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PubMed1983

Single-dose ceftriaxone kinetics in functionally anephric patients.

The disposition profile of ceftriaxone was studied in 12 functionally anephric patients (creatinine clearance less than 10 ml/min) who received bolus injections of 150, 500, and 1500 mg IV in a noncrossover fashion. As in healthy subjects, the kinetics in uremic patients were nonlinear for total (bound plus unbound) and linear for free (unbound) drug. The plasma protein binding was reduced due to a decreased association constant, resulting in a doubling of the free fraction in plasma. Ten of 12 patients showed nonrenal clearance values of unbound drug (ClFNR) identical to those in healthy adults and only minor increases in their biologic t1/2(beta) compared to normal (12 and 8 hr). These patients would require no dose adjustments in their dosing regimen. Two of the patients exhibited decreased ClFNR values and increased t1/2(alpha) of 20 and 34 hr. Anephric patients with impaired nonrenal elimination would require minor dose adjustments.

Adult↗
PubMed2000

Immediate urodynamic and anatomic response to colposuspension in female Beagles.

OBJECTIVE: To characterize urodynamic function and anatomy before and after colposuspension in anesthetized female Beagles. ANIMALS: 12 adult female Beagles. PROCEDURE; During general anesthesia (thiopental sodium induction and halothane maintenance), urethral pressure profiles, leak point pressure measurements with a 50-ml bladder volume, positive contrast cystograms, and retrograde vaginourethrocystograms were performed. A caudal midline laparotomy was used to perform colposuspension. Urodynamic and radiographic studies were repeated after surgery. RESULTS: Leak point pressures were increased (120 to 168.9 cm H2O), and maximum urethral closure pressures decreased (43.7 to 19.3 cm H2O ) after colposuspension. The urethra and bladder were moved cranially; the external urethral orifice was positioned closer to the pelvic cavity, and the neck of the bladder was positioned more cranially into the abdomen. Length of the urethra, as measured by use of vaginourethrocystograms, was increased by 3%. As measured by use of urethral pressure profiles, total profile length was increased by 19.9%, and functional profile length was increased by 19.2%. CONCLUSIONS AND CLINICAL RELEVANCE: Increased leak-point pressure correlated with the expected clinical improvement attributable to colposuspension. Increased exposure of the urethra to abdominal and pelvic cavity pressures may be the mechanism by which incontinent dogs become continent after colposuspension. Results of the leak-point pressure test may correlate with clinical behavior before and after colposuspension for treatment of incontinence.

Anesthesia, General↗
PubMed1978

Identification of the functional ionic groups of papain by pH/rate profile analysis.

The pH dependence of papain catalysis was analyzed by a scheme which evaluates the kinetic contribution of both protonated and unprotonated species of functional groups involved in catalysis. Kinetic measurements were made at constant pH, without buffers, by automatic titration. The rate-determining step for papain-catalyzed hydrolysis of alpha-N-benzoyl-L-arginine ethyl ester, determined by nucleophile competition, changed from acylation below pH 6.5 to mixed acylation-deacylation above pH 6.5. Kinetic analysis indicated that three prototropic groups governed the pH-specificity of alpha-N-benzoyl-L-arginine ethyl ester hydrolysis. These prototropic groups had pKa values of 4.8, 6.5 to 6.7, and 8.7. Theoretical treatment of the kinetics provided an excellent fit with the experimentally found profile when the contribution of all three prototropic groups was considered. Analysis showed that, in acid, the pathways of papain catalysis were functional with either two or three active-site protons. In base, a single functional ionic pathway is associated with an active site with only one proton. Pathways involving an unprotonated active site are catalytically inoperative in both acid and base. These results indicate that papain exhibits several catalytically functional ionic pathways. The results are discussed in terms of pKa assignments, and the mechanism of papain catalysis.

Arginine↗
PubMed2006

Randomised, controlled, cross-over trial of soy protein with isoflavones on blood pressure and arterial function in hypertensive subjects.

OBJECTIVE: To examine the effects of dietary soy/isoflavones on 24 hr blood pressure profiles and arterial function [systemic arterial compliance (SAC), pulse wave velocity (PWV) and brachial arterial flow mediated vasodilation (FMD)] compared to non legume-based plant protein without isoflavones, in hypertensive subjects. DESIGN: In a 6 month double-blind, placebo controlled, cross-over trial, 41 hypertensive subjects (26 men, 15 postmenopausal women), 30-75 years, received soy cereal (40 g soy protein, 118 mg isoflavones) and gluten placebo cereal, each for 3 months. RESULTS: Thirty-eight subjects completed protocol with results expressed as mean or mean change (+/-SEM) with each intervention. Soy increased urinary isoflavones (daidzein: 8-fold; genistein: 8-fold; equol: 9-fold; ODMA: 18-fold) with no change during gluten placebo. There was no difference in the change in individual 24 hr ambulatory BP parameters (SBP: 2 +/- 2 vs -1 +/- 1 mmHg, p = 0.21; DBP: 1 +/- 1 vs -1 +/- 1 mmHg, p = 0.06) central BP (cSBP: -4 +/- 2 vs 0 +/- 2 mmHg, p = 0.2) or the change in arterial function (FMD: 0.3 +/- 0.5 vs -0.2 +/- 0.5%, p = NS; SAC: 0.02 +/- 0.02 vs -0.02 +/- 0.02 U/mmHg, p = NS; PWV central: -0.2 +/- 0.2 vs 0.0 +/- 0.2 m/sec, p = NS; PWV peripheral: 0.01 +/- 0.3 vs -0.4 +/- 0.4 m/sec, p = NS) noted between interventions. Analysis of the area under curve of 24 hr BP outputs demonstrated that soy protein compared to gluten protein resulted in higher 24 hr systolic BP by 2.3 mmHg (p = 0.003), a higher daytime systolic BP by 3.4 mmHg (p = 0.0002) and a higher daytime diastolic BP by 1.4 mmHg (p = 0.008). Overall 24 hr diastolic BP, night systolic BP and night diastolic BP were not significantly different between groups. Furthermore, soy protein compared to gluten protein resulted in higher 24 hr heart rates by 3.5 bpm (p < 0.0001). CONCLUSIONS: In hypertensive subjects, compared to gluten placebo, soy dietary supplementation containing isoflavones had no effect on arterial function, on average 24 hr ambulatory blood pressure parameters or central blood pressure in men and women with hypertension. Area under the curve of 24 hr profiles demonstrated that daytime BP was higher after soy compared to gluten.

Adult↗
PubMed1995

Partially folded states of proteins: characterization by X-ray scattering.

Partially folded states of proteins are found to occur with a wide variety of degrees of unfolding, ranging from the compact molten globule to the fully unfolded forms, depending on solvent conditions and the specific protein involved. Small to intermediate angle X-ray scattering from partially folded states of proteins yields low resolution scattering profiles that may be used to explore the degree of folding of a protein under given solution conditions. By Monte Carlo simulation of a highly simplified homopolymer model, we show that such partially folded states will yield a characteristic scattering profile that may be written as a linear superposition of scattering from a compact core and of scattering from random coil loops that emerge from this core. We also find a term resulting from interference of X-rays scattering from the core with those scattering from the loops. This interference term oscillates in sign and tends to enhance the core portion of the scattering profile. We compare the model calculations of the scattering profile with measurements of the scattering profile as a function of salt concentration for cytochrome c at pH 2. Because of our characterization of the scattering profiles, we suggest that these results may be re-interpreted in terms of the presence of a range of partially folded states as a function of pH and salt concentration, and that the observed scattering profiles are consistent with the characterization of the partially folded states in terms of random coil loops emerging from a compact core with the loop fraction increasing as the salt concentration is decreased. This characterization is consistent with data on amide protection against H-2H exchange of compact regions within partially folded states observed for a number of proteins, including cytochrome c.

Computer Simulation↗
PubMed1994

Continuation of group physical therapy is necessary in ankylosing spondylitis: results of a randomized controlled trial.

PURPOSE: Group physical therapy in patients with ankylosing spondylitis was studied to determine whether beneficial effects persisted after cessation of the intervention. METHODS: After a 9-month period of supervised group physical therapy, 68 patients were randomized for another 9 months to unsupervised daily exercises at home (discontinuation group) or continuation of weekly sessions of supervised group physical therapy (continuation group). Endpoints were spinal mobility (thoraco-lumbar flexion and extension, chest expansion, cervical rotation), fitness (maximum work capacity), functioning (Sickness Impact Profile (SIP), Health Assessment Questionnaire for the Spondylarthropathies [HAQ-S], Functional Index [FI]), and patient's global health assessment on a visual analogue scale. RESULTS: Time for exercises at home was significantly higher in the continuation than in the discontinuation group (mean duration 1.9 versus 1.2 hr per week, P < 0.05). The continuation group improved in global health (mean improvement 1.6; 32%) and in SIP score. Scores for thoraco-lumbar mobility and HAQ-S did not change very much, whereas chest expansion, cervical rotation, fitness, and FI deteriorated. The average attendance for group therapy sessions was 62%. The discontinuation group improved only marginally (0.2; 4%) in global health, whereas all other endpoints decreased. Only for global health and HAQ-S were the differences statistically significant in favor of the continuation group. CONCLUSIONS: Global health and functioning are sustained or even improved further if group physical therapy is continued. Spinal mobility decreased slightly in both groups.

Activities of Daily Living↗
PubMedDate not supplied

Characterizing the effect of diagnosis on presenting deficits and outcomes after total shoulder arthroplasty.

This study compared self-assessed deficits in comfort, function, and health status before and after total shoulder arthroplasty for 4 different diagnoses: degenerative joint disease (DJD), secondary DJD (2 degrees DJD), rheumatoid arthritis (RA), and capsulorrhaphy arthropathy (CA). Deficits were assessed by the Simple Shoulder Test and Short Form 36 (SF-36) questionnaires. There was a significant difference among diagnoses for preoperative and postoperative functional deficits. The profiles of improvement within the categories of comfort, motion, strength, and function were different for each diagnosis. Patients with DJD and CA were most improved in the category of motion, whereas those with 2 degrees DJD and RA were most improved in the category of comfort. There was also a statistically significant difference in 5 of the 8 domains of the preoperative SF-36 among diagnoses. Factors associated with each diagnosis play a significant role in determining the magnitude of preoperative deficits and postoperative improvement in shoulder function.

Adult↗
PubMed2001

Impaired c-Jun amino terminal kinase activity and T cell differentiation in death receptor 6-deficient mice.

During an immune response naive T helper (Th) cells differentiate into two functionally distinct subsets, Th1 and Th2, based on their cytokine secretion profile and immunomodulatory function. c-Jun amino terminal kinase (JNK) regulates Th cell differentiation by activating a transcriptional program required for cytokine production. We have recently identified a TNFR superfamily death domain-containing molecule, death receptor (DR)6, which potently activates JNK. T cells from DR6-deficient mice are substantially impaired in JNK activation. When DR6(-/-) mice were challenged with protein antigen, their T cells hyperproliferate and display a profound polarization toward a Th2 response whereas Th1 differentiation is not equivalently affected. In addition, DR6(-/)- T cells showed preference toward Th2 differentiation in vitro. The phenotype seen in the DR6(-/)- mice is not due to the apoptotic pathway. Therefore, DR6, working through JNK, rather than apoptosis, functions to attenuate the Th2 response. This is the first demonstration of a role in the activation and differentiation of Th cells by DR6 in particular and DRs in general.

Amino Acid Sequence↗
PubMed2004

Classification of loratadine based on the biopharmaceutics drug classification concept and possible in vitro-in vivo correlation.

Loratadine was studied both in vitro and in vivo (in healthy humans) to classify it according to the Biopharmaceutics Classification System (BCS) in order to gain more understanding of the reasons for its highly variable nature with respect to plasma time profiles, and to determine the most appropriate dissolution test conditions for in vitro assessment of the release profile of the drug from solid dose forms. Based on the solubility of loratadine determined under various pH conditions and its permeability through Caco-2 monolayers, loratadine was classified as a Class II drug. Plasma profiles were predicted by convolution analysis using dissolution profiles obtained under various pH and hydrodynamic conditions as the input function and plasma time data obtained from a syrup formulation as the weighting function. The predicted profiles based on dissolution studies done at gastric pH values were in reasonable agreement with the mean bio-data suggesting dissolution testing should be done at gastric pH values. However, the bio-data were highly variable and it is suggested this may be due, at least in part, to high individual gastric pH variability and dissolution occurring in the intestine on some occasions, and therefore, dissolution testing should also be done in simulated intestinal fluid.

Area Under Curve↗
PubMed2003

Functional differentiation of peroxisomes revealed by expression profiles of peroxisomal genes in Arabidopsis thaliana.

It is well known that peroxisomal matrix proteins contain one of two targeting signals, PTS1 and PTS2. We comprehensively surveyed genes related to peroxisomal function and biogenesis in the entire Arabidopsis genome sequence. Here, we identified 256 gene candidates of PTS1- and PTS2-containing proteins and another 30 genes of non-PTS-containing proteins. Of these, only 29 proteins have been reported to be functionally characterized as peroxisomal proteins in higher plants. We extensively investigated expression profiles of genes described above in various organs of Arabidopsis: Statistical analyses of these expression profiles revealed that peroxisomal genes could be divided into five groups. One group showed ubiquitous expression in all organs examined, while the other four were classified as showing organ-specific expression in seedlings, cotyledons, roots and in both cotyledons and leaves. These data proposed more detailed description of differentiation of plant peroxisomes.

Arabidopsis↗
PubMed2006

A novel function of Nur77: physical and functional association with protein kinase C.

Despite the involvement in diverse physiological process and pleiotropic expression profile, the molecular functions of Nur77 are not likely to be fully elucidated. From the effort to find a novel function of Nur77, we detected molecular interaction between Nur77 and PKC. Details of interaction revealed that C-terminal ligand binding domain (LBD) of Nur77 specifically interacted with highly conserved glycine-rich loop of PKC required for catalytic activity. This molecular interaction resulted in inhibition of catalytic activity of PKCtheta by Nur77. C-terminal LBD of Nur77 is sufficient for inhibiting the phosphorylation of substrate by PKCtheta. Ultimately, inhibition of catalytic activity by Nur77 is deeply associated with repression of PKC-mediated activation of AP-1 and NF-kappaB. Therefore, these findings demonstrate a novel function of Nur77 as a PKC inhibitor and give insights into molecular mechanisms of various Nur77-mediated physiological phenomena.

Animals↗
PubMed2006

Functional neuroimaging with MEG: normative language profiles.

The reliability of language-specific brain activation profiles was assessed using Magnetoencephalography (MEG) in five experiments involving ninety-seven normal volunteers of both genders ranging in age from seven to eighty-four years. MEG data were analyzed with a fully automated method to eliminate subjective judgments in the process of deriving the activation profiles. Across all experiments, profiles were characterized by significant bilateral activity centered in the superior temporal gyrus, and in activity lateralized to the left middle temporal gyrus. These features were invariant across age, gender, variation in task characteristics, and mode of stimulus presentation. The absolute amount of activation, however, did decline with age in the auditory tasks. Moreover, contrary to the commonly held belief that left hemisphere dominance for language is greater in men than in women, our data revealed an opposite albeit a not consistently significant trend.

Adolescent↗
PubMed2004

CD27- CD4+ memory T cells define a differentiated memory population at both the functional and transcriptional levels.

The memory T-cell population is a heterogeneous population, including both effector cells, which exert a direct secondary immune response, and resting or intermediate cells, which serve as a reservoir and exert a possible regulatory role. To further dissect the T-cell memory population residing in the CD4+ CD45RO+ T-cell pool, we studied the functional properties of memory populations identified by the CD27 marker. This marker clearly divides the memory population into two groups. One group consists of effector cells lacking CD27 and displaying a high antigen recall response. The other group consists of an intermediate memory population, displaying CD27. This latter group lacks an antigen recall response and requires costimulation for T-cell receptor triggering. To evaluate the function of the CD27+ memory pool, we analysed the transcriptional profile, using high-density microarray technology. These gene data strongly support the different functional profiles of CD27+ and CD27- memory populations, in terms of protein expression and the capacity to respond to antigen.

CD4-Positive T-Lymphocytes↗
PubMed2005

Benefit in lung function improvement and side-effect profile of long-term responders: an analysis of 14 NSCLC patients treated for at least 9 months with gefitinib.

BACKGROUND: Gefitinib is the first approved EGFR tyrosine-kinase inhibitor indicated for the treatment of patients with locally advanced (IIIB) or metastatic NSCLC after failure of platinum-based first-line therapy and docetaxel chemotherapy. Following rapid approval in Japan and accelerated approval based on phase-II results in the US, a large compassionate-use program has been set up in parallel to extended phase-III testing. Offering therefore access to state-of-the-art therapy to patients who are not candidates for clinical studies; Iressatrade mark EAP allows physicians to test the new EGFR inhibitor across a heterogeneous patient population characteristic for advanced NSCLC. PATIENT AND METHODS: After having treated 240 patients at the Grosshansdorf hospital, we have retrospectively analysed the efficacy and tolerability of 250 mg/day gefitinib in patients showing a long-term tumor control. We reviewed the patient records of 14 patients with advanced NSCLC that received daily gefitinib for at least 9 months. RESULTS: Long-term tumor control, defined as confirmed objective tumor response for at least 6 months or disease stabilisation for above 9 months, was observed in chemo-naive patients as well as in fourth-line therapy patients for the latter ones independently of the composition of prior chemotherapy. Most patients (9/14) with such a lasting benefit were female; patients' histology was in most cases uniform: adenocarcinomas were dominant in women and bronchioloalveolar carcinoma in men. Patients with moderate to severe dyspnoea benefited from a measurable improvement of their respiratory capacity. No cumulative toxicity was observed; characteristic side-effects for gefitinib as grades 1-2 diarrhoea or mild to moderate skin toxicity were well manageable. CONCLUSION: For 14 (6%) out of 240 patients with patterns of diffuse disseminated metastatic disease, gefitinib offered a lasting tumor control with a disease progression-free survival interval between 9 and 25 months. In parallel to therapy, patients' performance status (PS) could be conserved or even improved in many cases. Patients with lung function impairment, as well as patients with other disease-related symptoms obtained additional therapy benefits.

Adenocarcinoma↗
PubMed1991

Influence of suckling and continuous cow-calf association on the resumption of post-partum ovarian function in Bos indicus cows monitored by plasma progesterone profiles.

The effect of suckling on post-partum ovarian function was monitored by weekly plasma progesterone determinations using enzyme immunoassay in 16 Small East African Zebu (Bos indicus) cows maintained with a fertile bull. Five cows continuously suckled their calves (COS), but starting 30 d after calving 6 cows remained with their calves which were prevented from suckling using nose plates (NOS) while 5 calves were separated and penned (PEN). The mean (+/- SE) interval from calving to first behavioural oestrus was 81 +/- 11 d and was significantly (P less than 0.001) shorter for PEN (43 +/- 10 d) than NOS (72 +/- 9 d) or COS cows (133 +/- 11 d). COS cows nonetheless weaned heavier (P less than 0.001) calves at 5 months. Ovarian activity determined by plasma progesterone levels greater than or equal to 1.3 ng/ml indicated that "silent ovulation" was initiated in 44% of cows by 40 +/- 6 d post-partum. The results indicate that continuous suckling or constant cow-calf interaction extend the post-partum anoestrous interval in Ethiopian Zebu cows. However, early-weaned calves or those on restricted suckling would need extra nutritional supplementation to ensure continued growth.

Animals↗
PubMed1997

[Urodynamic parameters and continence after radical Wertheim-Meigs-Okabayashi hysterectomy].

The aim of this study was to analyse the effects of radical hysterectomy on urodynamic parameters (urethral resistance, functional urethral length, pressure gradients, bladder capacity, residual urine volume, stress urethral pressure profile), on bladder function (detrusor pressure, urgency sensation, flow pattern) and on continence. We reviewed 33 patients who underwent a radical abdominal hysterectomy as described by Wertheim-Meigs-Okabayashi. They were investigated by urodynamic examination preoperatively and 4 resp. 8 months postoperatively. To ascertain bladder dysfunctions and changes of urinary continence as a long term effect of operative procedure a standardized questionnaire was mailed to all patients. The radical abdominal hysterectomy did not alter significantly the urethral resistance, functional urethral length or pressure gradients. The maximal bladder capacity decreased postoperatively from 615 ml to 503 ml (SD 148.5: p = 0.04). The maximal urine flow and the detrusor pressure decreased temporarily (p = 0.01). The residual urinary increased five-fold (p = 0.01) and the first sensation of bladder filling was recognized later, at 4 as at 8 months postoperatively (p = 0.07). Preoperatively 75% of the patients voided by detrusor activity, postoperatively only 16%. 20% of the preoperative continent patients were incontinent during the second measurement (8 months postoperatively). 47% of the previous continent patients complained about incontinence in the questionnaire (4 years postoperatively). Although the patients complained about pollakiuria, urgency (60%) and urge incontinence (39%), 73% of the patients were content with their situation. Although the urethral pressure profile showed no significant alteration, the clinical situation and the deterioration of the parameters bladder capacity, residual urine and flow pattern verified the postoperative disturbances of the lower urinary tract function and the negative effects on continence behaviour.

Adult↗
PubMed2006

How three-finger-fold toxins interact with various cholinergic receptors.

Three-finger-fold toxins, isolated from various snake venoms, are recognized by high affinity and various specificities by different nicotinic and muscarinic acetylcholine receptors (nAChRs and mAChRs, respectively) present in peripheral, as well as central, nervous systems (Karlsson et al., 2000; Servent and Ménez, 2001; Nirthanan and Gwee, 2004). The goal of our studies is (1) to identify, at the molecular level, the functional determinants involved in the various interaction profiles of nicotinic or muscarinic toxins on their respective receptors subtypes, (2) to model some of these toxin-receptor complexes using distance constraints obtained from cycle-mutant experiments, and (3) to understand how a unique scaffold (the three-finger fold) is able to support these different functional profiles and how molecular determinants have been selected during the evolution process to create these different specific properties. Finally, these structure/function analyses should be exploited to engineer non-natural peptides with new binding and functional properties useful as pharmacological tools or therapeutic agents.

Animals↗