the tracheobronchial tree. A foreign body such as this can potentially travel a considerable distance through the soft tissues and end up in an unsuspecting distant site. There must, therefore, be a high index of suspicion with the appropriate radiological investigations for appropriate management of such cases.     

Intraoperative navigation in surgery of paranasal sinus and anterior skull base

BACKGROUND AND OBJECTIVE: Based on physical laws, stage of technical development and the user's individual skills a number of possible errors have to be considered for the application of CAS in paranasal sinus and anterior skull base surgery. PATIENTS/METHODS: Based on our experiences of 436 navigated cases hard- and software errors, errors of image acquisition and transfer, errors of patient registration, user related errors as well as strategic errors are analyzed. RESULTS: Any hindrance of the camera field leads to a limitation of functionality of optical systems in the same extent as electromagnetic systems can be affected by ferromagnetic materials. The mode of image acquisition is dependent from the CAS-system involved. The reconstruction algorithm requires particular attention. The patient registration based on the headset proved to be reliable for endonasal sinus surgery. CONCLUSIONS: In dealing with navigation devices in paranasal and anterior skull base surgery the user must pay critical attention to possible malfunction in order to guarantee a successful image guided surgical procedure.     

Origin of left main and right coronary arteries from right aortic sinus of Valsalva

Coronary anomalies may be a part of complex congenital malformations of the heart or be an isolated defect. Anomalous coronary arteries are associated with a higher incidence of congenital heart diseases, but do not appear to be associated with an increased risk for development of coronary atherosclerosis. Coronary anomalies are recognized readily on angiography. Unexpected findings during invasive procedures would suggest a possibly existing coronary anomaly, especially when main branches cannot be opacified by selective contrast medium injection. This case report illustrates the clinical and angiographic findings of a patient undergoing coronary angiography for evaluation of ischemic heart disease with an unexpected presence of anomalous origin of the left coronary artery from the right aortic sinus.     

Rosacea: a cutaneous marker of Helicobacter pylori infection? Results of a pilot study

Given the long purported anecdotal association between rosacea and gastrointestinal disease, the discovery that Helicobacter pylori causes gastritis and duodenal ulcer disease has led to a hypothesized role for this organism in the aetiology of rosacea. We conducted a case-series study of 49 patients to assess the potential association between severity of rosacea and direct and serological evidence of H. pylori infection. Patients were classified by severity into non-inflammatory erythematotelangiectatic or inflammatory/papulopustular rosacea and were tested for current H. pylori infection and evidence of previous exposure. Positive 13C-urea breath test and ELISA tests were more likely to be observed in patients with inflammatory rosacea, although not statistically significantly so (OR = 3.0, p = 0.15 and OR = 2.9, p = 0.16, respectively). However, the proportion of patients who tested positive in both assays (versus negative in at least one) was even higher in the inflammatory rosacea group and neared statistical significance (OR = 4.5, p = 0.06). This pilot study provides sufficient evidence suggestive of a positive association between the severity of rosacea and the presence of H. pylori to warrant further research.     

Fibroblast migration on fibronectin requires three distinct functional domains

Mesenchymal cell movement is normally constrained; however, fibronectin can provide a pathway for stromal cell migration during embryogenesis, morphogenesis, and wound healing. Cells can adhere to fibronectin via integrin and nonintegrin receptors, which bind multiple unique peptide sequences. Synthetic peptides and recombinant proteins were used to delineate the functional domains needed for human fibroblast migration over fibronectin. The 9th and 10th fibronectin type III repeats, which contain RGD and PHSRN synergy cell attachment sequences, support almost maximal fibroblast attachment, but not migration of primary dermal fibroblasts. Specific sequences within the heparin domain and the IIICS region are also required for migration. These findings predict and additional data confirm the necessity for the cooperation of multiple integrin and nonintegrin receptors for fibroblast migration on fibronectin. Such stringency of migration most likely imposes an immense constraint on normal mesenchymal cell mobility in unperturbed tissue. Loss of such restraint may be critical for the migration cancer cells through the extracellular matrix.     

Dentistry as a possible route of hepatitis C transmission in Pakistan

AIMS AND OBJECTIVES: To identify the role of dental surgical procedures in contributing to the transmission of hepatitis C. DESIGN: Prospective observational pilot study. SETTING: Shaikh Zayed Federal Postgraduate Medical Institute Lahore, Pakistan. METHODS: Exposure to dental procedures, injections, tattooing, surgical intervention, blood transfusions, family history of hepatitis, diabetes mellitus and contact with jaundiced patients was evaluated in 78 consecutive adult patients of both sexes suffering from chronic hepatitis C. MAIN OUTCOME MEASURES: Distribution of risk factors for acquiring hepatitis C with emphasis on role of dentistry as a possible route of transmission. RESULTS: Dental procedures were the major source of exposure (39.7%) followed by injections (16.6%), surgical procedures (16.6%), diabetes (12.8%), family history of hepatitis (9%), blood transfusions (7%), tattooing (5.1%) and history of contact with a jaundiced patient (2.6%). There was a statistically significant difference in distribution of risk factors, with dental procedures being the commonest factor (p < 0.001). CONCLUSIONS: The high prevalence of dental procedures in patients with chronic hepatitis C stresses the importance of ineffective infection control methods practiced by dental surgeons as a risk factor for acquiring hepatitis C and which were probably the source of infection. Large epidemiological studies are needed to elucidate the role of dentistry in transmitting hepatitis C.