Engineering the Mucus Barrier.

Mucus selectively controls the transport of molecules, particulate matter, and microorganisms to the underlying epithelial layer. It may be desirable to weaken the mucus barrier to enable effective delivery of drug carriers. Alternatively, the mucus barrier can be strengthened to prevent epithelial interaction with pathogenic microbes or other exogenous materials. The dynamic mucus layer can undergo changes in structure (e.g., pore size) and/or composition (e.g., protein concentrations, mucin glycosylation) in response to stimuli that occur naturally or are purposely administered, thus altering its barrier function. This review outlines mechanisms by which mucus provides a selective barrier and methods to engineer the mucus layer from the perspective of strengthening or weakening its barrier properties. In addition, we discuss strategic design of drug carriers and dosing formulation properties for efficient delivery across the mucus barrier.

Studies on L-640,035: a novel antagonist of contractile prostanoids in the lung.

The effects of L-640,035 (3-hydroxymethyl-dibenzo [b,f] thiepin-5,5-dioxide) have been studied on pulmonary smooth muscle contraction in vitro and in vivo. When studied in vitro on guinea-pig tracheal chains, L-640,035 produced significant shifts in the dose-response curves to a prostaglandin (PG) endoperoxide analogue (U-44069) (pA2 7.0), PGF2 alpha (pA2 5.9) and PGD2 (pA2 6.5). L-640,035 produced no significant shift in the dose-response curves to leukotriene D4 or histamine and produced a small but statistically significant shift in the dose-response curve to 5-hydroxytryptamine (5-HT) (pA2 5.2). With the exception of PGF2 alpha, Schild analysis did not in general indicate competitive inhibition. The main metabolite of L-640,035, L-636,499, also produced significant parallel shifts in the dose-response curves to U-44069 (pA2 6.0) and PGF2 alpha (pA2 6.0), but with some reduction in the maximal contraction. When L-640,035 was administered intravenously to guinea-pigs, significant inhibition of increases in pulmonary resistance or insufflation pressure induced by U-44069 (ED50 0.16 mg kg-1), leukotriene D4 (ED50 0.25 mg kg-1) and 5-HT (ED50 3.4 mg kg-1) but not histamine (ED50 greater than 10 mg kg-1) was observed. When L-640,035 was administered intravenously to dogs a significant inhibition of increases in pulmonary resistance induced by U-44069 (ED50 0.85 mg kg-1) but not histamine (ED50 greater than 30 mg kg-1) was observed. 5 When L-640,035 was administered by the intraduodenal route to dogs at doses of 3 and 10 mg kg- significant inhibition of increases in pulmonary resistance induced by sodium arachidonate (3 mgkg1 i.v.) was observed with a duration of action of > 255 min. 6 It is concluded that L-640,035 is a novel, relatively selective, and orally active antagonist of the actions of contractile prostanoids on pulmonary smooth muscle.

Analytic clinical chemistry precision and medical needs. The Canadian Interlab Program (CIP).

Precision obtained with two different serum pools used daily as internal quality-control specimens by 130 laboratories throughout Canada (Canadian Interlab Program) is reported for 14 analytes assayed by either manual or automated methods over a period of 16 months. Precision criteria set by Barnett to meet medical needs were not met for calcium, glucose, phosphorus, and urea nitrogen by more than 10% of the laboratories studied. Specific guidelines for laboratory precision are suggested for optimal and minimal performance in the assays of albumin, bilirubin, calcium, chloride, cholesterol, creatinine, glucose, phosphorus, potassium, sodium, total protein, triglyceride, urea nitrogen, and uric acid.

Reference values for the oral glucose tolerance test at each trimester of pregnancy.

A 100-gram oral glucose tolerance test (OGTT) was performed on a selected group of normal women at each trimester of pregnancy to establish reference values for hyperglycemia and hypoglycemia. Ninety three OGTT were performed in the first trimester, 121 in the second trimester, and 98 in the last trimester. The fasting serum glucose did not differ significantly between the trimesters. The values at 60 and 120 minutes were significantly different for the fifth, fiftieth, and ninety-fifth percentiles between each trimester of pregnancy. For the 180-minute readings, the fifth and fiftieth percentiles were not significantly different between the first and second trimester of pregnancy, but the results of the third trimester were significantly higher than those of the other trimesters. The mean fasting insulinemia remained relatively constant during pregnancy. Insulin response to OGTT increased during the progression of the pregnancy. The interpretation of the glucose tolerance tests during pregnancy, either to detect gestational diabetes or hypoglycemia, should take these physiologic changes into account.

Radiation doses to patients in neurointerventional procedures.

PURPOSE: To evaluate stochastic and deterministic risks associated with neurointerventional procedures for the patient. METHODS: Eight neurovascular interventional procedures were evaluated to determine the entrance skin dose and effective dose for the patient. Dosimetry was done with thermoluminescence dosimeters. The highest dose on the patient's head was recorded as the maximum entrance skin dose. The equivalent dose was obtained by conversion of the dose-area product using published conversion tables. RESULTS: The maximum entrance skin dose varied from 129 to 1335 mGy. The mean effective dose was 1.67 mSv with a range of 0.44 to 3.44 mSv. No deterministic effect has been encountered. Stochastic risk linked to the highest effective dose value was approximately one death by fatal cancer for every 6000 procedures, according to the new International Commission on Radiological Protection coefficient. CONCLUSIONS: Because no deterministic effect has been detected, and stochastic risks were very low, radiation hazard to the patient is a minor consideration in deciding whether to undertake a neurointerventional procedure.

Phantom equivalent thicknesses in diagnostic radiology.

Some measurements in diagnostic radiology must be done with phantoms. The most frequently used phantoms are water, plexiglass, aluminium and copper. It is interesting to know the equivalent thicknesses between these phantoms in order to be able to relate these values to real anatomical organs of known thicknesses. The use of antiscatter grids, the choice of intensifier screens, the beam size and in general the scattering parameters considerably change the equivalent thicknesses. Many situations have been simulated by the Monte Carlo method and equivalent thicknesses are presented.

Analogous filters for beam shaping in diagnostic radiology.

A computer simulation based on photon transport calculation was used to evaluate the properties of a wide variety of materials that could be used for the filtration of x-ray beams. A single filter was added to the inherent filtration. For comparison, the concept of analogous filters was introduced: two filters were considered analogous if both produced the same ratio of entrance exposure at the patient to the energy absorbed in the detector consisting of a pair of intensifying screens positioned immediately behind the water phantom. The efficiency, contrast and integral dose were calculated for filters of odd atomic numbers from 1 to 91 with a large number of different parameters (48,600 different combinations). They include essentially all major diagnostic radiology procedures, except mammography. Only extreme cases are presented here. No magic filter was found which would produce increased contrasts or a decreased integral dose, while maintaining efficiency close to that of aluminium. Filters of some atomic numbers produced increased contrast, but had negligible efficiency. Analogous filters of atomic numbers between 7 and 37 and also between 71 and 91, had almost identical properties but varied efficiencies. Unpredictable behaviour was obtained with filters of atomic numbers 38 to 70, where small changes in atomic number may produce large changes in all the properties due to the presence of K-edge discontinuities.

An interactive workshop: An effective means of integrating the Canadian Cardiovascular Society clinical practice guidelines on congestive heart failure into Canadian family physicians' practice.

OBJECTIVE: To use an interactive workship as a means of integrating clinical practice guidelines on congestive heart failure into Canadian family physicians' practice. SETTING: Interested practitioners from the Association des Médecins Omnipraticiens de Québec, the Centre de Santé Publique de Québec and the continuing medical education (CME) department, Merck Frosst Canada, Montreal, formed the initial task force. Train-the-trainer sessions took place in many provinces in a variety of CME settings. DESIGN: The interactive, problem-based workshop was facilitated by local interested general practitioners, while local experts served as consultants to reinforce key messages from clinical practice guidelines and to guide participants through the learning process. MAIN RESULTS: By December 31, 1996, 187 family practitioners and 81 specialists had been trained in train-the-trainer sessions across the country. A total of 1698 general practitioners had participated in over 52 workshops during the same time. Pre- and postworkshop testing indicate that the workshops improved knowledge, and that the knowledge gained during the workshop was retained at three- and six-months' follow-up. Separate chart evaluations conducted before and after the workshop showed that participants provided more complete chart information related to congestive heart failure and that they significantly increased their use of angiotensin-converting enzyme inhibitor therapy after the workshop. Participant evaluation of the workshop also indicates a high index of satisfaction with the presentation and the content of the workshop as being relevant to clinical practice. CONCLUSION: An interactive, problem-based, small group workshop developed by a core group of interested practitioners and guided by local trained facilitators and experts is an effective teaching tool through which clinical practice guidelines can be successfully transferred into clinical practice in a timely and meaningful way.

Pilot study on the contamination of drinking water by organotin compounds from PVC materials.

Raw and treated water samples and tap water samples from four to six houses located on distribution lines where PVC pipe/tubing had been recently installed were collected in five Canadian municipalities for the analysis of organotin compounds. After derivatisation with sodium tetraethylborate the ethylated organotin compounds were extracted with hexane and analysed by gas chromatography-microwave induced plasma atomic emission spectrometry using a wavelength (326.234 nm) specific for tin. Organotin compounds, mainly methyltin and dimethyltin at concentrations ranging respectively from 0.5 to 257 ng Sn/L and from 0.5 to 6.5 ng Sn/L, were detected in samples from ten of the twenty-two houses. No organotin compounds were detected in raw water or treated water leaving the treatment plant, indicating that the organotin compounds were leaching into the water from some component of the distribution system.

[Exposure rates in fluoroscopy in Quebec]. / Taux d'exposition en fluoroscopie au Québec.

For the past two years, the authors have measured by means of an ionization chamber the exposure rates of 155 fluoroscopic systems. Of these, 42% measured beyond the maximum of 5 R/min recommended by radiation protection codes. Systems linked to a television chain functioned at generally lower levels. There was no significant difference between remote controlled and non remote systems. However, appreciable differences between the units of two manufacturers were observed. The corrective measures which must follow this survey will result for Quebec in a saving of 2.0 millions of rads to the population which becomes, without doubt, the single most important factor of radiation protection.

The Functional Autonomy Measurement System (SMAF): description and validation of an instrument for the measurement of handicaps.

The Functional Autonomy Measurement System (SMAF) is an instrument developed for the measurement of the needs of the elderly and the handicapped. Its elaboration was based on the World Health Organization's classification of impairments, disabilities and handicaps. A functional autonomy rating scale, using a four-level measurement scale, quantifies a subject's performance on 29 functions in five sectors of activity: activities of daily living, mobility, communication, mental functions and instrumental activities of daily living. For each function, the evaluator must also estimate available resources to compensate for any identified disability in order to estimate the handicap. The disability and handicap profile obtained is the basis for the prescription of home care or the allocation of chronic care beds. An inter-observer study concluded that the scale is reliable for evaluators from different professions in the community as well as in institutional settings. The instrument is rapid to administer (on average 42 min) and the reliability is not influenced by training. A study of concurrent validity has shown a strong correlation between the disability index obtained by the SMAF and the amount of required nursing-care time. This instrument can be used for clinical purposes and in epidemiological and evaluative research.

Guidelines for detection of breast cancer: an update on investigative methods. A report of the ad hoc committee on mammography of The Canadian Association of Radiologists.

The high incidence of breast cancer and its mortality make it imperative that women over 25 years of age have a clinical examination of their breasts at least every three years up to age 40 and annually thereafter. Before the age of 25, mammography is seldom indicated and then it should usually be limited to a spot film of a potential lesion. After 25, mammography is indicated for any woman with breast symptoms, women with metastases from cancer of an unknown primary site, and before any breast surgery. Women with a strong family history and those with large breasts should also have a mammogram between the ages of 25 and 35. Between the ages of 35 and 39 we recommend a baseline mammogram for asymptomatic women. After 39 and up to age 50, women should consult their physicians yearly to determine if, and how often, mammography should be performed. Finally, after age 50, annual mammography is suggested. In each of the above contexts, the radiologic examination should be coupled with clinical palpation of the breasts. A trained and experienced mammographer should recommend biopsy when mammograms show a typical spiculated mass; an ill-defined or even well defined mass that cannot be said to be benign; a suspicious distortion of local architecture; or a cluster of suspicious microcalcifications. Any cyst the nature of which is uncertain after puncture, or abnormal ducts on a galactogram also should make a biopsy mandatory. On the other hand, a normal mammogram should not prevent biopsy of a lesion of the nipple or of a lump detected clinically.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of two administration techniques of inhaled nitric oxide on nitrogen dioxide production.

The purpose of this study was to verify whether, compared with the introduction of the NO-N2 mixture at the air inlet of the ventilator (classical method), a direct injection of NO-N2 into the inspiratory line of the ventilator circuit with a new injection device (new method), would reduce NO2 formation by reducing contact time between O2 and NO. The effect of two FIO2(0.21 and 0.90) and NO concentrations on NO2 production was determined. In the classical method, NO and O2 were mixed with an air/oxygen blender before the gas mixture entered the ventilator. In the new method, NO was injected directly into the respiratory line with the injection system. Nitric oxide and nitrogen dioxide gases were measured using a chemiluminescence analyzer. For a FI02 of 0.90 and 90 ppm of NO2, the amount of NO2 produced was decreased from 8.9 +/- 0.8 ppm (mean +/- SD) with the classical injection system to 4.4 +/- 0.2 ppm with the new injection system (P = 0.0039, Mann-Whitney test), and NO2 production was decreased from 4.5 +/-0.2 ppm to 2.1 +/- 0.4 ppm (P = 0.02) at 60 ppm of NO. However, at a FIO2, no difference was found in the amount of NO2 produced. We conclude that, compared with the classical method of NO administration, the new NO injection system reduces considerably the concentration of inhaled NO2 when a high FIO2 and a high concentration of NO are used.

Gas exchange is essential for bioreactor cultivation of tissue engineered cartilage.

Tissue engineered cartilage can be grown in vitro if the necessary physical and biochemical factors are present in the tissue culture environment. Cell metabolism and tissue composition were studied for engineered cartilage cultured for 5 weeks using bovine articular chondrocytes, polymer scaffolds (5 mm diameter x 2 mm thick fibrous discs), and rotating bioreactors. Medium pH and concentrations of oxygen, carbon dioxide, glucose, lactate, ammonia, and glycosoaminoglycan (GAG) were varied by altering the exchange rates of gas and medium in the bioreactors. Cell-polymer constructs were assessed with respect to histomorphology, biochemical composition and metabolic activity. Low oxygen tension ( approximately 40 mmHg) and low pH ( approximately 6.7) were associated with anaerobic cell metabolism (yield of lactate on glucose, YL/G, of 2.2 mol/mol) while higher oxygen tension ( approximately 80 mmHg) and higher pH ( approximately 7.0) were associated with more aerobic cell metabolism (YL/G of 1.65-1.79 mol/mol). Under conditions of infrequent medium replacement (50% once per week), cells utilized more economical pathways such that glucose consumption and lactate production both decreased, cell metabolism remained relatively aerobic (YL/G of 1.67 mol/mol) and the resulting constructs were cartilaginous. More aerobic conditions generally resulted in larger constructs containing higher amounts of cartilaginous tissue components, while anaerobic conditions suppressed chondrogenesis in 3D tissue constructs.

Quality-control scheme for blood glucose measured outside the laboratory.

We propose a quality-control (QC) scheme to evaluate the performance of blood glucose estimates made with a reflectometer in hospital wards or at home. We constructed a chart illustrating the comparison by regression analysis of the results of 254 reflectometer readings (y) and simultaneous capillary blood glucose analyses in the laboratory (x). Arbitrary acceptance limits around the regression line (y = 0.5 + 0.87x; r = 0.97, Sy/x = 0.8 mmol/L) were established, based on the mean +/- 2 SD of the reflectometer readings of a series of classes of 1.1 mmol/L interval, made with the results from the laboratory analyzer. Each ward using a reflectometer is provided with the QC chart, and the first blood glucose estimation with the reflectometer on each working shift is controlled by re-assay in the laboratory. If the reflectometer reading is outside the limits, the next glucose estimation is also re-assayed. If two consecutive readings are outside the limits, the reflectometer procedure is considered to be failing, the instrument's readings are not used for medical decisions, and remedial action is taken. The chart can also be used as a teaching tool for training the patients or the nurses and to evaluate individual performance.