Temperature response to cold challenge and mobile phone thermography as outcome measures for systemic sclerosis-related Raynaud's phenomenon.

Objectives: Objective outcome measures of systemic sclerosis (SSc)-related Raynaud's phenomenon (RP) are badly needed. Our objectives were to validate the thermographic response to a standard hand cold challenge as an outcome measure by assessing sensitivity to change, and to explore mobile phone thermography as a feasible, ambulatory tool.Method: Twelve patients with an SSc-spectrum disorder admitted for intravenous iloprost infusions underwent a standard cold challenge before and after one infusion. Thermographic measurements included area under the rewarming curve (AUC) and maximum rewarming temperature (MAX). Before and during another infusion, each patient underwent monitoring of finger skin temperature by two methods: continuous thermocouple recording (standard method) and mobile phone thermography.Results: All cold challenge summary measures, including AUC and MAX, increased after iloprost (most not significantly). However, when the response curves were modelled after averaging across fingers (linear mixed models, three versions), significant change was detected. For example, with Model 1 (no interaction between period and time), temperature was on average 1.67ºC [95% confidence interval (CI) 1.49-1.85, p < 0.001] higher post-iloprost. Mobile phone and thermocouple temperature measurements showed a strong estimated latent correlation (0.88, 95% CI 0.81-0.92). The estimated increases/hour were 0.25ºC (95% CI 0.05-0.45) for the thermocouple and 0.36ºC (95% CI 0.13-0.60) for mobile phone thermography.Conclusion: Our pilot study suggests that the thermographic response to a cold challenge is sensitive to change and mobile phone thermography could bring feasibility to thermographic parameters as outcome measures in later-phase, large-scale, community-based clinical trials of RP.

Endovascular Versus Open Repair as Primary Strategy for Ruptured Abdominal Aortic Aneurysm: A National Population-based Study.

OBJECTIVE/BACKGROUND: In randomized trials, no peri-operative survival benefit has been shown for endovascular (EVAR) repair of ruptured abdominal aortic aneurysm (rAAA) when compared with open repair. The aim of this study was to investigate the effect of primary repair strategy on early and midterm survival in a non-selected population based study. METHODS: The Swedish Vascular Registry was consulted to identify all rAAA repairs performed in Sweden in the period 2008-12. Centers with a primary EVAR strategy (treating > 50% of rAAA with EVAR) were compared with centers with a primary open repair strategy. Peri-operative outcome, midterm survival, and incidence of rAAA repair/100,000 inhabitants aged > 50 years were assessed. RESULTS: In total, 1,304 patients were identified. Three primary EVAR centers (pEVARc) operated on 236 patients (74.6% EVAR). Twenty-six primary open repair centers (pORc) operated 1,068 patients (15.6% EVAR). Patients treated at pEVARc were more often referrals (28.0% vs. 5.3%; p < .01), had a higher rate of respiratory comorbidity (36.5% vs. 21.9%; p < .01), and higher pre-operative systolic blood pressure (84.3 vs. 72.3 mmHg; p < .01). There was no difference in mortality based on primary treatment strategy at 30 days (pEVARc 28.0%, n = 66; pORc 27.4%, n = 296 [p = .87]), 1 year (pEVARc 39.9%, n = 93; pORc 34.7%, n = 366 [p = .19]), or 2 years (42.1%, n = 94; 38.3%, n = 394 [p = .28]), either overall or in subgroups based on age or referral status. Overall, patients treated with EVAR were older (mean age 76.4 vs. 74.0 years; p < .01), and had a lower 30 day mortality (EVAR 21.6%, n = 74; odds ratio 29.6%, n = 288 [p = < .01]). Incidence of rAAA repair was lower in pEVARc regions (6.07, 95% confidence interval [CI] 5.01-7.13) when compared with pORc regions (8.15, 95% CI 7.64-8.66). CONCLUSION: There was no difference in mortality after rAAA repair among centers with a primary EVAR approach when compared with a primary open repair strategy, either peri-operatively or in the midterm. The study supports the early findings of the randomized controlled trials in a national population based setting.

Experimental determination of the ²4Mg I (3s3p)³P2 lifetime.

We present the first experimental determination of the electric-dipole forbidden (3s3p)³P2→(3s²)¹S0 (M2) transition rate in ²4Mg and compare to state-of-the-art theoretical predictions. Our measurement exploits a magnetic trap isolating the sample from perturbations and a magneto-optical trap as an amplifier converting each ³P2→¹S0 decay event into millions of photons readily detected. The transition rate is determined to be (4.87 ± 0.3)×10⁻4 s⁻¹ corresponding to a ³P2 lifetime of 2050(-110)(+140) sec. This value is in agreement with recent theoretical predictions, and to our knowledge the longest lifetime ever determined in a laboratory environment.

Ten-year risk for myocardial infarction in patients with first-ever stroke: a community-based study.

BACKGROUND: Stroke and coronary heart disease (CHD) share common risk factors. The risk for stroke patients to have a myocardial infarction (MI) has not been fully explored. METHODS: Three hundred and seventy-seven first-ever stroke patients were ascertained prospectively. The 10-year incidence of MI was examined by register searches. The results were compared to the general Swedish population. Predictors for MI were identified using univariate and multivariate analysis. RESULTS: The cumulative incidence of MI over 10 years was 25.0/100 (95% confidence interval (CI), 19.5-31.5), 26.5 for men, (95% CI, 18.9-45.8) and 23.4 for women (95% CI, 16.0-32.9). Compared to the general population, the relative risk for stroke patients having a MI was 1.6 for men (95% CI, 1.12-2.37) and 1.9 for women (95% CI, 1.27-2.90). In multivariate analysis, CHD before the stroke (MI, angina pectoris, coronary artery bypass grafting, or percutaneous transluminal coronary angioplasty) and peripheral artery disease were significant predictors for MI. CONCLUSION: The risk for MI is significantly higher, for both male and female stroke patients, compared to the general population. Stroke patients with previous CHD and peripheral artery disease are at highest risk. Stroke patients should receive adequate secondary prevention, and cardiac complaints must be taken seriously.

Coordination of rare earth element cations on the surface of silica-derived nanoadsorbents.

Silica (SiO2)-derived nanoadsorbents are a powerful and attractive tool for the extraction and separation of rare earth elements (REE) from many perspectives such as reusability, efficiency and minimum impact on the environment. In the present work, we investigated two different methods of adsorption down to the molecular level: (1) the mechanism of the coordination of different groups of REE (light, medium, heavy) with iminodiacetic acid (IDA) was revealed by exploiting models obtained from X-ray crystallography, explaining the selectivity of this type of ligand, and (2) the mechanism of the seeding of RE(OH)3 initiated by SiO2-based nanoadsorbents was investigated by EXAFS, both individually and in combination with mechanism (1), showing the coexistence of both mechanisms. The REE loaded nanoadsorbents possess a high magnetic susceptibility. This property was studied by magnetometry to quantify the REE adsorption efficiency and compared with the values obtained from complexometry.

Toxicological testing of cytotoxic drugs (review).

Cytotoxic drugs are a unique therapeutic class of fundamental importance in current antineoplastic chemotherapy. These drugs belong to many chemical and chemotherapeutic classes. They are cytotoxic by design and are able to cause serious dose-limiting adverse effects at therapeutic doses. Most antineoplastic dosing strategies focus on minimizing cytotoxicity rather than optimizing efficacy. In turn, cytotoxicity is interconnected with other therapeutic considerations, including cell status (renewing vs. non-renewing cell types), cell membrane transport integrity, intracellular activation status, immune system integrity, cellular repair status, and drug resistance. Regulatory requirements for the development of cytotoxic drugs are not well characterized, and differences exist in regional requirements. A safety assessment package which is utilized and accepted world-wide does not yet exist, despite many efforts of harmonization. In this report, the authors introduce a comprehensive safety assessment package for cytotoxic drugs, based on institutional experience acquired globally with this class of drugs, that fulfills both scientific and world-wide regulatory requirements for this very important therapeutic category.

Reproductive toxicity of exemestane, an antitumoral aromatase inactivator, in rats and rabbits.

Exemestane is an orally active, irreversible inactivator of aromatase, structurally related to the natural substrate androstenedione, in clinical use at 25 mg daily for the treatment of advanced breast cancer in postmenopausal women. The reproductive and developmental toxicity of exemestane was assessed in rats and rabbits with oral administration. Pivotal experiments included a fertility study (Segment I), in which female rats received exemestane doses of 4, 20, or 100 mg/kg/day from two weeks premating until GD 20 (cesarean-sectioned dams), or until GD 15 and then from D 1 to D 21 postpartum (dams allowed to deliver), and developmental toxicity studies (Segment II), in which rats and rabbits were treated from GD 6 through GD 17 (rats) or GD 18 (rabbits) at doses of 10, 50, 250, or 810 mg/kg/day and 30, 90, or 270 mg/kg/day, respectively. All rabbits and two-thirds of the rats were cesarean sectioned toward the end of pregnancy to determine litter parameters and examine structural abnormalities in the fetuses; the remaining one-third of the rats was allowed to litter and rear pups to weaning. No pivotal male fertility or peri- and postnatal studies were performed, taking into consideration the therapeutic use. Postnatal effects on the first generation offspring were assessed in both studies in rats, in the portion of dams allowed to deliver. Their F1 offspring were raised to adulthood, when they were evaluated for reproductive performance, and the F1 females were terminated on GD 20. The dosing schedule for the Segment I study in rats, which included a postnatal component, was established to exclude exposure before and during parturition (by withdrawing treatment from GD 16 until the end of parturition). This withdrawal of treatment was put in place because in a preliminary study with treatment including the peripartum period, doses from 5 to 200 mg/kg/day prolonged gestation and interfered with parturition.Overall, studies in rats showed that female fertility was not affected up to 100 mg/kg/day, but doses higher than 4 mg/kg/day, which is approximately the pharmacologically active dose (ED50 = 3.7 mg/kg), prolonged gestation and impaired parturition, leading to maternal deaths in labor and perinatal deaths of offspring. Rats killed on GD 20 showed nondose-related increases in resorptions at doses higher than 10 mg/kg/day, a reduction in fetal body weights at 20 and 100 mg/kg/day (fertility study) and 810 mg/kg/day (developmental toxicity study), and an increase in placental weights at all doses. Female fetuses exposed in utero until GD 20 at 100 mg/kg/day showed an increase in the anogenital distance, very likely related to an increase of the potent androgen DHT as a consequence of aromatase inhibition. Morphologic examinations in fetuses and born pups that were exposed in utero up to the end of the organogenesis period, as well as postnatal investigations on offspring up to adulthood, showed no treatment-related effects. In a developmental toxicity study in rabbits, treatment at 270 mg/kg/day affected maternal food intake and body weight gain, caused abortion or total resorption in about 30% of pregnant females, and reduced body weight and numbers of live fetuses, but did not affect fetal morphology. It was concluded that exemestane did not affect parturition in rats at 4 mg/kg/day or pregnancy in rabbits at 90 mg/kg/day (about 1.5 and 70 times the human dose, respectively, on a mg/m2 basis) and was not teratogenic in rats and rabbits. Exemestane is marketed for use only in postmenopausal women. Its labeling includes a contraindication to use in pregnant or lactating women.

Microscopic mechanisms influencing the volume amplified magnetic nanobead detection assay.

The volume amplified magnetic nanobead detection assay [Strömberg, M., Göransson, J., Gunnarsson, K., Nilsson, M., Svedlindh, P., Strømme, M., 2008. Nano Letters 8, 816-821] was investigated with respect to bead size, bead surface coverage of probe oligonucleotides, bead concentration and rolling circle amplification (RCA) time, with the objective to improve the understanding of the microscopic mechanisms influencing the assay. The most important findings for future biosensor development were the following: (i) small beads exhibit a much reduced tendency to cross-link several RCA products, thus enabling use of both complex magnetisation turn-on and turn-off detection strategies, whereas larger beads only allow for turn-off detection; (ii) small beads exhibit faster immobilisation kinetics, thus reducing the time for diagnostic test completion, and also immobilise in larger numbers than larger beads. Finally, (iii) by demonstrating qualitative dual-target detection of bacterial DNA sequences using 130 and 250nm beads, the bioassay was shown to allow for multiplexed detection.

Affinity-based biosensors for biomolecular interaction analysis.

This overview presents an introduction to affinity-based biosensors, most notably the BIACORE. These biosensors detect molecular interactions by immobilizing one of the interactants (the ligand or target molecule) on the surface of a sensor chip. A solution containing the other interactant is then applied to the chip. Binding of analyte to the surface results in a response proportional to the mass bound. A discussion of sensor chips and practical applications is also provided.

Effects of LS-2616 administration upon the autoimmune disease of (NZB x NZW) F1 hybrid mice.

Autoimmune (NZB X NZW) F1 female hybrid mice were treated with LS-2616, a recently developed substance with immunomodulating properties. Treatment was initiated at the age of 4 months (i.e. at the early stage of the disease) as well as at 7 months of age (i.e. after the development of established lupus-like disease). Control groups treated with cyclophosphamide and physiological saline were also studied. Beneficial therapeutic effects were obtained regardless of when the treatment was initiated and the dose of LS-2616 administered (1 and 8 mg/mouse/week). The effects of LS-2616 on longevity, splenomegaly and glomerulonephritis were pronounced and sometimes comparable to those of cyclophosphamide (1.8 mg/mouse/week). The results obtained suggest that LS-2616 may be useful in the treatment of autoimmune disease in man.

Capillary zone electrophoresis for the study of the binding of antithrombin to low-affinity heparin.

When low-affinity interactions between glycosaminoglycans and precious proteins are studied, it is imperative to design an experimental set-up that consumes as little material as possible. To evaluate the applicability of the CZE technique to this problem, we explored the interaction between antithrombin and low-affinity heparin. In a series of CZE experiments we demonstrated that the mobility of antithrombin increases gradually as increased concentrations of low-affinity heparin were added to the electrolyte. The results were, as expected, consistent with the general algorithm for monovalent binding. The binding constant was estimated at 20+/-6 microM in excellent agreement with the value reported in the literature.

Decreased erythrocyte cholesterol/phospholipid ratio in untreated patients with essential hypertension.

The erythrocyte cholesterol/phospholipid ratio was determined in eight patients with untreated essential hypertension and compared with that of eight age-matched control subjects. The ratio was significantly lower in patients (Wilcoxon's paired rank test; P less than 0.01), and a correlation existed between the ratio and serum cholesterol concentration in patients (r = 0.63) but not in controls (r = 0.02). A reduction in the cholesterol/phospholipid ratio may play a direct role in destabilizing the plasma membrane, which will in turn result in an increase in membrane permeability in essential hypertension.

Phase equilibria and molecular packing in the N,N-dimethyldodecylamine oxide/gramicidin D/water system studied by 2H nuclear magnetic resonance spectroscopy.

A partial phase diagram of the system N,N-dimethyldodecylamine oxide (DDAO)/water/gramicidin D was determined by 2H-NMR. Both 2H2O and perdeuterated DDAO (DDAO-d31) were studied by solid state NMR techniques. Addition of gramicidin D to the micellar (L1), normal hexagonal (HI) and cubic (I) phases of DDAO induces phase separations, giving two-phase regions, which all contain a lamellar (L alpha) phase. The L alpha phase containing gramicidin is characterized by larger order parameters for DDAO-d31 compared with the corresponding order parameters in the L alpha and HI phases of DDAO-d31/H2O. The L alpha phase may stay in equilibrium with any other phase in the phase diagram. The DDAO exchange between the coexisting phases is slow on the NMR timescale, which is why the recorded NMR spectrum consists of superimposed spectra from the different phases occurring in the sample. Gramicidin D can be solubilized in appreciable quantities only in the lamellar phase of DDAO-d31. Increasing amounts of gramicidin in the liquid crystalline phases result in a continuous increase in the molecular ordering up to about 5 mol% gramicidin, where a plateau is reached. This is consistent with a recent theoretical model describing the influence on the ordering of lipids by a membrane protein with larger hydrophobic thickness than the lipid bilayer. The solvent used for dissolving gramicidin at the incorporation of the peptide in the lipid aggregates has no effect on the 2H-NMR lineshapes of DDAO-d31. It is concluded that gramicidin is solubilized in the L alpha phase and that it always adopts the channel conformation independent of a particular solvent. The channel conformation is also supported by CD studies. In some of the samples, macroscopic orientation of the lipid aggregates is observed. It is concluded that DDAO-d31 in the binary system favors an orientation with the long axis of the hydrocarbon chain perpendicular to the magnetic field, whereas when gramicidin D is present the hydrocarbon chain orients parallel to the magnetic field. This is explained by the fact that gramicidin aligns with its helical axis parallel to the magnetic field, thereby forcing also the DDAO-d31 molecules to obtain such an orientation.

Mammary tumour inhibition and subacute toxicity in rats of prednimustine and of its molecular components chlorambucil and prednisolone.

Prednimustine, a chlorambucil ester of pregnisolone, retarded growth of DMBA-induced mammary tumours in rats and reduced the number of tumours. A combination of chlorambucil and prednisolone (C + P) in the same proportion as in prednimustine, had similar effects, 8 and 26 mg per kg of the C + P combination being equipotnet to 16 and 64 mg per kg of prednimustine, respectively. The mortality figures suggested that prednimustine was considerably less toxic than equipotent doses of C + P. This toxicity difference was confirmed in a parallel investigation of the subacute toxicity in rats of prednimustine and C + P. This study showed that the mortality, reduction of lymphocytes and platelets, and bone marrow depression was much lower after pregnimustine than after equimolar amounts of the C + P combination. The results suggest that the low toxicity of prednimustine makes this drug a better cytostatic agent than the C + P combination treatment.