Tumor localization using magnetic nanoparticle-induced acoustic signals.

Cancer is a major public health problem worldwide, especially in developed countries. Early detection of cancer can greatly increase both survival rates and quality of life for patients. A magnetoacoustic-based method had been previously proposed for early tumor detection, in a minimal invasive procedure, using magnetic nanoparticles (MNPs). This paper presents a supporting localization algorithm that can provide the clinician with essential tumor location data and could enable a sequential biopsy. It provides localization algorithm development, as well as its validation in both computerized simulations and in vitro experiments. Three-dimensional (3-D) tumor localization is demonstrated with an error of 2.14 mm and an overlapping volume of 84% of the actual tumor. The obtained results are promising and prove the feasibility of tumor localization using a time difference of arrival algorithm along with a magnetoacoustic detection scheme.

Overall survival benefit for sequential doxorubicin-docetaxel compared with concurrent doxorubicin and docetaxel in node-positive breast cancer--8-year results of the Breast International Group 02-98 phase III trial.

Background In women with node-positive breast cancer, the Breast International Group (BIG) 02-98 tested the incorporation of docetaxel (Taxotere) into doxorubicin (Adriamycin)-based chemotherapy, and compared sequential and concurrent docetaxel. At 5 years, there was a trend for improved disease-free survival (DFS) with docetaxel. We present results at 8-year median follow-up and exploratory analyses within biologically defined subtypes. Methods Patients were randomly assigned to one of four treatments: (i) sequential control: doxorubicin (A) (75 mg/m(2)) × 4 →classical cyclophosphamide, methotrexate, 5-fluorouracil (CMF); (ii) concurrent control: doxorubicin, cyclophosphamide (AC)(60/600 mg/m(2)) × 4 →CMF; (iii) sequential docetaxel: A (75 mg/m(2)) × 3 → docetaxel (T) (100 mg/m(2)) × 3 → CMF and (iv) concurrent docetaxel: AT(50/75 mg/m(2)) × 4 →CMF. The primary comparison evaluated docetaxel efficacy regardless of the schedule. Exploratory analyses were undertaken within biologically defined subtypes. Results Two thousand eight hundred and eighty-seven patients were enrolled. After 93.4 months of median follow-up, there were 916 DFS events. For the primary comparison, there was no significant improvement in DFS from docetaxel [hazard ratio (HR) = 0.91, 95% confidence interval (CI) = 0.80-1.05, P = 0.187]. In secondary comparisons, sequential docetaxel significantly improved DFS compared with sequential control (HR = 0.81, 95% CI = 0.67-0.99, P = 0.036), and significantly improved DFS (HR = 0.84, 95% CI = 0.72-0.99, P = 0.035) and overall survival (OS) (HR = 0.79, 95% CI = 0.65-0.98, P = 0.028) compared with concurrent doxorubicin-docetaxel. Luminal-A disease had the best prognosis. HRs favored addition of sequential docetaxel in all subtypes, except luminal-A; but this observation was not statistically supported because of limited numbers. Conclusion With further follow-up, the sequential docetaxel schedule resulted in significantly better OS than concurrent doxorubicin-docetaxel, and continued to show better DFS than sequential doxorubicin-based control.

Measurement of odour with focus on sampling techniques.

The treatment of waste and many manufacturing processes cause odour emissions. In order to prevent odours, the residents and businesses in the neighbourhood of such plants complain about odour, and it becomes necessary to reduce the emissions. To achieve that, the emissions have to be investigated and evaluated in a representative and reproducible manner. The DIN EN 13725 (2003) [DIN EN 13725. 2003. Luftbeschaffenheit--Bestimmung der Geruchsstoffkonzentration mit dynamischer Olfaktometrie--Air quality--Determination of odour concentration by dynamic olfactometry, Deutsche Fassung EN 13725:2003. Beuth Verlag, Berlin (DE)] provides a European standard for the measurement of odour. Nevertheless, the subject of sampling is not standardised; even though it has a substantial influence on the results of the measurements. In this paper, the odour measurement itself, as well as the different kinds of sampling methods (depending on the specific type of source), will be presented and discussed.

Influence of mechanical-biological waste pre-treatment methods on the gas formation in landfills.

In order to minimise emissions and environmental impacts, only pre-treated waste should be disposed of. For the last six years, a series of continuous experiments has been conducted at the Institute WAR, TU Darmstadt, in order to determine the emissions from pre-treated waste. Different kinds of pre-treated waste were incubated in several reactors and various data, including production and composition of the gas and the leachate, were collected. In this paper, the interim results of gas production and the gas composition from different types of waste after a running time of six years are presented and discussed.

Increase of the purification efficiency of biofilters by the use of a complementary ionisation step.

The biofilter and the ionisation system are two oxidative treatment techniques for purification of waste gas streams with low concentrations of volatile organic compounds. In this paper, the authors present the investigations of an ionisation technique aimed at increasing the efficiency of the reduction of the odorant concentration in waste gas streams from biological waste treatment plants. The objective is to enable advanced odour emission reduction and to adjust the existing biofilters to stricter requirements. In a first step, the odorous substances which are major contributors to the overall odorant concentration are identified on basis of various emission data sets with the help of a method of life cycle impact assessment. Thereby limonene, alpha-pinene, ethyl butyrate and dimethyl disulphide were identified as crucial indicators. In a second step, experimental investigations using limonene as a model compound were conducted to gain an understanding of the ionisation process itself and at last for the evaluation of the system.

Ecological assessment of waste air treatment systems in the case of biological waste treatment.

In this paper, the authors present a technique aimed at increasing the efficiency of biological waste air treatment. The objective is to modify the existing biological waste air treatment systems (i.e. biofilters) to reduce the emitted substances and their potential environmental impacts. The principle of the ionization system is described, along with the first experiences of applying those methods during the rotting process. The investigated system is evaluated by means of life cycle impact assessment, with a focus on odour. It is demonstrated which of the measured substances (i.e. VOC) can potentially contribute to the odorant concentration. Further, it is shown which odour-intensive substances can be reduced by deploying ionization. Finally, the authors respond to the fact that the cleaning efficiency of ionization strongly depends on the humidity of the treated waste gas stream.

Influence of an antivertiginous combination preparation of cinnarizine and dimenhydrinate on event-related potentials, reaction time and psychomotor performance--a randomized, double-blind, 3-way crossover study in healthy volunteers.

In the present comparative, double-blind, 3-way crossover study, possible effects of an antivertiginous combination preparation on event-related potentials (ERPs) and performance were investigated. Twenty-one healthy volunteers received 4 doses (within 24 h) of a fixed combination of cinnarizine 20 mg and dimenhydrinate 40 mg (Arlevert, ARL), dimenhydrinate 50 mg, or a placebo, in randomized order at 1-week intervals. Auditory event-related potentials (ERPs), reaction time (RT) and psychometric tests were assessed before as well as 60 and 150 minutes after the intake of the 1st (Day 1) and the 4th (Day 2) dose of study medication. The evaluation was primarily based on the difference in the outcomes measured 150 min after the 4th dose (t5) and those before the start of medication intake (t0). None of the medications affected the latency and amplitude of the sensory ERP component N100, neither under passive listening nor under discrimination task conditions. The latency of P300 in response to the rare target tones (oddball paradigm and binary series), showed significant (p < 0.05) delays after 4 doses of dimenhydrinate (18-24 ms), and no significant differences between ARL (3-17 ms) and either dimenhydrinate or placebo (4-13 ms). Responses to nontarget tones remained almost unaffected after medication intake. The secondary analysis of the P300 amplitude showed the greatest decreases under DH in both active series, with no significant differences between ARL and either DH or placebo. The 3 medications did not significantly prolong RT nor did they impair the performance of psychometric tests, or cause significant shifts of current mood. The combination preparation ARL showed the lowest rate of adverse events (n = 1), followed by dimenhydrinate (n = 3) and placebo (n = 6). Two subjects withdrew because of adverse events, both after the intake of placebo. In conclusion, the results gave no evidence for an impairment of central information processing and psychomotor performance after multiple dosing with the fixed combination ARL in healthy volunteers, which might, when present, represent an adverse reaction limiting its use in antivertiginous therapy. No significant differences were found between ARL and placebo.

Influence of 3 antivertiginous medications on the vigilance of healthy volunteers.

In the present randomized, comparative, double-blind, 3-way crossover study, possible effects of 3 antivertiginous medications on vigilance were investigated. 30 healthy volunteers received single doses of a fixed combination of cinnarizine 20 mg and dimenhydrinate 40 mg (Arlevert, ARL), dimenhydrinate 50 mg, or betahistine dimesylate 12 mg, in randomized order at 1-week intervals. Spontaneous brain electrical activity (EEG), acoustic late evoked potentials (ALEP) with P300, and reaction time were measured before and 90 (t90) and 180 minutes (t180) after drug intake. All 3 medications led to a delay of P300 (primary criterion) and a decrease of its amplitude. The maximum delay at t180 was found for dimenhydrinate (16.42 ms) and the lowest for betahistine (6.33 ms). Differences ARL vs dimenhydrinate and ARL vs betahistine were not statistically significant (p > 0.05). Spectral analysis of spontaneous EEG showed slight and similar decreases in the power in the a-band under dimenhydrinate and ARL (p = 0.07 and p = 0.03 with respect to baseline, respectively), but basically no change under betahistine. There was no effect on reaction time by either medication. None of the subjects reported drowsiness or any other adverse event. The findings confirm the reported suitability of P300 latency for measurement of drug effects on brain activity, but provide no indication of concomitant impairment of performance capacity by the tested drugs. Global assessment of the results suggests that the fixed combination cinnarizine 20 mg/dimenhydrinate 40 mg exerts only a minor effect on vigilance, not significantly different from betahistine, which is commonly regarded as a non-sedating antivertiginous drug

Clinical choices of antibiotics: judging judicious use.

Scientific literature widely documents the current overuse of antibiotics but often does not address the issue of the judicious use of antibiotics. Multiple analyses of prescribing patterns consistently reveal inappropriate prescribing of antibiotics, even when the clinician is aware of appropriate antibiotic use. In addition to overprescribing antibiotics, providers frequently address therapy failures by switching to same-class antibiotic agents. Additional investigations report that prescribing of antibiotics at the first office visit tends to increase, rather than decrease, costs and has marginal impact on patient outcomes. Patient education interventions, delivered prior to illness, can significantly reduce inappropriate use of antibiotics and reverse resistance trends. A variety of developments in antimicrobial use and resistance and newer antibiotic and respiratory infection management strategies are discussed.

Renal tolerance with the use of intralipid-amphotericin B in low-birth-weight neonates.

Amphotericin B is still the first-line therapy for neonatal fungal infections. With several comparative trials of intralipid-based amphotericin B (IL-AmB) demonstrating its clinical effectiveness and reduced renal toxicity in adults, we examined the renal tolerance and infection outcome in low-birth-weight infants in our 48-bed NICU treated with IL-AmB. Over 2 years, 52 patients (58 courses) received > or = 10 days of IL-AmB. Nineteen charts (23 episodes) were randomly accessed and reviewed. Mean birthweight = 747 grams, gestational age = 25.6 weeks, total IL-AmB dosage = 19.8 +/- 3.3 mg/kg (n = 23); 20 of these episodes were fungal culture positive (9 fungemias). Only one patient (who died during therapy) had a rise in creatinine of > 0.3 mg/dL. Overall, serum creatinine decreased significantly after Day 10 of IL-AmB therapy, from 0.93 +/- 0.42 mg/dL at baseline, to 0.54 +/- 0.24 after 19 days of therapy (p < 0.0001). Serial urine output, serum potassium and potassium supplementation data showed no significant differences from baseline. No interruption of therapy nor infusion reactions occurred. Only one death occurred attributable to fungal infection. Intralipid-amphotericin B may provide an effective alternative in the antifungal therapy of low birthweight neonates, without nephrotoxicity. Further prospective, comparative trials are warranted.

On the analytic solution of electrotonic spread in branched passive dendritic trees.

From the classical work of Rall it is known that the spread of electric potential in a passive dendritic tree may be obtained by expressing the initial conditions as a linear combination of a set of trigonometric eigenfunctions, each decaying with the associated time constant. It is shown here that in order to evaluate the permissible parameters in these eigenfunctions one may formulate the boundary conditions at all the junctions and endings of the dendritic tree as a set of homogeneous linear equations in which the parameters in the eigenfunctions are the unknowns. These equations have a nontrivial solution if the relevant determinant vanishes, a condition that permits the evaluation of the various parameters, thus providing an analytic approach to the expression of the eigenfunctions as well as the decay time constants. The above approach is illustrated by application to a dendritic tree that has a parent segments and two generations of offspring segments, without any restrictions as to the relative diameters or lengths of the various segments in the tree. General properties of the tree may be readily derived, like the variation of the eigenvalues on scaling of the lengths or diameters of all the segments. A few special cases with specified dimensions of the various segments are derived from the general case. In the case of a dendritic tree that fulfills the "equivalent cylinder" conditions, all of the eigenvalues and eigenfunctions of the tree may be determined by the proposed method, including those that do not apply to the equivalent cylinder. The orthogonality properties of the eigenfunctions are discussed.

Informatics integration in a medical residency program: early experiences.

In 1992, Informatics training was integrated into the medical residency program at Norwalk Hospital. The program objective was to familiarize the residents with clinical applications of information technology that could enhance their productivity in clinical practice. In its first year, the curriculum was theory oriented. Evaluation of the program at the end of the first year led to a significant restructuring of the program format and curriculum. The trainees did not find theory to be of immediate clinical value, in the second year the program emphasis was redirected toward the development of practical skills. Next year, in 1993, 'Informatics Clinics' were initiated to develop practical Informatics skills that would be useful in a clinical setting. This approach was more successful but did not offer a complete solution. The degree to which the concepts and methods learned are clinically utilized by residents will depend upon the degree of reinforcement provided in the clinical residency years. In addition, there is a need for the development of assessment standards for the evaluation of Informatics literacy levels. In the absence of assessment standards the level of Informatics literacy in medical graduates remains undetermined Consequently, it is difficult to determine whether the training received has transformed expectations into reality.

Brownian motion of the end-to-end distance in oligopeptide molecules: numerical solution of the diffusion equations as coupled first order linear differential equations.

The Brownian motion of one end of an oligopeptide molecule relative to its other end was previously studied by the measurement of non-radiative energy transfer between chromophores attached to the molecular ends, and was found to conform to a model which describes this motion as a diffusional process in a force field (Haas et al., 1978a). The theoretical treatment of this diffusional problem is performed here by an approach which is different from the one used previously. In this approach advantage is taken of the fact that in the case under consideration the rate of change of the concentration of molecules with a given end-to-end distance is linearly dependent on the instantaneous concentration at this and neighboring end-to-end distances. One thus obtains a set of coupled first-order linear differential equations, which can be solved by standard techniques involving the diagonalization of the matrix of the rate constants in the above set of coupled equations. The concentration distribution at any instant is subsequently obtained as a linear combination of the eigenvectors weighted according to their respective exponential decay with time with rate constants which are related to their respective eigenvalues. Some of the advantages offered by this approach are as follows: one does not have to start the procedure from the beginning if new initial conditions are desired, and the concentration distribution at any given instant is obtained directly without the need of a stepwise build-up of the solution with time. The latter point is especially useful if one is interested in the asymptotic behavior of the changes in concentration at long times, since this behavior can be readily expressed as an exponential decay of the longest-lived eigenvector (or the sum of a few exponentially decaying eigenvectors which have the longest decay times). The above approach is used to treat the energy-transfer experiments performed previously by Haas et al. (1978b), as well as to simulate the dynamics of ring-opening of cyclic oligopeptides and ring closure of linear peptides.

Computer simulations of the effect of non-inactivating sodium channels on the electric behavior of excitable cells.

Non-inactivating sodium channels have been discovered in various cell types. Additionally, normal voltage-gated sodium channels can be induced to lose their ability to inactivate by treatment with proteolytic enzymes, with certain chemical reagents, or with toxins. The presence of non-inactivating sodium channels in the outer membrane of a cell is expected to profoundly modify the electrical properties of the cell, because the electrical depolarization of the cell and the opening of these channels reciprocally reinforce each other without intrinsic control. The normal resting state may thus be destabilized and a new resting state at depolarized resting potentials may become possible. In this study, computer simulations were carried out to systematically explore the patterns of behavior of excitable cells which have non-inactivating sodium channels in their plasma membrane. The cells were assumed to be space clamped and the relevant Hodgkin and Huxley equations were assumed to describe the electrical behavior of the cells, except that some or all of the sodium channels could not inactivate. The sodium currents were thus represented by the sum of two terms: FI.gNa.m3.h.(V-ENa) + (1-FI).gNa.m3(V-ENa), where FI(0 less than or equal to FI less than or equal to 1) is the fraction of sodium channels which inactivate normally, and the other symbols have their usual significance. The behavior of non-inactivating sodium channels created by pronase treatment or reaction with chemical reagents was found to conform with that predicted by the second term in this expression. The simulations thus quantitatively apply to excitable cells thus treated, but may serve additionally to qualitatively illustrate patterns of electrical activity induced by non-inactivating sodium channels also in other cases. A variety of possible types of electrical behavior was obtained: Normal behavior, including capability of firing action potentials, requires values of FI which are not far from unity, the permissible range depending on the fully activated potassium ion conductance, gK. Bistability, at which the cell may exist in one of two stable states of different resting potential, occurs when the value of FI is lowered. Transitions from the polarized to the depolarized resting states, and vice versa, may be brought about by depolarizing and hyperpolarizing triggers, respectively. Such behavior is like that of memory storage devices. Monostability at depolarized potentials is favored by low FI values and can occur if gK is less than the Hodgkin and Huxley value.(ABSTRACT TRUNCATED AT 400 WORDS)

Frequencies of paired open-closed durations of ion channels. Method of evaluation from single-channel recordings.

The probability of the occurrence of consecutive closed-open or open-closed intervals of specified durations in single-channel recordings may be of enormous help in the establishment of the kinetic scheme that describes the behavior of the channel. The relevant probability functions are linear combinations of products of exponential functions of the closed durations and the open durations. A method is presented for the evaluation of the coefficients of the exponential functions using a set of auxiliary functions that are each orthogonal to all but one of the exponential functions. The coefficients in the probability functions may then be obtained from the experimental data by multiplication by the auxiliary functions and subsequent simple integration operations. Furthermore, the variance to be expected in the evaluated numerical magnitude of the parameters, due to the stochastic nature of the transitions in the channel conductance, is also readily estimated by use of the above auxiliary functions. The procedure is illustrated by analysis of synthetic data obtained from computer simulated experiments.

The pharmacokinetics of antiarrhythmic agents in pregnancy and lactation.

The pharmacokinetics of various drugs may be profoundly altered during different stages of pregnancy, parturition, and lactation. Gastrointestinal absorption or bioavailability of drugs may vary due to changes in gastric secretion and motility. Various haemodynamic changes such as an increase in cardiac output, blood volume, and renal plasma flow may affect drug disposition and elimination. The increase in blood volume and total body water which occurs during pregnancy can alter the volume of distribution for various drugs. Although exact quantifications are not easy, these changes in pharmacokinetic parameters should be considered when dosing antiarrhythmic agents in pregnant women. Plasma protein concentrations and drug binding capacity are altered in the mother and fetus as pregnancy advances. With highly protein bound drugs, these changes may be clinically significant, as the pharmacological efficacy and toxicity are presumed to be related to the concentration of free drug in both the mother and fetus. In some instances, the fetus may be susceptible to greater drug toxicity as free drug concentrations may be underestimated by measurement of total drug concentrations. Changes in maternal drug metabolism and metabolism by the fetoplacental unit also contribute to alterations in the pharmacokinetics of drugs. As the placenta contains many metabolising enzymes, biotransformation of drugs at this site could potentially convert a drug into an active metabolite, or prevent fetal exposure to a toxic drug. Placental transfer of drugs, leading to toxicity in the fetus, is a major concern in the pharmacological management of the pregnant patient. The passage of individual drugs will vary depending on their apparent volumes of distribution, degree of protein binding the rates of metabolic conversion and excretion within the placenta and fetus, the pH difference between the maternal and fetal fluids, and maternal haemodynamic changes. Drug properties such as lipid solubility, protein binding characteristics, and ionisation constant (pKa) also influence the placental passage of drugs. For weakly basic antiarrhythmic agents, the fetal drug concentration may potentially exceed the maternal plasma concentration when the fetal pH is lowered as in the case of fetal acidosis; this is due to 'ion trapping'. Additionally, higher free drug concentrations of these basic drugs may exist, due to decreased alpha 1-acid glycoprotein concentration and binding affinity in the fetus. Lignocaine (lidocaine) has been shown to enter fetal plasma rapidly with fetal-maternal concentration ratios in the range of 0.52 to 0.66.(ABSTRACT TRUNCATED AT 400 WORDS)

Relationship between statistical properties of single ionic channel recordings and the thermodynamic state of the channels.

Recordings of the electric conductivity of a single ionic channel usually exhibit two levels of conductance: a zero and a finite level. The channel may, however, be in a few states which have the same conductivity level, and the distribution of dwell time durations at this conductivity level is thus not monoexponential. It is shown that the joint probability p(tc,to) of the occurrence of a time interval tc during which the channel is not conducting, immediately followed by a time interval to during which the channel is conducting may or may not be equal to the joint probability pr(tc,to) of the occurrence of a non-conducting interval tc preceded by a conducting interval to. If the interconversions between the various states in which the channel can exist obey detailed balance, i.e., if the channel behaves like a system at thermodynamic equilibrium, then p(tc,to) = pr(tc,to). This should help to reveal whether irreversible processes, like metabolic reactions or flows of substances across the membrane, are coupled to the gating process of the ionic channels.

Vancomycin-induced neutropenia during treatment of osteomyelitis in an outpatient.

A case of vancomycin-associated neutropenia occurring during long-term outpatient therapy with vancomycin is described. Pharmacokinetic studies demonstrated that the patient's vancomycin serum levels were within an acceptable range during treatment. Eighteen other reported cases of vancomycin-associated leukopenia are discussed in brief. An immunologic mechanism has been proposed but a clear understanding is lacking. Patients receiving long-term vancomycin therapy should have their white blood cell counts periodically monitored.