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PubMed1991

Experimental examination of factors that affect dust generation.

A method is presented to examine factors that affect the amount and size distribution of dust generated by falling granular material in still air. This work was conducted by using an apparatus with separate dust generating and dust measuring sections. The dust generated by a falling material was carried into an elutriation column equipped with a slotted Sierra high-volume impactor at the top. This apparatus can measure dust generation rates for particles between 0.4 and 25 microns in aerodynamic diameter as well as the amount of air entrained by the falling material. Four granular materials were tested, and a simple model was developed to describe the dust generation rate of these materials as a function of particle size, drop height, material flow, and moisture content. Moisture content strongly influenced the interparticle binding forces and the amount of dust generated. Drop height and material flow influenced the material separation forces and also significantly influenced the amount of dust generated.

Air Pollutants↗
PubMed1992

An investigation of dust generation by free falling powders.

To identify the dust generation processes, aluminum oxide powder was dropped as a free falling slug in a test chamber. The effect of the slug's mass, diameter, and drop height upon the aerosol concentration and size distribution was measured with an aerodynamic particle sizer. To differentiate between aerosol generated during the free fall and at the end of the fall, the slug was dropped either onto a flat surface or into a container of water that suppressed dust generation associated with the impact at the end of the fall. Aerosol generation occurred during the slug's free fall as well as at the end of the fall. The falling solid induced an airflow that followed the falling solid to the end of the fall. This induced airflow contained the aerosol generated during the free fall. At the end of the free fall, the induced airflow, combined with air jets created on impact, dispersed the aerosol throughout the test chamber. Additional measurements were made by using "neutral buoyancy" helium-filled bubbles to visualize the airflow in the test chamber. The airflow and ensuing turbulence were sufficient to keep large, inspirable particles suspended throughout the test chamber for periods greater than 10 min. During experimental work, the effect of drop height, mass, and slug diameter upon aerosol generation by a single slug of powder was studied. The results indicated that the manner in which a powder is handled may be as important as material dustiness as measured by a dustiness tester. Aerosol generation can be reduced by minimizing the contact between the falling powder and the air.

Aerosols↗
PubMed1978

H-2-restricted cytotoxic effectors generated in vitro by the addition of trinitrophenyl-conjugated soluble proteins.

Murine spleen cells from normal donors were cultured in vitro with trinitrobenzene sulfonate (TNBS)-conjugated soluble proteins, i.e., bovine gamma globulin (TNP-BGG) or bovine serum albumin (TNP-BSA). Addition of 100 mug of any of these TNP-proteins to the spleen cell cultures led to the generation of cytotoxic T-cell effectors which were H-2-restricted and TNP- specific. The lytic potential of such effectors was comparable to that generated by sensitization with TNBS-modified syngeneic cells, and was restricted to haplotypes shared at the K or K plus I-A, or the D regions of the H-2 complex. Greater effecter cell activity was generated by addition of TNP-BGG against TNBS-modified targets which shared K plus I-A than against modified targets which shared the D region with the responding cells, which suggests that the same immune response genes are involved when the response is generated by the addition of TNP-conjugated soluble proteins or of TNBS- modified cells. H-2-restricted, TNP-specific effecter cells were generated by culturing mouse spleen cells with syngeneic cells which had been preincubated with TNP- BGG or TNP-BSA for 1.5 h. The addition of unconjugated soluble proteins to the cultures did not result in cytotoxic effectors detectable on H-2-matched targets, whether the targets were prepared by modification with TNBS, or by incubation with either the unconjugated or TNP-conjugated proteins. Depletion of phagocytic cells in the tumor preparation by Sephadex G-10 column fractionation before incubation with TNP-BSA had no effect on their lysis by the relevant effector cells. Immunofluorescent staining of tumor target cells with anti-TNP antibodies indicated that TNP could be detected on the tumor cells within 10 rain of incubation with TNP-BSA. The cytotoxic response generated by addition of the TNP-proteins to spleen cell cultures was found to be T-cell dependent at the effector phase, as shown by the sensitivity of the lytic phase to absorbed RAMB and complement. Furthermore, the response did not appear to be attributable to antibody-dependent cellular cytotoxicity. Three mechanisms were considered which could account for the generation of H-2-restricted, TNP-specific, cytotoxic T-cell effectors by the addition of soluble TNP-proteins. These include covalent linkage of activated TNP groups from the soluble proteins to cell surface components, macrophage processing of the soluble conjugates and presentation to the responding lymphocytes in association with H-2-coded self structures, or hydrophobic interaction of the TNP-proteins to cell surfaces. Results obtained from sodium dodecyl sulfate gel patterns indicating that cell-bound TNP was still linked to BSA, and the observation that phagocytic-depleted cells could interact with the soluble TNP-proteins and function as H-2-restricted targets, appear not to favor the first two proposed mechanisms.

Animals↗
PubMed1982

Helper activity is required for the in vivo generation of cytotoxic T lymphocytes.

B6.T1a(a) (Qa-1(a)) mice that are primed in vivo and restimulated in vitro with Qa-1 congenic spleen cells from B6 (Qa-1(b)) animals are unable to generate anti-Qa-1(b) cytotoxic T lymphocytes (CTL). This nonresponsive pattern was observed regardless of the route of immunization or the time of testing in vitro. Although B6.T1a(a) mice are nonresponders to Qa-1(b) when presented on B6 cells, these mice can generate anti-Qa-1(b) CTL when primed in vivo with Qa-1 and H-Y alloantigens (females primed with B6 male cells) or Qa-1 and minor-H- alloantigens (primed with sex-matched A.BY cells). Therefore, the inability to generate anti-Qa-1(b) CTL is due to a lack of helper or accessory antigens on B6 immunizing cells obligatory during in vivo priming, rather than an absence of anti-Qa-1(b) CTL precursors (CTL-P). Demonstration that the additional determinants required during in vivo priming actually function as carrier or helper determinants was shown by the requirement for linked recognition of Qa-1 and the helper determinants (H-Y) in vivo, and the fact that H-Y was not present on susceptible target ceils. Animals primed in vivo with H-Y only could not generate anti-Qa-1 CTL activity when challenged in vitro with both Qa-1 and H-Y, indicating that recognition of the helper determinant causes in vivo priming of CTL-P rather than generating helper activity that might activate unprimed CTL-P in vitro. Whereas unprimed peripheral CTL-P require the presence of both Qa-1 (CTL) and H-Y (helper) determinants for successful in vivo priming, helper determinants were not required in vitro because primed CTL-P from B6.T1a(a) mice could be driven to CTL in vitro using sex-matched B6 stimulator cells. The generation of anti-Qa-1(b) CTL is under immune response (Ir) gene control because F(1) mice, obtained by crossing responder A/J with nonresponder B6.T1a(a) animals, generated CTL to the Qa-1(b) alloantigen when presented on B6 spleen cells. Progeny testing of backcross mice further demonstrated that the Ir gene(s) is linked to the H-2 complex. These data indicate that an H-2-linked Ir gene controls the recognition of helper determinants required for CTL priming in vivo. These helper determinants can be distinguished from CTL determinants and both must be recognized together for successful priming of CTL-P.

Animals↗
PubMed1994

Generation of polarized antigen-specific CD8 effector populations: reciprocal action of interleukin (IL)-4 and IL-12 in promoting type 2 versus type 1 cytokine profiles.

We have generated primary effector populations from naive CD8 T cells in response to antigen and determined their patterns of cytokine secretion upon restimulation. The effect of exogenous factors on the effector generation was examined and compared with responses of antigen-specific CD4 effectors generated under comparable conditions. CD8 cells from bm1 mice were stimulated with C57BL/6 (B6) antigen presenting cells (APCs) bearing allogeneic class I and CD8 cells from female severe combined immunodeficiency (SCID) B6 mice, transgenic for a T cell receptor alpha/beta (TCR-alpha/beta) that recognizes H-Y on Db, were stimulated with APCs from male mice. In parallel, CD4 cells from bm12 mice were stimulated with alloantigen and CD4 cells from V beta 3/V alpha 11 TCR transgenics were stimulated with a peptide of pigeon cytochrome c on IEk. T cells from both transgenic mice were of naive phenotype whereas normal mice contained 10-20% memory cells. Effector CD8 populations generated were L-selectin low, CD45RB high, and CD44 high. Naive CD8 cells from SCID anti-H-Y mice made little or no cytokine immediately upon stimulation in contrast to naive CD4 which produced large amounts of interleukin 2 (IL-2). Both populations, however, generated primary effectors over 4-5 d that made substantial quantities of many cytokines upon restimulation. Both CD8 and CD4 effectors produced similar patterns of cytokines with alloantigen or specific antigen. Cytokines present during naive CD8 stimulation influenced the cytokine secretion profile of the effectors, as previously shown for CD4 cells, although secretion by CD8 effectors was generally lower than that of CD4 effectors. CD8 cells cultured with IL-2 alone made predominantly interferon gamma (IFN-gamma) and no IL-4 or IL-5, similar to CD4 cells. Priming with IFN-gamma increased IFN-gamma secretion from CD4 effectors, but had little if any effect on CD8 cells. In contrast, priming with IL-12 generated CD8 effectors, as well as CD4 effectors, producing elevated quantities of IFN-gamma, with similar levels from both the CD4 and CD8 populations. The presence of IL-4 during effector cell generation promoted synthesis of IL-4 and IL-5 from both CD8 and CD4 cells while downregulating IFN-gamma secretion. CD8 cells made only small amounts of IL-4, more than 100-fold less than CD4 cells, whereas significant levels of IL-5 were induced, only 3-10-fold lower than from CD4.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2001

Variant effect of first- and second-generation antihistamines as clues to their mechanism of action on the sneeze reflex in the common cold.

Treatment with first-generation antihistamines reduces sneezing, rhinorrhea, nasal mucus weight, and, in some instances, cough in subjects with experimental or natural colds; however, treatment with second-generation antihistamines has not been effective for these complaints in trials in subjects with natural colds. This article reports the negative results of a clinical trial with loratadine, a second-generation antihistamine, in adults in the rhinovirus challenge model. This finding in the highly controlled setting of the challenge model confirms the earlier negative studies with second-generation antihistamines in natural colds. First-generation antihistamines block both histaminic and muscarinic receptors as well as passing the blood-brain barrier. Second-generation antihistamines mainly block histaminic receptors and do not pass the blood-brain barrier. The effectiveness of first-generation antihistamines in blocking sneezing in colds may be due primarily to neuropharmacological manipulation of histaminic and muscarinic receptors in the medulla.

Adult↗
PubMed2004

Evaluation of hematopoietic potential generated by transplantation of muscle-derived stem cells in mice.

Muscle tissue of adult mice has been shown to contain stem cells with hematopoietic repopulation ability in vivo. To determine the functional characteristics of stem cells giving rise to this hematopoietic activity, we have performed hematopoietic reconstitution experiments by the use of muscle versus marrow transplantation in lethally irradiated mice and followed the fate of transplanted cells by Y-chimerism using PCR and fluorescence in situ hybridization (FISH) analysis. We report here that transplantation of murine muscle generate a major hematopoietic chimerism at the level of CFU-C, CFU-S, and terminally-differentiated cells in three generations of lethally irradiated mice followed up to 1 year after transplantation. This potential is totally abolished when muscle grafts were performed by the use of muscle from previously irradiated mice. As compared to marrow transplantation, muscle transplants were able to generate similar potencies to give rise to myeloid, T, B, and natural killer (NK) cells. Interestingly, marrow stem cells that have been generated in primary and then in secondary recipients were able to contribute efficiently to myofibers in the muscle tissue of tertiary recipients. Altogether, our data demonstrate that muscle-derived stem cells present a major hematopoietic repopulating ability with evidence of self-replication in vivo. They are radiation-sensitive and similar to marrow-derived stem cells in terms of their ability to generate multilineage hematopoiesis. Finally, our data demonstrate that muscle-derived hematopoietic stem cells do not lose their ability to contribute to myofiber generation after at least two rounds of serial transplantation, suggesting a potential that is probably equivalent to that generated by marrow transplantation.

Animals↗
PubMed1995

Evaluation of third-generation hepatitis C antibody assay in chronic hepatitis C and chronic non-B, non-C hepatitis.

Second-generation hepatitis C virus (HCV) antibody assays are more sensitive and specific than first-generation assays in the detection of HCV infection; such tests are widely used. However, there are still HCV-infected patients who test seronegative for anti-HCV even by second-generation assays. In this study we evaluated the performance of the new third-generation HCV assay (HCV 3.0) in 230 individuals with different second-generation anti-HCV (HCV 2.0) and HCV RNA patterns. Our results showed the followings: only one healthy adult had a discrepant result in 200 subjects negative (group I) or positive (group II) for HCV 2.0 and HCV RNA; 7 of 13 (54%) HCV 2.0-negative but HCV RNA-positive patients (group III) were HCV 3.0-positive; two of 17 (12%) so-called chronic non-B, non-C hepatitis patients (group IV) were positive for HCV 3.0. We conclude that third-generation anti-HCV assays are more sensitive and specific than second-generation assays in the detection of chronic HCV infection; however false-positive results may be observed among low-risk healthy persons.

Adult↗
PubMed2002

Both lipid and protein intakes stimulate increased generation of reactive oxygen species by polymorphonuclear leukocytes and mononuclear cells.

BACKGROUND: It was recently shown that glucose challenge leads to increased generation of reactive oxygen species (ROS) by polymorphonuclear leukocytes (PMNs) and mononuclear cells (MNCs). OBJECTIVE: To further elucidate the relation between nutrition and ROS generation, we investigated the effect of lipid and protein challenges on ROS generation by leukocytes. DESIGN: After having fasted overnight, one group of healthy subjects consumed a carbohydrate- and protein-free cream preparation (1257 kJ) and another group of healthy subjects consumed an equienergetic pure preparation of casein. Sequential blood samples were obtained after the intake of cream and casein. ROS were measured by chemiluminescence after stimulation by N-formyl-methionyl-leucinyl-phenylalanine. Lipid peroxidation was measured as thiobarbituric acid-reactive substances (TBARS) and alpha-tocopherol was measured by HPLC. RESULTS: ROS generation by MNCs and PMNs increased significantly 1, 2, and 3 h after cream intake and 1 h after protein intake. Cholesterol concentrations did not change significantly, whereas triacylglycerol concentrations increased significantly 2 h after cream intake. Total TBARS concentrations increased 1 h after cream intake and remained elevated 3 h after intake, but the increase was not significant when corrected for changes in triacylglycerol. After casein intake, total cholesterol, triacylglycerol, and TBARS concentrations did not change significantly. alpha-Tocopherol concentrations did not change significantly after either cream or casein intake. CONCLUSIONS: Both fat and protein intakes stimulate ROS generation. The increase in ROS generation lasted 3 h after cream intake and 1 h after protein intake. Cream intake also caused a significant and prolonged increase in lipid peroxidation. These data are important because increased ROS generation and lipid peroxidation are key events in atherogenesis.

Aged↗
PubMed2005

Helicobacter pylori infection in different generations of Hispanics in the San Francisco Bay Area.

To quantify the contributions of household and environmental factors to Helicobacter pylori infection, the authors examined H. pylori infection among several generations of Hispanics in the San Francisco Bay Area. Between 2000 and 2004, household members were tested for H. pylori and interviewed about demographic factors and household pedigree. An immigrant was defined as someone born in Latin America with at least one Latin America-born parent; a first-generation US-born Hispanic was defined as someone born in the United States with at least one Latin America-born parent; and a second-generation US-born Hispanic was defined as someone born in the United States with at least one US-born parent. Prevalences of H. pylori in immigrants and first- and second-generation US-born Hispanics were 31.4% (102/325), 9.1% (98/1,076), and 3.1% (2/64), respectively. Compared with second-generation US-born Hispanics, the age-adjusted odds ratios for H. pylori were 9.70 (95% confidence interval (CI): 1.57, 60.00) for immigrants and 4.32 (95% CI: 0.69, 26.96) for first-generation US-born Hispanics (p(trend) < 0.001). These odds ratios decreased to 6.19 (95% CI: 1.13, 33.77) and 3.24 (95% CI: 0.59, 17.82), respectively, after adjustment for parental infection (odds ratio (OR) = 2.94, 95% CI: 1.59, 4.38), low education (OR = 1.76, 95% CI: 1.20, 2.68), and crowding (OR = 1.23, 95% CI: 0.84, 1.79). Both the household and birth-country environments probably contributed to declining H. pylori prevalence among successive generations of Hispanics.

Adult↗
PubMed1998

The effects of transcranial magnetic stimulation over the dorsolateral prefrontal cortex on suppression of habitual counting during random number generation.

Random number generation is an attention-demanding task that engages working memory and executive processes. Random number generation requires holding information 'on line', suppression of habitual counting, internally driven response generation and monitoring of responses. Evidence from PET studies suggests that the dorsolateral prefrontal cortex (DLPFC) is involved in the generation of random responses. We examined the effects of short trains of transcranial magnetic stimulation (TMS) over the left or right DLPFC or medial frontal cortex on random number generation in healthy normal participants. As in previous evidence, in control trials without stimulation participants performed poorly on the random number generation task, showing repetition avoidance and a tendency to count. Brief disruption of processing with TMS over the left DLPFC changed the balance of the individuals' counting bias, increasing the most habitual counting in ones and reducing the lower probability response of counting in twos. This differential effect of TMS over the left DLPFC on the balance of the subject's counting bias was not obtained with TMS over the right DLPFC or the medial frontal cortex. The results suggest that, with disruption of the left DLPFC with TMS, habitual counting in ones that has previously been suppressed is released from inhibition. From these findings a network modulation model of random number generation is proposed, whereby suppression of habitual responses is achieved through the modulatory influence of the left DLPFC over a number-associative network in the superior temporal cortex. To allow emergence of appropriate random responses, the left DLPFC inhibits the superior temporal cortex to prevent spreading activation and habitual counting in ones.

Adult↗
PubMed1999

Interference with the development of early generated neocortex results in disruption of radial glia and abnormal formation of neocortical layers.

Early generated layers of neocortex are important factors in forming the subsequent architecture of the cerebral cortex. To further explore the role of early generated cortex, we disrupted formation of an early generated cohort of cells by intraperitoneal injections of the mitotic inhibitor methylazoxymethanol (MAM) into pregnant ferrets timed to coincide with generation of subplate neurons in the ventricular zone. Our studies demonstrate that if early development of the neocortex is interrupted by injection of MAM during embryogenesis (on embryonic day 24 or 28; E24 or E28), a distinct laminar pattern fails to form properly in the parietal cortex. A reduced number of MAP2-positive cells were observed in the region of the subplate when compared with the number of MAP2-positive cells found in normal animals. Interference with the superficial neocortical layers that form later during development (on embryonic day 33) by appropriately timed MAM injections does not result in a severely disrupted laminar pattern. The interrupted laminar pattern that arises after early MAM injections coincides with distorted radial glial cells (identified by immunoreactivity to the intermediate filament protein, vimentin), which occur after early, but not late, MAM injections. Further analysis suggests that interference with early development of neocortex leads to premature differentiation of radial glial cells into astrocytes, as demonstrated by the presence of glial fibrillary acidic protein (GFAP). Experiments involving injections of the thymidine analog, bromodeoxyuridine (BRDU), demonstrated that 4 days after E24 MAM injection cells are generated and migrate into the thin cortical plate. By E38, however, cells continue to be generated in animals treated with MAM on E24 but do not reach their normal positions in the cortical plate. In addition, immunoreactivity using the CR50 antibody, which identifies presumptive Cajal-Retzius cells present in layer 1, demonstrates that the CR50-positive cells, normally precisely located in the outer portion of layer 1, are distributed in disarray throughout the thickness of the neocortex and intermediate zone in early MAM-treated animals, but not in those treated with MAM injections later during gestation. These findings are consistent with the idea that early generated layers are important in providing factors that maintain the environment necessary for subsequent neuronal migration and formation of neocortical layers.

Animals↗
PubMed2006

The effect of age at immigration and generational status of the mother on infant mortality in ethnic minority populations in The Netherlands.

BACKGROUND: Migrant populations consist of migrants with differences in generational status and length of residence. Several studies suggest that health outcomes differ by generational status and duration of residence. We examined the association of generational status and age at immigration of the mother with infant mortality in migrant populations in The Netherlands. METHODS: Data from Statistics Netherlands were obtained from 1995 through 2000 for infants of mothers with Dutch, Turkish and Surinamese ethnicity. Mothers were categorized by generational status (Dutch-born and foreign-born) and by age at immigration (0-16 and >16 years). The associations of generational status and age at immigration of the mother with total and cause-specific infant mortality were examined. RESULTS: The infant mortality rate in Turkish mothers rose with lower age at immigration (from 5.5 to 6.4 per 1000) and was highest for Dutch-born Turkish mothers (6.8 per 1000). Infant death from perinatal and congenital causes increased with lower age at immigration and was highest in the Dutch-born Turkish women. In contrast, in Surinamese mothers infant mortality declined with lower age at immigration (from 8.0 to 6.3 per 1000) and was lowest for Dutch-born Surinamese mothers (5.5 per 1000). Generational status and lower age at immigration of Surinamese women were associated with declining mortality of congenital causes. CONCLUSIONS: Total and cause-specific infant mortality seem to differ according to generational status and age at immigration of the mother. The direction of these trends however differs between ethnic populations. This may be related to acculturation and selective migration.

Acculturation↗
PubMed1990

Pedigree analyses of yeast cells recovering from DNA damage allow assignment of lethal events to individual post-treatment generations.

Haploid cells of Saccharomyces cerevisiae were treated with different DNA damaging agents at various doses. A study of the progeny of individual such cells (by pedigree analyses up to the third generation) allowed the assignment of lethal events to distinct post treatment generations. By microscopically inspecting those cells which were not able to form visible colonies we could discriminate between cells dying from immediately effective lethal hits and those generating microcolonies (three to several hundred cells) probably as a consequence of lethal mutation(s). The experimentally obtained numbers of lethal events (which we call apparent lethal fixations) were mathematically transformed into mean probabilities of lethal fixations as taking place in cells of certain post treatment generations. Such analyses give detailed insight into the kinetics of lethality as a consequence of different kinds of DNA damage. For example, X-irradiated cells lost viability mainly by lethal hits (which we call 00-fixations); only at a higher dose also lethal mutations fixed in the cells that were in direct contact with the mutagen (which we call 0-fixations), but not in later generations, occurred. Ethyl methanesulfonate (EMS)-treated cells were hit by 00-fixations in a dose dependent manner; 0-fixations were not detected for any dose of EMS applied; the probability for fixation of lethal mutations was found equally high for cells of the first and second post treatment generation and, unexpectedly, was well above control in the third post-treatment generation. The distribution of all sorts of lethal fixations taken together, which occurred in the EMS-damaged cell families, was not random.(ABSTRACT TRUNCATED AT 250 WORDS)

DNA Damage↗
PubMed2004

Influences on childhood height: comparing two generations in the 1958 British birth cohort.

BACKGROUND: Genetics and early environment are known to influence height, but evidence is sparse on changes in these influences over time. METHODS: The 1958 British birth cohort study includes all children born between March 3, 1958 and March 9, 1958, who were followed to age 41 yr, and one-third of their offspring in 1991. Childhood height in each generation (measured at 7 yr for cohort members and 4-18 yr for offspring) was converted to a standard deviation score based on the 1990 British growth reference. We used multilevel models to analyse influences on height in order to allow for the hierarchical within-family data structure. RESULTS: Childhood height increased by 1 cm between 1958 cohort members and their offspring. Several influences on childhood height in the older generation (maternal smoking, breastfeeding, maternal age, social class, maternal education, and parental divorce) did not affect childhood height in the younger generation. Parental height was most strongly associated with childhood height and effects did not diminish between generations [adjusted increase approximately 2 cm for 1 maternal or paternal height standard deviation score (SDS)]. Third- or later-borns and those with three or more siblings had deficits of 1-2 cm (adjusted estimates) in both generations. Other factors, particularly indicators of socioeconomic position, showed weaker effects in the younger generation. For example, the growth deficit of 1.1 cm (adjusted estimate) among cohort members from households with >1.5 persons/room had disappeared in the offspring. CONCLUSIONS: Within Great Britain, the adverse effects of environmental factors on childhood height have lessened between recent generations.

Adolescent↗
PubMed2003

A mathematical model of lipid-mediated thrombin generation.

Thrombin is an enzyme that is generated in both vascular and non-vascular systems. In blood coagulation, a fundamental process in all species, thrombin induces the formation of a fibrin clot. A dynamical model of thrombin generation in the presence of lipid surfaces is presented. This model also includes the self-regulating thrombin feedback reactions, the thrombomodulin-protein C-protein S inhibitory system, tissue factor pathway inhibitor (TFPI), and the inhibitor, antithrombin (AT). The dynamics of this complex system were found to be highly lipid dependent, as would be expected from experimental studies. Simulations of this model indicate that a threshold lipid level is required to generate physiologically relevant amounts of thrombin. The dependence of the onset, the peak levels, and the duration of thrombin generation on lipid was saturable. The lipid concentration affects the way in which the inhibitors modulate thrombin production. A novel feature of this model is the inclusion of the dynamical protein C pathway, initiated by thrombin feedback. This inhibitory system exerts its effects on the lipid surface, where its substrates are formed. The maximum impact of TFPI occurs at intermediate vesicle concentrations. Inhibition by AT is only indirectly affected by the lipid since AT irreversibly binds only to solution phase proteins. In a system with normal plasma concentrations of the proteins involved in thrombin formation, the combination of these three inhibitors is sufficient both to effectively stop thrombin generation prior to the exhaustion of its precursor, prothrombin, and to inhibit all thrombin formed. This model can be used to predict thrombin generation under extreme lipid conditions that are difficult to implement experimentally and to examine thrombin generation in non-vascular systems.

Animals↗
PubMed1992

The natural history of infection with hepatitis C virus (HCV) in chimpanzees: comparison of serologic responses measured with first- and second-generation assays and relationship to HCV viremia.

The sensitivity of first- and second-generation tests for antibody to hepatitis C virus (HCV) and the relationship among the patterns of antibody response and HCV viremia were examined in serial serum samples from 6 chimpanzees experimentally infected with HCV and followed less than or equal to 3 years. HCV infection was transient in 4 chimpanzees and became chronic in 2. All chimpanzees developed antibodies to HCV detectable by second-generation assays, while only 5 of the 6 became positive by first-generation assay. Second-generation were consistently more sensitive than first-generation assays for the early diagnosis of primary HCV infection. The pattern observed with second-generation assays was not influenced by the outcome of HCV infection, since antibodies remained persistently detectable throughout follow-up regardless of whether viremia was transient or persistent. In contrast, the first-generation antibody response was variable: It usually disappeared after loss of viremia, whereas its presence paralleled HCV viremia in chimpanzees with chronic infection.

Animals↗
PubMed1984

Do we need the third-generation cephalosporins?

Third-generation cephalosporins have been available for the past 5 years. The continued increase in resistance of bacteria to older antimicrobial agents and the safety profile of a number of the third-generation agents have established situations in which these compounds are useful. Upper respiratory infections such as epiglottitis, lower respiratory tract infections due to Enterobacteriaceae are examples of illnesses in which third-generation cephalosporins would be preferred to older drug programmes. Bone and joint infections due to Enterobacteriaceae can be treated with third-generation cephalosporins with less risk of toxicity than that associated with aminoglycoside use. But this is an area in which resistance may develop. Meningitis in the elderly due to Escherichia coli or Klebsiella pneumoniae are best treated with cefotaxime and the third-generation cephalosporins are alternative therapy for neonatal and the other forms of meningitis except Listeria or Pseudomonas. These drugs have proved extremely useful in treatment of penicillinase-producing Neisseria gonorrhoeae. Hospital-acquired urinary tract infections in the elderly can be treated with these agents since they provide excellent urinary levels and have a low risk of nephrotoxicity. The need for third-generation cephalosporins in gynaecological and intra-abdomonal infections is less clear. Selected patients will benefit from their use. Closer attention to the excellent in vitro activity and pharmacological activity of third-generation cephalosporins should establish other areas of need for these compounds, but it will be necessary to follow closely the development of resistance to these compounds since species such as Enterobacter, Serratia and Citrobacter can become resistant.

Abdomen↗