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PubMed1983

Analysis of cloned T cell function. II. Differential blockade of various cloned T cell functions by cyclosporine.

Cyclosporine has profound suppressive effects on selected in vitro functions of cloned T lymphocytes. Cyclosporine inhibits the antigen-induced proliferation of the helper T cell clone 12-11. The effective dose required to reduce this response by 50% (ED50) is 28 ng/ml. In contrast, the proliferation of clone 12-11 induced by exogenous growth factors in secondary mixed lymphocyte culture supernatant (2 degrees MLC SN), is relatively insensitive to cyclosporine (ED50 = 4600 ng/ml). Furthermore, cyclosporine abrogates both antigen-induced and mitogen-induced secretion of lymphokines by clone 12-11, indicating that cloned helper T cell function is sensitive to cyclosporine even when interactions between specific alloantigens and their cell surface receptors are bypassed with mitogen. The suppressive effect of cyclosporine is not limited to helper T cell clones. The cytolytic T lymphocyte (CTL) clone 5MD2-2 is also sensitive to cyclosporine. Again, cyclosporine (100 ng/ml) blocks the antigen-driven, but not the exogenous lymphokine-driven, component of clone 5MD2-2 proliferation. This suppression does not result from the occlusion of antigen receptors or from antigen deformation by cyclosporine, because clone 5MD2-2 remains capable of antigen-specific cytolysis in the presence of cyclosporine concentrations that can suppress its proliferation. Finally, the ability of clone 5MD2-2 to remove IL-2 activity from culture media, a function that is significantly enhanced by contact with specific alloantigen, is not influenced by suppressive cyclosporine concentrations.

Animals↗

PubMed1993

Characterization of maturation and function of natural killer cells in xenogeneic (rat-->mouse) bone marrow chimeras. Evidence that rat NK cells are present and functional in a xenogeneic environment.

Reconstitution of B10 recipient mice, conditioned with total body irradiation (950 rads), with 40 x 10(6) untreated F344 or WF rat bone marrow cells results in stable rat stem-cell engraftment with multilineage lymphohematopoietic chimerism. We have now characterized NK cell generation, maturation, and function in fully xenogeneic chimeras (WF rat-->B10 mouse; F344-->B10 mouse). Early during xenogeneic reconstitution, rat-derived NK cells predominated in splenic lymphoid tissue, composing 14-18% of total cells at week 1 and increasing to 35.6-59.9% of total cells at week 2. By week 6, levels of rat NK cells had decreased and stabilized to that expected for normal rat (9-14.2%). The NK chimerism was reliably stable for up to 7 months following reconstitution. Most importantly, rat-derived NK cells were functional in both YAC tumor cytolysis and ADCC assays, suggesting that the xenogeneic mouse host environment was sufficient to support the generation, maturation, and function of rat-derived NK cells.

Animals↗

PubMed2004

Functionality of allelic variations in human alcohol dehydrogenase gene family: assessment of a functional window for protection against alcoholism.

Alcohol dehydrogenase (ADH) catalyses the rate-determining reaction in ethanol metabolism. Genetic association studies of diverse ethnic groups have firmly demonstrated that the allelic variant ADH1B*2 significantly protects against alcoholism but that ADH1C*1, which is in linkage with ADH1B*2, produces a negligible protection. The influence of other potential candidate genes/alleles within the human ADH family, ADH1B*3 and ADH2, remains unclear or controversial. To address this question, functionalities of ADH1B3 and ADH2 were assessed at a physiological level of coenzyme and substrate range. Ethanol-oxidizing activities of recombinant ADH1B1, ADH1B2, ADH1B3, ADH1C1, ADH1C2 and ADH2 were determined at pH 7.5 in the presence of 0.5 mm NAD with 2-50 mm ethanol. The activity differences between ADH1B2 and ADH1B1 were taken as a threshold for effective protection against alcoholism and those between ADH1C1 and ADH1C2 as a threshold for null protection. Over 2-50 mm ethanol, the activities of ADH1B3 were found 2.9-23-fold lower than those of ADH1B2, largely attributed to the Km effect (ADH1B2, 1.8 mm; ADH1B3, 61 mm). Strikingly, the ADH1B3 activity was only 84% that of ADH1B1 at a low ethanol concentration, 2 mm, but increased 10-fold at 50 mm. Corrected for relative expression levels of the enzyme in liver, the hepatic ADH2 activities were estimated to be 18-97% those of ADH1B1 over 2-50 mm ethanol and were 28-140% of the activity differences between ADH1C1 and ADH1C2. The assessment based on the proposed functional window for the human ADH gene family indicates that ADH1B*3 may show some degree of protection against alcoholism and that the ADH2 functional variants appear to be negligible for this protection.

Alcohol Dehydrogenase↗

PubMed2003

Disturbed function and plasticity in multiple sclerosis as gleaned from functional magnetic resonance imaging.

PURPOSE OF REVIEW: This review is intended to provide an up-to-date summary of the main functional magnetic resonance imaging studies conducted in patients with multiple sclerosis, and to show how such studies are changing our views on the ability of the multiple sclerosis brain to limit the clinical consequences of irreversible structural tissue damage. RECENT FINDINGS: Brain cortical reorganization is a common phenomenon occurring in patients with multiple sclerosis, independent of disease duration and clinical phenotype, which can be elicited by macroscopic lesions, as well as by the presence of 'occult' multiple sclerosis-related damage of the brain and cervical cord. An increased recruitment of the cerebral networks involved in the performance of given tasks might represent a first step in cortical reorganization with the potential to maintain a normal level of function in the course of multiple sclerosis. The progressive failure of these mechanisms, because of accumulating tissue damage, might, on the one hand, result in the activation of previously silent 'second-order' compensatory areas, and, on the other, contribute to the accumulation of irreversible disability. SUMMARY: Functional magnetic resonance imaging has the potential to provide important information about cortical reorganization following multiple sclerosis-related tissue damage, which should improve our understanding of the factors associated with the accumulation of irreversible disability in this disease. The enhancement of any beneficial effects of this cortical adaptive plasticity should be considered as a potential target of therapy for multiple sclerosis.

Cerebral Cortex↗

PubMed2006

Adiabatic approximation of the correlation function in the density-functional treatment of ionization processes.

The ionization of a one-dimensional model helium atom in short laser pulses using time-dependent density-functional theory is investigated. We calculate ionization probabilities as a function of laser intensity by approximating the correlation function of the system adiabatically with an explicit dependence on the fractional number of bound electrons. For the correlation potential we take the derivative discontinuity at integer numbers of bound electrons explicitly into account. This approach reproduces ionization probabilities from the solution of the time-dependent Schrödinger equation, in particular, the so-called knee due to nonsequential ionization.

Journal Article↗

PubMed2005

Functional genomic analysis of the AUXIN RESPONSE FACTOR gene family members in Arabidopsis thaliana: unique and overlapping functions of ARF7 and ARF19.

The AUXIN RESPONSE FACTOR (ARF) gene family products, together with the AUXIN/INDOLE-3-ACETIC ACID proteins, regulate auxin-mediated transcriptional activation/repression. The biological function(s) of most ARFs is poorly understood. Here, we report the identification and characterization of T-DNA insertion lines for 18 of the 23 ARF gene family members in Arabidopsis thaliana. Most of the lines fail to show an obvious growth phenotype except of the previously identified arf2/hss, arf3/ett, arf5/mp, and arf7/nph4 mutants, suggesting that there are functional redundancies among the ARF proteins. Subsequently, we generated double mutants. arf7 arf19 has a strong auxin-related phenotype not observed in the arf7 and arf19 single mutants, including severely impaired lateral root formation and abnormal gravitropism in both hypocotyl and root. Global gene expression analysis revealed that auxin-induced gene expression is severely impaired in the arf7 single and arf7 arf19 double mutants. For example, the expression of several genes, such as those encoding members of LATERAL ORGAN BOUNDARIES domain proteins and AUXIN-REGULATED GENE INVOLVED IN ORGAN SIZE, are disrupted in the double mutant. The data suggest that the ARF7 and ARF19 proteins play essential roles in auxin-mediated plant development by regulating both unique and partially overlapping sets of target genes. These observations provide molecular insight into the unique and overlapping functions of ARF gene family members in Arabidopsis.

Arabidopsis↗

PubMed2002

Fine-tuning function: correlation of hinge domain interactions with functional distinctions between LacI and PurR.

LacI and PurR are highly homologous proteins. Their functional units are homodimers, with an N-terminal DNA binding domain that comprises the helix-turn-helix (HTH), N-linker, and hinge regions from both monomers. Hinge structural changes are known to occur upon DNA dissociation but are difficult to monitor experimentally. The initial steps of hinge unfolding were therefore examined using molecular dynamics simulations, utilizing a truncated, chimeric protein comprising the LacI HTH/N-linker and PurR hinge. A terminal Gly-Cys-Gly was added to allow "dimerization" through disulfide bond formation. Simulations indicate that differences in LacI and PurR hinge primary sequence affect the quaternary structure of the hinge x hinge' interface. However, these alternate hinge orientations would be sterically restricted by the core domain. These results prompted detailed comparison of recently available DNA-bound structures for LacI and truncated LacI(1-62) with the PurR structure. Examination revealed that different N-linker and hinge contacts to the core domain of the partner monomer (which binds effector molecule) affect the juxtapositions of the HTH, N-linker, and hinge regions in the DNA binding domain. In addition, the two full-length repressors exhibit significant differences in the interactions between the core and the C-linker connection to the DNA binding domain. Both linkers and the hinge have been implicated in the allosteric response of these repressors. Intriguingly, one functional difference between these two proteins is that they exhibit opposite allosteric response to effector. Simulations and observed structural distinctions are correlated with mutational analysis and sequence information from the LacI/GalR family to formulate a mechanism for fine-tuning individual repressor function.

Bacterial Proteins↗

PubMed2005

Normal opioid tone and hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome despite marked functional impairment.

OBJECTIVE: To determine whether the functional impairment seen in chronic fatigue syndrome (CFS) is associated with reduced levels of central opioids and/or deficiency of the hypothalamic-pituitary-adrenal (HPA) axis. DESIGN: Single-blinded case-control study measuring functional and psychological status, basal hormonal parameters and ACTH/cortisol response to naloxone and ovine corticotrophin-releasing hormone (oCRH) vs. placebo in people with CFS and healthy controls. PATIENTS: Twelve people with CFS and 11 age-matched controls. MEASUREMENTS: Hormonal parameters: basal levels of 09:00 h plasma cortisol, dehydroepiandrosterone sulfate (DHEAS) and IGF-1. 24-h urinary free cortisol. Plasma ACTH and cortisol response to naloxone 125 microg/kg, oCRH 1 microg/kg and placebo (normal saline). Psychological parameters: SF-36, Hamilton Depression Score, Hospital Anxiety and Depression Scale and Fatigue Scale. RESULTS: There were highly significant differences between the CFS subjects and the controls with respect to the measures of fatigue and physical functioning. However, there were no differences in basal levels of 09:00 h cortisol (367 +/- 37 vs. 331 +/- 39 nmol/l, P = 0.51), DHEAS (4.2 +/- 0.6 vs. 4.0 +/- 0.5 micromol/l, P = 0.81), 24-h urinary free cortisol (182 +/- 27 vs. 178 +/- 21 nmol/24 h, P = 0.91) or IGF-1 (145 +/- 19 vs. 130 +/- 11 microg/l, P = 0.52) between the CFS group and controls, respectively. There was also no difference between the groups with respect to the ACTH and cortisol response to either oCRH or naloxone. CONCLUSIONS: Our data do not support an aetiological role for deficiency in central opioids or the HPA axis in the symptoms of CFS.

Adrenocorticotropic Hormone↗

PubMed2004

Functional imaging: new views on lens structure and function.

1. We have developed an experimental imaging approach that allows the distribution of lens membrane proteins to be mapped with subcellular resolution over large distances as a function of fibre cell differentiation. 2. Using this approach in the rat lens, we have localized precisely histological sites of connexin 46 cleavage, quantitatively mapped changes in gap junction distribution and fibre cell morphology and correlated these changes to differences in intercellular dye transfer. 3. Profiling of glucose transporter isoform expression showed that lens epithelial cells express GLUT1, whereas deeper cortical fibre cells express the higher-affinity GLUT3 isoform. Near the lens periphery, GLUT3 was located in the cytoplasm of fibre cells, but it underwent a differentiation-dependent membrane insertion. 4. Similarly, the putative adhesion protein membrane protein 20 is inserted into fibre cell membranes at the stage when the cells lose their nuclei. This redistribution is strikingly rapid in terms of fibre cell differentiation and correlates with a barrier to extracellular diffusion. 5. Our imaging-orientated approach has facilitated new insights into the relationships between fibre cell differentiation and lens function. Taken together, our results indicate that a number of strategies are used by the lens during the course of normal differentiation to change the subcellular distribution, gross spatial location and functional properties of key membrane transport proteins.

Animals↗

PubMed2006

Granulocyte functions and changes in ability with age in newborns; Report no. 1: flow cytometric analysis of granulocyte functions in whole blood.

BACKGROUND: Serious bacterial infections occur with higher frequency in the first weeks of life than in other age groups and this may be, in part, related to functional impairment of neonatal granulocytes. The purpose of the present study was to estimate the characteristics of granulocyte function during the neonatal period. METHODS: The expression of adhesive molecules on the surface of granulocytes present in umbilical cord blood and peripheral blood obtained at 5 days and 1 month after birth, H(2)O(2) production and protease activity in granulocytes were studied by comparison with adult blood. RESULTS: Although there were no significant differences observed with respect to the expression of CD11b on the surface of granulocytes between each age group and adults, l-selectin was significantly lower in cord blood as compared with adult blood. Production of H(2)O(2) by granulocytes was significantly lower for cord blood than peripheral blood from 1 month old infants or that from adults in the presence of either phorbol myristate acetate or N-formyl-methionyl-leucyl-phenylalanine stimulation. The intracellular activity of elastase and collagenase within granulocytes exhibited a higher tendency for cord blood as compared with adult blood. CONCLUSIONS: Decreased functions of part of the phagocyte system during early infancy were clearly observed.

Adult↗

PubMed2006

Functional urinary and fecal incontinence in neurologically normal children: symptoms of one 'functional elimination disorder'?

OBJECTIVE: To clarify the relationship between disordered defecation and non-neuropathic bladder-sphincter dysfunction (NNBSD) by comparing the prevalence of symptoms of disordered defecation in children with NNBSD before and after treatment for urinary incontinence (UI), and assessing the effect of such symptoms on the cure rate for UI. PATIENTS AND METHODS: In the European Bladder Dysfunction Study, a prospective multicentre study comparing treatment plans for children with NNBSD, 202 children completed questionnaires on voiding and on defecation, at entry and after treatment for UI. Four symptoms of disordered defecation were evaluated; low defecation frequency, painful defecation, fecal soiling, and encopresis. RESULTS: At entry, 17 of the 179 children with complete data sets had low defecation frequency and/or painful defecation (9%), classified as functional constipation (FC). Of the 179 children, 57 had either isolated fecal soiling or soiling with encopresis (32%), classified as functional fecal incontinence (FFI). After treatment for UI, FFI decreased to 38/179 (21%) (statistically significant, P = 0.035); for FC there were too few children for analysis. After treatment for UI, 19 of the 179 children (11%) reported de novo FFI. Symptoms of disordered defecation did not influence the cure rate of treatment for UI. CONCLUSIONS: FFI improved significantly after treatment for UI only, but not in relation to the outcome of such treatment. FFI did not influence the cure rate for UI. There was little to support a causal relation between disordered defecation and NNBDS ('functional elimination syndrome').

Child↗

PubMed1997

Determinants of functional status in healthy Italian nonagenarians and centenarians: a comprehensive functional assessment by the instruments of geriatric practice.

OBJECTIVE: To evaluate the physical ability and psychocognitive status of a population more than 90 years of age with regard to sociodemographic, behavioral, and biomedical variables known to affect functional status in old age. DESIGN: A survey design was used. SETTING: Emilia Romagna, Northern Italy. PARTICIPANTS: Eighty-four healthy community-dwelling subjects aged 90 to 106 years. MEASUREMENTS: Sociodemographic variables, health behavior, anthropometric indices, and serum DHEAS levels were recorded. Functional assessment was performed by instruments currently used in geriatric practice: the Mini-Mental State Examination (MMSE), Geriatric Depression Scale (GDS), and Activities of Daily Living (ADL) scale. A stepwise multiple regression analysis was performed. RESULTS: GDS scores correlated directly with MMSE scores and inversely with ADL severity scores. Poor education, institutionalization, sensory impairment, muscular mass loss, and lower DHEAS levels were the variables with the highest correlation to functional impairment. Smoking, alcohol consumption, and marital status were relatively unimportant. An inverse association was found between DHEAS levels and dependency scores of single ADLs (continence, mobility). CONCLUSION: Impaired cognitive and physical ability with no increase in depression prevalence was found in a sample of subjects more than 90 years of age free of major age-related disease. Muscular mass and DHEAS levels seem to play a role in maintaining physical independence. In turn, physical independence, as well as social and cultural factors, strongly affect the compliance of long-lived subjects with psychocognitive tests currently used in the clinical evaluation of younger old people, suggesting that these instruments are not reliable for screening for cognitive impairment and depression in the oldest old subjects.

Activities of Daily Living↗

PubMed1997

Psychosocial functioning in adolescent psychiatric patients: a prospective study on changes in psychosocial functioning among severely and moderately impaired adolescent out-patients.

Changes in psychosocial functioning during out-patient treatment among 73 adolescent male and 100 female subjects, aged 12 to 19 years, were studied. The mean number of total treatment sessions was 15 sessions among the severely impaired and 14 sessions among the moderately impaired patients. The level of psychosocial functioning improved among the severely impaired (Global Assessment Scale (GAS) at treatment entry 3.9 vs. 4.7 at the last session, 95% CI, -1.085 to -0.577) and the moderately impaired patients (GAS 5.5 vs. 6.0, 95% CI, -0.682 to -0.355). The improvement was highly dependent on the psychiatric diagnosis. The level of psychosocial impairment improved in about two-thirds of subjects with adjustment and non-comorbid mood disorders, in about one-third of those with non-comorbid personality disorders, and in about a quarter of those with disruptive disorders. Careful diagnostic evaluation and assessment of psychosocial functioning are essential elements in the development of adolescent psychiatric services.

Adjustment Disorders↗

PubMed2005

Functional assessment of a washing emulsion for sensitive skin: mild impairment of stratum corneum hydration, pH, barrier function, lipid content, integrity and cohesion in a controlled washing test.

BACKGROUND/PURPOSE: Sensitive skin has been described as a skin type with higher reactivity than normal skin and exaggerated reactions to external irritants. Washing with soaps is harmful for barrier-related parameters. Cutaneous irritation induced by cleansing products under exaggerated test conditions, e.g. patch testing, is not necessarily predictive of the irritation occurring under standardized daily use conditions. The purpose of the study was to assess the effect of an improved washing solution for sensitive skin in a half-site comparison on barrier-related parameters. METHODS: Thirty healthy volunteers with self-reported sensitive and so-called problematic skin performed standardized washings with a soap-free washing emulsion with mild acidity (pH 5.5) for 3 weeks. Test areas were both forearms and the cheek. Non-invasive biophysical measurements of the following skin parameters, epidermal permeability barrier function measured as transepidermal water loss (TEWL), stratum corneum (SC) hydration, pH value, skin surface lipids, skin temperature and SC integrity/cohesion, were assessed prior to the first washing, on days 7, 14 and 21 after beginning the washing procedure. SC cohesion was quantified using two independent methods on D-Squame tapes: optical spectroscopy measuring the absorbance and a protein assay assessing the total protein (Bradford). Both methods showed a good correlation. SC integrity was quantified by measuring TEWL after sequential stripping with D-Squame tapes. RESULTS: The use of the washing emulsion led to a mild damage of the epidermal permeability barrier function with no marked difference to water application. Furthermore, a mild but significant dehydration was assessed after 21 days vs. baseline without any differences between the water-treated and the washing emulsion-treated forearm. On the cheek no dehydration was detectable but the lipid content was reduced under the washing emulsion. The pH value increased in all three test areas after 21 days, again without significant differences between water and the washing solution. SC cohesion was quantified using two independent methods on D-Squame tapes: optical spectroscopy measuring the absorbance and a protein assay assessing the total protein (Bradford). Both methods showed a good correlation. The SC cohesion decreased after 21 days on the water-treated as well as on the washing emulsion-treated arm. The decrease over time was significant when used the optical spectroscopy measuring. A standardized questionnaire revealed positive characteristics of the washing emulsion and good acceptance. CONCLUSION: The investigated standardized washing model with the endpoints epidermal barrier function, SC hydration, surface pH, skin surface lipids, skin temperature and SC integrity/cohesion showed only mild damage comparable to washing with water.

Administration, Topical↗

PubMed1986

Activated T cells with immunoregulatory functions at different sites of involvement in sarcoidosis. Phenotypic and functional evaluations.

Cells from recovered BAL fluid and from infiltrates in different involved tissues (lungs, lymph nodes, conjunctiva, liver, spleen, and skin) were studied in 22 patients with active sarcoidosis in order to define the surface phenotype, functional in vitro properties, and topographic distribution of the cells in granulomatous lesions. Our data demonstrated a compartmentalization of activated T cells with immunoregulatory functions from the blood to all sites of disease activity. In fact, these cells were found to express the T4+ Leu 8- 5/9+ T17- phenotype, which belongs to cells with helper activity, and that provide heightened responses in functional assays of helper activity, IL-2 release, and the ability to respond in AMLR's. Both a cellular redistribution and a local in vitro replication account for this tissue compartmentalization in sarcoidosis. The microanatomic location of activated T cells, as defined by immunohistological evaluation, showed that the state of activation in these T cells may be a consequence of an intimate contact between helper cells and macrophages within the sarcoidosis granulomas.

Adult↗

PubMed2004

Ligand-directed functional heterogeneity of histamine H1 receptors: novel dual-function ligands selectively activate and block H1-mediated phospholipase C and adenylyl cyclase signaling.

The autacoid and neurotransmitter histamine activates the H(1) G protein-coupled receptor (GPCR) to stimulate predominantly phospholipase C (PLC)/inositol phosphate (IP) signaling and, to a lesser extent, adenylyl cyclase (AC)/cAMP signaling in a variety of mammalian cells and tissues, as well as H(1)-transfected clonal cell lines. This study reports that two novel H(1) receptor ligands developed in our laboratory, (-)-trans-1-phenyl-3-dimethylamino-1,2,3,4-tetrahydronaphthalene (trans-PAT) and (+/-)-cis-5-phenyl-7-dimethylamino-5,6,7,8-tetrahydro-9H-benzocycloheptane (cis-PAB), activate H(1) receptors to selectively stimulate AC/cAMP formation and PLC/IP formation, respectively, in Chinese hamster ovary cells transfected with guinea pig H(1) receptor cDNA. trans-PAT and cis-PAB also are shown to be functionally selective antagonists of H(1)-linked PLC/IP and AC/cAMP signaling, respectively. Whereas cis-PAB H(1) receptor activity is shown to be typically competitive, trans-PAT displays a complex interaction with the H(1) receptor that is not competitive regarding antagonism of saturation binding by the standard H(1) antagonist radioligand [(3)H]mepyramine or H(1)/PLC/IP functional activation by histamine. trans-PAT, however, does competitively block H(1)/PLC/IP functional activation by cis-PAB. Molecular determinants for trans-PAT versus cis-PAB differential binding to H(1) receptors, which presumably leads to differential activation of AC/cAMP versus PLC/IP signaling, likely involves stereochemical factors as well as more subtle steric influences. Results suggest the trans-PAT and cis-PAB probes will be useful to study molecular mechanisms of ligand-directed GPCR multifunctional signaling. Moreover, because most untoward cardiovascular-, respiratory-, and gastrointestinal H(1) receptor-mediated effects proceed via the PLC/IP pathway, PAT-type agonists that selectively enhance H(1)-mediated AC/cAMP signaling provide a mechanistic basis for exploiting H(1) receptor activation for drug design purposes.

Adenylyl Cyclases↗

PubMed1988

Pharmacokinetics of cefoperazone (2.0 g) and sulbactam (1.0 g) coadministered to subjects with normal renal function, patients with decreased renal function, and patients with end-stage renal disease on hemodialysis.

The single-dose pharmacokinetics of intravenously administered cefoperazone (2.0 g) and sulbactam (1.0 g) were studied in normal subjects and in patients with various degrees of renal failure. In an open, parallel experimental design, six normal subjects (creatinine clearance, greater than 90 ml/min), two patients with mild renal failure (creatinine clearance, 31 to 60 ml/min), eight patients with moderate renal failure (creatinine clearance, 7 to 30 ml/min), and four functionally anephric patients (creatinine clearance, less than 7 ml/min) were studied. The functionally anephric patients were given two test doses to allow study of drug disposition both on and off hemodialysis. Serial blood and urine samples were collected from time zero to 12 h after dosing in normal subjects and from 0 to 72 h in renal patients. Serum concentrations of both drugs declined biexponentially. For cefoperazone, the terminal elimination half-lives averaged from 1.6 to 3.0 h and were similar in subjects and patients. No cefoperazone pharmacokinetic parameters were appreciably altered by renal failure or hemodialysis, and there was no correlation between the total body clearance of cefoperazone and estimated creatinine clearance. In contrast, the sulbactam total body clearance was highly correlated with estimated creatinine clearance (r = 0.92, P less than 0.01) and was significantly higher in normal volunteers than in the renally impaired groups (P less than 0.01). The sulbactam terminal elimination half-life in functionally anephric patients (9.7 +/- 5.3 h) differed significantly from that of normal volunteers (1.0 +/- 0.2 h) and patients with mild renal failure (1.7 +/- 0.7 h, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed2005

Functional conservation and specialization among eukaryotic anti-silencing function 1 histone chaperones.

Chromatin disassembly and reassembly, mediated by histone chaperones such as anti-silencing function 1 (Asf1), are likely to accompany all nuclear processes that occur on the DNA template. In order to gain insight into the functional conservation of Asf1 across eukaryotes, we have replaced the budding yeast Asf1 protein with Drosophila Asf1 (dAsf1) or either of the two human Asf1 (hAsf1a and hAsf1b) counterparts. We found that hAsf1b is best able to rescue the growth defect of Saccharomyces cerevisiae lacking Asf1. Moreover, dAsf1 and hAsf1b but not hAsf1a can replace the role of yeast Asf1 in protecting against replicational stress and activating the PHO5 gene, while only hAsf1a can replace the role of Asf1 in protecting against double-stranded-DNA-damaging agents. Furthermore, it appears that the interaction between Asf1 and the DNA damage checkpoint protein Rad53 is not required for Asf1's role in maintaining genomic integrity. In addition to indicating the functional conservation of the Asf1 proteins across species, these studies suggest distinct roles for the two human Asf1 proteins.

Acid Phosphatase↗