Gene/Protein Disease Symptom Drug Enzyme Compound
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The effects of mucosal application of 1 mg% Alcian blue (a trivalent cationic phthalocyanine dye) on functional and ultrastructural parameters of the isolated rabbit gallbladder have been studied. Apart from minor changes in the shape of the group of central microvilli observed in thin-section electron microscopy and scanning electron microscopy, the major ultrastructural change induced by Alcian blue was an almost complete collapse of intercellular spaces in the region above the tight junctions up to the bases of the marginal microvilli as revealed by thin-section electron microscopy. Freeze-fracture electron microscopy demonstrated a complete disappearance of intramembrane particles of neighboring cell membranes corresponding to the region of interspace collapse. Transepithelial electrical resistance (RT) increased from 44.5 to 58.7 ohm . cm2 upon treatment with Alcian blue. This increase could be well accounted for by the observed structural changes in the paracellular pathway if this pathway determines the low resistance of the rabbit gallbladder epithelium. Despite the increase in RT, net mucosa-to-serosa fluid transport and the spontaneous mucosa-positive potential difference of 3 mV were unaltered by Alcian blue treatment, supporting the hypothesis that the transepithelial transport mechanism per se is electroneutral. A calculation of the maximal paracellular mucosa-to-serosa waterflow in response to a lateral intercellular space hypertonicity of 20 mosM demonstrates that in the Alcian blue-treated gallbladder the resulting figure is about three orders of magnitude too low to keep up with the unaltered spontaneous transepithelial net fluid transport. It is therefore concluded that the tight junction pathway in rabbit gallbladders does not serve as a route for net fluid transport.
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PMID:Lack of correlation between transepithelial transport capacity and paracellular pathway ultrastructure in Alcian blue-treated rabbit gallbladders. 50 Jul 86

Freeze-dried samples of sucrose with buffer salts, amino acids, or dextran have been analyzed with differential scanning calorimetry (DSC) to evaluate the use of DSC thermograms in predicting the physical storage stability. The glass transition temperature, Tg, of the amorphous cake, crystallization, and melting of sucrose are observed with DSC. Tg appeared to be an important characteristic of the physical stability of the amorphous freeze-dried cake. A storage temperature above Tg results in collapse or shrinkage of the cake, which for a sucrose-based formulation, may be accompanied by crystallization of the sucrose. The Tg of the amorphous sucrose is influenced by other components present in the cake. Dextran-40 raised Tg, while the addition of glycine to the formulation lowered Tg. The residual moisture content strongly influences Tg, since water acts as a plasticizer of the system; the higher the moisture content, the lower the Tg and the less physically stable the freeze-dried cake. Crystallization of amorphous sucrose is shown to be inhibited by high molecular weight components or ionic compounds. DSC analysis of freeze-dried cakes proved to be a powerful tool in formulation studies.
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PMID:Evaluation of the physical stability of freeze-dried sucrose-containing formulations by differential scanning calorimetry. 158 94

The hyaline layer (HL) is a multilayered extracellular matrix (ECM) that coats the external surfaces of sea urchin and starfish embryos. It is thought to protect and lubricate the embryo, stabilize the blastomeres during morphogenesis, and regulate nutrient intake. Ultrastructural studies of chemically fixed embryos have shown the HL to consist of two to four sublayers. However, since chemical fixatives may cause collapse and alter the positions and antigenicity of the extracellular components, fixation methods that exclude chemicals may reveal a picture of the HL closer to what is present in vivo. Freeze substitution, a fixation method whereby tissues are rapidly frozen and dehydrated at low temperatures, has proved useful for fixing material rich in ECM. In this study, embryos of the starfish Pisaster ochraceus were fixed for microscopy using freeze substitution and three chemical methods in order to determine, as accurately as possible, the structure of the HL. Embryos appear to be best preserved by freeze substitution and demonstrate a HL consisting of at least six distinct sublayers. Based on staining with anionic dyes, most sublayers appear to contain glycosaminoglycans. Freeze substituted embryos, which were also stained with monoclonal antibodies raised against their ECM, revealed that some molecules are common to all six sublayers, whereas other molecules may be restricted to specific sublayers. This suggests that each sublayer could have a different function. Additional evidence suggests that microvillus associated bodies, present in other marine invertebrate embryos, may anchor the asteroid HL to the cell surface microvilli.
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PMID:Ultrastructural study of the hyaline layer of the starfish embryo, Pisaster ochraceus. 172 6

The effect of different substitution times, temperatures and the incorporation of fixatives on the preservation of three species of nematode for scanning electron microscopy by freeze substitution with methanol, followed by critical point drying, is investigated. Hammerschmidtiella diesingi adults and Trichostrongylus colubriformis infective juveniles were successfully preserved using methanol at 253 K as the substitution medium. Preservation deteriorated with long substitution times, suggesting the extraction of material and that substitution times should be kept as brief as possible. Panagrolaimus davidi was not successfully preserved using pure methanol, but preservation was improved by using fixatives in the substitution medium, the best results being obtained with 1% OsO4/3% glutaraldehyde in methanol. A substitution temperature of 193 K did not give any improvement in preservation. The differences in the quality of preservation between the three species may be due to the relative ability of the cuticle to withstand collapse during critical point drying. Chemical fixation using cold fixative resulted in the retention of a natural posture but poor preservation, whereas hot fixatives resulted in good preservation but the loss of a natural posture. Freeze substitution in methanol may prove useful in the preparation of specimens possessing cuticles or cell walls which have sufficient strength to withstand the drying process (e.g. arthropods, plants, fungi, nematodes). More delicate specimens may require the incorporation of fixatives into the substitution medium or conventional fixation.
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PMID:Freeze-substitution techniques for preparing nematodes for scanning electron microscopy. 179 82

Titanium dioxide (TiO2) dust has generally been regarded as a "nuisance dust" in experimental animals and men. In this experiment, 16 dogs were exposed intratracheally to TiO2 dust for 9-15 months. The scanning electron microscopy with energy dispersive analysis of X-ray (SEM-EDAX), performed to identify the elemental composition of dust particles used in the study and in the focal lesions of the lungs, showed that dust particles were nearly pure titanium. Dust in the lung deposited mainly in the respiratory bronchioles and adjacent alveoli, with many alveoli filled by compacted dust particles. The pulmonary responses consisted of slight alveolitis, centrilobular emphysema, focal collapse of alveoli, and fibroblast hyperplasia with a few collagen fibres surrounding some of the TiO2-dust foci. Electron microscopically, many alveolar macrophages with intact nuclei contained a great amount of dust particles in their lysosomes, and in the dust foci, most of type I pneumocytes disappeared and type I pneumocytes showed hyperplasia. The alveolar subepithelial basement membrane were markedly thickened and bundles of collagen fibres were formed in the interstice. These findings suggest that TiO2 dust is one of the sorts which probably induce mild lung fibrosis in case a large amount is deposited in the lung tissue.
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PMID:[Pathogenic effects of titanium dioxide dust on the lung of dogs--a histopathological and ultrastructural study]. 279 52

In some epithelia, mucosal exposure to osmotic loads produces an increase in transepithelial resistance that is presumed to relate to the collapse of the paracellular spaces. Since proximal small intestinal epithelium may transiently encounter osmotic loads during normal digestion, we examined the short-term effect of osmotic loads on resistance and on epithelial structure of mucosal sheets prepared from guinea pig jejunum using Ussing-chamber, thin-section electron-microscopic, and freeze-fracture techniques. After equilibration of mucosal sheets in chambers, mucosal buffer tonicity was increased to 600 mosM with mannitol. This resulted in a 64% increase in resistance within 20 min. Concomitantly, 600 mosM produced a decrease in tight-junction cation selectivity as judged from dilution potentials, collapse of paracellular spaces, decreased cytoplasmic electron density in 10-40% of absorptive cells, and focal absorptive-cell subjunctional lateral-membrane evaginations often associated with microfilament arrays. Freeze-fracture replicas of absorptive-cell tight junctions revealed significant increases in both strand count and depth. Preincubation with 5 micrograms/ml cytochalasin D reduced the 600 mosM resistance increase caused by 600 mosM exposure by 48% but did not prevent the collapse of paracellular spaces. Lowered temperatures that produced morphologic evidence consistent with a gel-phase transition of absorptive-cell lateral membranes prevented both the resistance response and the alterations in tight-junction structure. In conclusion, transient osmotic loads produce an increase in resistance in jejunal epithelium and alter both absorptive-cell tight-junction charge selectivity and structure. These responses, which may have physiologic implications, can be reduced by cytoskeletal inhibitors and ablated by conditions that restrict mobility of absorptive-cell lateral-membrane molecules.
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PMID:Increases in guinea pig small intestinal transepithelial resistance induced by osmotic loads are accompanied by rapid alterations in absorptive-cell tight-junction structure. 686 87

The sublimation rate of frozen solutions was studied as a function of freezing rate, thickness of dried product (l), temperature, residual air pressure, and solute concentration. Data are presented for pure water, aqueous potassium chloride, aqueous povidone, and aqueous dobutamine hydrochloride-mannitol (System I). The resistance of the dried product to water vapor flow (Rp) was evaluated from the sublimation rate and the sample temperature. The primary experimental technique was based on freeze-drying a cylindrical microsample isothermally, with the sample suspended from one arm of a vacuum microbalance. Methodology to evaluate resistance data from vial freeze-drying experiments is also described. In separate experiments, samples in the form of a thin (15-microns) film were visually observed through a microscope during freeze-drying. Freeze-drying of most samples appeared to occur by water vapor escaping through open channels created by prior sublimation of ice. Contrary to the usual theoretical model, Rp is neither independent of temperature nor directly proportional to l. Rather, Rp decreases with increasing temperature and the l dependence is normally of the form Rp = (A0 + A1l)/(1 + A2l), where Ai (i = 0, 1, 2) are constants. In several cases, Rp is very large near l = 0, decreases sharply at l congruent to 0.1 cm, and obeys the above equation where l greater than 0.2 cm, a result suggesting an amorphous surface skin which cracks on desorption of water. The temperature dependence of Rp suggests that, as the sample temperature approaches the eutectic (or collapse) temperature, hydrodynamic surface flow of adsorbed water is an important flow mechanism.
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PMID:Physical chemistry of freeze-drying: measurement of sublimation rates for frozen aqueous solutions by a microbalance technique. 687 25

Pneumoconioses produced by intratracheal applications of various dusts (quartz, coal, cadmium and lead sulfide) in rats were investigated by electron microscopy in order to follow the pathway of the dust particles from the alveoli into the pulmonary interstitium. As postulated by Spencer in 1977 on the basis of light microscopic investigations, the dust particles produce necroses of the alveolar septae ('alveolar ulcers'). TWo forms of necroses appear to occur: with a less severe dust exposure, individual pneumocytes and their basement membrane are destroyed by dust particles. Dust-laden, macrophages are deposited here which are displaced into the stroma after re-epithelization of the alveolar defect. On the other hand, with massive dust exposure, almost all pneumocytes of the affected alveoli become necrotic. The affected alveoli collapse and are replaced by connective tissue, so that the dust is situated in the connective tissue stroma. A transcellular penetration of the dust particles into the pulmonary interstitium or an immigration of dust-laden macrophages into the pulmonary stroma through the intercellular junctions of intact pneumocytes was not observed in any of the pneumoconiosis models.
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PMID:Electron microscopic investigations on dust penetration into the pulmonary interstitium in experimental pneumoconioses. 710 Jun 60

Freeze drying provides a valuable tool to the formulation scientist by permitting dehydration of heat-sensitive drugs and biologicals at low temperature. The final product is quickly and easily reconstituted, and the process is compatible with aseptic operations. Freezing is a critical step, since the microstructure established by the freezing process usually represents the microstructure of the dried product. The product must be frozen to a low enough temperature to be completely solidified. If the solute crystallizes during freezing, this temperature is the eutectic temperature. If the solute remains substantially amorphous with freezing, the relevant temperature is the collapse temperature. Understanding the physical form of the solute--crystalline or amorphous--after freezing can be important from the standpoint of drying characteristics, appearance of the final product, and even product stability during storage. Supercooling is a significant factor in freezing of formulations intended for freeze drying--prior to both primary and secondary (eutectic) crystallization. The driving force for freeze drying is the difference in vapor pressure of ice between the sublimation zone and the condenser. Because the vapor pressure of ice increases sharply with increased product temperature, it is important from the standpoint of process efficiency to maintain product temperature as high as possible during primary drying without damaging the product. The upper limit of product temperature during primary drying again depends on the physical form of the solute. Exceeding either the eutectic temperature (crystalline solute) or the collapse temperature (amorphous solute) results in loss of the desirable properties of a freeze dried product. Freeze drying is a coupled heat and mass transfer process, where either heat transfer or mass transfer may be rate limiting with respect to the overall drying rate. Heat transfer is often the rate-limiting transfer operation because of the high heat of sublimation of ice and the inefficiency of heat transfer. Conduction is the primary mechanism of heat transfer, as opposed to convection or thermal radiation. The rate-limiting resistance to heat transfer is usually the interfacial, or contact, resistance caused by poor contact between materials--the heated shelf, metal trays, and the bottom surface of glass vials. Since the thermal conductivity of a gas is directly proportional to pressure in the free molecular flow regime, the chamber pressure during primary drying is an important determinant of the overall heat transfer rate. As a result, the drying rate for a heat transfer-limited process increases sharply with chamber pressure up to a pressure where free molecular flow conditions no longer apply.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Protein purification process engineering. Freeze drying: A practical overview. 776 73

The objective of this study was to characterize the thermal properties of systems containing various ratios of amorphous and crystalline components using both differential scanning calorimetry (DSC) and freeze-drying microscopy. The glycine/sucrose system was used as a model system, since it is routinely used in protein formulations. DSC analysis revealed that the addition of glycine to sucrose solutions resulted in a decrease in the glass transition (T'g) of the system. The T'g of a pure sucrose solution (7% w/v) decreased from -32.3 to -51.5 degrees C for a mixture containing a sucrose/glycine ratio of 2:5. The glass transition of the sucrose/glycine mixture decreased linearly as more glycine was added to the system. This decrease in glass transition resulted in severe collapse during freeze-drying of these mixtures above T'g. However, collapse was not observed during freeze-drying if the DSC thermogram of the sucrose/glycine mixture exhibited a transition resulting from recrystallization of the amorphous glycine. Mixtures having a sucrose/glycine ratio of 3:4 and 2:5 had a glass transition of -48 degrees C and -51.5 degrees C, respectively. Despite their low glass transition temperatures, these samples freeze-dried readily at a product temperature > T'g using a fast freeze-drying cycle (primary drying at a shelf temperature of +20 degrees C and chamber pressure of 100 mTorr) without any sign of collapse. The crystallization of the amorphous glycine from the frozen mixture of sucrose and glycine provided support during freeze-drying which prevented the macroscopic collapse of the final product. Freeze-drying microscopy visually revealed the crystallization and allowed for prediction of cake quality upon lyophilization. Although the freeze-drying microscope is not as sensitive as the DSC in detecting all transitions (it cannot detect a glass transition), it clarifies the interpretation of DSC, and together they provide valuable information regarding the relevance of each of the transitions to the final freeze-dried product elegance.
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PMID:Characterization of the sucrose/glycine/water system by differential scanning calorimetry and freeze-drying microscopy. 965 61


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