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PubMed2000

Differential effects of interleukin-3, interleukin-7, interleukin 15, and granulocyte-macrophage colony-stimulating factor in the generation of natural killer and B cells from primitive human fetal liver progenitors.

The regulatory roles of a number of early-acting growth factors on the generation of natural killer (NK) cells and B cells from primitive progenitors were studied. Experiments focused on the contributions of granulocyte-macrophage colony-stimulates factor (GM-CSF) and interleukin-3 (IL-3) to the regulation of the early events of lymphopoiesis.Two progenitor populations isolated from human fetal liver were studied, CD38(-)CD34(++)lineage(-) (Lin(-)) cells (candidate hematopoietic stem cells [HSCs]) and the more mature CD38(+)CD34(++)Lin(-) cells. The effects of different cytokines on the generation of CD56(+)CD3(-) NK cells and CD19(+) B cells were studied in serum-deprived cultures in the absence of stroma.NK cells generated in vitro were able to kill NK-sensitive target cells, expressed NK-associated marker CD161 (NKR-P1A), but exhibited little or no expression of CD2, CD8, CD16, CD94/NKG2A, or killer cell inhibitory receptors (KIRs). Among the cytokine combinations tested, kit ligand (KL) and IL-15 provided the best conditions for generating CD56(+) NK cells from CD38(+)CD34(++)Lin(-) cells. However, either flk-2/flt3 ligand (FL), GM-CSF, IL-3, or IL-7 could partially substitute KL. All of these cytokines also supported the growth of NK-cell progenitors from candidate HSC, with the combination of IL-15, KL, GM-CSF, and FL generating the greatest number of CD56(+) cells. B cells were generated from both progenitor populations in response to the combined effects of KL, FL, and IL-7. Both B and NK cells were generated with the further addition of IL-15 to these cultures. The in vitro generated B cells were CD10(+), CD19(+), HLA-DR(+), HLA-DQ(+), and some were CD20(+), but no cytoplasmic or surface immunoglobulin M expression was observed. In contrast with NK lymphopoiesis, GM-CSF, IL-3, and IL-15 had no effect on the generation of B cells from CD38(-)CD34(++)Lin(-) cells, and GM-CSF inhibited B-cell generation from CD38(+)CD34(++)Lin(-) progenitors. These findings indicate a differential regulation of NK and B lymphopoiesis beginning in the early stages of hematopoiesis as exemplified by the distinctive roles of IL-7, IL-15, GM-CSF, and IL-3.

ADP-ribosyl Cyclase↗

PubMed1998

The effects of serum iminodipeptides and prednisolone on superoxide generation and tyrosyl phosphorylation of proteins in neutrophils from a patient with prolidase deficiency.

The aim of this study was to examine the effects of serum iminodipeptides and prednisolone on superoxide generation and tyrosyl phosphorylation of proteins in neutrophils from a patient with prolidase deficiency, and also to find the causative effects of superoxide on inflammatory skin lesions. When the neutrophils from a patient with prolidase deficiency (PDPPMN) were preincubated with prolyl-proline (Pro-Pro), which is one of the iminodipeptides found at high concentration in the serum of patients with prolidase deficiency, the N-formyl-methionyl-leucyl-phenylalanine (fMLP)-induced superoxide generation was enhanced in a concentration-dependent manner, although the extent of enhancing effect was lower than that in neutrophils from healthy humans (HPPMN). Pro-Pro also enhanced superoxide generation induced by opsonized zymosan (OZ) in PDPPMN but not that induced by arachidonic acid or phorbol 12-myristate 13-acetate. Herbimycin A and genistein decreased the fMLP- and OZ-induced superoxide generations after priming by Pro-Pro. 1-(5-isoquinoline-sulfonyl)-2-methyl-piperazine (H-7) and staurosporine did not decrease, but rather enhanced, the superoxide generation in a low concentration range. When PDPPMN were prepared, tyrosyl phosphorylation of 45 kDa protein in PDPPMN had already occurred. The phosphorylation was scarcely increased by incubation of the cells with Pro-Pro, in contrast to that in HPPMN. Genistein decreased the phosphorylation of 45 kDa protein in both PDPPMN and HPPMN. These results suggest that the priming effect of iminodipeptides on superoxide generation in PDPPMN is coupled with phosphorylation of 45 kDa protein by protein tyrosine kinase. Protein tyrosine kinase may play a critical role(s) in the regulatory mechanism of priming by iminodipeptides and activation of NADPH oxidase in the patient's neutrophils. In prolidase deficiency, the characteristic skin manifestations are inflammatory indurations and chronic leg ulcers. Prednisolone improves the ulcers, and this compound decreased the fMLP- and OZ-induced superoxide generation and tyrosyl phosphorylation of 45 kDa protein in the patient's neutrophils after priming by Pro-Pro. When inflammatory skin lesions were present, the levels of iminodipeptides in the patient's serum were elevated and the superoxide generation by neutrophils was up-regulated. When skin lesions were healing or absent, the levels of iminodipeptides in the patient's serum and superoxide generation by neutrophils were higher than those of healthy controls but lower than those in the inflammatory stages. Thus, the enhancement of superoxide generation by neutrophils via serum iminodipeptides would be one of the inducers of inflammatory skin lesions. Corticosteroid administration might be a therapeutic modality of choice for skin lesions.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed2001

Evidence for a diagnostic window in fourth generation assays for HIV.

BACKGROUND: The routine HIV screening essentially depends on the detection of HIV specific antibodies. However, HIV p24 antigen can be detected in individuals with recent HIV infection about 2-18 days prior to seroconversion. New fourth generation HIV screening assays combine the detection of anti-HIV antibodies with the simultaneous detection of HIV p24 antigen. This may result in a reduction of the diagnostic window after primary infection. OBJECTIVES: The performance of two novel fourth generation assays in routine diagnostic was evaluated. STUDY DESIGN: We compared two third generation, two fourth generation and one antigen HIV assays in a case with acute primary HIV infection. RESULTS: In our case, the HIV infection was detected 11 days earlier with the fourth generation assays compared to third generation assays. Interestingly, after the initial reactive results the fourth generation assays became negative resulting in a second diagnostic window. During this second diagnostic window neither third nor fourth generation HIV assays were reactive. This second diagnostic window was caused by the absence of HIV specific antibodies and the decline of HIV p24 antigen concentrations below the detection limits of the fourth generation assays. CONCLUSIONS: Fourth generation assays markedly improve the diagnosis of recent HIV infections but the possibility of a second diagnostic window must be considered.

Acute Disease↗

PubMed2006

Generation and context memory.

Generation enhances memory for occurrence but may not enhance other aspects of memory. The present study further delineates the negative generation effect in context memory reported in N. W. Mulligan (2004). First, the negative generation effect occurred for perceptual attributes of the target item (its color and font) but not for extratarget aspects of context (location and background color). Second, nonvisual generation tasks with either semantic or nonsemantic generation rules (antonym and rhyme generation, respectively) produced the same pattern of results. In contrast, a visual (or data-driven) generation task (letter transposition) did not disrupt context memory for color. Third, generating nonwords produced no effect on item memory but persisted in producing a negative effect on context memory for target attributes, implying that (a) the negative generation effect in context memory is not mediated by semantic encoding, and (b) the negative effect on context memory can be dissociated from the positive effect on item memory. The results are interpreted in terms of the processing account of generation. The original, perceptual-conceptual version of this account is too narrow, but a modified processing account, based on a more generic visual versus nonvisual processing distinction, accommodates the results.

Color Perception↗

PubMed2006

Urinary isoflavonoid excretion and soy consumption in three generations of Japanese women in Hawaii.

OBJECTIVE: To explore soy intake and urinary isoflavonoid excretion within several generations of American-Japanese women based on the hypothesis that earlier generations excrete higher levels of urinary isoflavonoids, in particular the metabolite equol, than later generations. SUBJECTS: A convenience sample of 43 women from 19 families aged 18-78 years, all of whom reported at least 50% Japanese ancestry. INTERVENTIONS: Each woman collected overnight urine samples at baseline and after consuming one serving of soymilk, both samples were analyzed for the isoflavonoids daidzein, genistein and equol using liquid chromatography-mass spectrometry. RESULTS: Median isoflavone intakes during the last year were 7.2 mg/day for the first generation, 7.3 mg/day for the second generation and 6.3 mg/day for the third generation (P=0.36). At baseline, the median isoflavonoid excretion for the first generation was nonsignificantly higher than for later generations (190, 86 and 42 nmol/h; P=0.20) but after intervention, the median urinary isoflavonoid excretion was very similar for the three groups: 2465, 1895 and 2775 nmol/h (P=0.70). Following intervention, a nonsignificantly higher proportion of older than younger women (53 vs 32 and 33%; P=0.41) excreted the metabolite equol. The respective median equol excretion rates by generation following intervention were 39.5, 4.2 and 3.5 nmol/h (P=0.04). CONCLUSIONS: This small investigation among three generations of Japanese-Americans detected a higher equol production among older women after a soy challenge, but no difference in the excretion of total isoflavonoids after a standardized dose of soymilk was observed.

Adolescent↗

PubMed1992

Dissociation between phytohaemagglutinin-stimulated generation of inositol phosphates and Ca2+ increase in human mononuclear leucocytes.

We have tested whether phytohaemagglutinin (PHA)-stimulated generation of inositol phosphates (IP) and increases in intracellular Ca2+ can be dissociated in human mononuclear leucocytes. Lowering the incubation temperature from 37 degrees to 25 degrees C decreased PHA-stimulated IP generation by more than 80%, but only marginally affected PHA-stimulated Ca2+ increases. In the absence of extracellular Ca2+, PHA did not stimulate IP generation or Ca2+ increases, although PHA binding to its acceptor sites was not impaired. Increasing extracellular Ca2+ up to 0.15 mM enhanced PHA-stimulated PHA generation but this increase was attenuated by further increasing extracellular Ca2+ to 2.6 mM. Increasing extracellular Ca2+ to 0.3 mM also enhanced PHA-stimulated Ca2+ increases, and further increasing extracellular Ca2+ did not affect it. Co-treatment with 100 microM-prostaglandin E2 completely abolished PHA-stimulated IP generation, but inhibited Ca2+ increases by only 20-30%. These results could be explained by IP-generation-independent Ca2+ increases or by non-linear coupling of IP generation to Ca2+ increases. Since the PHA concentrations required to increase Ca2+ were greater than those required for IP generation, the latter hypothesis can be excluded. Furthermore, the Ca2+ ionophore ionomycin increased intracellular Ca2+ and weakly stimulated IP generation, but with very similar concentration-response relationships. Our data suggest that PHA-stimulated IP generation and Ca2+ increases in human mononuclear leucocytes mainly occur independently of one another rather than sequentially.

Calcium↗

PubMed1998

Changes in serum IGF-I and IGFBP-3 concentrations during the IGF-I generation test performed prospectively in children with short stature.

OBJECTIVE: Genotype and phenotype heterogeneity in patients with GH insensitivity syndrome suggests that partial defects exist in the GH receptor. Children with partial GH resistance would be expected to have short stature, elevated GH levels and relatively low levels of IGF-I and IGFBP-3. Provocation tests of the GH-IGF-I axis may help to identify such children. The IGF-I generation test in particular may demonstrate impaired secretion of IGF-I and IGFBP-3. This prospective study assesses the usefulness of the IGF-I generation test in the identification of short children with possible GH insensitivity. DESIGN: Prepubertal children referred for assessment of short stature underwent a standard GH provocation test followed by an IGF-I generation test. SUBJECTS: Thirty-seven prepubertal children (14 girls, 23 boys) with short stature (height < 2nd centile UK standards 1990) aged 4.5-12.6 years were investigated prospectively. METHODS: Assessment included history, physical examination, auxological observations (height, weight, bone age). GH provocation tests (glucagon 15 micrograms/kg i.m. or insulin 0.15 U/kg/i.v.) was followed by an IGF-I generation test (hGH 0.1 iu/kg/s.c. daily for 4 days). MEASUREMENTS: GH was assayed during the provocation test. IGF-I and IGFBP-3 were measured at 0900 h on day 0 and 4 of the IGF-I generation test. GH and IGF-I were measured by radioimmunoassay, IGFBP-3 by IRMA and basal GHBP by HPLC. STATISTICAL ANALYSIS: Height SDS was calculated according to the UK Height Standards 1990. The absolute and percentage changes of IGF-I and IGFBP-3 during the IGF-I generation test were calculated. RESULTS: The 37 children were divided into three groups according to the peak GH level (mean +/- SEM) during the provocation test: Group 1 (peak GH < 20 mU/l) n = 11, five girls, six boys age 7.1 +/- 0.7 years, height SDS -2.5 +/- 0.1, peak GH 14.5 +/- 1.6 mU/l, IGF-I 92.0 +/- 10.4 micrograms/l, IGFBP-3 2.6 +/- 0.4 mg/l. Group 2 (peak GH 20-40 mU/l) n = 12, six girls, six boys age 8.6 +/- 0.7 years, height SDS -2.6 +/- 0.1, peak GH 28.4 +/- 1.6 mU/l, IGF-I 121-5 +/- 13.4 micrograms/l, IGFBP-3 2.9 +/- 0.2 mg/l. Group 3 (peak GH > 40 mU/l) n = 14, three girls, 11 boys, aged 8.5 +/- 0.6 years, height SDS -2.3 +/- 0.1, peak GH 60.7 +/- 4.1 mU/l, IGF-I 112.4 +/- 10.9 micrograms/l, IGFBP-3 3.1 +/- 0.3 mg/l. There were no significant differences in the absolute increases of IGF-I or IGFBP-3 (mean +/- SEM) during the IGF-I generation test, IGF-I; Group 1, 48.8 +/- 9.5 micrograms/l, Group 2, 42.7 +/- 4.8 micrograms/l. Group 3, 45.5 +/- 5.1 micrograms/l, IGFBP-3; Group 1, 1.1 +/- 1.2 mg/l. Group 2, 1.2 +/- 0.2 mg/l, Group 3, 0.85 +/- 0.1 mg/l. There were no significant differences in the percentage increases (mean +/- SEM) of IGF-I; Group 1, 55 +/- 9%, Group 2, 35 +/- 5%, Group 3, 42 +/- 8%, or IGFBP-3; Group 1, 64 +/- 17%, Group 2, 44 +/- 8%, Group 3.32 +/- 6%. GHBP values were normal in all three groups. In Group 3 (peak GH > 40 mU/l) four individual patients had either low basal IGF-I levels (n = 2) (< 5th centile of normal range for age) or low basal IGFBP-3 levels (n = 1) (< 5th centile of normal range for age) or low IGF-I responses in the IGF-I generation test (2 x CV of IGF-I assay) (n = 1). No single subject had all the characteristics of GH insensitivity syndrome. CONCLUSION: The responses during an IGF-I generation test did not identify a clear group of children with GH insensitivity. Individual patients had low basal IGF-I or IGFBP-3 values and a poor response in the generation test, features which, in the presence of high GH levels on provocation, are consistent with partial GH insensitivity.

Carrier Proteins↗

PubMed1994

Anti-hepatitis C virus (anti-HCV) seroconversion in patients undergoing hemodialysis: comparison of second- and third-generation anti-HCV assays.

BACKGROUND: The results obtained in sequential specimens from recently infected subjects generally provide the best means of comparing the sensitivity of assays. STUDY DESIGN AND METHODS: The sensitivity of second- and third-generation assays for antibody to hepatitis C virus (HCV) was compared on sequential specimens, generally collected at monthly intervals from 45 patients undergoing hemodialysis who seroconverted for HCV between 1980 and 1990. RESULTS: Fifteen patients (33%) were positive earlier in the third-generation enzyme-linked immunosorbent assay (ELISA), with a mean difference of 17 days (range, 7-30) between the last negative and the first positive specimens. At the first rise in alanine aminotransferase, and at its peak, 63 and 91 percent of the patients, respectively, were anti-HCV positive in the third-generation ELISA. Third-generation recombinant immunoblot assay (RIBA) reacted at the same time as third-generation ELISA. Of the first specimens that were positive in second-generation ELISA, 44 percent reacted and 56 percent were indeterminate in third-generation RIBA, while 10 percent reacted, 72 percent were indeterminate, and 18 percent did not react in second-generation RIBA. From the beginning to the end of the follow-up, antibody to c33c was the most prevalent, followed in descending order by antibody to c22-3, antibody to c100-3, and antibody to NS5: 56, 54, 26, and 18 percent, respectively, at time 0, and 100, 86, 83, and 31 percent, respectively, 12 months later. CONCLUSION: Third-generation assays (both ELISA and RIBA) were more sensitive than second-generation assays in the diagnosis of HCV infection, in that positive results were obtained earlier and a higher proportion of specimens were confirmed positive in RIBA testing.

Alanine Transaminase↗

PubMed1985

Usefulness of fibrinopeptide A generation tests in experimental and clinical studies with low molecular weight heparin fractions.

FPA generation test provides a sensitive tool to study the events leading to the production of fibrin from fibrinogen. Drug modulation of pathways resulting in thrombin generation can be readily assessed utilizing the FPA generation test. In circumstances in which conventional clotting and amidolytic methods fail to detect any antiprotease effects, the FPA generation test provides the sensitivity to study these actions. The FPA generation test demonstrates the collective action of antithrombotic agents on inhibition of activation of the pathways leading to the generation of thrombin. The generation systems are easily modified by activators to provide identification of sites, components, and modulating interaction of various heparin derivatives on the hemostatic system. The FPA generation test assesses the overall inhibitory effects of heparin and thus provides insight into the pharmacokinetics of the biologically active components of these agents. Currently, the FPA generation test may be utilized to demonstrate pharmacokinetics and pharmacodynamics but has limited quantitative capacity in this regard. The FPA generation test performed on native plasma may provide insight into the great variation in individual hemostatic parameters important to dosage determinations.

Blood Coagulation Tests↗

PubMed1995

Indirect coupling of phosphate release to de novo tension generation during muscle contraction.

A key question in muscle contraction is how tension generation is coupled to the chemistry of the actomyosin ATPase. Biochemical and mechanochemical experiments link tension generation to a change in structure associated with phosphate release. Length-jump and temperature-jump experiments, on the other hand, implicate phase 2slow, a significantly faster, markedly strain-sensitive kinetic process in tension generation. We use a laser temperature jump to probe the kinetics and mechanism of tension generation in skinned rabbit psoas fibers--an appropriate method since both phosphate release and phase 2slow are readily perturbed by temperature. Kinetics characteristic of the structural change associated with phosphate release are observed only when phosphate is added to fibers. When present, it causes a reduction in fiber tension; otherwise, no force is generated when it is perturbed. We therefore exclude this step from tension generation. The kinetics of de novo tension generation by the temperature-jump equivalent of phase 2slow appear unaffected by phosphate binding. We therefore propose that phosphate release is indirectly coupled to de novo tension generation via a steady-state flux through an irreversible step. We conclude that tension generation occurs in the absence of chemical change as the result of an entropy-driven transition between strongly bound crossbridges in the actomyosin-ADP state. The mechanism resembles the operation of a clock, with phosphate release providing the energy to tension the spring, and the irreversible step functions as the escapement mechanism, which is followed in turn by tension generation as the movement of the hands.

Actomyosin↗

PubMed1997

Mitochondrial ubiquinone homologues, superoxide radical generation, and longevity in different mammalian species.

Rates of mitochondrial superoxide anion radical (O-2) generation are known to be inversely correlated with the maximum life span potential of different mammalian species. The objective of this study was to understand the possible mechanism(s) underlying such variations in the rate of O-2 generation. The hypothesis that the relative amounts of the ubiquinones or coenzyme Q (CoQ) homologues, CoQ9 and CoQ10, are related with the rate of O-2 generation was tested. A comparison of nine different mammalian species, namely mouse, rat, guinea pig, rabbit, pig, goat, sheep, cow, and horse, which vary from 3.5 to 46 years in their maximum longevity, indicated that the rate of O-2 generation in cardiac submitochondrial particles (SMPs) was directly related to the relative amount of CoQ9 and inversely related to the amount of CoQ10, extractable from their cardiac mitochondria. To directly test the relationship between CoQ homologues and the rate of O-2 generation, rat heart SMPs, naturally containing mainly CoQ9 and cow heart SMPs, with high natural CoQ10 content, were chosen for depletion/reconstitution experiments. Repeated extractions of rat heart SMPs with pentane exponentially depleted both CoQ homologues while the corresponding rates of O-2 generation and oxygen consumption were lowered linearly. Reconstitution of both rat and cow heart SMPs with different amounts of CoQ9 or CoQ10 caused an initial increase in the rates of O-2 generation, followed by a plateau at high concentrations. Within the physiological range of CoQ concentrations, there were no differences in the rates of O-2 generation between SMPs reconstituted with CoQ9 or CoQ10. Only at concentrations that were considerably higher than the physiological level, the SMPs reconstituted with CoQ9 exhibited higher rates of O-2 generation than those obtained with CoQ10. These in vitro findings do not support the hypothesis that differences in the distribution of CoQ homologues are responsible for the variations in the rates of mitochondrial O-2 generation in different mammalian species.

Animals↗

PubMed2005

Incidence of mental disorders in second-generation immigrants in sweden: a four-year cohort study.

BACKGROUND: Few studies have investigated mental health among second-generation immigrants who have reached adulthood. The aim of this study was to examine whether second-generation adult immigrants have a higher risk of being hospitalised for mental disorders than the Swedish majority population after adjustment for socio-economic status. METHODS: In total 1.9 million Swedish-born women and men aged 16-34 were followed from 1 January 1995 to 31 December 1998 for first hospital admissions for mental disorders, categorised in four main diagnosis groups. Second-generation immigrants comprised four groups and the Swedish majority population was used as reference group. Cox proportional hazard models were used to analyse the data. RESULTS: Second-generation immigrants with one parent born in Sweden and second-generation Finns had higher risks of being hospitalised for psychotic disorders, affective disorders, neurotic disorders, and personality disorders than the Swedish majority population. For second-generation Finns the age- and sex-adjusted hazard ratio for psychotic disorders was 2.42 (CI = 2.09-2.80). No significant hazard ratios were found for second-generation labour immigrants. For second-generation refugees the risk of being hospitalised was higher than for the Swedish majority population but only for psychotic disorders. All results remained significant and decreased only slightly after adjustment for income and education. CONCLUSIONS: Many groups of second-generation immigrants have a higher risk of being hospitalised for mental disorder than the majority population. With increasing global migration it is crucial for all industrialised countries to take measures to improve mental health among second-generation immigrants.

Adolescent↗

PubMed1983

Adenosine: a physiological modulator of superoxide anion generation by human neutrophils.

The effects of adenosine were studied on human neutrophils with respect to their generation of superoxide anion, degranulation, and aggregation in response to soluble stimuli. Adenosine markedly inhibited superoxide anion generation by neutrophils stimulated with N-formyl methionyl leucyl phenylalanine (FMLP), concanavalin A (Con A), calcium ionophore A23187, and zymosan-treated serum; it inhibited this response to PMA to a far lesser extent. The effects of adenosine were evident at concentrations ranging from 1 to 1,000 microM with maximal inhibition at 100 microM. Cellular uptake of adenosine was not required for adenosine-induced inhibition since inhibition was maintained despite the addition of dipyridamole, which blocks nucleoside uptake. Nor was metabolism of adenosine required, since both deoxycoformycin (DCF) and erythro-9-(2-hydroxy-3-nonyl) adenine did not interfere with adenosine inhibition of superoxide anion generation. The finding that 2-chloroadenosine, which is not metabolized, resembled adenosine in its ability to inhibit superoxide anion generation added further evidence that adenosine metabolism was not required for inhibition of superoxide anion generation by neutrophils. Unexpectedly, endogenously generated adenosine was present in supernatants of neutrophil suspensions at 0.14-0.28 microM. Removal of endogenous adenosine by incubation of neutrophils with exogenous adenosine deaminase (ADA) led to marked enhancement of superoxide anion generation in response to FMLP. Inactivation of ADA with DCF abrogated the enhancement of superoxide anion generation. Thus, the enhancement was not due to a nonspecific effect of added protein. Nor was the enhancement due to the generation of hypoxanthine or inosine by deamination of adenosine, since addition of these compounds did not affect neutrophil function. Adenosine did not significantly affect either aggregation or lysozyme release and only modestly affected beta-glucuronidase release by neutrophils stimulated with FMLP. These data indicate that adenosine (at concentrations that are present in plasma) acting via cell surface receptors is a specific modulator of superoxide anion generation by neutrophils.

2-Chloroadenosine↗

PubMed2004

High-intensity focused ultrasound for ex vivo kidney tissue ablation: influence of generator power and pulse duration.

BACKGROUND AND PURPOSE: The therapeutic application of noninvasive tissue ablation by high-intensity focused ultrasound (HIFU) requires precise physical definition of the focal size and determination of control parameters. The objective of this study was to measure the extent of ex-vivo porcine kidney tissue ablation at variable generator parameters and to identify parameters to control lesion size. MATERIALS AND METHODS: The ultrasound waves generated by a cylindrical piezoceramic element (1.04 MHz) were focused at a depth of 100 mm using a parabolic reflector (diameter 100 mm). A needle hydrophone was used to measure the field distribution of the sound pressure. The morphology and extent of tissue necrosis were examined at generator powers of up to 400 W (P(el)) and single pulse durations of as long as 8 seconds. RESULTS: The two-dimensional field distribution resulted in an approximately ellipsoidal focus of 32 x 4 mm (-6 dB). A sharp demarcation between coagulation necrosis and intact tissue was observed. Lesion size was controlled by both the variation of generator power and the pulse duration. At a constant pulse duration of 2 seconds, a generator power of 100 W remained below the threshold doses for inducing a reproducible lesion. An increase in power to as high as 400 W induced lesions with average dimensions of as much as 11.2 x 3 mm. At constant total energy (generator power x pulse duration), lesion size increased at higher generator power. CONCLUSIONS: This ultrasound generator can induce defined and reproducible necrosis in ex-vivo kidney tissue. Lesion size can be controlled by adjusting the generator power and pulse duration. Generator power, in particular, turned out to be a suitable control parameter for obtaining a lesion of a defined size.

Animals↗

PubMedDate not supplied

The role of selective prescribing in the increased risk of VTE associated with third-generation oral contraceptives.

In the early 1960s, it became apparent that oral contraception (OC) with oestroprogestogens increased the cardiovascular, venous thromboembolic (VTE), myocardial infarction (MI) and cerebrovascular accident (CVA) risk. The change in medical prescribing patterns, the reduction in ethinyloestradiol dosage and the use of less androgenic progestogens made prescribers confident that the risks would subsequently decrease. At the end of 1995 and early 1996, four publications called into question that optimism by showing that third-generation pills induced a two-fold increase in VTE risk compared with second-generation pills. A biological rationale was due to be announced later. Since then, re-analysis of the data has shown that the thrombotic risk factors are increased in third-generation OC users but, more importantly, that those users (unlike those using second-generation pills) are the women who have not had the opportunity of revealing a latent thrombophilia and are, therefore, at a greater risk of expressing it during third-generation OC intake. When these data are considered, the difference between second- and third-generation OC users in terms of VTE risk is completely destroyed. In addition and although the risk factors (smoking in particular) are concentrated in third-generation OC users, the MI risk is less in those users than in second-generation pill users. This is particularly true in the presence of a risk factor such as smoking. No difference in risk has been observed for CVA in the general population between second- and third-generation OC users, but once more among smoking women the risk is lower with third-generation OC.

Contraceptives, Oral↗

PubMed1998

Response to ten generations of divergent selection for tibial dyschondroplasia in broiler chickens: growth, egg production, and hatchability.

Continued genetic selection for improved BW gain has met an obstacle of skeletal disorders in broiler chickens. Two broiler chicken lines (HTD and LTD) were developed by 10 generations of divergent selection for tibial dyschondroplasia (TD) incidence originating from commercial primary breeders. The reference population was a randombred control line maintained along with the selected lines. Relationships of TD incidence with BW, egg production (EP), and hatchability were assessed using these lines. The response of TD to selection was asymmetric, favoring an increased TD incidence. Mean TD incidence increased 7.6 percentage points per generation during Generation 1 through 10 in males and 9.1 percentage points in females of the HTD line but did not change significantly in the LTD line at 4 wk of age. Responses of the HTD line in early (1 to 4) generations were greater than in later (6 to 10) generations, in contrast to nonsignificant responses for both durations in the LTD line. The 4-wk BW of the HTD line was slightly heavier than or similar to that of the LTD line within generations. The HTD line birds tended to decrease 7-wk BW with advancing generations. The trend of changes in BW was not as clear in the LTD lines as in the HTD line. The variability of 7-wk BW had an increased trend with advancing generations in the HTD line, accompanied by a decreased additive genetic variability of TD due to continued selection. The average EP in the LTD hens was 7.6 percentage points higher than in the HTD from Generations 1 through 10. Mean hatchability in the LTD line did not differ from that in the HTD line within generation. Responses of EP and hatchability, components associated with fitness, appeared slower towards increased fitness than towards decreased fitness.

Alabama↗

PubMed2006

Familial Ménière's disease in five generations.

OBJECTIVE: Clinical characterization of a Swedish family followed for five generations. Several members of each generation had Ménière's disease (MD). Possible modes of genetic transmission were assessed. STUDY DESIGN: Retrospective family survey. SETTING: University hospital. Tertiary referral center. PATIENTS: Members of a large family in which several members in each generation were affected by MD. INTERVENTIONS: Hearing levels were assessed, and the patients were asked to complete a questionnaire regarding age at onset, hearing loss, tinnitus, aural fullness, vertigo, and if MD was unilateral or bilateral. Glycerol tests were performed in a few cases. For deceased relatives, information was obtained from patient charts and interviews with relatives. Genetic studies with linkage analysis was performed for the loci DFNA 1, DFNA6/14, DFNA9, and DFNA15. RESULTS: One member of Generation I and, according to patient charts, two members of Generation II could have suffered from MD. In Generations III to V, 9 of 25 members developed inner ear dysfunction. Six of these individuals developed MD that was strictly in accordance with American Academy of Otolaryngology and Head and Neck Surgery, 1995 guidelines criteria, whereas three individuals had unilateral or bilateral hearing impairment, one in combination with benign paroxysmal positioning vertigo, which could represent an incomplete expression of the disease. The mean age at disease onset was 64.5 years in Generation III, 43 years in Generation IV, and 25 years in Generation V. In the genetic studies, none of the regions investigated showed linkage to the disease gene with a significant calculated log of odds ratio (LOD) score above three. CONCLUSION: The pattern of inheritance suggested that familial MD was autosomal dominant and exhibited incomplete expression of inner ear symptoms in some affected members. The decreasing age at onset of disease with succeeding generations could indicate anticipation. None of the hitherto-known DFNA loci, which has phenotypes bearing some resemblance to MD, had haplotypes in common with this large family affected by MD.

Adult↗

PubMed2006

Coronary heart disease risks in first- and second-generation immigrants in Sweden: a follow-up study.

OBJECTIVES: To analyse whether there is an association between country of birth in first-generation immigrants and first hospitalization for or death from coronary heart disease (CHD) and to analyse whether this association remains in second-generation immigrants. DESIGN: In this follow-up study, the MigMed database at the Karolinska Institute, Stockholm, was used to identify all hospital diagnoses of and deaths from incident CHD in first- and second-generation immigrants in Sweden between 1 January 1987 and 31 December 2001. Incidence ratios standardized by age, geographical region and socio-economic status were estimated by sex in first- and second-generation immigrants; the reference group was Swedish-born people whose parents were both born in Sweden. SUBJECTS: The total Swedish population aged 25-69 years. RESULTS: First-generation immigrants from Finland, central European countries, other eastern European countries and Turkey had higher rates of CHD than men or women in the reference group. First-generation immigrant women born in southern Europe, other western European countries and Baltic countries had lower CHD risks than the reference group. Sons of both male and female first-generation immigrants showed CHD risks similar to or slightly higher than those of their parents. Amongst second-generation women, only subjects with Finnish fathers or mothers had higher risks of developing CHD than the reference. CONCLUSIONS: Increased risks of CHD found in some first-generation immigrant groups often persist in second-generation immigrant men. Healthcare professionals and policy makers should take this into account when designing and undertaking measures to prevent CHD.

Adult↗