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PubMed2004

Predictors for spread of clinical group A streptococcal tonsillitis within the household.

OBJECTIVE: The objectives of this study were to explore how frequently group A streptococci (GAS) were giving additional cases of clinical GAS tonsillitis within the households and to analyse predictors for such spread of GAS infection. SETTING: Two Norwegian general practice populations in Stokke and Kongsberg communities. PATIENTS: 110 households with at least one member with sore throat lasting less than 7 days, and GAS demonstrated in throat culture. Among the 110 index patients 51 (46%) were parents, 35 mothers and 16 fathers; 23 were children 6 years and younger, while 36 were children aged 7-15 years. MAIN OUTCOME MEASURES: Frequency of spread of clinical GAS infection to another household member within 4 weeks. Distribution of age and size of household in families with and without spread of GAS infection. RESULTS: In 30 (27%) households one or more new cases of GAS tonsillitis was found, adding 40 new infections. No spread of GAS disease was found in households with only adult members. A significantly higher proportion of spread was found in households with 4 or more members compared with households with fewer members, and low age of the index person. Short duration of symptoms before seeing a doctor was also associated with spread of GAS. In a logistic regression analysis carried out in the households with children, short duration of symptoms before diagnosis and treatment and low age of index person were significantly associated with spread of the infection. CONCLUSIONS: Even with standard penicillin treatment, GAS infection is frequently spread within households, and most frequently in households with children and many members.

Adolescent↗
PubMed1996

Syndecan-1 mediates cell spreading in transfected human lymphoblastoid (Raji) cells.

Syndecan-1 is a cell surface proteoglycan containing a highly conserved transmembrane and cytoplasmic domain, and an extracellular domain bearing heparan sulfate glycosaminoglycans. Through these domains, syndecan-1 is proposed to have roles in growth factor action, extracellular matrix adhesion, and cytoskeletal organization that controls cell morphology. To study the role of syndecan-1 in cell adhesion and cytoskeleton reorganization, mouse syndecan-1 cDNA was transfected into human Raji cells, a lymphoblastoid cell line that grows as suspended cells and exhibits little or no endogenous cell surface heparan sulfate. High expressing transfectants (Raji-Sl cells) bind to and spread on immobilized thrombospondin or fibronectin, which are ligands for the heparan sulfate chains of the proteoglycan. This binding and spreading as not dependent on the cytoplasmic domain of the core protein, is mutants expressing core proteins with cytoplasmic deletions maintain the ability to spread. The spreading is mediated through engagement of the syndecan-1 core protein, as the Raji-S 1 cells also bind to and spread on immobilized mAb 281.2, an antibody specific for the ectodomain of the syndecan-1 core protein. Spreading on the antibody is independent of the heparan sulfate glycosaminoglycan chains and can be inhibited by competition with soluble mAb 281.2. The spreading can be inhibited by treatment with cytochalasin D or colchicine. These data suggest that the core protein of syndecan-1 mediates spreading through the formation of a multimolecular signaling complex at the cell surface that signals cytoskeleton reorganization. This complex may form via intramembrane or extracellular interactions with the syndecan core protein.

Animals↗
PubMed2003

Spread supplemented with moderate doses of vitamin E and carotenoids reduces lipid peroxidation in healthy, nonsmoking adults.

BACKGROUND: High doses of vitamin E have been shown to decrease lipid peroxidation in persons under oxidative stress. At present, the data are insufficient to predict whether lower doses offer the same benefit in healthy persons. OBJECTIVE: We studied the effect of moderate doses of a combination of vitamin E and carotenoids, incorporated into a food product, on markers of antioxidant status and lipid peroxidation in healthy persons. DESIGN: One hundred five healthy adults were randomly, evenly assigned in this double-blind, placebo-controlled, parallel, 11-wk intervention study. After a 2-wk stabilization period during which the subjects consumed a commercial unfortified spread, the subjects consumed 25 g/d of spread containing 43 mg alpha-tocopherol equivalents (alpha-TE; 2-3 fold the US dietary reference intake) and 0.45 mg carotenoids (spread A), 111 mg alpha-TE and 1.24 mg carotenoids (spread B), or 1.3 mg RRR-alpha-tocopherol without carotenoids (spread C). RESULTS: In subjects consuming spread A, plasma alpha-tocopherol concentrations increased 31% to 32 micromol/L, with small but significant increases in concentrations of alpha-carotene and lutein. This resulted in LDL with significantly higher total antioxidant capacity (17%) and an increased resistance to oxidation, as determined by lag time (18%). These improvements were dose dependent: larger increases in these variables were observed in subjects consuming spread B. Furthermore, consumption of spread B significantly reduced concentrations of the plasma lipid peroxidation biomarker F(2 alpha)-isoprostane (15%). CONCLUSION: The consumption of food products containing moderate amounts of vitamin E and carotenoids can lead to measurable and significant improvements in antioxidant status and biomarkers of oxidative stress in healthy persons.

Adult↗
PubMed2002

Molecular and cytogenetic analysis of the spreading of X inactivation in X;autosome translocations.

We have performed detailed studies of the spreading of X inactivation in five unbalanced human X;autosome translocations. Using allele-specific RT-PCR we observed long-range silencing of autosomal genes located up to 45 Mb from the translocation breakpoint, directly demonstrating the ability of X inactivation to spread in cis through autosomal DNA. Spreading of gene silencing occurred in either a continuous or discontinuous fashion in different cases, suggesting that some autosomal DNA is resistant to the X inactivation signal. This spread of inactivation was accompanied by, but not dependent upon, CpG island methylation. Observations of late-replication, histone acetylation and histone methylation show that X inactivation can spread in the absence of cytogenetic features normally associated with the inactive X. However, the distribution of histone modifications which distinguish the inactive X are more accurate cytogenetic measures of the spread of X inactivation than late-replication. Overall, despite remarkable variation in the spread of X inactivation among the five cases there was good correlation between the pattern of gene silencing and the attenuation of clinical phenotype associated with each partial autosomal trisomy. We discuss our observations in the context of hypotheses which address the spread of X inactivation.

Cell Line, Transformed↗
PubMed2005

Surgical significance of superficial cancer spread in early gallbladder cancer.

BACKGROUND: A considerable percentage of gallbladder cancers are accompanied by superficial cancer spread adjacent to the main tumor, therefore cholecystectomy for early gallbladder cancer must be performed carefully to avoid leaving cancer cells at the surgical margins. METHODS: Thirty-two patients with gallbladder cancer invading no more than perimuscular connective tissue underwent surgical resection at our medical center. After the operation, resected specimens were investigated macroscopically and microscopically to clarify the clinicopathological features and the risk factors of superficial cancer spread. RESULTS: Sixty-six percent of all cases (21 cases) had superficial cancer spread. Comparison between the cases having superficial cancer spread and the cases without it revealed that the macroscopic morphology of the primary tumor and the depth of cancer invasion in the gallbladder wall were significantly different between the two groups. Furthermore, multivariate analysis indicated that 'superficial raised type' in macroscopic morphology was an independent predictive factor for having superficial cancer spread. Superficial cancer spread from the main tumor located in the neck of the gallbladder grows predominantly in the direction of the fundus. More advanced gallbladder cases were accompanied by more extensive superficial spread. CONCLUSIONS: Superficial cancer spread is frequently observed adjacent to the gallbladder cancer, especially in the superficial raised type. A negative margin should be confirmed by intraoperative frozen section histology while performing cholecystectomy.

Adult↗
PubMed2006

Transtubal spread of serous adenocarcinoma of the endometrium: an underrecognized mechanism of metastasis.

Most endometrial carcinomas metastasize by invading myometrial lymphatics and spreading to regional lymph nodes. However, uterine serous carcinomas (USCs) metastasize frequently to peritoneal surfaces even when only minimally invasive. This study examines the methods of spread and the role of retrograde transtubal spread. Eighty-seven USCs treated by hysterectomy were identified. Primary peritoneal cases and cases with significant ovarian involvement were excluded. Eighty (92%) cases were pure serous, and the remainder had at least 25% serous histology. Fifty-four of 87 (62%) had extrauterine spread at hysterectomy, most commonly to peritoneal surfaces and sometimes to the pelvic lymph nodes. Twenty-six of 54 (48%) cases had no lymphatic/vascular (LV) invasion and 18/54 (33%) had no myometrial invasion. Eleven of these 54 (20%) patients with metastases lacked both myometrial and LV invasion, and the metastases involved the peritoneal surface more often than the lymph nodes (p<0.001). Three of the 11 cases had tumor clusters in the fallopian tube lumen. Another 13 cases also had clusters of tumor within the fallopian tube lumen, and all 16 cases had peritoneal spread (p<0.001). Extrauterine spread correlated highly with LV invasion (p<0.001) but not with the presence or depth of myometrial invasion. Retrograde transtubal implantation as well LV invasion are two important mechanisms by which USC spreads; all cases with tumor clusters in the fallopian tube lumen had peritoneal spread. This explains the phenomenon whereby patients with serous carcinomas confined to the endometrium and lacking LV invasion have widespread metastases to the peritoneum.

Adenocarcinoma, Scirrhous↗
PubMed1986

Phorbol ester serves as a coepibolin in the spreading of primary guinea pig epidermal cells.

In earlier studies, it was shown that the human plasma-spreading glycoprotein, epibolin (the 65 kD species of serum-spreading factor or vitronectin), requires a second plasma component, termed coepibolin, in order to support maximal dissociated epidermal cell spreading in tissue culture. Whereas epibolin alone in defined medium supports some cell spreading, the purified plasma coepibolin preparations do not effect spreading in the absence of epibolin. Although not yet entirely purified, coepibolin associates with some plasma fractions but not with others; it is certainly not a property of all proteins, e.g., while bovine serum albumin (BSA) has coepibolin activity, ovalbumin does not. The data presented here show that the phorbol ester, 12-tetra-decanoyl-1-phorbol-13-acetate (TPA) can act as a potent coepibolin and support maximal spreading over a concentration range of 10-100 ng/ml. In the absence of epibolin TPA does not stimulate the spreading of epidermal cells when given alone or in the presence of BSA or ovalbumin. Coepibolin activity appears to associate with tumor-promoting activity in that the phorbol derivative, phorbol-12,13-didecanoate, shows coepibolin activity, while its inactive non-tumor-promoting isomer, phorbol-4 alpha-phorbol-12,13-didecanoate, does not. These data suggest that the proteinaceous plasma-derived cofactor acts in a fashion similar to TPA and that this as yet unexplained mechanism of TPA action is important to the full expression of epibolin and to the early phase of epidermal cell spreading.

Animals↗
PubMed1994

Pharmacokinetics and retrograde colonic spread of budesonide enemas in patients with distal ulcerative colitis.

METHODS: The retrograde spread of two budesonide enema formulations with different viscosities was investigated. The study design was open, randomized and two-period crossover. Three female and two male patients (age range: 35-45 years) with distal ulcerative colitis or proctitis participated. Both enema formulations contained a dose of 2 mg budesonide/100 mL. An unabsorbable radioactive marker (99mTc-labelled human serum albumin microcolloid) was added to the enema just before administration. All doses were given in the evening with the patients lying in a supine position during the whole investigation. The intestinal spread was followed for 8 h using scintigraphic imaging. Plasma samples for budesonide assay were taken during the 12 h after administration of the low viscosity enema. RESULTS: Budesonide plasma levels were measurable for up to 4-6 h. Cmax was 2.5 nmol/L (range: 0.9-4.5 nmol/L) and was attained in 1.5 h (range 1-3 h). The patients had no difficulty in retaining the enemas. There was a statistically significant difference in spread between the low and high viscosity enema. The low viscosity enema spread over an area situated between the rectum and the splenic flexure. The spread occurred mainly in the first 15 min after administration. In contrast, the high viscosity enema, in most cases, spread only over a minor part of this area and the rate and extent of spreading was also more variable with this formulation. CONCLUSION: The spread of a low viscosity enema appears to be well suited for the treatment of proctitis and distal colitis.

Administration, Topical↗
PubMed1995

Epileptiform activity in the guinea-pig neocortical slice spreads preferentially along supragranular layers--recordings with voltage-sensitive dyes.

The spread of epileptiform activity was monitored in guinea-pig neocortical slices by the use of a voltage-sensitive dye (RH795) and a fast optical recording technique. Epileptiform activity induced by bicuculline methiodide (10-20 microM) and single-pulse stimulation spread from the stimulation site in layer I or in the white matter across most of the slice. Different lesions were made in the slice in order to specify the neuronal connections used for spread in the horizontal direction. In the slice, intracortical connections are necessary for the spread of epileptiform activity, as shown by vertical cuts through all cortical layers but sparing the white matter. Horizontal connections were interrupted by cuts parallel to the axis of pyramidal neurons through either supragranular or infragranular layers. Vertical connections were interrupted by cuts perpendicular to the axis of pyramidal neurons separating supragranular and infragranular layers. Spread of epileptiform activity in the horizontal direction was not hindered by horizontal cuts. Vertical cuts through infragranular layers also did not hinder the spread of epileptiform activity. In contrast, vertical cuts through supragranular layers either abolished completely (nine slices) or delayed significantly (ten slices) the spread of epileptiform activity. The mean delay at the supragranular lesion was 44 ms in layer III and 30 ms in layer V; at the infragranular lesion the mean delay was 2 ms in layer III and 6 ms in layer V. Also, with horizontal cuts, in three out of five slices the velocity of spread was significantly lower in infragranular as compared to supragranular layers. It is concluded that both supra- and infragranular layers if isolated possess the ability to initiate and propagate epileptiform activity independently. However, in the intact slice the influence of the supragranular networks on initiation and propagation of epileptiform activity appears to dominate.

Animals↗
PubMed2004

Patterns of detection of superficial spreading and nodular-type melanoma: a multicenter Italian study.

BACKGROUND: Nodular histotype represents the condition that is mostly associated with diagnosis of thick melanoma. OBJECTIVE: The objectives were to evaluate variables associated with and pattern of detection of nodular melanomas and to investigate variables associated with early diagnosis in accordance with histotype (nodular vs. superficial spreading melanomas). METHODS: From the original data set of 816 melanomas, all the invasive lesions classified as superficial spreading (n=500) and nodular (n=93) melanomas were considered for the study. A multivariate logistic analysis was performed. Results. Nodular melanomas did not significantly differ from superficial spreading melanomas regarding sex, anatomic site, number of whole-body nevi, and the presence of atypical nevi. As expected, nodular melanomas were represented by a higher percentage of thick (>2 mm) lesions compared to superficial spreading melanomas (64.5% vs. 9.6%, p<0.001). The pattern of detection significantly differed between nodular and superficial spreading melanomas, the former being more frequently self-detected (44.1% vs. 38.0%) or detected by the family doctor (34.4% vs. 11.4%). Female sex, high level of education, and detection made by a dermatologist had an independent, protective effect against late (>1 mm in thickness) diagnosis in superficial spreading melanomas. No protective variable associated with nodular melanomas was found. CONCLUSION: Patterns of detection for nodular melanomas significantly differ from those for superficial spreading melanomas. For superficial spreading, but not for nodular, melanomas, variables associated with protective effect against late diagnosis can be identified.

Adult↗
PubMed1995

Neuropeptide gene expression and capsaicin-sensitive primary afferents: maintenance and spread of adjuvant arthritis in the rat.

1. Many experimental and clinical arthritides are characterized by their bilateral nature. There is strong evidence to suggest that this bilateral spread may be mediated by a neuronal mechanism. We have previously shown early and sustained induction of mRNAs encoding preprotachykinin (PPT) and calcitonin gene-related peptide (CGRP) in dorsal root ganglion (DRG) neurons innervating an inflamed, arthritic joint. We have now investigated the involvement of capsaicin-sensitive primary afferents and the expression of neuropeptide mRNAs in the maintenance and bilateral spread of mild adjuvant-induced arthritis in the rat. 2. Capsaicin was applied perineurally to either the left (Cap-L) or right (Cap-R) sciatic nerve of halothane-anaesthetized male Han Wistar rats. Two weeks after capsaicin lesioning, arthritis was induced by injection of Freund's complete adjuvant (FCA) around the left ankle at a dose that caused inflammation of the left ankle joint, and a delayed (14 days) contralateral (right) ankle arthritis. Arthritis was monitored for 15 days after injection, when animals were killed and the lumbar DRG dissected. PPT, CGRP, somatostatin (SS), and vasoactive intestinal polypeptide (VIP) mRNA expression was determined in L5 DRG using in situ hybridization. 3. Spread of inflammation/arthritis to the right limb was associated with bilateral rises in PPT and CGRP mRNA expression in L5 DRG. SS mRNA expression in right DRG was unaffected by spread of inflammation. FCA-L+Cap-L reduced left joint swelling and prevented spread of arthritis to the right joint when assessed by joint swelling. This inhibition of spread of arthritis was associated with significant reductions in all left L5 DRG neuropeptide mRNAs compared with controls, and the rise in right L5 DRG PPT mRNA expression seen in FCA-L-alone animals was blocked. FCA-L+Cap-R also reduced left joint swelling and prevented the spread of inflammation to the right ankle. This lesion prevented the rise in PPT and CGRP mRNA expression seen in right DRG with FCA-L alone. 4. These findings suggest a role for capsaicin-sensitive primary afferents and the primary afferent neuropeptides encoded by PPT and CGRP mRNA in the maintenance and spread of arthritis.

Animals↗
PubMed2003

Herpes simplex virus gE/gI expressed in epithelial cells interferes with cell-to-cell spread.

The herpes simplex virus (HSV) glycoprotein heterodimer gE/gI plays an important role in virus cell-to-cell spread in epithelial and neuronal tissues. In an analogous fashion, gE/gI promotes virus spread between certain cell types in culture, e.g., keratinocytes and epithelial cells, cells that are polarized or that form extensive cell junctions. One mechanism by which gE/gI facilitates cell-to-cell spread involves selective sorting of nascent virions to cell junctions, a process that requires the cytoplasmic domain of gE. However, the large extracellular domains of gE/gI also appear to be involved in cell-to-cell spread. Here, we show that coexpression of a truncated form of gE and gI in a human keratinocyte line, HaCaT cells, decreased the spread of HSV between cells. This truncated gE/gI was found extensively at cell junctions. Expression of wild-type gE/gI that accumulates at intracellular sites, in the trans-Golgi network, did not reduce cell-to-cell spread. There was no obvious reduction in production of infectious HSV in cells expressing gE/gI, and virus particles accumulated at cell junctions, not at intracellular sites. Expression of HSV gD, which is known to bind virus receptors, also blocked cell-to-cell spread. Therefore, like gD, gE/gI appears to be able to interact with cellular components of cell junctions, gE/gI receptors which can promote HSV cell-to-cell spread.

Adenoviruses, Human↗
PubMed1999

Risk factors for spread of primary adult onset blepharospasm: a multicentre investigation of the Italian movement disorders study group.

OBJECTIVES: Little is known about factors influencing the spread of blepharospasm to other body parts. An investigation was carried out to deterrmine whether demographic features (sex, age at blepharospasm onset), putative risk, or protective factors for blepharospasm (family history of dystonia or tremor, previous head or face trauma with loss of consciousness, ocular diseases, and cigarette smoking), age related diseases (diabetes, hypertension), edentulousness, and neck or trunk trauma preceding the onset of blepharospasm could distinguish patients with blepharospasm who had spread of dystonia from those who did not. METHODS: 159 outpatients presenting initially with blepharospasm were selected in 16 Italian Institutions. There were 104 patients with focal blepharospasm (mean duration of disease 5.3 (SD 1.9) years) and 55 patients in whom segmental or multifocal dystonia developed (mainly in the cranial cervical area) 1.5 (1.2) years after the onset of blepharospasm. Information was obtained from a standardised questionnaire administered by medical interviewers. A Cox regression model was used to examine the relation between the investigated variables and spread. RESULTS: Previous head or face trauma with loss of consciousness, age at the onset of blepharospasm, and female sex were independently associated with an increased risk of spread. A significant association was not found between spread of dystonia and previous ocular diseases, hypertension, diabetes, neck or trunk trauma, edentulousness, cigarette smoking, and family history of dystonia or tremor. An unsatisfactory study power negatively influenced the validity and accuracy of the negative findings relative to diabetes, neck or trunk trauma, and cigarette smoking. CONCLUSIONS: The results of this exploratory study confirm that patients presenting initially with blepharospasm are most likely to experience some spread of dystonia within a few years of the onset of blepharospasm and suggest that head or face trauma with loss of consciousness preceding the onset, age at onset, and female sex may be relevant to spread. The suggested association between edentulousness and cranial cervical dystonia may be apparent because of the confounding effect of both age at onset and head or face trauma with loss of consciousness. The lack of influence of family history of dystonia on spread is consistent with previous findings indicating that the inheritance pattern is the same for focal and segmental blepharospasm.

Age of Onset↗
PubMed2000

Multielectrode evidence for spreading activity across the superior colliculus movement map.

The monkey superior colliculus (SC) has maps for both visual input and movement output in the superficial and intermediate layers, respectively, and activity on these maps is generally related to visual stimuli only in one part of the visual field and/or to a restricted range of saccadic eye movements to those stimuli. For some neurons within these maps, however, activity has been reported to spread from the caudal SC to the rostral SC during the course of a saccade. This spread of activity was inferred from averages of recordings at different sites on the SC movement map during saccades of different amplitudes and even in different monkeys. In the present experiments, SC activity was recorded simultaneously in pairs of neurons to observe the spread of activity during individual saccades. Two electrodes were positioned along the rostral-caudal axis of the SC with one being more caudal than the other, and 60 neuron pairs whose movement fields were large enough to see a spread of activity were studied. During individual saccades, the relative time of discharge of the two neurons was compared using 1) the time difference between peak discharge of the two neurons, 2) the difference between the "median activation time" of the two neurons, and 3) the shift required to align the two discharge patterns using cross-correlation. All three analysis methods gave comparable results. Many pairs of neurons were activated in sequence during saccade generation, and the order of activation was most frequently caudal to rostral. Such a sequence of activation was not observed in every neuron pair, but over the sample of neuron pairs studied, the spread was statistically significant. When we compared the time of neuronal activity to the time of saccade onset, we found that the caudal neuronal activity was more likely to be before the saccade, whereas the rostral neuronal activity was more likely to be during the saccade. These results demonstrate that when individual pairs of neurons are examined during single saccades there is evidence of a caudal to rostral spread of activity within the monkey SC, and they confirm the previous inferences of a spread of activity drawn from observations on averaged neuronal activity during multiple saccades. The functional contribution of this spread of activity remains to be determined.

Animals↗
PubMed1992

Endothelial cell spreading on fibrin requires fibrinopeptide B cleavage and amino acid residues 15-42 of the beta chain.

Adhesion and spreading of cultured human umbilical vein endothelial cells on fibrin surfaces of varying structure were characterized to understand better the interactions occurring between endothelium and fibrin at sites of vascular injury. Fibrin prepared with reptilase, which cleaves only fibrinopeptide A from fibrinogen, and fibrin prepared with thrombin, which cleaves both fibrinopeptide A and fibrinopeptide B, equally supported endothelial cell adhesion. In contrast, only fibrin made with thrombin mediated endothelial cell spreading, as assessed by fluorescence microscopy of cells stained with rhodamine phalloidin to identify actin stress fibers or by scanning electron microscopy. Fibrin prepared with reptilase failed to support cell spreading. To further investigate the role of the amino terminus of the fibrin beta chain after fibrinopeptide B cleavage in promoting cell spreading, protease III from Crotalus atrox venom was used to specifically cleave the amino-terminal 42 residues of the fibrinogen B beta chain. After clotting with thrombin, this fibrin derivative lacking B beta 1-42 failed to support significant cell spreading. Spreading on fibrin was unaffected by depletion of Weibel-Palade bodies from endothelial cells, indicating that the spreading was independent of stimulated von Willebrand factor release. We conclude that endothelial cell spreading on fibrin requires fibrinopeptide B cleavage and involves residues 15-42 of the fibrin beta chain.

Batroxobin↗
PubMed1987

A major difference between serum and fibronectin in the divalent cation requirement for adhesion and spreading of BHK21 cells.

Adhesion and spreading of BHK21 cells on adsorbed bovine and foetal bovine serum require addition to the medium of a divalent cation. Divalent cations are effective in the order Mn2+ greater than Co2+ greater than Mg2+ greater than Ca2+, with Ca2+ ineffective below 10(-4)M. On purified fibronectin, however, no added divalent cation is required, since the requirement is largely met by adventitious Ca2+ (circa 10(-5)M) in nominally divalent cation-free saline. In such background Ca2+, adhesion and spreading on fibronectin are only slightly slower than in optimal Mg2+, and appear identical, morphologically, and in sensitivity to cytochalasin D. Cells also spread on fibronectin in response to Mg2+, when Ca2+ is buffered below 10(-6)M, showing that external Ca2+ is not needed as a source for an increase in internal Ca2+. Cells can be induced to spread on serum in low Ca2+ by substantially increasing the fibronectin concentration; this supports other evidence that at its unsupplemented concentration, fibronectin contributes little to the spreading of these cells on serum. The Ca2+ requirement for spreading on preparations of vitronectin (serum spreading factor), partially purified from bovine serum, is similar to that on whole serum. Thus the difference in divalent cation requirement between serum and fibronectin may arise because, on serum, the dominant protein responsible for induction of spreading is vitronectin rather than fibronectin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

The spread: pilot study of an undocumented source of pharmacy benefit manager revenue.

OBJECTIVE: To document the difference between what pharmacy benefits management companies (PBMs) charge employers and what they pay dispensing pharmacies for the drug ingredient portion of prescription transactions (the "spre DESIGN: Descriptive, cross-sectional study. PARTICIPANTS: Two large employer groups, each of which used a different PBM, and six independent community pharmacies participating in these plans during 2002. INTERVENTIONS: Two sets of financial records issued by each of two PBMs were reviewed retrospectively, including 129 line-item prescription transactions billed to the employer and the line-item transaction information that accompanies the PBM payment to the dispensing pharmacy. MAIN OUTCOME MEASURE: Spread between drug ingredient cost billed to the employer by the PBM and drug ingredient cost paid to the dispensing pharmacy by the PBM for brand name versus generic drug products. RESULTS: For both PBMs, the mean (+/- SD) spread was dollar 12.29 +/- 27.93 per prescription, with a range of -dollar 1.67 to dollar 201.65. Considering all 129 transactions, the mean spreads for brand name and generic medications were significantly different from one another, with mean (+/- SD) spreads of dollar 4.65 +/- 10.47 and dollar 23.45 +/- 39.47 per prescription, respectively. The two PBMs differed significantly in their spreads for brand name drugs (dollar 3.20 +/- 2.85 and dollar 5.93 +/- 14.12), but the spreads for generic products did not achieve statistical significance in absolute dollars (dollar 10.83 +/- 13.58 and dollar 31.74 +/- 48.11) because of their greater variation (as reflected in the larger standard deviations). However, the percentages difference for generic products differed significantly. CONCLUSION: This pilot study indicates the possibility of substantial and widely varying differences in the spread and spread percentage between PBMs for brand name and generic medications. A more transparent business model for the PBM industry could produce better relations with PBM clients and business partners, including community pharmacies.

Contracts↗
PubMed1998

Colony stimulating factor-1-induced osteoclast spreading depends on substrate and requires the vitronectin receptor and the c-src proto-oncogene.

The colony stimulating factor 1 (CSF-1) regulates osteoclastogenesis and bone resorption. Mutations in the CSF-1 gene cause an osteopetrosis characterized by the absence of osteoclasts. Mature osteoclasts respond to CSF-1 with inhibition of bone resorption and an increment of cell spreading. Herein we demonstrate that CSF-1-induced osteoclast spreading depends on the substrate the osteoclast interacts with and requires integrity of the vitronectin receptor and of the c-src proto-oncogene. Rabbit osteoclasts were allowed to attach to glass, serum, osteopontin, and bone substrates, and were treated with 10 ng/ml human recombinant CSF-1 for 4 h. In osteoclasts plated on glass, the cytokine induced 70% inhibition of bone resorption and 1.8-fold stimulation of cell spreading, without changes in podosome expression and microfilament array. In contrast, CSF-1 induced a 2.5-fold increase of osteoclasts showing filopodia, and a 9.5-fold increase of osteoclasts presenting lamellipodia, indicating that membrane motility was required for cell spreading. Osteoclasts plated on serum substrates showed a 50% reduction of spontaneous spreading. However, in this circumstance, CSF-1 still stimulated an increase of osteoclast area. In osteoclasts cultured on osteopontin substrate or on bone slices, an inhibition of CSF-1-induced osteoclast spreading was observed. To establish involvement of the vitronectin receptor and c-src proto-oncogene, cells were treated with the alpha vbeta3 integrin neutralizing antibody, LM609, or c-src antisense oligonucleotides, which reduced CSF-1-induced osteoclast spreading by 57% and 60%, respectively. The results demonstrate that CSF-1-induced osteoclast spreading requires both the vitronectin receptor and the c-src proto-oncogene and that this action is modulated by the adhesion substrata.

Actin Cytoskeleton↗