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PubMed1998

Repressor titration: a novel system for selection and stable maintenance of recombinant plasmids.

The propagation of recombinant plasmids in bacterial hosts, particularly in Escherichia coli, is essential for the amplification and manipulation of cloned DNA and the production of recombinant proteins. The isolation of bacterial transformants and subsequent stable plasmid maintenance have traditionally been accomplished using plasmid-borne selectable marker genes. Here we describe a novel system that employs plasmid-mediated repressor titration to activate a chromosomal selectable marker, removing the requirement for a plasmid-borne marker gene. A modified E.coli host strain containing a conditionally essential chromosomal gene (kan) under the control of the lac operator/promoter, lac O/P, has been constructed. In the absence of an inducer (allolactose or IPTG) this strain, DH1 lackan , cannot grow on kanamycin-containing media due to the repression of kan expression by LacI protein binding to lac O/P. Transformation with a high copy-number plasmid containing the lac operator, lac O, effectively induces kan expression by titrating LacI from the operator. This strain thus allows the selection of plasmids without antibiotic resistance genes (they need only contain lac O and an origin of replication) which have clear advantages for use as gene therapy vectors. Regulation in the same way of an essential, endogenous bacterial gene will allow the production of recombinant therapeutics devoid of residual antibiotic contamination.

Amino Acid Sequence↗

PubMed1976

Satellite DNA sequence content of polylysine-titratable and nuclease-resistant fractions of mouse liver hepatoma chromatin.

Micrococcal nuclease digestion of mouse TLT liver hepatoma chromatin proceeds rapidly to the point where approximately 35% of the DNA is recoverable by centrifugation of the chromatin DNA through 3M CsCl. The satellite DNA sequence content of this recoverable DNA is the same as whole chromatin DNA (10%). The 11s (penultimate digestion product) monomer, as well as intermediate multiples and relatively undigested large chromatin segments are separable on steep hlycerol gradients. The DNA isolated from these fractions also contains the normal 10% satellite DNA content. Progressive polylysine titration of chromatin followed by nuclease digestion gives anomalous recoveries of DNA but, nonetheless, the satellite sequence content titration of chromatin, followed by pronase and then nuclease digestion, again gave recoverable DNA with a satellite sequence content of 10%. These results are discussed in terms of the conclusion that nucleosome (or upsilon-body) structures are distributed in a random fashion over the genome.

Base Sequence↗

PubMed1988

Fluorescence titration and fluorescence stopped-flow studies of skeletal muscle troponin-nonpolymerizable tropomyosin complex.

The midpoint pCa value of the fluorescence titration curve of the complex of 2-[4'-iodoacetamido)anilino)-naphthalene-6-sulfonic acid-labeled troponin (IAANS-Tn) and nonpolymerizable tropomyosin (NPTm) was much larger than that for the complex of Tn containing dansylaziridine-labeled troponin C (DANZ-TnC) and NPTm. The midpoint was pCa 8.25 for the former protein and 6.80 for the latter protein in 0.1 M KCl, 50 mM Na-cacodylate-HCl (pH 7.0); and pCa 7.90 for the former protein and 6.70 for the latter protein in the presence of 3 mM MgCl2 in the same solvent system. The time course of the fluorescence intensity change of the protein complex subsequent to rapid decrease of free Ca2+ concentration of the solution was measured with a stopped-flow spectrophotometer: The process was exponential and its rate constant was 9.9 s-1 for IAANS-Tn-NPTm at pCa 8.95 and 26.6 s-1 for Tn(DANZ-TnC)-NPTm at pCa 8.99 in the absence of MgCl2 in the same solvent system as in the fluorescence titration experiment. IAANS binds to Cys-133 of TnI and DANZ to Met-25 in the low affinity Ca2+-binding sites of TnC. These results suggest that IAANS bound to Cys-133 of TnI does not directly detect the Ca2+-binding to the low affinity Ca2+-binding site of TnC, but does detect the conformational change of the Tn-NPTm complex induced by the Ca2+-binding.(ABSTRACT TRUNCATED AT 250 WORDS)

Macromolecular Substances↗

PubMed1995

A simple algorithm for the calculation of multiple site titration curves.

A simple algorithm for the calculation of multiple site titration curves is proposed. It is based on a hybridization of two computational techniques: (i) a modified Tanford-Roxby iterative procedure [Tanford and Roxby (1972) Biochemistry, 11, 2193-2198] and (ii) the Boltzmann statistics. The sites characterized by strong electrostatic coupling were selected for statistical mechanical treatment, whereas all other sites were treated by means of the modified Tanford-Roxby procedure. The selection of the two sets was made on the basis of a criterion related to the interaction energy between the titratable sites in the protein molecule. The algorithm was tested for bovine pancreatic trypsin inhibitor and the pK values calculated were discussed in the light of experimental data and theoretical results obtained by other authors. The algorithm can easily be coded and incorporated into any program package for the calculation of electrostatic interactions in proteins.

Algorithms↗

PubMed2002

Dose titration using the Disease Activity Score (DAS28) in rheumatoid arthritis patients treated with anti-TNF-alpha.

OBJECTIVE: Anti-tumour necrosis factor alpha (TNF-alpha) therapy yields high response rates shortly after institution of therapy in patients with rheumatoid arthritis (RA), and on theoretical grounds large differences in the effective dose between patients can be expected. Together with the high costs, these differences warrant new approaches to the way patients are dosed. METHODS: We used the Disease Activity Score (DAS28), a composite disease activity index, to titrate the dose of anti-TNF-alpha (adalimumab, D2E7; Knoll) in 21 patients with low disease activity in an open extension study lasting 40 weeks. The dose of anti-TNF-alpha was reduced stepwise and dosing intervals were kept stable. Disease activity and flares were assessed using the DAS28. Patients who flared received the previous effective dose. RESULTS: Dose reduction was accomplished in 15 patients. The total amount of anti-TNF-alpha given to the patients was reduced by 67%. At the end of the study the mean DAS28 had not changed and no patients dropped out because of persistent worsening of the RA. CONCLUSION: Dose titration of anti-TNF-alpha treatment using the DAS28 is feasible and leads to overall dose reduction while maintaining clinical efficacy. This approach will save costs and possibly prevent long-term side-effects.

Adalimumab↗

PubMed2000

The impact of split-night polysomnography for diagnosis and positive pressure therapy titration on treatment acceptance and adherence in sleep apnea/hypopnea.

STUDY OBJECTIVES: The time and resource intensive nature of the traditional two-night paradigm for diagnosing and titrating positive pressure therapy for Obstructive Sleep Apnea/Hypopnea (OSA/H) contributes to patient care cost and limitation of service availability. Although split night polysomography (PSG(SN)) algorithms can establish a diagnosis of OSA/H and establish a positive pressure prescription for many patients, there has been only limited evidence that this strategy does not impair acceptance and adherence to treatment. The objective of this study was to test the null hypothesis that PSG(SN) does not adversely impact acceptance and adherence to positive pressure therapy for OSA/H compared with a standard two-night PSG strategy (PSG(TN)). DESIGN: Retrospective case-controlled study. SETTING: University-based sleep disorders program PATIENTS: Both PSG(SN) and PSG(TN) (control) patients were selected on the basis of having an initial medical/sleep evaluation by a full-time physician member of the University of Pittsburgh Sleep Disorders Program, must not have had prior diagnostic PSG or treatment for sleep-disordered breathing, and must have been followed by the Sleep Program team. Selection of PSG(SN) patients required the ability to be matched with a control patient. Both groups underwent evaluation during the same time period. Of 146 patients who underwent PSG(SN) between October 1995 and September 1997, 51 had their initial evaluation and subsequent follow-up by physician-staff members of our Program. Of these, 15 were excluded from analysis because of a previous diagnostic PSG's or prior OSA/H therapy. Also, matches were unavailable for 5 patients. Seven patients refusal to use positive pressure at home and were not available for assessment of adherence, but were included in analysis of therapeutic acceptance. Thus, analysis of the impact of PSG(SN) on adherence to positive pressure therapy was based on a data set of 24 patients in whom a PSG(SN) was performed and 24 patients who had PSG(TN). The two groups were matched for age, Apnea+Hypopnea Index (AHI) and gender. MEASUREMENT AND RESULTS: There were no significant differences between the PSG(SN) and PSG(TN) groups with respect to age, body mass index (BMI), Desaturation Event Frequency (DEF), Arousal Index (ArI) or the Epworth Sleepiness Score (ESS). The nadir of oxyhemoglobin saturation (SpO2) during sleep was lower in the PSG(TN) than PSG(SN) group (69.3+/-15 vs. 79.8+/-9, mean+/-SD, p=0.012). During positive pressure titration, the time spent at the final pressure which was prescribed for the patients were comparable in both groups (123.4+/-64 vs. 161+/-96 minutes, PSG(SN) and PSG(TN), respectively, p=0.17). Adherence to therapy was objectively assessed by the average daily run-time of the positive pressure device at the first meter-read following initiation of treatment (55.1+/-44 vs. 40.8+/-16 days following home set-up, PSG(SN) and PSG(TN), respectively, p=0.14). Depending whether or not patients with previous exposure to positive pressure therapy were included in the analysis, 84-86% of patients undergoing PSG(SN) accepted therapy. There was no difference between the groups with respect to adherence (5.1+/-4 vs. 4.6+/-3 hours, PSG(SN) and PSG(TN), respectively, p=0.64). CONCLUSIONS: In a population of predominantly moderate-to-severe OSA/H patients, PSG(SN) strategy does not adversely impact on adherence to positive pressure therapy over the first six weeks of treatment. Acceptance of therapy is comparable to that reported in the literature following PSG(TN).

Adult↗

PubMed2004

Auto-titrating versus standard continuous positive airway pressure for the treatment of obstructive sleep apnea: results of a meta-analysis.

STUDY OBJECTIVE: To compare the effectiveness of auto-titrating continuous positive airway pressure (APAP) versus conventional continuous positive airway pressure (CPAP) in reducing the apnea-hypopnea index (AHI), reducing the mean airway pressure, improving subjective sleepiness, and improving treatment adherence in patients with obstructive sleep apnea (OSA). DESIGN: Meta-analysis and metaregression of published randomized trials comparing APAP to CPAP. SETTING: N/A. PARTICIPANTS: N/A. INTERVENTIONS: N/A. RESULTS: We identified 9 randomized trials studying a total of 282 patients. Compared to CPAP, there was no significant advantage of APAP in reducing AHI or sleepiness (pooled APAP-CPAP posttreatment AHI and Epworth Sleepiness Scale score = -0.20 events per hour, 95% confidence interval:[-0.74,0.35], and -0.56 [-1.4,0.3] respectively). The use of APAP reduced the mean applied pressure across the night by 2.2 cm water [1.9,2.5] compared to CPAP. Adherence with therapy was not substantially improved with APAP; pooled estimate of improvement was 0.20 hours per night ([-0.16,0.57], P = .28) using a random-effects model. CONCLUSIONS: Compared to standard CPAP, APAP is associated with a reduction in mean pressure. However, APAP and standard CPAP were similar in adherence and their ability to eliminate respiratory events and to improve subjective sleepiness. Given that APAP is more costly than standard CPAP, APAP should not be considered first-line chronic therapy in all patients with OSA. However, APAP may be useful in other situations (eg, home titrations, detection of mouth leak) or in certain subgroups of patients with OSA. Identifying circumstances in which APAP is a definite improvement over CPAP in terms of costs or effects should be the focus of future studies.

Humans↗

PubMed1996

Hemodynamic effects of spinal anesthesia in the elderly: single dose versus titration through a catheter.

Sixty elderly patients (> 70 yr old) undergoing surgery for hip fracture were prospectively studied in order to compare hemodynamic tolerance of titrated doses of hyperbaric bupivacaine using continuous spinal anesthesia (CSA) versus single-dose spinal anesthesia (SDSA). Patients were randomized into two groups (CSA group: n = 30; SDSA group: n = 30). The SDSA patients received 10-15 mg of 0.5% hyperbaric bupivacaine (based on age and height), and the CSA patients received a starting dose of 5 mg of 0.5% hyperbaric bupivacaine, followed after 15 min by optional reinjection of 2.5 mg every 5 min until a T10 level sensory block was reached. Onset of anesthesia, noninvasive hemodynamic variables and the need for ephedrine were studied for 4 h after induction of anesthesia. Spinal anesthesia was successful in all patients. Decreases in mean arterial pressure were significantly less frequent and less pronounced in the CSA group (19.9% +/- 1.6% of the baseline value) than in the SDSA group (40.2% +/- 1.9%, P < 0.0001). The mean dose of ephedrine was significantly less in the CSA group (1.8 +/- 0.7 mg, administered to only 37% of patients) than in the SDSA group (19.4 +/- 3.3 mg administered to all patients, P < 0.0001). No late complications related to the spinal anesthesia technique were observed in either group. We concluded that CSA, using small titrated doses of 0.5% hyperbaric bupivacaine, is safe, efficient, and provides better hemodynamic stability than SDSA in elderly patients.

Aged↗

PubMed1993

Titration of intravenous anesthetics for cardioversion: a comparison of propofol, methohexital, and midazolam.

OBJECTIVE: To compare propofol, methohexital, and midazolam administered as titrated infusions for sedation during electrical cardioversion. DESIGN: A prospective, randomized, single-blind comparative study. SETTING: Coronary care unit in a military teaching hospital. PATIENTS: Thirty adult patients with atrial fibrillation, atrial flutter, or paroxysmal supraventricular tachycardia. Each patient required electrical cardioversion. Patients were randomized to receive one of the three study drugs. Ten patients composed one drug group. MEASUREMENTS AND MAIN RESULTS: Demographic variables were similar between groups. Patients were randomized to receive propofol (10 mg/mL), methohexital (5 mg/mL), or midazolam (0.5 mg/mL) administered at 10 mL/min until the patients failed to follow verbal commands and demonstrated a degradation of the lid response to stimulation. Dose requirements (mean +/- SD) were propofol 1.69 +/- 0.46 mg/kg, methohexital 1.07 +/- 0.34 mg/kg, and midazolam 0.16 +/- 0.06 mg/kg. Hemodynamic assessment at baseline, after induction, after cardioversion, and at recovery demonstrated no difference in mean arterial pressure between the three groups. The time to awakening was significantly prolonged in the group that received midazolam (33 +/- 11 mins, p < .05) as compared with the times of the groups that received propofol (11 +/- 4 mins) and methohexital (9 +/- 3 min). Side-effects were similar between groups, with the exception of an increase in pain on injection with propofol and an increased frequency of confusion in those patients receiving midazolam. Recall of the electrical discharges at one hour after the procedure occurred in two patients in the propofol group. In both cases, there were technical problems which caused the duration of the procedure to extend into the anticipated recovery period. Unit dose costs at our institution for a 70-kg patient are: methohexitol, $3.14 (500-mg bottle); medazolam, $14.88 (5-mg vials x 3); and propofol, $6.60 (200-mg ampule). CONCLUSIONS: All three drugs are acceptable choices for use during elective direct-current cardioversion. Titration of the agent results in a total drug dose which is usually less than the typical induction dose. There were no significant differences in the hemodynamic actions of these drugs at any time interval. Both propofol and methohexital proved superior in their ability to provide a more rapid anesthetic onset and recovery as compared with midazolam. Propofol offers the advantage of requiring no premixing or dilution, and it is not a controlled substance, although it does result in more pain on injection.

Aged↗

PubMed2001

Positive end-expiratory pressure titration in acute respiratory distress syndrome patients: impact on right ventricular outflow impedance evaluated by pulmonary artery Doppler flow velocity measurements.

OBJECTIVE: Positive end-expiratory pressure (PEEP) titration in acute respiratory distress syndrome patients remains debatable. We used two mechanical approaches, calculation of the compliance of the respiratory system and determination of the lower inflexion point of the pressure-volume curve of the respiratory system, to identify specific PEEPs (PEEPS and PEEPA) whose impact on right ventricular (RV) outflow was compared with Doppler analysis of pulmonary artery flow velocity. DESIGN: Prospective, open, clinical study. SETTING: Medical intensive care unit of a university hospital. PATIENTS: Sixteen consecutive ventilator-dependent acute respiratory distress syndrome patients. INTERVENTIONS: Two PEEPs were determined: PEEPS was the highest PEEP associated with the highest value of respiratory compliance, and PEEPA was the coordinate of the lower inflexion point of the inspiratory pressure-volume curve on the pressure axis plus 2 cm H2O. MEASUREMENTS AND MAIN RESULTS: We observed a large difference between the two PEEPs, with PEEPA (13 + 4 cm H2O) > PEEPS (6 + 3 cm H2O). Changes in RV outflow impedance produced by tidal ventilation with zero end-expiratory pressure (ZEEP) and after application of these two PEEPs were assessed by Doppler study of pulmonary artery flow velocity obtained by a transesophageal approach, with particular reference to the end-expiratory and end-inspiratory pulmonary artery velocity-time integral, as reflecting RV stroke output, and mean acceleration as reflecting RV outflow impedance during an unchanged flow period. A significant inspiratory reduction in pulmonary artery velocity-time integral (from 11.8 + 0.3 to 10.0 + 0.3 cm) and mean acceleration (from 11.9 + 0.9 to 8.0 + 0.9 m/sec2) was observed with ZEEP, showing a reduction in RV stroke index (from 29.0 + 0.9 to 26.0 + 0.6 cm3/m2) by a sudden increase in outflow impedance during tidal ventilation. Application of PEEPA, which improved Pao2 (102 + 40 vs. 65 + 18 torr with ZEEP), worsened the inspiratory drop in RV stroke index (21.6 + 0.8 cm3/m2), resulting in a significant reduction in cardiac index compared with ZEEP (from 3.0 + 1.0 to 2.7 + 1.1). Application of PEEPS, which also significantly improved Pao2 (81 + 21 torr), was associated with a lesser impact on RV outflow impedance (inspiratory mean acceleration: 9.5 + 1 m/sec2) and cardiac index (3.2 + 1.0) than PEEPA. CONCLUSION: RV outflow impedance evaluated by the Doppler technique appeared sensitive to PEEP titration. Application of PEEPA worsened RV systolic function impairment produced by tidal ventilation. Conversely, application of PEEPS reduced RV systolic function impairment, suggesting an association with a lower pulmonary vascular resistance.

Analysis of Variance↗

PubMed2001

The antidepressant effect of sertraline is not enhanced by dose titration: results from an outpatient clinical trial.

A previous report suggested that 5 weeks of continued treatment with 20 mg of fluoxetine was approximately as effective as double-blind titration to a dose of 60 mg in patients who had failed to respond to 3 weeks of initial treatment at 20 mg. The current study was undertaken to evaluate whether 150 mg of sertraline was any more effective than 50 mg in treating depressed patients who were non-responders at 3 weeks. Ninety-one outpatients with DSM-IV major depressive disorder who had a 17-item Hamilton Depression Rating Scale (HAM-D) score > or = 18 were treated with open label sertraline for 3 weeks. Patients who did not achieve remission (defined as 17-item HAM-D total score < or = 8 by week 3) were then randomized to 5 more weeks of double-blind treatment with either 50 mg of sertraline or immediate titration to 150 mg of sertraline. Efficacy was assessed at each visit with the HAM-D, Clinical Global Impressions (CGI)-severity and improvement scale, and the Hopkins Symptom Checklist. There were no significant between-group differences in clinical or demographic features at baseline for the three treatment groups. After 3 weeks of open-label treatment, 16 patients were not randomized, of whom 11 (69%) met responder criteria. The remaining patients were randomized, double-blind, to 50 mg of sertraline (n = 37; HAM-D = 19.2 +/- 5.0) or 150 mg of sertraline (n = 38; HAM-D = 18.4 +/- 5.0). PROC-Mixed analyses found no significant difference in slopes for any outcome measure when comparing 50 mg and 150 mg sertraline treatment groups. At week 8 (LOCF), the overall remission rate (HAM-D < or = 8) for 3-week non-responders was 40%, with no statistically significant between-group difference for the 50 mg versus 150 mg doses of sertraline (P > 0.10). A completer analysis yielded similar results. Adverse events were mostly mild on both doses of sertraline and led to few treatment discontinuations. The results suggest that for most patients continued treatment with 50 mg dose of sertraline yields a rate of antidepressant response that is comparable to what is achieved by dose escalation from 50 mg to 150 mg of sertraline after 3 weeks of treatment. While some patients clearly benefit from higher doses, the results of the current study are consistent with the lack of any evidence for a dose-response curve with sertraline in the treatment of depression.

Adult↗

PubMed1992

EEG-assisted titration of propofol infusion during neuroanesthesia: effect of nitrous oxide.

Total intravenous anesthesia (TIVA) with propofol is an alternative to standard techniques for neuroanesthesia. The present study compared the hemodynamic and recovery profiles of 46 neurosurgical patients randomly assigned to one of three different anesthetic treatment groups. Group 1 was anesthetized with a TIVA technique in which propofol was titrated using an EEG-assisted quantification method. Group 2 received a similar propofol-based infusion technique in combination with nitrous oxide. Group 3 (control) received a standard anesthetic technique consisting of thiopental, nitrous oxide, fentanyl, and isoflurane. Significantly less propofol was required in group 2 than in group 1 (7.4 +/- 1.9 vs. 9.0 +/- 1.0 mg/kg/h, respectively). The propofol blood concentration at the first appearance of EEG burst suppression was also higher in group 1 compared to group 2 (5.8 +/- 1.1 vs. 4.8 +/- 0.8 microg/ml). However, 25% of the patients in group 2 were treated for hypotension after induction, compared to none in groups 1 and 3. Hypertensive episodes, on the other hand, were more frequent in groups 1 (43%) and 3 (31%) than in group 2 (12%). Time to awakening was significantly shorter in the control group (6 +/- 6 min) than in groups 1 (14 +/- 10 min) or 2 (12 +/- 16 min). In conclusion, titration of propofol to achieve a burst suppressive EEG pattern resulted in a slower emergence from anesthesia than a standard "balanced" technique. Use of nitrous oxide with propofol produced more hypotension during induction; however, its use improved hemodynamic stability during the maintenance period.

Journal Article↗

PubMed1995

Optimal preoperative titrated dosage of hypertonic-hyperoncotic solutions in cardiac risk patients.

Hypertonic-iso/hyperoncotic solutions have been the subject of numerous studies, mostly used in a fixed dosage (4 mL/kg bw or 250 mL). Nearly no study exists to prove whether this is the appropriate dosage especially in cardiac risk patients with accompanying diseases. We have compared preoperative volume loading with either 10% hydroxyethyl-starch/7.5% NaCl (HHT-HES) or 10% hydroxyethyl-starch/.9% NaCl (HES) in 50 mL bolus infusions. Volume loading was done with either HES or HHT-HES in 2 x 20 patients before aortic aneurysmectomy. The endpoint of stepwise infusion represented the highest cardiac index (CI) at the lowest possible wedge pressure (PCWP) (turning point of each individual Frank Starling relation). 167.5 mL (+/- 45.5 mL = 2.41 mL/kg bw) of HHT-HES and 440 mL (+/- 26.15 mL = 6.33 mL/kg bw) of HES were necessary. We observed a significant higher increase of the CI in the HHT-HES group. Significant increases of PCWP, pulmonary artery pressure, and central venous pressure occurred within the groups without any significant differences between the groups (p < .05). Results of the study showed: 1) The commonly used fixed dosage of 4 mL/kg bw of HHT-HES is too high in cardiac risk patients with slight hypovolemia. 2) HHT-HES should be given in an individual titration. 3) In the HHT-HES group we observed a positive inotropic effect (higher CI). 4) With the individual titration of HHT-HES no negative side effects occurred (especially no hypotension).

Aged↗

PubMed2004

Auto-titrating continuous positive airway pressure for treating adult patients with sleep apnea syndrome.

PURPOSE OF REVIEW: The treatment of sleep apnea syndrome (SAS) is continuous positive airway pressure (CPAP) as the first line of therapy. The current standard is for an attendant technician to titrate CPAP by means of an in-laboratory polysomnography to obtain a fixed single pressure. Over the past decade and a half, some devices able to modify the pressure delivered to the patient overnight and from night to night have become available. The efficacy of such devices to manage SAS has been demonstrated, however the question of their use either as unattended APAP to determine pressures for fixed CPAP or for self-adjusting APAP treatment on a long-term basis is still matter of debate. RECENT FINDINGS: However, if cost considerations may render reluctant to APAP, off note, using APAP could allow initiation of treatment more quickly, reduce in-laboratory time, and reduce healthcare costs. SUMMARY: Auto-titrating continuous positive airway pressure and CPAP are to date equivalent in terms of efficacy to treat SAS, but APAP could allow quick initiation of treatment and therefore reduce healthcare costs.

Adult↗

PubMed2000

Scrapie infections initiated at varying doses: an analysis of 117 titration experiments.

An analysis of 117 titration experiments in the murine scrapie model is presented. The experiments encompass 30 years' work and a wide range of experimental conditions. To check that the experimental designs were reasonably consistent over time, comparisons were made of size, duration, source of inoculum, etc., in each experiment. These comparisons revealed no systematic trends that would render invalid comparisons across experiments. For 114 of the experiments it was possible to calculate the dose at which half of the challenged animals were infected (the ID50). These 114 experiments were then combined on the basis of relative dose (i.e. tenfold dilution relative to the ID50). This created a data set in which over 4000 animals were challenged with doses of scrapie ranging from four orders of magnitude below to five orders of magnitude above the ID50. Analysis of this data reveals that mean incubation periods rise linearly with logarithmic decreases in dose. A one unit increase in relative dose (i.e. a tenfold increase in actual dose) will, on average, decrease the incubation period by 25 days. At ID50 the average incubation period in this data set is 300 days. Within a single dose, in a single experimental model, incubation periods have a distribution close to normal. Variability in incubation period also rises linearly as dose decreases. There is no age or sex effect upon the probability of infection, but female mice have incubation periods that are, on average, nine days shorter than their male counterparts and young mice have incubation periods that are longer by seven days. Although many of these patterns are apparent in the results of single titration curves, they can be more rigorously investigated by considering the outcome for thousands of mice.

Age Factors↗

PubMed2000

The unfolding enthalpy of the pH 4 molten globule of apomyoglobin measured by isothermal titration calorimetry.

The unfolding enthalpy of the pH 4 molten globule from sperm whale apomyoglobin has been measured by isothermal titration calorimetry, using titration to acid pH. The unfolding enthalpy is close to zero at 20 degrees C, in contrast both to the positive values expected for peptide helices and the negative values reported for holomyoglobin and native apomyoglobin. At 20 degrees C, the hydrophobic interaction should make only a small contribution to the unfolding enthalpy according to the liquid hydrocarbon model. Our result indicates that some factor present in the unfolding enthalpies of native proteins makes the unfolding enthalpy of the pH 4 molten globule less positive than expected from data for peptide helices.

Apoproteins↗

PubMed2026

Efficacy and Safety of Once-Weekly Semaglutide 2.0 mg as an Add-On to Dose-Reduced Insulin Glargine versus Dose-Titrated Insulin Glargine in People With Type 2 Diabetes and Overweight (SUSTAIN OPTIMIZE).

AIMS: Type 2 diabetes (T2D) management with basal insulin can lead to hypoglycaemia and weight gain. SUSTAIN OPTIMIZE compared once-weekly semaglutide 2.0 mg as add-on to dose-reduced insulin glargine (Sema+IGlarreduced) versus dose-titrated IGlar (IGlartitrated) on glycated haemoglobin (HbA1c), body weight (BW), daily insulin dose, and participant satisfaction. MATERIALS AND METHODS: SUSTAIN OPTIMIZE was a 40-week, phase 3b, open-label, randomised study. Adults with T2D, overweight (body mass index ≥ 25 kg/m2), and treatment with basal insulin ≤ 40 units/day were randomised 1:1 into Sema+IGlarreduced or IGlartitrated. The primary endpoint was change in HbA1c using a non-inferiority approach. Secondary endpoints assessed superiority of Sema+IGlarreduced versus IGlartitrated in reducing HbA1c, BW, daily insulin dose, and improving Diabetes Treatment Satisfaction Questionnaire change version (DTSQc) scores. RESULTS: Overall, 573 participants were randomised. Sema+IGlarreduced achieved both non-inferiority and superiority versus IGlartitrated in HbA1c reduction (estimated treatment difference [ETD]: -0.74%; 95% confidence interval [CI95]: -0.90, -0.59) and superiority in BW change (ETD: -8.5 kg; CI95: -9.5, -7.4), relative daily insulin dose change (ETD: -121.9%; CI95: -143.1, -100.6), and DTSQc scores (ETD: 2.6; CI95: 1.6, 3.5) (p < 0.0001 for all endpoints). No new safety concerns were identified. Severe hypoglycaemia was reduced (rate ratio: 0.45; CI95: 0.23, 0.87; p = 0.02), while gastrointestinal events were higher for Sema+IGlarreduced (310 vs. 32 events). CONCLUSIONS: Once-weekly subcutaneous semaglutide 2.0 mg as add-on to dose-reduced IGlar achieved superior reductions in HbA1c, BW, and daily insulin dose in people with T2D and overweight, while reducing their risk for severe hypoglycaemia compared to dose-titrated IGlar alone.

Adult↗

PubMed1990

Bolus or slow titrated injection of midazolam prior to upper gastrointestinal endoscopy? Relative effect on oxygen saturation and prophylactic value of supplemental oxygen.

A total of 131 patients undergoing upper gastrointestinal endoscopy were sedated with midazolam given as a bolus injection over 5 seconds. The oxygen saturation was continuously measured using a pulse oximeter. Supplemental oxygen was given via nasal cannulae at a rate of 3 litres per minute to 54 patients, while the remaining 77 patients only received oxygen if their oxygen saturation dropped below 85%. Both groups in the present series were compared with 3 previously published series of patients, in whom we had used intravenous midazolam as a slow titrated injection. Despite using on average only two-thirds of the dose of midazolam, following bolus injection the degree of oxygen desaturation during the endoscopic procedure was greater, and the ability of supplemental oxygen delivered via nasal cannulae to prevent hypoxia was less (P less than 0.01), than with a slow titrated injection.

Adult↗