Characterization of rat vertebrae cortical bone microstructures using confocal Raman microscopy combined to tomography and electron microscopy.

BACKGROUND: The rat vertebrae is a good model to study bone regeneration after implantation of biomaterials used to treat bone loss, a major problem in oral and dental surgery. However, the precise characterization of bone microstructures in the rat vertebrae has not been reported. Therefore, the aim of this study was to achieve the complete analysis of such bone, at different scales, in order to have a clear model of healthy bone for comparison with regenerated bone. METHODS: In order to image the cortical bone of rat caudal vertebra, confocal Raman microscopy was combined with high resolution X-ray micro computed tomography (micro-CT), with scanning electron microscopy (SEM) using backscatter electron imaging and with more conventional histology coloration techniques. SEM and Raman microscopy were done in various regions of the cortical bone corresponding to external, middle and internal areas. The spongy bone was imaged in parallel. Micro-CT was performed on the whole vertebra to monitor the network of haversian canals in the cortical bone. Osteonic canals characteristics, and relative chemical composition were analysed in several regions of interest, in cortical and spongy bone. Five rats were included in this study. RESULTS: On micro-CT images, differences in intensity were observed in the cortical bone, substantiated by SEM. Chemical analysis with Raman spectra confirmed the difference in composition between the different regions of the cortical and spongy bone. PCA and k-mean cluster analysis separated these groups, except for the external and middle cortical bone. Peak intensity ratio confirmed these results with a CO3 to ν2 PO4 ratio significantly different for the internal cortical bone. Grayscale images stack extracted from micro-CT showed that global architecture of cortical bone was characterized by a dense and complex network of haversian osteonic canals, starting from the surface towards the vertebrae center. The mean diameter of the canals was 18.4 µm (SD 8.6 µm) and the mean length was 450 µm (SD 152 µm). Finally, Raman reconstructed images of the lamellar bone showed an enlargement of the lamellar layer width, both in circumferential lamellar bone and around haversian canals. CONCLUSIONS: Micro-CT and confocal Raman microscopy are good tools to complete classical analysis using optical and electron microscopy. The results and measurements presented in a rat model known for its small inter-individual differences provide the main characteristics of a mature bone. This study will allow the community working on this rat vertebrate model to have a set of characteristics, in particular on the structure of the haversian canals.

Prevalence of Thrombocytopenia in the First Week After Burn Injury and Its Relationship With Burn Severity in Shahid Motahari Hospital Over a Period of 6 Months in 2017.

A platelet count of less than 150,000 per microliter of blood is called thrombocytopenia. Platelet count monitoring is essential in the care of burn patients. The aim of this study was to evaluate platelet count in groups of patients with different percentage of burns on the body surface and its relationship with the severity of burns and mortality. This retrospective descriptive cross-sectional study was performed on patients admitted to Shahid Motahari Hospital over a period of six months. The study was conducted on burn patients who were admitted to the hospital on the first day after injury. Patients were divided into two groups of with or without thrombocytopenia in the first week. Demographic information and treatment information about the patients were recorded. SPSS V.26 software was used for the statistical analysis of data. In this study, the prevalence of thrombocytopenia in the first week after burns was 36%. The variables of age, sex, duration of hospitalization, burn agent, percentage of burns and use of silver sulfadiazine ointment were significantly different in the two groups of patients. The group without thrombocytopenia had a mortality rate of 5.1%, while the group with thrombocytopenia had a rate of 32.2%. Based on the results of this study, thrombocytopenia is significantly associated with mortality in burn patients. Furthermore, the results of this study indicate that age, sex, burn agent, percentage of burns, and the use of silver sulfadiazine ointment have a clear impact on the thrombocytopenic status of patients.

La thrombopénie est définie par un compte plaquettaire <150 000/mm3, et la surveillance de la numération plaquettaire (NP) fait partie de la biologie de routine chez les brûlés. Cette étude a pour but l'évaluation de la cinétique de la NP chez des brûlés sur des surfaces variables et sa relation avec la sévérité de la brûlure et la mortalité. Il s'agit d'une étude rétrospective auprès de patients admis dans les 24h suivant leur brûlure dans le CTB de l'hôpital Shahid Motahari durant une période de 6 mois. Nous avons comparé ceux ayant subi une thrombopénie dans la première semaine aux autres (démographie, traitement), les statistiques ayant été réalisées avec SSPS version 26. La prévalence de la thrombopénie précoce est de 36%. Âge, sexe, cause, surface brûlée, recours à la sulfadiazine argentique et durée d'hospitalisation étaient différents entre les deux groupes. La mortalité des patients thrombopénique était de 32,2% VS 5,1%. Elle est significativement associée à la mortalité. L'âge, le sexe, la cause, la surface et la sulfadiazine argentique sont associées à la survenue de thrombopénie.

Variability of amino acid digestibility of lupin and pea grains in caecectomised laying hens.

1. The objective of this study was to investigate the variations in amino acid (AA) digestibility of lupin and pea grains in caecectomised laying hens. The relationship between AA digestibility and chemical constituents of the grains was determined. 2. Twelve variants of lupins and peas were each added to a basal diet at a concentration of 300 g/kg, at the expense of maize starch. The lupin and pea variants were separately investigated in two subsequent trials. Each trial consisted of two 7 × 7 Latin squares, each comprising the basal diet and six diets with lupins or peas. 3. Fourteen caecectomised laying hens (LSL-classic) were individually housed in metabolism cages and 120 g/d of experimental diets were provided for eight days. During the last four days, excreta were collected quantitatively and feed intake was recorded. A regression approach was used to determine the AA digestibility of the lupin and pea variants. 4. Amino acid digestibility of the lupins and peas was high, although significant differences in AA digestibility among the lupins and peas were detected. The digestibility of lysine was in the range of 0.87-0.91 and 0.87-0.93 for lupins and peas, respectively. The digestibility of methionine in lupins and peas varied between 0.80-0.88 and 0.72-0.90. Variations in AA digestibility in peas were more pronounced than in lupins. 5. Significant correlations between chemical constituents of lupins, such as alkaloids, and AA digestibility were detected in some cases, without a consistent pattern. In peas, tannin concentration and the insoluble protein fraction were negatively correlated with digestibility of some AAs, but only when one colour flower variant was considered. Trypsin inhibitor activity in peas was negatively correlated with AA digestibility, particularly for the white flower variants.

Chemical & Nano-mechanical Study of Artificial Human Enamel Subsurface Lesions.

White lesions represent an early phase of caries formation. 20 human sound premolars were subjected to pH cycling procedure to induce subsurface lesions (SLs) in vitro. In addition, 2 teeth with naturally developed white spot lesions (WSLs) were used as references. All specimens characterized by confocal Raman microscopy being used for the first time in examining white & subsurface lesions and providing a high resolution chemical and morphological map based on phosphate peak intensity alterations at 960 cm-1. Nanoindentation technique was used to measure Hardness (H) and Young's modulus (E) of enamel. Phosphate map of examined samples exhibited presence of intact surface layer (ISL) followed by severe depletion in (PO43-) peak in the area corresponding to the body of the lesion. In all examined groups, the mechanical properties of enamel were decreased in lesion area and found to be inversely related to penetration depth of indenter owing to enamel hierarchical structure. By combining the above two techniques, we linked mechanical properties of enamel to its chemical composition and ensured that the two methods are highly sensitive to detect small changes in enamel composition. Further work is required to bring these two excellent tools to clinical application to perceive carious lesions at an early stage of development.

Evaluation of Diversity Based on Morphological Variabilities and ISSR Molecular Markers in Iranian Cynodon dactylon (L.) Pers. Accessions to Select and Introduce Cold-Tolerant Genotypes.

The main goals of the present study were to screen Iranian common bermudagrasses to find cold-tolerant accessions and evaluate their genetic and morphological variabilities. In this study, 49 accessions were collected from 18 provinces of Iran. One foreign cultivar of common bermudagrass was used as control. Morphological variation was evaluated based on 14 morphological traits to give information about taxonomic position of Iranian common bermudagrass. Data from morphological traits were evaluated to categorize all accessions as either cold sensitive or tolerant using hierarchical clustering with Ward's method in SPSS software. Inter-Simple Sequence Repeat (ISSR) primers were employed to evaluate genetic variability of accessions. The results of our taxonomic investigation support the existence of two varieties of Cynodon dactylon in Iran: var. dactylon (hairless plant) and var. villosous (plant with hairs at leaf underside and/or upper side surfaces or exterior surfaces of sheath). All 15 primers amplified and gave clear and highly reproducible DNA fragments. In total, 152 fragments were produced, of which 144 (94.73%) being polymorphic. The polymorphic information content (PIC) values ranged from 0.700 to 0.928. The average PIC value obtained with 15 ISSR primers was 0.800, which shows that all primers were informative. Probability identity (PI) and discriminating power between all primers ranged from 0.029 to 0.185 and 0.815 to 0.971, respectively. Genetic data were converted into a binary data matrix. NTSYS software was used for data analysis. Clustering was done by the unweighted pair-group method with arithmetic averages and principle coordinate analysis, separated the accessions into six main clusters. According to both morphological and genetic diversity investigations of accessions, they can be clustered into three groups: cold sensitive, cold semi-tolerant, and cold tolerant. The most cold-tolerant accessions were: Taft, Malayear, Gorgan, Safashahr, Naein, Aligoudarz, and the foreign cultivar. This study may provide useful information for further breeding programs on common bermudagrass. Selected genotypes can be evaluated for other abiotic stresses such as drought and salinity.

Comparing the effect of colactive plus ag dressing versus nitrofurazone and vaseline gauze dressing in the treatment of second-degree burns.

Wound care quality and speed of burn healing are important factors that affect the treatment, prognosis and complications of burns. Burn care is challenging, and the ideal method controversial. The aim of this study was to compare the effects of a new dressing (ColActive dressing) in the treatment of superficial second-degree burns versus traditional dressing including Vaseline and Nitrofurazone. This was a randomized clinical trial study involving 25 cases. A superficial second-degree burn area was divided into two parts in each patient; randomly, traditional dressing was used on one area, and ColActive plus Ag dressing on the other. Every 3 days, after removing the dressings and washing the wounds, wound surface area was evaluated by medical photographic records and J image software. Wound surface area in the two groups was compared before dressing and on the 3rd, 6th, 9th and 12th day afterwards. The difference was not significant before dressing, but significant on the 3rd, 6th, 9th and 12th post-operative day. The difference was significant in both groups, but it was more prominent in the ColActive group (p<0.001) than in the traditional group (p<0.05). Considering the results of this study and good results in previous case reports, ColActive may be more effective than traditional dressing. We suggest a more comprehensive study for a longer period with a larger number of cases to compare other important variables such as scar quality, cost, and pain in the two dressings.

La qualité des soins locaux et la vitesse de cicatrisation sont d'importants paramètres affectant le traitement, le pronostic et les complications des brûlures. La méthode idéale reste encore à trouver. Le but de cet étude est de comparer un nouveau pansement (ColActive ®) au traditionnel nitrofurazone/vaseline sur les brûlures du 2ème superficiel. Il s'agit d'une étude randomisée portant sur 25 patients. Les zones de 2ème superficiel étaient divisées en 2 recevant, après tirage au sort, l'une ColActive® Plus Ag, l'autre nitrofurazone/vaseline. Après nettoyage, les photographies des brûlures étaient évaluées en utilisant Image J, à l'entrée et à J3, 6, 9 et 12. Les différences étaient significatives à J3, 6, 9, 12 avec une valeur de p plus prononcée (<0,001) dans le groupe ColActive® Plus Ag que dans le groupe contrôle (<0,05). Considérant ces résultats en faveur de l'utilisation de ColActive® Plus Ag, nous suggérons une étude plus globale, sur un nombre plus élevé de patients, comparant aussi la qualité cicatricielle, le coût et la douleur.

Silver Nanoparticles: An Influential Element in Plant Nanobiotechnology.

Profound interest and progress has been made since the invention of nanotechnology in 1959. However, its application in plant tissue culture and biotechnology has not been fully acknowledged in parallel with other facets of this technology. In this manuscript, the AgNPs effects on plant tissue culture and biotechnology encompass their antimicrobial effects and their mechanisms of action addressed to some extends. Moreover, their effects on seedling growth also reviewed. Most of the presented papers in the field of plant science have focused on antimicrobial effects of silver nanoparticles but its interesting inhibitory effects of plant senescence phytohormone ethylene, most likely can open a new window for future research.

The Effect of Lavender Aromatherapy on the Pain Severity of Primary Dysmenorrhea: A Triple-blind Randomized Clinical Trial.

BACKGROUND: Primary dysmenorrhea is the most common complaint in adolescents and adult young women that disturbs their daily life performance. AIM: The current study investigated the effect of lavender aromatherapy on pain severity in primary dysmenorrhea. SUBJECTS AND METHODS: This triple-blind randomized clinical trial was conducted on 200 students of Ardabil University of Medical Sciences, Iran. Subjects were allocated randomly into intervention (lavender) and control (placebo) groups. The researcher assistant asked the participants to smell the lavender in the first 3 days of menstruation, 30 min in a day in two menstrual cycles. Control group was also administered placebo (diluted milk) to be used as lavender in treatment group. Pain severity was scored by visual analog scale in the first 3 days of menstruation before intervention and 2 months after intervention. Data were analyzed through descriptive statistics and independent and paired samples t-tests. RESULTS: There was a significant difference in average pain severity between treatment and control groups after intervention. However, students in the treatment group reported significantly less pain severity 2 months after intervention (P < 0.01). CONCLUSION: Using lavender aromatherapy for 2 months may be effective in decreasing the pain severity of primary dysmenorrhea.

Marine organisms as heavy metal bioindicators in the Persian Gulf and the Gulf of Oman.

In the present study, cadmium and lead concentrations were compared in barnacles, ghost shrimps, polychaetes, bivalves, and sediment from ten different locations along the intertidal zone of the Persian Gulf and the Gulf of Oman. The results revealed significant differences in the heavy metal concentrations between the organisms with barnacles showing, by far, the highest metal concentrations. The bioaccumulation factor of Cd in different animals follows this pattern with barnacles>bivalves>polychaetes>ghost shrimps, while the pattern for Pb was barnacles>polychaetes>bivalves>ghost shrimps. In most of the stations, sediments showed the lowest lead and cadmium concentrations. Therefore, it is concluded that barnacles with Pb concentrations between 0.17 and 2,016.1 µg/g and Cd concentrations ranging from 0.4 to 147.1 µg/g are the best organisms to be employed in monitoring programs designed to assess pollution with bioavailable metals in the Persian Gulf and the Gulf of Oman.

Anterior Teeth Splinting After Orthodontic Treatment: 3D Analysis Using Finite Element Method.

OBJECTIVE: Retention after orthodontic treatment is still an important part of the treatment. Splints are considered as an alternative for removable retainers. The main goal of this study was to assess splinting biomechanically. MATERIALS AND METHODS: Three dimensional finite element models (3D) were designed of a mandibular anterior segment which included six anterior teeth with their supporting tissues (model 1 as control) and with a bonded lingual fixed retainer in the two other models. The wire cross section was round (0.016") in model 2 and rectangular (0.016" × 0.022") in model 3. The models were designed in Solid Works 2006 and analyzed in ANSYS Workbench Ver. 11.0 SolidWorks Incisors were loaded with a vertical force of 187 N. PDL stress and tooth displacements were evaluated. RESULTS: The numeric findings showed an increase after splinting in the central incisors [2.42 MPa to 4.57 MPa (round) and 16.66 (rectangular) MPa] in biting with four incisors. Biting with two incisors decreased the stress after splinting [2.42 MPa to 1.7 MPa (round wire) and 1.77 MPa (rectangular wire)]. In lateral movement, all teeth showed an increased stress except for the working side canine. CONCLUSION: Splinted cases (with round or rectangular wires) can benefit from stress redistribution when biting small food particles and in lateral movement.

Nano silver treatment is effective in reducing bacterial contaminations of Araucaria excelsa R. Br. var. glauca explants.

The downside of plant tissue culture techniques is an unwanted microbial contamination. Elimination of contaminants is the first step of any successful investigation on plant tissue culture. Preliminary experiments on Araucaria excelsa R. Br. var. glauca (Norfolk-Island pine) (syn.: A. heterophylla) showed that most common decontaminants could not successfully eliminate the contamination. Therefore, nano silver (NS) colloids were evaluated for controlling contamination. Treatments were included soaking the explants in NS solution or adding NS to the culture medium. Explants were cultured on MS medium supplemented with appropriate growth regulators for their establishment. Results showed that surface sterilization followed by treatment with 200 mg l-1 of NS with soaking time of 180 min reduced the bacterial contamination from 61.5% to 11.3% and adding 400 mg l-1 NS to the medium reduced the bacterial contamination from 81.25% to 18.75%. Nano silver could be applied without adverse effects on plant growth and development. This is the first report on in vitro establishment of A. excelsa R. Br. using NS to reduce bacterial infections.

Effect of ethanol extract of saffron (Crocus sativus L.) on the inhibition of experimental autoimmune encephalomyelitis in C57bl/6 mice.

In this study, effect of ethanol extract of Saffron (Crocus sativus L.) in the treatment of Experimental Autoimmune Encephalomyelitis (EAE) in C57BL/6 mice was evaluated. EAE was induced by immunization of 8 week old mice with MOG(35-55) with complete Freunds adjuvant. Therapy with saffron was started on day the immunization. Total Antioxidant Capacity (TAC) was assessed by Ferric Reducing-Antioxidant Power (FRAP) method. Nitric oxide (NO) production was also estimated by Griess reaction. For histological analysis, mice brain was harvested and sections were stained with Hematoxylin-Eosin. After daily oral dosage the saffron significantly reduced the clinical symptoms in C57BL/6 mice with EAE. Also, treated mice displayed a delayed disease onset compared with control mice. TAC production was significantly elevated in saffron treated mice. Effect of saffron on serum NO production was not significant. Typical spinal cord leukocyte infiltration was observed in control mice compared with saffron treated mice. These results suggest for the first time that saffron is effective in the prevention of symptomatic EAE by inhibition of oxidative stress and leukocyte infiltration to CNS and may be potentially useful for the treatment of Multiple Sclerosis (MS).

Effect of sesame oil on the inhibition of experimental autoimmune encephalomyelitis in C57BL/6 mice.

Sesame oil was evaluated in the treatment of in C57BL/6 mice. It has profound anti-inflammatory activity and been traditionally used to treat inflammatory disorders. EAE was induced by immunization of 6-8 week old mice with MOG(35-55) with complete Freunds adjuvant. Therapy with sesame oil was started on day 3 before the immunization. Total Antioxidant Capacity (TAC) was assessed by Ferric Reducing-antioxidant Power (FRAP) method. Nitric Oxide (NO) production was also estimated by Griess reaction. For histological analysis, mice brain was harvested and sections were stained with Hematoxylin-Eosin. After daily intraperitoneal dosage the sesame oil significantly reduced the clinical symptoms in C57BL/6 mice with EAE. Also, treated mice displayed a significantly delayed disease onset compared with control mice. Sesame oil significantly increased TAC, but it's effect on serum nitrite production was not significant. Typical brain leukocyte infiltration was observed in control mice compared with treated mice. Present results suggest for the first time that sesame oil therapy may be effective in the prevention of symptomatic EAE. This resistance to encephalomyelitis may be associated with inhibition of oxidative stress.

Interstitial fluid pressure in intracranial tumours in patients and in rodents.

Fluid transport parameters in intracranial tumours influence the delivery of therapeutic agents and the resolution of peritumoral oedema. The tumour and cortex interstitial fluid pressure (IFP) and the cerebrospinal fluid pressure (CSFP) were measured during the growth of brain and pial surface tumours [R3230AC mammary adenocarcinoma (R3230AC) and F98 glioma (F98)] in rats. Intratumoral and intracranial pressures were also measured in rodents and patients treated with dexamethasone, mannitol and furosemide (DMF), and hypocapnia. The results show that (1) for the R3230AC on the pial surface, IFP increased with tumour volume and CSFP increased exponentially for tumours occupying a brain volume of 5% or greater; (2) in F98 with volumes of approximately 10 mm3, IFP decreased from the tumour to the cortex, whereas for tumour volumes > 16 mm3 IFP equilibrates between F98 and the cortex; (3) DMF treatment reduced the IFP of intraparenchymal tumours significantly and induced a pressure gradient from the tumour to the cortex; and (4) in 11 patients with intracranial tumours, the mean IFP was 2.0 +/- 2.5 mmHg. In conclusion, the IFP gradient between intraparenchymal tumours and the cortex decreases with tumour growth, and treatment with DMF can increase the pressure difference between the tumour and surrounding brain. The results also suggest that antioedema therapy in patients with brain tumours is responsible in part for the low tumour IFP.

Quantitation and physiological characterization of angiogenic vessels in mice: effect of basic fibroblast growth factor, vascular endothelial growth factor/vascular permeability factor, and host microenvironment.

A prerequisite for the development of novel angiogenic and anti-angiogenic agents is the availability of routine in vivo assays that permit 1) repeated, long-term quantitation of angiogenesis and 2) physiological characterization of angiogenic vessels. We report here the development of such an assay in mice. Using this assay, we tested the hypothesis that the physiological properties of angiogenic vessels governed by the microenvironment and vessel origin rather than the initial angiogenic stimulus. Gels containing basic fibroblast growth factor (bFGF) or vascular endothelial growth (VEGF) were implanted in transparent windows in the dorsal skin or cranium of mice. Vessels could be continuously and non-invasively monitored and easily quantified for more than 5 weeks after gel implantation. Newly formed vessels were first visible on day 4 in the cranial window and day 10 in the dorsal skinfold chamber, respectively. The number of vessels was dependent on the dose of bFGF and VEGF. At 3000 ng/ml, bFGF- and VEGF-induced blood vessels had similar diameters, red blood cell velocities, and microvascular permeability to albumin. However, red blood cell velocities and microvascular permeability to albumin were higher in the cranial window than in the dorsal skinfold chamber. Leukocyte-endothelial interaction was nearly zero in both sites. Thus, newly grown microvessels resembled vessels of granulation and neoplastic tissue in many aspects. Their physiological properties were mainly determined by the microenvironment, whereas the initial angiogenic response was stimulated by growth factors.

Tumor necrosis factor alpha-induced leukocyte adhesion in normal and tumor vessels: effect of tumor type, transplantation site, and host strain.

Tumor necrosis factor alpha (TNF-alpha) can lead to tumor regression when injected locally or when used in an isolated limb perfusion, and it can enhance the tumoricidal effect of various therapies. TNF-alpha can also up-regulate adhesion molecules, and thus, facilitate the binding of leukocytes to normal vessels. The present study was designed to investigate the extent to which the host leukocytes roll and adhere to vessels of different tumors (MCaIV, a murine mammary adenocarcinoma; HGL21, a human malignant astrocytoma) at a given site or to the same tumor at different sites (dorsal skin and cranium), in different mouse strains [C3H and severe combined immunodeficient (SCID)], both with and without TNF-alpha-activation. There was no significant difference in hemodynamic parameters such as RBC velocity, diameter, or shear rate between PBS-treated control groups and corresponding TNF-alpha-treated groups. Under PBS control conditions, the leukocyte rolling count in MCaIV tumor vessels in the dorsal chamber in C3H and SCID mice and in the cranial window in C3H mice was significantly lower than that in normal vessels (P < 0.05), but stable cell adhesion was similar between normal and tumor vessels. TNF-alpha led to an increase (P < 0.05) in leukocyte-endothelial interaction in vessels in the following cases: normal tissue regardless of sites and strains, MCaIV tumor in the cranial window in C3H mice, and HGL21 tumor in the cranial window in SCID mice. However, the increase in rolling and adhesion in the MCaIV tumor in response to TNF-alpha was significantly lower than in the corresponding normal vessels (P < 0.05) in the dorsal chamber in C3H and SCID mice and in the cranial window in C3H mice. The HGL21 tumor in the cranial window in SCID mice showed leukocyte rolling and adhesion comparable to that in normal pial vessels. These findings suggest that (a) in general, basal leukocyte rolling is lower in tumor vessels than in normal vessels; (b) leukocyte rolling and adhesion in tumors can be enhanced by TNF-alpha-mediated activation; and (c) the TNF-alpha response is dependent on tumor type, transplantation site, and host strain. These results have significant implications in the gene therapy of cancer using TNF-alpha-gene-transfected cancer cells or lymphocytes.

Interaction of activated natural killer cells with normal and tumor vessels in cranial windows in mice.

A mammary carcinoma, MCa IV, was grown in syngeneic C3H mice in a cranial window preparation which permitted the in vivo observation of the growth and microcirculation of the tumors. Fluorescently labeled activated natural killer (A-NK) cells were injected into the external carotid artery and their interactions with normal and tumor vessels were quantified by video microscopy. Cells which entered the tumor vessels adhered heterogeneously to these vessels, regardless of vessel size or blood flow rates and bound with an efficiency ranging from 0 to 82% of the incoming cell flux. Normal brain tissue showed significantly fewer binding cells per microscopic field (9 +/- 5 vs 85 +/- 27 cells/1.3 mm2) and the few cells which were retained by the normal tissue were highly deformed, suggesting mechanical rather than adhesive entrapment. These studies indicate that A-NK cells bind in high numbers to segments of the vessels of mammary tumors growing in an intracranial site when administered through an arterial route; however, some tumor vessels may escape recognition by these cells. These findings suggest that A-NK cells may be used as carriers of genes for anti-cancer agents.

Vascular permeability and microcirculation of gliomas and mammary carcinomas transplanted in rat and mouse cranial windows.

Many brain tumors are highly resistant to chemotherapy, presumably due to the presence of a tight blood-tumor barrier. For a better understanding of the regulation of this barrier by the brain environment, a new intravital microscopy model was established by transplanting tumor tissue into cranial windows in both rats and mice. The model was characterized by RBC velocities, vessel diameters, and vascular permeabilities of various tumors: R3230AC (a rat mammary adenocarcinoma), MCaIV (a mouse mammary adenocarcinoma), and U87 and HGL21 (human malignant astrocytomas). Our results showed that tumor blood flow in cranial windows was one to three orders of magnitude lower than the blood flow in pial vessels and similar to that in dorsal skin-fold chambers observed in previous studies. The mean vessel diameter ranged from 6.8 +/- 1.3 microns for HGL21 to 30.4 +/- 8.5 microns for MCaIV. At least one order of magnitude difference in vascular permeability to albumin was observed between tumor lines: 0.11 +/- 0.05 x 10(-7) cm/s for HGL21 versus 3.8 +/- 1.2 x 10(-7) cm/s for U87. The low vascular permeability of HGL21, which was also confirmed by both sodium fluorescein and Lissamine green injections, suggests that not all tumors are leaky to tracer molecules and that the blood-tumor barrier of this tumor still possesses some characteristics of blood-brain barrier as observed in other intracranial tumors. The model presented here will allow us to manipulate the vascular permeability in brain tumors and thus may provide new information on the regulation of the blood-tumor barrier and new strategies for improving drug delivery in brain tumors.

The social drug lag: an examination of pharmaceutical approval delays in Medicaid formularies.

Several states have enacted restrictive drug formularies in order to control the costs of their Medicaid pharmaceutical programs. This study investigates the restrictiveness of these formularies by analyzing the delay in approving new drug products for Medicaid reimbursement. A restrictiveness index is developed which relates the drug product months which are denied to Medicaid patients to the potential product months of availability if all products which were newly approved for general use were simultaneously made available to the Medicaid population. The study then relates the restrictiveness of state formularies to Medicaid drug program costs and to total Medicaid program costs. We find that restrictiveness of formularies is not associated with lower drug costs, but that total Medicaid costs are lower in states with more restrictive formularies. We suggest that restrictive formularies may occur in states with other Medicaid cost-containment measures, so that total Medicaid expenditures are contained in those states, even though there is no reduction in drug expenditures.

Economic aspects of drug substitution.

One of the major directions of health policy is the attempt to contain expenditures on pharmaceuticals by encouraging substitution of generic for brand name drug products. Yet, a major marketing survey of prescribing and dispensing patterns in California in 1977 found relatively little drug substitution occurring, and in fact substitution of more expensive products occurred more frequently than did substitution of less expensive products. This article tests alternative models of pharmacy dispensing behavior to better explain substitution patterns and it estimates price functions to measure the extent to which cost savings on generic products are passed on to consumers.