Towards Neutron Capture on Exotic Nuclei: Demonstrating (d,pγ) as a Surrogate Reaction for (n,γ).

The neutron-capture reaction plays a critical role in the synthesis of the elements in stars and is important for societal applications including nuclear power generation and stockpile-stewardship science. However, it is difficult-if not impossible-to directly measure neutron capture cross sections for the exotic, short-lived nuclei that participate in these processes. In this Letter we demonstrate a new technique which can be used to indirectly determine neutron-capture cross sections for exotic systems. This technique makes use of the (d,p) transfer reaction, which has long been used as a tool to study the structure of nuclei. Recent advances in reaction theory, together with data collected using this reaction, enable the determination of neutron-capture cross sections for short-lived nuclei. A benchmark study of the ^{95}Mo(d,p) reaction is presented, which illustrates the approach and provides guidance for future applications of the method with short-lived isotopes produced at rare isotope accelerators.

Constraining Neutron Capture Cross Sections for Unstable Nuclei with Surrogate Reaction Data and Theory.

Obtaining reliable data for nuclear reactions on unstable isotopes remains an extremely important task and a formidable challenge. Neutron capture cross sections-crucial ingredients for models of astrophysical processes, national security applications, and simulations of nuclear energy generation-are particularly elusive, as both projectile and target in the reaction are unstable. We demonstrate a new method for determining cross sections for neutron capture on unstable isotopes, using ^{87}Y(n,γ) as a prototype. To validate the method, a benchmark experiment is carried out to obtain the known ^{90}Zr(n,γ) cross section analogously. Our approach, which employs an indirect ("surrogate") measurement combined with theory, can be generalized to a larger class of nuclear reactions. It can be used both with traditional stable-beam experiments and in inverse kinematics at rare-isotope facilities.

Low-energy enhancement in the photon strength of 95Mo.

A new experimental technique is presented using proton-γ-γ correlations from (94)Mo(d,p)(95)Mo reactions which allows for the model-independent extraction of the photon strength function at various excitation energies using primary γ-ray decay from the quasicontinuum to individual low-lying levels. Detected particle energies provide the entrance excitation energies into the residual nucleus while γ-ray transitions from low-lying levels specify the discrete states being fed. Results strongly support the existence of the previously reported low-energy enhancement in the photon strength function.

Similar lipid profile but improved long-term outcomes with sirolimus after cyclosporine withdrawal compared to sirolimus with continuous cyclosporine.

Renal transplant recipients show an increased risk of cardiovascular disease compared with a nontransplant population. Herein we have shown an analysis of a randomized controlled trial wherein 525 patients receiving a first or second (9.7%) renal allograft from a deceased (89.1%), a living-related (7.8%), or a living-unrelated donor (3.1%) received sirolimus (SRL), cyclosporine (CsA), and steroids (ST) at the time of transplantation with randomization at 3 months after transplantation of 430 eligible patients to continue on SRL-CsA-ST or to have CsA withdrawn with increased SRL trough targets (SRL-ST group). Graft survival, patient survival, and renal function at 5 years were analyzed by average fasting total cholesterol (200 mg/dL) and triglyceride (240 mg/dL) subgroups. At 5 years, total, high-density lipoprotein (HDL), and low-density lipoprotein [LDL] cholesterol and triglyceride values were similar between the groups. Statins ( approximately 80% of patients of both groups) were most effective to lower cholesterol ( approximately 50 mg/dL; P < .001; both groups), and fibrates ( approximately 25% of patients of both groups) were most effective to decrease triglycerides ( approximately 100 mg/dL; P < .001; both groups). Renal function and blood pressure were significantly better with SRL-ST. Hypercholesterolemia and hypertriglyceridemia were associated with reduced graft survival, patient survival, and calculated GFR, but the only significant difference was lower graft survival among SRL-CsA-ST patients with hypertriglyceridemia. Cardiovascular-related deaths were reported in 3.7% and 2.8% of patients in the SRL-CsA-ST and SRL-ST groups, respectively. In conclusion, when compared with continuous SRL-CsA-ST, CsA withdrawal at 3 months followed by SRL-ST significantly improved glomerular filtration rate (GFR) and blood pressure without a further increase in lipid parameters or an incidence of untoward effects from hyperlipidemia, despite a 2-fold higher SRL exposure.

Lifetime measurement of the first excited 2+ state in 16C.

The lifetime of the 2_+(1) state in 16C has been measured with the recoil distance method using the 9Be(9Be,2p) fusion-evaporation reaction at a beam energy of 40 MeV. The mean lifetime was measured to be 11.7(20) ps corresponding to a B(E2;2_+(1)-->0+) value of 4.15(73)e_2 fm_4 [1.73(30) W.u.], consistent with other even-even closed shell nuclei. Our result does not support an interpretation for "decoupled" valence neutrons.

Sirolimus-based therapy with or without cyclosporine: long-term follow-up in renal transplant patients.

This open-label, phase 3b, extension trial in renal transplant recipients (Sirolimus Study 311) assessed the long-term safety of sirolimus (SRL) administered with cyclosporine (CsA) (SRL + CsA group, n = 98) or without CsA (SRL group, n = 69). Renal transplant recipients who had either completed one of seven previous SRL studies sponsored by Wyeth Research or had participated for > or =3 months and reached a protocol-designated endpoint were eligible for enrollment. Data were available for 167 patients, all of whom initially received steroids. Mean total SRL exposure was 1526 days, including previous study participation. After enrollment in the extension study, there were significantly more acute rejections in the SRL + CsA group (6.1% vs 0%, P < .05). Differences in rates of graft loss (3.1% vs 1.4%) and death (6.1% vs 1.4%) were not significantly different between SRL + CsA and SRL groups, respectively. At 48 months after transplantation, calculated GFR (53.4 vs 70.9 mL/min) and hemoglobin (124.9 vs 136.6 g/L) were significantly better in the SRL group. Lipid values were not significantly different between groups at 48 months. The incidence of treatment-emergent increased creatinine, anemia, hypertension, headache, epistaxis, abnormal kidney function, and upper respiratory infection were significantly higher in the SRL + CsA group, whereas no adverse events were significantly higher in the SRL group. Malignancies were reported more frequently (11.2% vs 0%) with SRL + CsA. Results from this extension study indicate that SRL-based therapy without CsA is a safe alternative to combination therapy with CsA, offering long-term improvement in renal function with no increased risk of late acute rejection.

Cardiovascular risk factors of sirolimus compared with cyclosporine: early experience from two randomized trials in renal transplantation.

INTRODUCTION: Renal transplant recipients are at a higher risk of cardiovascular events, including death. This paper examines cardiovascular risk factors in two phase II studies comparing cyclosporine (CsA) with sirolimus-based therapy. METHODS: In two phase II studies, patients (n = 161) were randomized at the time of transplantation to receive either sirolimus or CsA in triple-therapy regimens with either azathioprine (Study A) or mycophenolate mofetil (Study B), and corticosteroids. Sirolimus whole blood trough levels were targeted to 30 ng/mL for 2 months and 15 ng/mL thereafter. Pooled results of the two studies are reported. RESULTS: When patients receiving sirolimus were compared with those receiving CsA, peak cholesterol and trigylcerides at 2 months were markedly and significant higher with sirolimus therapy. The difference between groups decreased thereafter and was not significant from 12 through 24 months. Control of lipid parameters in sirolimus-treated patients was achieved by decreasing the target trough levels after 2 months and by using lipid-lowering agents. Sirolimus-based therapy was associated with a lower incidence of treatment-emergent hypertension (47.5% vs 29.6%, P <.024). At 24 months, the calculated glomerular filtration rate was significantly better with sirolimus (51.3 vs 65.1 mL/min, P <.001). There were no significant differences in the incidences of diabetes or death due to cardiovascular events. CONCLUSION: Patients receiving sirolimus experience an initial increase in lipid levels, but these effects are manageable with the use of lipid-lowering agents. Hypertension was less frequent and renal function was improved with CsA-free, sirolimus-based therapy. Based on this early experience, overall cardiovascular risk does not appear to be increased with sirolimus-based compared with CsA-based therapy.

Sirolimus steady-state trough concentrations are not affected by bolus methylprednisolone therapy in renal allograft recipients.

AIMS: To determine whether bolus doses of methylprednisolone affect the steady-state trough concentrations of sirolimus. METHODS: Fourteen renal transplant recipients received concentration-controlled sirolimus therapy in combination with azathioprine and steroids (n=8) or mycophenolate mofetil and steroids (n=6). Bolus doses of methylprednisolone (mean total dose over 1-5 days, 1694 mg; range, 500-3000 mg) were given for the treatment of acute rejection. For each patient, the sirolimus dose (mean, 24.1 mg; range, 3.3-52.5 mg) was the same before and during methylprednisolone therapy. RESULTS: Mean sirolimus whole blood trough concentrations before and after treatment with methylprednisolone were 28.8 ng ml-1 (range, 13.9-45.3 ng ml-1), and 28.5 ng ml-1 (range, 13.0-47.9 ng ml-1), respectively (P=0.85; 95% confidence interval on the difference -3.3, 4.0 ng ml-1). CONCLUSIONS: Bolus methylprednisolone treatment does not affect steady-state sirolimus trough concentrations.

The effect of wall thickness on the response of a spherical ionization chamber.

Air-filled ionization chambers are used widely for radiation dosimetry. For some applications it is important to know the effect on the chamber response of photon attenuation and scattering in the chamber walls. Traditionally, the wall effect is determined by measuring the chamber response as a function of wall thickness and extrapolating linearly to zero thickness. We have constructed a spherical graphite chamber with variable wall thickness. The change in the chamber response with wall thickness has been measured in a 137Cs gamma-ray beam. Our data show that the change in response is not linear with wall thickness, in agreement with the theoretical prediction of Bielajew (1990 Med. Phys. 17 583-7). A linear versus non-linear extrapolation of the measured data to zero wall thickness leads to a difference of almost 1% in the estimate of the wall correction factor, Kw. The value of Kw obtained using the non-linear extrapolation is in good agreement with the result obtained using Monte Carlo techniques.

Pharmacokinetic interaction between single oral doses of diltiazem and sirolimus in healthy volunteers.

AIM AND BACKGROUND: The pharmacokinetic interaction between sirolimus, a macrolide immunosuppressant metabolized by CYP3A4, and the calcium channel blocker diltiazem was studied in 18 healthy subjects. Several clinically important interactions have previously been reported for other immunosuppressive drugs that are metabolized by the same enzyme and for calcium antagonists. METHODS: Healthy subjects who were 20 to 43 years old participated in an open, three-period, randomized, crossover study of the pharmacokinetics of a single 10-mg oral dose of sirolimus, a single oral 120-mg dose of diltiazem, and the two drugs given together. The three study periods were separated by a 21-day washout phase. RESULTS: The geometric mean (90% confidence interval) whole blood sirolimus area under the plasma concentration time-curve increased 60% (35%-90%), from 736 to 1178 ng x h/mL, and maximum concentration increased 43% (14%-81%), from 67 to 96 ng/mL, with diltiazem coadministration, whereas the mean elimination half-life of sirolimus decreased slightly, from 79 to 67 hours. Apparent oral clearance and volume of distribution of sirolimus decreased with 38% and 45%, respectively, when sirolimus was given with diltiazem. The plasma maximum concentration and area under the plasma concentration-time curve of diltiazem, desacetyldiltiazem, and desmethyldiltiazem were unchanged after coadministration of sirolimus, and no potentiation of the effects of diltiazem on diastolic or systolic blood pressure or on the electrocardiographic parameters was seen. CONCLUSIONS: Single-dose diltiazem coadministration leads to higher sirolimus exposure, presumably by inhibition of the first-pass metabolism of sirolimus. Because of the pronounced intersubject variability in the extent of the sirolimus-diltiazem interaction, whole blood sirolimus concentrations should be monitored closely in patients treated with the two drugs.

Pharmacokinetics and safety of single oral doses of sirolimus (rapamycin) in healthy male volunteers.

A phase I study was conducted to determine the pharmacokinetics, safety, and tolerability of sirolimus, a new immunosuppressive drug, in 45 healthy men between 19 and 36 years of age. Nine subjects in each group were randomly assigned to receive single oral doses of either sirolimus (n = 6) or placebo (n = 3) in group I (0.3 mg/m2), group II (1 mg/m2), group III (3 mg/m2), group IV (5 mg/m2) and group V (8 mg/m2). No serious adverse events occurred during the study. Twenty-eight of the 45 volunteers (62%) reported an adverse event; 19 of 30 (63%) were in the sirolimus group and 9 of 15 (60%) were in the placebo group (ns). Asthenia was the most common adverse event, occurring in 7 of 30 (23%) in the sirolimus group compared with 6 of 15 (40%) in the placebo group (ns). Absorption occurred within 1 hour in all volunteers. Whole blood peak concentration and area under the concentration-time curve increased proportionally with dose. Mean (+/- SD) whole blood terminal disposition half-life (t1/2), apparent oral dose clearance (Cl/F), and volume of distribution (Vss/F) were 82 +/- 12 hours, 278 +/- 117 mL/h x kg and 23 +/- 10 L/kg, respectively. Distribution of sirolimus into formed blood elements was extensive, with a mean whole blood-to-plasma ratio of 36. Single oral doses of sirolimus (0.3 to 8 mg/m2) solution were well tolerated in healthy male volunteers.

Clinical pharmacokinetics and therapeutic drug monitoring of sirolimus.

BACKGROUND: Sirolimus is a novel macrocyclic antibiotic that has an immunosuppressive mechanism of action distinct from that of cyclosporine and tacrolimus. OBJECTIVE: The objective of this report is to provide an overview of the clinical development of sirolimus with emphasis on the mechanism of immunosuppressive activity, prevention of acute renal allograft rejection, clinical pharmacokinetics, concentration-effect relationships, and therapeutic drug monitoring (TDM). RESULTS: Pharmacokinetic studies in adult renal transplant patients have shown that sirolimus may be characterized as a drug with rapid absorption (t(max) = 1 to 2 hours), low systemic availability (F = 14%), linear dose proportionality (2 to 24 mg), extensive partitioning into formed blood elements (B/P = 36), large apparent volume of distribution (1.7 L/kg), prolonged terminal half-life (62 hours), and large intersubject (CV = 52%) and intrasubject (CV = 26%) variability in oral-dose clearance. Results from phase 111 pivotal trials showed that sirolimus (2 or 5 mg/d) reduced acute renal graft rejection (generally, P < 0.01) without TDM. Although TDM may not be required for a regimen consisting of full-dose cyclosporine and corticosteroids with sirolimus 2 mg/d (4 hours after cyclosporine), it may be warranted in patients (1) with hepatic impairment, (2) who are young children, (3) who are receiving concurrent doses of strong CYP3A/p-glycoprotein inhibitors or inducers, (4) in whom cyclosporine dosing is markedly reduced or discontinued, and (5) who are at a high risk for rejection. A whole-blood sirolimus therapeutic window of 5 to 15 ng/mL (measured by microparticle enzyme immunoassay) is recommended for patients at standard risk of rejection. The large intrapatient variability observed in trough sirolimus concentrations indicates that dose adjustments should be optimally based on more than a single trough sample. Because of the time required to reach steady state, sirolimus dose adjustments would optimally be based on trough levels obtained >5 to 7 days after a dose change. CONCLUSIONS: The effective use of sirolimus in an immunosuppressive regimen for the prevention of acute renal allograft rejection requires an understanding of the drug's clinical pharmacokinetics, concentration/adverse-effect relationship, concentration-efficacy relationship, and TDM.

Pharmacokinetics, brain distribution and pharmaco-electrocorticographic profile of zolpidem, a new hypnotic, in the rat.

Zolpidem [N,N-6-trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3- acetamide] administered as the hemitartrate salt has proven to be an effective hypnotic agent in animals and humans. This study describes the pharmacokinetic behavior of zolpidem in plasma and brain of rat after i.v. and p.o. administration of 2.63 mg.kg-1 of [14C]zolpidem (dose expressed as the base). Autoradiography was used to examine the regional distribution of the compound and the metabolic profile of zolpidem in the plasma and brain was also investigated. The pharmacokinetic data were related to electrocorticogram power spectral analysis. After i.v. administration, the disappearance of zolpidem from plasma fitted a biexponential model with a rapid phase of 0.2 to 0.3 hr and a slower phase of 1.3 to 1.5 hr. After p.o. dosing, peak plasma concentrations where already attained at 15 min (first sampling time). Independent of the route of administration, the concentrations of zolpidem in the brain at shorter times were 30 to 50% those of the plasma values. Furthermore, up to 1 hr, zolpidem accounted for 80 to 90% of brain radioactivity. The rate of disappearance from brain paralleled that from plasma. Autoradiographic studies confirmed the rapid absorption and elimination of zolpidem as well as the relatively homogenous distribution throughout the brain. Electrocorticogram analysis in immobilized rats after i.v. administration of zolpidem showed a rapid onset and a short-acting sedative effect compatible with the kinetic profile of the parent compound. Metabolites of zolpidem displayed a poor penetration into the brain and no significant hypnotic activity. At the dose of zolpidem used, no alteration of the sleep pattern was observed.

Acute injuries of the axis vertebra.

A retrospective analysis of 165 patients admitted to Hermann Hospital with acute injuries of the axis vertebra revealed 68 (41%) dens fractures, 62 (38%) cases of traumatic spondylolisthesis ("hangman's" fracture), 21 (13%) extension teardrop fractures, 10 (6%) hyperextension dislocations, and 2 (1.0%) fractures each of the laminae and spinous processes. Of the 68 dens fractures, none (0%) were of the Anderson and D'Alonzo Type I; 21 (31%) were Type II ("high"); and 47 (69%) were Type III ("low"). The 62 traumatic spondylolistheses included 13 (21%) Effendi type I, 35 (56%) type II and 3 (5%) type III. This review disclosed an additional 11 (18%) patients with an atypical variety of traumatic spondylolisthesis, not previously reported, in which one or both fractures involved the posterior cortex of the axis body. Of the axis injuries 31 (18%) were limited to the axis body alone. Of these, 21 (61%) were hyperextension teardrop fractures and 10 (32%) were hyperextension dislocations. Axis injuries were associated with acute injuries of other cervical vertebrae in 14 (8%) of the patients.

Direct enantiomeric separation of betaxolol with applications to analysis of bulk drug and biological samples.

A direct method is described for the resolution of the enantiomers of betaxolol, a novel cardioselective beta-adrenergic blocking agent, using a tris(3,5-dimethylphenylcarbamate)cellulose chiral column. An excellent resolution of the two antipodes is obtained (Rs greater than 2) with high peak symmetries. The method is simple and ideally suited to the routine control of the enantiomeric excess in the bulk drug and the analysis of the enantiomers of betaxolol in hepatocyte suspensions. With modification of the polar modifier in a hexane-based mobile phase, most commercially available beta-blockers can be baseline resolved.

Radiology of the urinary system in the emergency department.

Three straightforward radiologic examinations are the cornerstone of the diagnosis of a wide variety of urinary tract pathology that may be encountered in the emergency department. This article reviews some technical aspects of the examinations, the radiologic findings, and some controversial aspects of the diagnosis and subsequent management of these patients.

Determination of antiepileptic drugs.

The present paper reviews gas and liquid chromatographic methods for the determination of the most commonly monitored antiepileptic drugs: phenobarbital, phenytoin, carbamazepine, primidone, ethosuximide, valproic acid and clonazepam along with a new compound, progabide. The individual classes of drugs are first treated separately to highlight specific aspects of their quantification, and this is followed by an overview of those methods permitting the concomitant analysis of two or more antiepileptic compounds. Sample preparation techniques as well as comparisons between chromatographic and other techniques are treated more fully in separate sections.

Low (type III) odontoid fracture: a new radiographic sign.

Dens fractures are frequently difficult to identify radiographically, particularly when it is only possible to obtain a lateral radiograph of the upper cervical spine. Further, when a dens fracture is identified in lateral projection, it is often difficult to distinguish the "high" (Type II) from the "low" (Type III) fracture. The authors describe an elongated "ring" density superimposed upon the body of the axis in the lateral cervical radiograph which, when horizontally disrupted, indicates a dens fracture and is a specific radiographic sign of the "low" variety.