Distribution by Scientific Domains
Distribution within Medical Sciences

Terms modified by Unaffected

  • unaffected area
  • unaffected control
  • unaffected eye
  • unaffected family member
  • unaffected individual
  • unaffected parent
  • unaffected pregnancy
  • unaffected relative
  • unaffected sibling
  • unaffected side
  • unaffected skin

  • Selected Abstracts

    Increased number of offspring in first degree relatives of psychotic individuals: a partial explanation for the persistence of psychotic illnesses

    M. Weiser
    Objective:, As patients with psychotic illness have fewer offspring than controls, the persistence of psychotic illness is puzzling. We hypothesized that unaffected first-degree relatives of patients have more offspring than controls. Method:, Probands were 4904, individuals with non-affective psychotic disorders identified from a hospitalization registry. Unaffected first degree relatives and matched controls were identified from the Israeli Population Registry. The number of offspring of unaffected parents, biological siblings and controls was ascertained. Results:, Unaffected parents of psychotic patients had more offspring/person than controls; 4.5 ± 2.7 vs. 3.4 ± 2.2, P = 0.000. Unaffected parents from familial psychosis families (more than one affected family member) had 1.83 more offspring than controls; unaffected parents from non-familial psychosis families had 0.97 more offspring than controls (both P < 0.001). Conclusion:, These findings might imply that genes which increase susceptibility for schizophrenia may be associated with increased number of offspring, perhaps supplying a partial explanation for the persistence of psychosis. [source]

    Stroke Injury in Rats Causes an Increase in Activin A Gene Expression Which is Unaffected by Oestradiol Treatment

    M. Böttner
    Abstract Activins are members of the transforming growth factor-, superfamily that exert neurotrophic and neuroprotective effects on various neuronal populations. To determine the possible function of activin in stroke injury, we assessed which components of the activin signalling pathway were modulated in response to middle cerebral artery occlusion (MCAO). Furthermore, because oestradiol replacement protects against MCAO-induced cell death, we explored whether oestradiol replacement influences activin gene expression. Female Sprague-Dawley rats underwent permanent MCAO and the expression of activins and their corresponding receptors was determined by semiquantitative reverse transcriptase-polymerase chain reaction at 24 h after onset of ischaemia. We observed up-regulation of activin ,A and activin type I receptor A mRNA in response to injury. Dual-label immunocytochemistry followed by confocal z-stack analysis showed that the activin A expressing cells comprised neurones. Next, we monitored the time course of activin ,A mRNA expression in oestradiol- or vehicle-treated rats at 4, 8, 16 and 24 h after MCAO via in situ hybridisation. Starting at 4 h after injury, activin ,A mRNA was up-regulated in cortical and striatal areas in the ipsilateral hemisphere. Activin ,A mRNA levels in the cortex increased dramatically with time and were highest at 24 h after the insult, and oestradiol replacement did not influence this increase. [source]

    Automatic muscle generation for character skin deformation

    Xiaosong Yang
    Abstract As skin shape depends on the underlying anatomical structure, the anatomy-based techniques usually afford greater realism than the traditional skeleton-driven approach. On the downside, however, it is against the current animation workflow, as the animator has to model many individual muscles before the final skin layer arrives, resulting in an unintuitive modelling process. In this paper, we present a new anatomy-based technique that allows the animator to start from an already modelled character. Muscles having visible influence on the skin shape at the rest pose are extracted automatically by studying the surface geometry of the skin. The extracted muscles are then used to deform the skin in areas where there exist complex deformations. The remaining skin areas, unaffected or hardly affected by the muscles, are handled by the skeleton-driven technique, allowing both techniques to play their strengths. In order for the extracted muscles to produce realistic local skin deformation during animation, muscle bulging and special movements are both represented. Whereas the former ensues volume preservation, the latter allows a muscle not only to deform along a straight path, but also to slide and bend around joints and bones, resulting in the production of sophisticated muscle movements and deformations. Copyright © 2006 John Wiley & Sons, Ltd. [source]

    Design of an MR-compatible piezoelectric actuator for MR elastography

    Kai Uffmann
    Abstract Magnetic Resonance (MR) elastography is a method for measuring tissue elasticity via phase images acquired with an MR scanner. The propagation of periodic mechanical waves through the tissue can be captured by means of a modified phase contrast sequence. These waves are generated with a mechanical oscillator (actuator) and coupled into the tissue through the skin. The actuator must be capable of generating a sinusoidal excitation with excellent phase and amplitude stability, while not disturbing the MR imaging process. In this work, an actuator based on a piezoelectric principle was developed. Based on the imaging evaluation of several material samples, the housing for the piezoelectric ceramic was constructed of aluminum. Smaller parts of the housing were manufactured from brass and titanium to fulfill the mechanical constraints. A lever was used to transfer the oscillation generated by the piezoelectric ceramic to the point of excitation. The lever amplifies the piezoelectric motion, allowing for a more compact design. Three different lever designs were characterized by an acceleration sensor both outside and inside the magnet. It was shown that the rigidity of the lever, as determined by its material and form, was decisive in determining the resonant frequency of the system and therefore the maximum practical frequency of operation. It was also shown that the motion of the oscillator is unaffected by the electromagnetic fields of the MR imager. The final design can be placed directly in the magnet bore within a few centimeters of the tissue volume to be imaged without generating significant artifacts. An amplitude range of 0,1 mm in the frequency range from 0 to over 300 Hz was achieved, sufficient for performing most MR elastography applications. © 2002 Wiley Periodicals, Inc. Concepts in Magnetic Resonance (Magn Reson Engineering) 15: 239,254, 2002 [source]

    Effects of in utero exposure to 2,2,,4,4,,5,5,-hexachlorobiphenyl (PCB 153) on somatic growth and endocrine status in rat offspring

    Kenichi Kobayashi
    ABSTRACT Exposure to polychlorobiphenyl (PCB) mixtures at an early stage of development has been reported to affect endocrine glands; however, little is known about the precise toxicological properties of individual PCB. The present study was undertaken to determine whether prenatal exposure to 2,2,,4,4,,5,5,-hexachlorobiphenyl (PCB 153), a di- ortho -substituted non-coplanar congener, affects postnatal development in rat offspring. Pregnant Sprague-Dawley rats (Crj: CD (SD) IGS) were given PCB 153 (0, 16, or 64 mg/kg/day) orally from gestational day (GD) 10 through GD 16, and developmental parameters in the male and female offspring were examined. We found no dose-dependent changes in body weight, body length (nose,anus length), tail length, or the weights of kidneys, testes, ovaries and uterus in offspring at 1 or 3 weeks of age. Liver weights were increased in the PCB 153,treated groups, although we observed a significant difference only in males. Anogenital distance was unaffected in the PCB 153,treated groups. We observed a significant dose-dependent decrease in the plasma concentrations of thyroxine and tri-iodothyronine, whereas those of thyroid-stimulating hormone were not significantly changed. In addition, there were no dose-dependent changes in plasma concentrations of growth hormone and insulin-like growth factor-I in any dose group. These findings suggest that prenatal exposure to PCB 153 (GD 10,16, 16,64 mg/kg/day) may alter the thyroid status in rat offspring to some extent without affecting somatic growth or its related hormonal parameters. [source]

    Cardiac basal metabolism: energetic cost of calcium withdrawal in the adult rat heart

    ACTA PHYSIOLOGICA, Issue 3 2010
    P. Bonazzola
    Abstract Aim:, Cardiac basal metabolism upon extracellular calcium removal and its relationship with intracellular sodium and calcium homeostasis was evaluated. Methods:, A mechano-calorimetric technique was used that allowed the simultaneous and continuous measurement of both heat rate and resting pressure in arterially perfused quiescent adult rat hearts. Using pharmacological tools, the possible underlying mechanisms related to sodium and calcium movements were investigated. Results:, Resting heat rate (expressed in mW g,1dry wt) increased upon calcium withdrawal (+4.4 ± 0.2). This response was: (1) unaffected by the presence of tetrodotoxin (+4.3 ± 0.6), (2) fully blocked by both, the decrease in extracellular sodium concentration and the increase in extracellular magnesium concentration, (3) partially blocked by the presence of either nifedipine (+2.8 ± 0.4), KB-R7943 (KBR; +2.5 ± 0.2), clonazepam (CLO; +3.1 ± 0.3) or EGTA (+1.9 ± 0.3). The steady heat rate under Ca2+ -free conditions was partially reduced by the addition of Ru360 (,1.1 ± 0.2) but not CLO in the presence of EGTA, KBR or Ru360. Conclusion:, Energy expenditure for resting state maintenance upon calcium withdrawal depends on the intracellular rise in both sodium and calcium. Our data are consistent with a mitochondrial Ca2+ cycling, not detectable under normal calcium diastolic levels. The experimental condition here analysed, partially simulates findings reported under certain pathological situations including heart failure in which mildly increased levels of both diastolic sodium and calcium have also been found. Therefore, under such pathological conditions, hearts should distract chemical energy to fuel processes associated with sodium and calcium handling, making more expensive the maintenance of their functions. [source]

    Low Recruitment of Trees Dispersed by Animals in African Forest Fragments

    N. J. Cordeiro
    We compared adult and juvenile trees in forest transects in a 3500,ha submontane forest with those in four forest fragments of 521, 30, 9, and 0.5 ha. Preliminary results show that recruitment of seedlings and juveniles of 31 animal-dispersed tree species was more than three times greater in continuous forest and large forest fragments (,30 ha) than in small forest fragments (,9 ha), whereas recruitment of eight wind- and gravity-dispersed trees of the forest interior was unaffected. Recruitment of 10 endemic, animal-dispersed tree species was 40 times lower in small fragments than in continuous forest or large fragments. Counts of diurnal primates and birds in all five sites indicated that frugivorous species have declined with decreasing fragment size. These results are consistent with the idea that loss of dispersal agents depresses tree recruitment in the course of forest fragmentation. Resumen: Investigamos los efectos de la fragmentación del bosque en la desaparición de animales frugívoros y el reclutamiento de árboles dispersados por animales y viento en parches de bosques de 80 años de edad en las montañas del este de Usambara, Tanzania. Comparamos árboles adultos y juveniles en transectos de bosque en un bosque submontañoso de 3500 ha con transectos de cuatro fragmentos de bosque de 521, 30, 9 y 0.5 ha. Los resultados preliminares muestran que el reclutamiento de plántulas y juveniles especies de árboles dispersados por animales fue tres veces mayor en el bosque continuo y fragmentos grandes (,30 ha) que en fragmentos pequeños (,9 ha), mientras que el reclutamiento de ocho árboles dispersados por viento y gravedad del interior del bosque no fue afectado. El reclutamiento de 10 especies endémicas de árboles dispersados por animales fue 40 veces menor en los fragmentos pequeños que en el bosque continuo o en los fragmentos grandes. Los conteos de primates diurnos y aves en los cinco sitios indican que las especies frugívoras han disminuido con la disminución del tamaño del fragmento. Estos resultados son consistentes con la idea de que la pérdida de los agentes dispersores deprime el reclutamiento de los árboles en el transcurso de la fragmentación del bosque. [source]

    Prescribed Burning to Restore Mixed-Oak Communities in Southern Ohio: Effects on Breeding- Bird Populations

    Vanessa L. Artman
    We studied the effects of repeated burning (1,4 years of annual burning) and recovery (1 year after burning,) on the breeding bird community. Burning resulted in incremental but temporary reductions in the availability of leaf litter, shrubs, and saplings, but it did not affect trees, snags, or understory vegetation cover. Of 30 bird species monitored, 4 were affected negatively and 2 were affected positively by burning. Population densities of Ovenbirds ( Seiurus aurocapillus), Worm-eating Warblers ( Helmitheros vermivorus), and Hooded Warblers ( Wilsonia citrina) declined incrementally in response to repeated burning and did not recover within 1 year after burning, suggesting a lag time in response to the changes in habitat conditions. Densities of Northern Cardinals ( Cardinalis cardinalis) fluctuated among years in the control units, but remained low in the burned units. Densities of American Robins ( Turdus migratorius) and Eastern Wood-Pewees ( Contopus virens) increased in response to burning, but these increases were apparent only after several years of repeated burning. In general, burning resulted in short-term reductions in the suitability of habitat for ground- and low-shrub-nesting birds, but it improved habitat for ground- and aerial-foraging birds. Overall, there were no changes in the composition of the breeding-bird community. Total breeding bird population levels were also unaffected by burning. Our results suggest that prescribed burning applied on a long-term basis or across large spatial scales is likely to have adverse effects on ground- and low-shrub-nesting bird species, but other changes in the composition of the breeding-bird community are likely to be minimal as long as the closed-canopy forest structure is maintained within the context of prescribed burning. Resumen: Se está reintroduciendo fuego artificialmente en los bosque del sur de Ohio para determinar su efectividad para restaurar y mantener comunidades de bosques mixtos de encino ( Quercus spp.). Estudiamos los efectos de quemas repetidas (1,4 años de quema anual,) y de recuperación (1 año después de la quema) sobre la comunidad de aves reproductivas. La quema resultó en reducciones temporales en la disponibilidad de hojarasca, arbustos y renuevos, pero no afectó a los árboles, tocones o la cubierta vegetal del sotobosque. De 30 especies de aves monitoredas, 4 fueron afectadas negativamente por la quema y 2 fueron afectadas positivamente. Las densidades de población de Seiurus aurocapillus, de Helmitheros vermivorus y de Wilsonia citrina declinaron incrementalmente en respuesta a quemas repetidas y no se recuperaron en un año después de la quema, sugiriendo un retraso en el tiempo de respuesta a los cambios en las condiciones del hábitat. Las densidades de Cardinalis cardinalis fluctuaron entre años en las unidades control, pero permanecieron bajas en las unidades quemadas. Las densidades de Turdus migratorius y de Contopus virens aumentaron en respuesta a la quema, pero estos incrementos fueron evidentes sólo hasta varios años después de quemas repetidas. En general, en el corto plazo la quema resultó en reducciones en la calidad del hábitat para aves que anidan sobre el suelo y en arbustos bajos, pero mejoró el hábitat para aves que forrajean en el suelo y el aire. En general, no hubo cambios en la composición de la comunidad de aves reproductivas. Los niveles totales de poblaciones de aves reproductivas tampoco fueron afectados por la quema. Nuestros resultados sugieren la posibilidad de que la quema prescrita aplicada a largo plazo o en escalas espaciales grandes tenga efectos adversos sobre especies de aves que anidan sobre el suelo y en arbustos bajos, pero la posibilidad de cambios en la composición de la comunidad de aves reproductivas es mínima. [source]

    FS04.6 Dose/unit area and time , key factors influencing the elicitation capacity of MCI/MI

    CONTACT DERMATITIS, Issue 3 2004
    Claus Zachariae
    The objective of the study was to investigate, using the Repeated Open Application Test (ROAT), two key parameters of exposure , allergen concentration (dose/unit area) and time in terms of the elicitation capacity of methylchloroisothiazolinone and methylisothiazolinone (MCI/MI) in MCI/MI-sensitised individuals and to explore the inter-relationship between these two key factors. The study was designed as a double-blind, placebo-controlled, dose-response ROAT preceded by a Diagnostic Patch Test (DPT). 79 patients with a known MCI/M allergy were contacted, 29 were diagnostically patch tested and 25 had their allergy confirmed. 25 MCI/M-allergic subjects and 10 healthy non-allergic control subjects were challenged with 2 ppm of MCI/MI/unit area of skin for 4 weeks. After a wash out period of at least 4 weeks the subjects were challenged with 7.5 ppm of MCI/MI/unit area of skin for 4 weeks. A ROAT with 2 drops of solution twice a day was conducted on the volar aspect of the left and right forearms on a 3 × 3 cm area resulting in dose/unit area of MCI/MI of 0.025 mg/cm2 and 0.095 mg/cm2 for 2 ppm and 7,5 ppm MCI/MI respectively. The elicitation capacity of MCI/MI in MCI/MI sensitive patients is dependent on the exposure dose/unit area and time The results of this study will be a useful addition to the risk assessment information available for MCI/MI. The risk assessment for the use of MCI/MI in rinse off consumer products is unaffected by the results of this study. [source]

    Cerebral oxygenation decreases during exercise in humans with beta-adrenergic blockade

    ACTA PHYSIOLOGICA, Issue 3 2009
    T. Seifert
    Abstract Aim:, Beta-blockers reduce exercise capacity by attenuated increase in cardiac output, but it remains unknown whether performance also relates to attenuated cerebral oxygenation. Methods:, Acting as their own controls, eight healthy subjects performed a continuous incremental cycle test to exhaustion with or without administration of the non-selective beta-blocker propranolol. Changes in cerebral blood flow velocity were measured with transcranial Doppler ultrasound and those in cerebral oxygenation were evaluated using near-infrared spectroscopy and the calculated cerebral mitochondrial oxygen tension derived from arterial to internal jugular venous concentration differences. Results:, Arterial lactate and cardiac output increased to 15.3 ± 4.2 mm and 20.8 ± 1.5 L min,1 respectively (mean ± SD). Frontal lobe oxygenation remained unaffected but the calculated cerebral mitochondrial oxygen tension decreased by 29 ± 7 mmHg (P < 0.05). Propranolol reduced resting heart rate (58 ± 6 vs. 69 ± 8 beats min,1) and at exercise exhaustion, cardiac output (16.6 ± 3.6 L min,1) and arterial lactate (9.4 ± 3.7 mm) were attenuated with a reduction in exercise capacity from 239 ± 42 to 209 ± 31 W (all P < 0.05). Propranolol also attenuated the increase in cerebral blood flow velocity and frontal lobe oxygenation (P < 0.05) whereas the cerebral mitochondrial oxygen tension decreased to a similar degree as during control exercise (delta 28 ± 10 mmHg; P < 0.05). Conclusion:, Propranolol attenuated the increase in cardiac output of consequence for cerebral perfusion and oxygenation. We suggest that a decrease in cerebral oxygenation limits exercise capacity. [source]

    Lithium and KB-R7943 effects on mechanics and energetics of rat heart muscle

    ACTA PHYSIOLOGICA, Issue 1 2002
    P. Bonazzola
    ABSTRACT The role of calcium influx on energy expenditure during cardiac contraction was studied. For this purpose, the described ability of lithium and KB-R 7943 (KBR) to diminish Ca entry through Na,Ca exchanger (Ponce-Hornos & Langer, J Mol Cell Cardiol 1980, 12, 1367, Satoh et al., Circulation 2000, 101, 1441) were used. In isolated contractions (contractions elicited after at least 5 min of rest) LiCl 45 mmol L,1 decreased pressure developed and pressure,time integral from 42.3 ± 2.7 and 14.5 ± 1.2 to 32.1 ± 3.4 mN mm,2 and 8.3 ± 0.9 mN mm,2 s, respectively. A similar effect was observed in regular contractions (at 0.16 Hz stimulation). The presence of KBR (5 ,mol L,1) in the perfusate induced a slight but not significant decrease in pressure developed and pressure,time integral in steady-state contractions. As it was previously described, the heat involved in a heart muscle contraction can be decomposed into several components (H1, H2, H3 and H4), but only one (H3) was associated with force generation. While H3 decreased with lithium in both types of contractions, H3/PtI ratio remained unaltered, indicating that the economy for pressure maintenance was unaffected. To further investigate the role of Ca entry on force development, a condition in which the contraction is mainly dependent on extracellular calcium was studied. An ,extra' stimulus applied 200 ms after the regular one in a muscle stimulated at 0.16 Hz induces a contraction with this characteristic (Marengo et al., Am J Physiol 1999, 276, H309). Lithium induced a strong decrease in pressure,time integral and H3 associated with this contraction (43 and 45%, respectively) with no change in H3/PtI ratio. Lithium also reduced (53%) an energy component (H2) associated with Ca cycling. The use of KBR showed qualitatively similar results [i.e. a 33% reduction in pressure,time integral associated with the extrasystole (ES) with no changes in H3/PtI ratio and a 30% reduction in the H2 component]. Li and KBR effects appear to be additive and in the presence of 45 mmol L,1 Li and 5 ,mol L,1 KBR the extrasystole was abolished in 77%. Lithium and KBR effects particularly for the extrasystole can be explained through the inhibition of Ca entry via Na,Ca exchange giving support to the participation of the Na,Ca exchanger in the Ca influx from the extracellular space. In addition, the results also suggest the possibility of an effect of Li on an additional Ca sensitive locus (different than the Na,Ca exchanger). In this connection, in isolated contractions lithium decreased the energy release fraction related to mitochondrial processes (H4) increasing the economy of the overall cardiac contraction. [source]

    Myosin Vb localises to nucleoli and associates with the RNA polymerase I transcription complex

    CYTOSKELETON, Issue 12 2009
    Andrew J. Lindsay
    Abstract It is becoming increasingly clear that the mammalian class V myosins are involved in a wide range of cellular processes such as receptor trafficking, mRNA transport, myelination in oligodendrocytes and cell division. Using paralog-specific antibodies, we observed significant nuclear localisation for both myosin Va and myosin Vb. Myosin Vb was present in nucleoli where it co-localises with RNA polymerase I, and newly synthesised ribosomal RNA (rRNA), indicating that it may play a role in transcription. Indeed, its nucleolar pattern was altered upon treatment with RNA polymerase I inhibitors. In contrast, myosin Va is largely excluded from nucleoli and is unaffected by these inhibitors. Myosin Vb was also found to physically associate with RNA polymerase I and actin in co-immunoprecipitation experiments. We propose that myosin Vb serves a role in rRNA transcription. Cell Motil. Cytoskeleton 2009. © 2009 Wiley-Liss, Inc. [source]

    TOGp regulates microtubule assembly and density during mitosis and contributes to chromosome directional instability

    CYTOSKELETON, Issue 8 2009
    Lynne Cassimeris
    Abstract TOGp, a member of the XMAP215 MAP family, is required for bipolar mitotic spindle assembly. To understand how TOGp contributes to spindle assembly, we examined microtubule dynamics after depleting TOGp by siRNA. Fluorescence recovery after photobleaching of GFP-tubulin demonstrated that spindle microtubule turnover is slowed two-fold in the absence of TOGp. Consistent with photobleaching results, microtubule regrowth after washout of the microtubule depolymerizing drug nocodazole was slower at the centrosomes and in the vicinity of mitotic chromatin in cells depleted of TOGp. The slower microtubule turnover is likely due to either nucleation or the transitions of dynamic instability because TOGp depletion did not effect the rate of plus end growth, measured by tracking EB1-GFP at microtubule ends. In contrast, microtubule regrowth after nocodazole washout was unaffected by prior depletion of TACC3, a centrosomal protein that interacts with TOGp. Kinetochore fibers in both untreated and TOGp-depleted cells were stable to incubation at 4°C or lysis in buffer containing calcium indicating that stable kinetochore-microtubule attachments are formed in the absence of TOGp. Depletion of TOGp, but not TACC3, reduced kinetochore oscillations during prometaphase/metaphase. Defects in oscillations are not due simply to multipolarity or loss of centrosome focus in the TOGp-depleted cells, since kinetochore oscillations appear normal in cells treated with the proteosome inhibitor MG132, which also results in multipolar spindles and centrosome fragmentation. We hypothesize that TOGp is required for chromosome motility as a downstream consequence of reduced microtubule dynamics and/or density. Cell Motil. Cytoskeleton 2009. © 2009 Wiley-Liss, Inc. [source]

    The effect of combined hypergravity and microgrooved surface topography on the behaviour of fibroblasts

    CYTOSKELETON, Issue 7 2006
    W. A. Loesberg
    Abstract This study evaluated in vitro the differences in morphological behaviour between fibroblast cultured on smooth and microgrooved substrata (groove depth: 1 ,m, width: 1, 2, 5, 10 ,m), which undergo artificial hypergravity by centrifugation (10, 24 and 50 g; or 1 g control). The aim of the study was to clarify which of these parameters was more important to determine cell behaviour. Morphological characteristics were investigated using scanning electron microscopy and fluorescence microscopy in order to obtain qualitative information on cell spreading and alignment. Confocal laser scanning microscopy visualised distribution of actin filaments and vinculin anchoring points through immunostaining. Finally, expression of collagen type I, fibronectin, and ,1 - and ,1 -integrin were investigated by PCR. Microscopy and image analysis showed that the fibroblasts aligned along the groove direction on all textured surfaces. On the smooth substrata (control), cells spread out in a random fashion. The alignment of cells cultured on grooved surfaces increased with higher g-forces until a peak value at 25 g. An ANOVA was performed on the data, for all main parameters: topography, gravity force, and time. In this analysis, all parameters proved significant. In addition, most gene levels were reduced by hypergravity. Still, collagen type 1 and fibronectin are seemingly unaffected by time or force. From our data it is concluded that the fibroblasts primarily adjust their shape according to morphological environmental cues like substratum surface whilst a secondary, but significant, role is played by hypergravity forces. Cell Motil. Cytoskeleton 2006. © 2006 Wiley-Liss, Inc. [source]

    Expression of WASP and Scar1/WAVE1 actin-associated proteins is differentially modulated during differentiation of HL-60 cells

    CYTOSKELETON, Issue 4 2003
    Sophie Launay
    Abstract The Wiskott-Aldrich Syndrome (WAS) is a disease associated with mutations in the WAS gene and characterised by developmental defects in haematopoietic cells such as myeloid cells. The Wiskott-Aldrich Syndrome protein (WASP)-family includes Scar1 and WASP, which are key regulators of actin reorganization in motile cells. To understand the roles of Scar1 and WASP in myeloid cells and their cytoskeletal control in haematopoietic tissues, we have explored their expression during differentiation of the promyeloid cell line HL-60. Undifferentiated HL-60 cells expressed Scar1 and WASP, and differentiation to neutrophils, induced by retinoic acid or non-retinoid agent treatments, led to a decrease in the level of expression of Scar1, whereas WASP expression was unaffected. Differentiation to monocytes/macrophages, induced by phorbol ester treatment, resulted in a decreased expression of both proteins in the adherent mature cells. Vitamin D3 treatment or cytochalasin D in combination with PMA treatment did not affect WASP expression suggesting that adhesion and cytoskeletal integrity were both essential to regulate WASP expression. Scar1 expression was regulated by differentiation, adhesion, and cytoskeletal integrity. Recently, WASP was found to colocalize with actin in the podosomes. In contrast, we show here that Scar1 did not localize with the podosomes in mature monocytes/macrophages. These observations show for the first time that modulation of Scar1 and WASP expression is a component of the differentiation program of myeloid precursors and indicate that WASP and Scar1 have different roles in mature myeloid cells. Cell Motil. Cytoskeleton 54:274,285, 2003. © 2003 Wiley-Liss, Inc. [source]

    Contractility of single human dermal myofibroblasts and fibroblasts

    CYTOSKELETON, Issue 2 2002
    Louise K. Wrobel
    Abstract Human dermal myofibroblasts, characterised by the expression of ,-smooth muscle actin, are part of the granulation tissue and implicated in the generation of contractile forces during normal wound healing and pathological contractures. We have compared the contractile properties of single human dermal fibroblasts and human dermal myofibroblasts by culturing them on flexible silicone elastomers. The flexibility of the silicone substratum permits the contractile forces exerted by the cells to be measured [Fray et al., 1998: Tissue Eng. 4:273,283], without changing their expression of ,-smooth muscle actin. The mean contractile force produced by myofibroblasts (2.2 ,N per cell) was not significantly different from that generated by fibroblasts (2.0 ,N per cell) when cultured on a substrata with a low elastomer stiffness. Forces produced by fibroblasts were unaffected by increases in elastomer stiffness, but forces measured for myofibroblasts increased to a mean value of 4.1 ,N/cell. This was associated with a higher proportion of myofibroblasts being able to produce wrinkles on elastomers of high stiffness compared to fibroblasts. We discuss the force measurements at the single cell level, for both fibroblast and myofibroblasts, in relation to the proposed role of myofibroblasts in wound healing and pathological contractures. Cell Motil. Cytoskeleton 52:82,90, 2002. © 2002 Wiley-Liss, Inc. [source]

    Splinting duration and periodontal outcomes for replanted avulsed teeth: a systematic review

    Susan Elisabeth Hinckfuss
    The principles of evidence-based dentistry can be used to assess whether these guidelines are based on currently-available evidence. A qualitative systematic review was conducted of relevant clinical literature to examine the evidence on splinting duration and periodontal healing outcomes. The review was constrained markedly by small sample sizes, retrospective nature of clinical audits, dissimilarities of selected studies in their design, methodology and observation periods, and lack of uniformity in terminology for outcomes. A total of 138 replanted avulsed permanent teeth pooled from four papers each reporting both short-term splinting (14 days or less) and long-term splinting (over 14 days) in accord with current clinical guidelines, were studied. The evidence for an association between short-term splinting and an increased likelihood of functional periodontal healing, acceptable healing, or decreased development of replacement resorption, appears inconclusive. The study found no evidence to contraindicate the current guidelines and suggests that the likelihood of successful periodontal healing after replantation is unaffected by splinting duration. Pending future research to the contrary, it is recommended that dentists continue to use the currently-recommended splinting periods when replanting avulsed permanent teeth. [source]

    Antidepressant use in a nationally representative sample of community-dwelling US Latinos with and without depressive and anxiety disorders,

    Hector M. González Ph.D.
    Abstract Background: Antidepressant drugs are among the most widely prescribed drugs in the United States; however, little is known about their use among major ethnic minority groups. Method: Collaborative Psychiatric Epidemiology Surveys (CPES) data were analyzed to calculate nationally representative estimates of Latino and non-Latino White adults antidepressant use. Setting: The 48 coterminous United States was the setting. Participants: Household residents aged 18 years and older (N=9,250). Main outcome: Past year antidepressant use. Results: Compared to non-Latino Whites, few Latinos, primarily Mexican Americans, with 12-month depressive and/or anxiety disorders reported past year antidepressant use. Mexican Americans (OR=0.48; 95%CI=0.30,0.77) had significantly lower odds of use compared to non-Latino Whites, which were largely unaffected by factors associated with access to care. Over half of antidepressant use was by respondents not meeting 12-month criteria for depressive or anxiety disorders. Lifetime depressive and anxiety disorders explained another 21% of past year antidepressant use, leaving another 31% of drug use unexplained. Discussion: We found a disparity in antidepressant use for Mexican Americans compared to non-Latino Whites that was not accounted for by differences in need and factors associated with access to care. About one third of antidepressant use was by respondents not meeting criteria for depressive or anxiety disorders. Our findings underscore the importance of disaggregating Latino ethnic groups. Additional work is needed to understand the medical and economic value of antidepressant use beyond their primary clinical targets. Depression and Anxiety, 2009. Published 2009 Wiley-Liss, Inc. [source]

    Retinoic acid controls expression of tissue remodeling genes Hmgn1 and Fgf18 at the digit,interdigit junction

    Xianling Zhao
    Abstract Previous studies on retinoic acid receptor (RAR) mutants suggested that retinoic acid (RA) is required for loss of interdigital mesenchyme during digit formation. Here, we report that the RA-generating enzyme retinaldehyde dehydrogenase-2 (Raldh2) is expressed in the interdigital mesenchyme whereas Cyp26b1, controlling RA degradation, is expressed in digits, limiting autopodal RA action to the interdigital zones. Embryonic day 13.5 Raldh2,/, mouse embryos lose expression of the RARE-lacZ RA-reporter transgene and matrix metalloproteinase-11 (Mmp11) throughout the interdigital mesenchyme, while expression of RARb, Fgf18, and high mobility group N1 (Hmgn1) is lost at the digit,interdigit junction. Raldh2,/, autopods exhibit reduced interdigital apoptosis associated with loss of Bmp7 expression, but Bmp2, Bmp4, Msx2, and Fgf8 were unaffected. Although interdigital expression of Hmgn1 was greatly down-regulated in Raldh2,/, autopods, complementary expression of Sox9 in digit cartilage was unaffected. Regulation of Hmgn1 and Fgf18 at the digit,interdigit junction suggests RA controls tissue remodeling as well as apoptosis. Developmental Dynamics 239:665,671, 2010. © 2009 Wiley-Liss, Inc. [source]

    Gli3 -deficient mice exhibit cleft palate associated with abnormal tongue development

    Xi Huang
    Abstract Palatogenesis depends on appropriate growth, elevation, and fusion of the palatal shelves and aberration in these processes can lead to palatal clefting. We observed a high incidence of palate clefting in mice deficient in Gli3, known for its role as a repressor in the absence of Shh signaling. In contrast with several current mouse models of cleft palate, Meckel's cartilage extension, cranial neural crest migration, palatal shelf proliferation, apoptosis, and key signaling components mediated by Shh, Bmp, Fgf, and Tgf,, appeared unaffected in Gli3,/, mice. Palatal clefting in Gli3,/, mice was consistently associated with tongue abnormalities such as failure to flatten and improper positioning, implicating a critical role of Gli3 and normal tongue morphogenesis for timely palatal shelf elevation and joining. Furthermore, Gli3,/, palatal shelves grown in roller cultures without tongue can fuse suggesting that the abnormal tongue is likely an impediment for palatal shelf joining in Gli3,/, mutants. Developmental Dynamics 237:3079,3087, 2008. © 2008 Wiley-Liss, Inc. [source]

    Analysis of pancreatic endocrine development in GDF11-deficient mice

    Darwin S. Dichmann
    Abstract Here, we examine the role of GDF11 in pancreatic development. Using in situ hybridization and reverse transcriptase-polymerase chain reaction analyses, we show that Gdf11 transcripts are expressed in embryonic pancreas epithelium before the secondary transition but decrease rapidly afterward. To determine the function of GDF11 during pancreas development, we analyzed Gdf11,/, mouse embryos. In such embryos, pancreas size is twofold reduced at embryonic day (E) 18 compared with wild-type littermates. Quantification of the different tissue compartments shows a specific hypoplasia of the exocrine compartment, while the endocrine and ductal compartments are unaffected. Notably, NGN3+ endocrine precursor cells are increased fourfold at E18, although the amount of endocrine cells in the pancreas of these animals is unchanged compared with wild-type littermates. Similarly, the maturation of endocrine cells as well as the ratio between ,- and ,-cells appears normal. Developmental Dynamics 235:3016,3025, 2006. © 2006 Wiley-Liss, Inc. [source]

    Differential regulation of GDF-5 and FGF-2/4 by immobilisation in ovo exposes distinct roles in joint formation,

    E. Kavanagh
    Abstract Members of the fibroblast growth factor (FGF) family and growth and differentiation factor 5 (GDF-5) have been implicated in joint specification, but their roles in subsequent cavity formation are not defined. Cavity formation (cavitation) depends upon limb movement in embryonic chicks and factors involved in joint formation are often identified by their expression at the joint-line. We have sought support for the roles of FGF-2, FGF-4, and GDF-5 in cavitation by defining expression patterns, immunohistochemically, during joint formation and establishing whether these are modified by in ovo immobilisation. We found that FGF-2 exhibited low level nuclear expression in chondrocytes and fibrocartilage cells close to presumptive joints, but showed significantly higher expression levels in cells at, and directly bordering, the forming joint cavity. This high-level joint line FGF-2 expression was selectively diminished in immobilised limbs. In contrast, we show that FGF-4 does not exhibit differential joint-line expression and was unaffected by immobilisation. GDF-5 protein also failed to show joint-line selective labelling, and although immobilisation induced a cartilaginous fusion across presumptive joints, it did not affect cellular GDF-5 expression patterns. Examining changes in GDF-5 expression in response to a direct mechanical strain stimulus in primary embryonic chick articular surface (AS) cells in vitro discloses only small mechanically-induced reductions in GDF-5 expression, suggesting that GDF-5 does not exert a direct positive contribution to the mechano-dependent joint cavitation process. This notion was supported by retroviral overexpression of UDPGD, a characteristic factor involved in hyaluronan (HA) accumulation at presumptive joint lines, which was also found to produce small decreases in AS cell GDF-5 expression. These findings support a direct mechano-dependent role for FGF-2, but not FGF-4, in the cavitation process and indicate that GDF-5 is likely to influence chondrogenesis positively without contributing directly to joint cavity formation. Developmental Dynamics 235:826,834, 2006. © 2006 Wiley-Liss, Inc. [source]

    Vascular regression is required for mesenchymal condensation and chondrogenesis in the developing limb

    Melinda Yin
    Abstract Vascular regression occurs during limb mesenchymal cell condensation and chondrogenesis, but it is unclear whether it is required for these processes or is a secondary phenomenon without major regulatory roles. To address this issue, beads presoaked with the potent angiogenic factor vascular endothelial growth factor (VEGF) were implanted in the vicinity of the prospective digit 2 in early chick embryo wing buds and the effects on angiogenesis and digit development were determined over time. We found that VEGF treatment caused a marked local increase in blood vessel number and density. Strikingly, this was accompanied by inhibition of digit 2 development as revealed by lack of expression of chondrogenic transcription factor Sox9 and absence of Alcian blue staining. Vascular distribution and skeletal development in adjacent areas remained largely unaffected. Inhibition of digit formation and excess vascularization were both reversible upon further embryonic growth and dissipation of VEGF activity. When supernumerary digits were induced at the anterior limb margin by retinoic acid treatment, their development was also preceded by vascular regression; interestingly, cotreatment with VEGF inhibited supernumerary digit development as well. Direct exposure of limb mesenchymal cells in micromass cultures to VEGF caused no obvious effects on condensation and chondrogenesis, indicating that VEGF effects are not due to direct action on skeletal cells. Our results are the first to provide evidence that vascular regression is required for mesenchymal condensation and chondrogenesis. A model of how patterning mechanisms and vascular regression may intersect and orchestrate limb skeletogenesis is proposed. © 2001 Wiley-Liss, Inc. [source]

    Neonatal estrogen exposure inhibits steroidogenesis in the developing rat ovary

    Yayoi Ikeda
    Abstract Treatment of newborn female rats with estrogens significantly inhibits the growth and differentiation of the ovary. To understand the molecular mechanism of estrogen action in the induction of abnormal ovary, we examined the expression profiles of steroidogenic factor 1 (SF-1) and several of its target genes in the developing ovaries after neonatal exposure to synthetic estrogen, estradiol benzoate (EB) by using reverse transcriptase polymerase chain reaction, in situ hybridization, and immunohistochemistry. Morphologic examination indicated inhibitory effects of estrogen on the stratification of follicles and development of theca and interstitial gland during postnatal ovarian differentiation. The expression of the steroidogenic acute regulatory protein (StAR) and cholesterol side-chain cleavage cytochrome P450 (P450SCC), which are both essential for steroid biosynthesis, markedly decreased in theca and interstitial cells throughout the postnatal development of the EB-treated ovary. However, expression of the transcriptional activator of the two genes, SF-1 was unaffected in theca and interstitial cells, although the number of these cells was lower in the EB-treated ovary than in the control ovary. The expression of the estrogen mediator, estrogen receptor-, (ER-,), diminished specifically in theca cells at P6 and recovered by P14 in the EB-treated ovary. These results indicate that the effect of estrogens is mediated by means of ER-, resulting in the down-regulation of StAR and P450SCC genes during early postnatal development of the ovary. These results suggest that the abnormal ovarian development by neonatal estrogen treatment is closely correlated with the reduced steroidogenic activity, and the data obtained by using this animal model may account in part the mechanism for aberrant development and function of the ovary in prenatally estrogen-exposed humans. © 2001 Wiley-Liss, Inc. [source]

    Aromatase expression and cell proliferation following injury of the adult zebra finch hippocampus

    R. Scott Peterson
    Abstract Estrogens can be neuroprotective following traumatic brain injury. Immediately after trauma to the zebra finch hippocampus, the estrogen-synthetic enzyme aromatase is rapidly upregulated in astrocytes and radial glia around the lesion site. Brain injury also induces high levels of cell proliferation. Estrogens promote neuronal differentiation, migration, and survival naturally in the avian brain. We suspect that glia are a source of estrogens promoting cell proliferation after neural injury. To explore this hypothesis, we examined the spatial and temporal relationship between glial aromatase expression and cell proliferation after neural injury in adult female zebra finches. Birds were ovariectomized and given a blank implant or one filled with estradiol; some birds were also administered an aromatase inhibitor or vehicle. All birds received penetrating injuries to the right hippocampus. Twenty-four hours after lesioning, birds were injected once with BrdU to label mitotically active cells and euthanized 2 h, 24 h, or 7 days later. The brains were processed for double-label BrdU and aromatase immunocytochemistry. Injury-induced glial aromatase expression was unaffected by survival time and aromatase inhibition. BrdU labeling was significantly reduced at 24 h by ovariectomy and by aromatase inhibition; effects were partially reversed by E2 replacement. Irrespective of ovariectomy, the densities of aromatase immunoreactive astrocytes and BrdU-labeled cells at known distances from the lesion site were highly correlated. These data suggest that injury-induced glial aromatization may influence the reorganization of injured tissue by providing a rich estrogenic environment available to influence cellular incorporation. © 2007 Wiley Periodicals, Inc. Develop Neurobiol, 2007. [source]

    Activation of a calcium entry pathway by sodium pyrithione in the bag cell neurons of Aplysia

    Ronald J. Knox
    Abstract The ability of sodium pyrithione (NaP), an agent that produces delayed neuropathy in some species, to alter neuronal physiology was accessed using ratiometric imaging of cytosolic free Ca2+ concentration ([Ca2+]i) in fura PE-filled cultured Aplysia bag cell neurons. Bath-application of NaP evoked a [Ca2+]i elevation in both somata and neurites with an EC50 of ,300 nM and a Hill coefficient of ,1. The response required the presence of external Ca2+, had an onset of 3,5 min, and generally reached a maximum within 30 min. 2-Methyl-sulfonylpyridine, a metabolite and close structural analog of NaP, did not elevate [Ca2+]i. Under whole-cell current-clamp recording, NaP produced a ,14 mV depolarization of resting membrane potential that was dependent on external Ca2+. These data suggested that NaP stimulates Ca2+ entry across the plasma membrane. To minimize the possibility that a change in cytosolic pH was the basis for NaP-induced Ca2+ entry, bag cell neuron intracellular pH was estimated with the dye 2,,7,-bis(carboxyethyl-5(6)-carboxy-fluorescein acetoxy methylester. Exposure of the neurons to NaP did not alter intracellular pH. The slow onset and sustained nature of the NaP response suggested that a cation exchange mechanism coupled either directly or indirectly to Ca2+ entry could underlie the phenomenon. However, neither ouabain, a Na+/K+ ATPase inhibitor, nor removal of extracellular Na+, which eliminates Na+/Ca2+ exchanger activity, altered the NaP-induced [Ca2+]i elevation. Finally, the possibility that NaP gates a Ca2+ -permeable ion channel in the plasma membrane was examined. NaP did not appear to activate two major forms of bag cell neuron Ca2+ -permeable ion channels, as Ca2+ entry was unaffected by inhibition of voltage-gated Ca2+ channels using nifedipine or by inhibition of a voltage-dependent, nonselective cation channel using a high concentration of tetrodotoxin. In contrast, two potential store-operated Ca2+ entry current inhibitors, SKF-96365 and Ni2+, attenuated NaP-induced Ca2+ entry. We conclude that NaP activates a slow, persistent Ca2+ influx in Aplysia bag cell neurons. © 2004 Wiley Periodicals, Inc. J Neurobiol 411,423, 2004 [source]

    Nicotinic synapses formed between chick ciliary ganglion neurons in culture resemble those present on the neurons in vivo

    Min Chen
    Abstract We studied nicotinic synapses between chick ciliary ganglion neurons in culture to learn more about factors influencing their formation and receptor subtype dependence. After 4,8 days in culture, nearly all neurons displayed spontaneous excitatory postsynaptic currents (sEPSCs), which occurred at about 1 Hz. Neurons treated with tetrodotoxin displayed miniature EPSCs (mEPSCs), but these occurred at low frequency (0.1 Hz), indicating that most sEPSCs are actually impulse driven. The sEPSCs could be classified by decay kinetics as fast, slow, or biexponential and, reminiscent of the situation in vivo, were mediated by two major nicotinic acetylcholine receptor (AChR) subtypes. Fast sEPSCs were blocked by ,-bungarotoxin (,Bgt), indicating dependence on ,Bgt-AChRs, most of which are ,7 subunit homopentamers. Slow sEPSCs were unaffected by ,Bgt, and were blocked instead by the ,3/,2-selective ,-conotoxin-MII (,CTx-MII), indicating dependence on ,3*-AChRs, which lack ,7 and contain ,3 subunits. Biexponential sEPSCs were mediated by both ,Bgt- and ,3*-AChRs because they had fast and slow components qualitatively similar to those comprising simple events, and these were reduced by ,Bgt and blocked by ,CTx-MII, respectively. Fluorescence labeling experiments revealed both ,Bgt- and ,3*-AChR clusters on neuron somata and neurites. Colabeling with antisynaptic vesicle protein antibody suggested that some ,3*-AChR clusters, and a few ,Bgt-AChR clusters are associated with synaptic sites, as is the case in vivo. These findings demonstrate the utility of ciliary ganglion neuron cultures for studying the regulation of nicotinic synapses, and suggest that mixed AChR subtype synapses characteristic of the neurons in vivo can form in the absence of normal inputs or targets. © 2001 John Wiley & Sons, Inc. J Neurobiol 47: 265,279, 2001 [source]

    The eyes have it: visual pop-out in infants and adults

    Scott A. Adler
    Visual search studies with adults have shown that stimuli that contain a unique perceptual feature pop out from dissimilar distractors and are unaffected by the number of distractors. Studies with very young infants have suggested that they too might exhibit pop-out. However, infant studies have used paradigms in which pop-out is measured in seconds or minutes, whereas in adults pop-out occurs in milliseconds. In addition, with the previous infant paradigms the effects from higher cognitive processes such as memory cannot be separated from pop-out and selective attention. Consequently, whether infants exhibit the phenomenon of pop-out and have selective attention mechanisms as found in adults is not clear. This study was an initial attempt to design a paradigm that would provide a comparable measure between infants and adults, thereby allowing a more accurate determination of the developmental course of pop-out and selective attention mechanisms. To this end, we measured 3-month-olds' and adults' saccade latencies to visual arrays that contained either a + among Ls (target-present) or all Ls (target-absent) with set sizes of 1, 3, 5 or 8 items. In Experiment 1, infants' saccade latencies remained unchanged in the target-present conditions as set size increased, whereas their saccade latencies increased linearly in the target-absent conditions as set size increased. In Experiment 2, adults' saccade latencies in the target-present and target-absent conditions showed the same pattern as the infants. The only difference between the infants and adults was that the infants' saccade latencies were slower in every condition. These results indicate that infants do exhibit pop-out on a millisecond scale, that it is unaffected by the number of distractors, and likely have similar functioning selective attention mechanisms. Moreover, the results indicate that eye movement latencies are a more comparable and accurate measure for assessing the phenomenon of pop-out and underlying attentional mechanisms in infants. [source]

    Effects of sulfonylureas on mitochondrial ATP-sensitive K+ channels in cardiac myocytes: implications for sulfonylurea controversy

    Toshiaki Sato
    Abstract Background Mitochondrial ATP-sensitive K+ (mitoKATP) channel plays a key role in cardioprotection. Hence, a sulfonylurea that does not block mitoKATP channels would be desirable to avoid damage to the heart. Accordingly, we examined the effects of sulfonylureas on the mitoKATP channel and mitochondrial Ca2+ overload. Methods Flavoprotein fluorescence in rabbit ventricular myocytes was measured to assay mitoKATP channel activity. The mitochondrial Ca2+ concentration was measured by loading cells with rhod-2. Results The mitoKATP channel opener diazoxide (100 µM) reversibly increased flavoprotein oxidation to 31.8 ± 4.3% (n = 5) of the maximum value induced by 2,4-dinitrophenol. Glimepiride (10 µM) alone did not oxidize the flavoprotein, and the oxidative effect of diazoxide was unaffected by glimepiride (35.4 ± 3.2%, n = 5). Similarly, the diazoxide-induced flavoprotein oxidation was unaffected both by gliclazide (10 µM) and by tolbutamide (100 µM). Exposure to ouabain (1 mM) for 30 min produced mitochondrial Ca2+ overload, and the intensity of rhod-2 fluorescence increased to 197.4 ± 7.2% of baseline (n = 11). Treatment with diazoxide significantly reduced the ouabain-induced mitochondrial Ca2+ overload (149.6 ± 5.1%, n = 11, p < 0.05 versus ouabain alone), and the effect was antagonized by the mitoKATP channel blocker 5-hydroxydecanoate (189.8 ± 27.8%, n = 5) and glibenclamide (193.1 ± 7.7%, n = 8). On the contrary, cardioprotective effect of diazoxide was not abolished by glimepiride (141.8 ± 7.8%, n = 6), gliclazide (139.0 ± 9.4%, n = 5), and tolbutamide (141.1 ± 4.5%, n = 7). Conclusions Our results indicate that glimepiride, gliclazide, and tolbutamide have no effect on mitoKATP channel, and do not abolish the cardioprotective effects of diazoxide. Therefore, these sulfonylureas, unlike glibenclamide, do not interfere with the cellular pathways that confer cardioprotection. Copyright © 2006 John Wiley & Sons, Ltd. [source]

    Improved glycaemic control with metformin,glibenclamide combined tablet therapy (Glucovance®) in Type 2 diabetic patients inadequately controlled on metformin

    DIABETIC MEDICINE, Issue 8 2002
    M. Marre
    Abstract Aims To evaluate the efficacy and safety of two dosage strengths of a single-tablet metformin,glibenclamide (glyburide) combination, compared with the respective monotherapies, in patients with Type 2 diabetes mellitus (DM) inadequately controlled by metformin monotherapy. Methods In this 16-week, double-blind, multicentre, parallel-group trial, 411 patients were randomized to receive metformin 500 mg, glibenclamide 5 mg, metformin,glibenclamide 500 mg/2.5 mg or metformin,glibenclamide 500 mg/5 mg, titrated with the intention to achieve fasting plasma glucose (FPG) , 7 mmol/l. Results Decreases in glycated haemoglobin (HbA1c) and FPG were greater (P < 0.05) for metformin,glibenclamide 500 mg/2.5 mg (,1.20% and ,2.62 mmol/l) and 500 mg/5 mg (,0.91% and ,2.34 mmol/l), compared with metformin (,0.19% and ,0.57 mmol/l) or glibenclamide (,0.33% and ,0.73 mmol/l). HbA1c < 7% was achieved by 75% and 64% of patients receiving metformin,glibenclamide 500 mg/2.5 mg and 500 mg/5 mg, respectively, compared with 42% for glibenclamide and 38% for metformin (P = 0.001). These benefits were achieved at lower mean doses of metformin or glibenclamide with metformin,glibenclamide 500 mg/2.5 mg and 500 mg/5 mg (1225 mg/6.1 mg and 1170 mg/11.7 mg) than with glibenclamide (13.4 mg) or metformin (1660 mg). Treatment-related serious adverse events occurred in two patients receiving glibenclamide. Plasma lipid profiles were unaffected and mean changes in body weight were , 1.0 kg. Conclusions Intensive management of Type 2 DM with a new metformin,glibenclamide combination tablet improved glycaemic control and facilitated the attainment of glycaemic targets at lower doses of metformin or glibenclamide compared with the respective monotherapies, without compromising tolerability. Diabet. Med. 19, 673,680 (2002) [source]