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The effect of thermotherapy using magnetic nanoparticles on rat malignant glioma.

Thermotherapy using magnetic nanoparticles is a new technique for interstitial hyperthermia and thermoablation based on magnetic field-induced excitation of biocompatible superparamagnetic nanoparticles. To evaluate the potential of this technique for minimally invasive treatment, we carried out a systematic analysis of its effects on experimental glioblastoma multiforme in a rat tumor model. Tumors were induced by implantation of RG-2-cells into the brains of 120 male Fisher rats. Animals were randomly allocated to 10 groups of 12 rats each, including controls. Animals received two thermotherapy treatments following a single intratumoral injection of two different magnetic fluids (dextran- or aminosilane-coated iron-oxide nanoparticles). Treatment was carried out on days four and six after tumor induction using an alternating magnetic field applicator system operating at a frequency of 100 kHz and variable field strength of 0-18 kA/m. The effectiveness of treatment was determined by the survival time of the animals and histopathological examinations of the brain and the tumor.Thermotherapy with aminosilane-coated nanoparticles led up to 4.5-fold prolongation of survival over controls, while the dextran-coated particles did not indicate any advantage. Intratumoral deposition of the aminosilane-coated particles was found to be stable, allowing for serial thermotherapy treatments without repeated injection. Histological and immunohistochemical examinations after treatment revealed large necrotic areas close to particle deposits, a decreased proliferation rate and a reactive astrogliosis adjacent to the tumor.Thus, localized interstitial thermotherapy with magnetic nanoparticles has an antitumoral effect on malignant brain tumors. This method is suitable for clinical use and may be a novel strategy for treating malignant glioma, which cannot be treated successfully today. The optimal treatment schedules and potential combinations with other therapies need to be defined in further studies.

Animals↗

Prescription errors with cytotoxic drugs and the inadequacy of existing classifications.

OBJECTIVE: To quantify the amount of potential prescription errors for anticancer drugs in order to improve the quality of care. SETTING: The cytotoxic reconstitution unit at the Laennec Hospital in Paris, France during 6 months in the year 2000. METHOD: Pharmacist carried out a systematic analysis (e.g. dose, protocol, physicochemical properties) of the prescriptions for anticancer drugs (ACDs) before the compounding and handling at the cytotoxic unit of the pharmacy took place. The detected errors and potential errors were documented and analysed. MAIN OUTCOME MEASURE: Numbers and kinds of medication errors. RESULTS: Documenting data was difficult because of the inadequacy of existing classifications that usually do not include potential errors in prescriptions for with ACDs. Despite the presence of a formulary on the clinical wards, 349 errors were detected and documented, mainly concerning pharmaceutical aspects. Physicians were not aware of this type of errors due to lack of studies about their impact. Teaching aids such as a computer program for prescribing and production of ACDs could help in minimising these errors. CONCLUSION: The 349 detected errors involved mainly the physicochemical properties of preparations. A computerised prescription network could possibly reduce the number of such errors. Furthermore, a redefinition of the classifications of errors for cytotoxic preparations seems desirable, and such classifications should include typical pharmaceutical problems, and potential errors that do not reach the patient.

Antineoplastic Agents↗

Mapping and measuring social disparities in premature mortality: the impact of census tract poverty within and across Boston neighborhoods, 1999-2001.

The identification and documentation of health disparities are important functions of public health surveillance. These disparities, typically falling along lines defined by gender, race/ethnicity, and social class, are often made visible in urban settings as geographic disparities in health between neighborhoods. Recognizing that premature mortality is a powerful indicator of disparities in both health status and access to health care that can readily be monitored using routinely available public health surveillance data, we undertook a systematic analysis of spatial variation in premature mortality in Boston (1999-2001) across neighborhoods and sub-neighborhoods in relation to census tract (CT) poverty. Using a multilevel model based framework, we estimated that the incidence of premature mortality was 1.39 times higher (95% credible interval 1.09-1.78) among persons living in the most economically deprived CTs (>/=20% below poverty) compared to those in the least impoverished tracts (<5% below poverty). We present maps of model-based standardized mortality ratios that show substantial within-neighborhood variation in premature mortality and a sizeable decrease in spatial variation after adjustment for CT poverty. Additionally, we present maps of model-based direct standardized rates that can more readily be compared to externally published rates and targets, as well as maps of the population attributable fraction that show that in some of Boston's poorest neighborhoods, the proportion of excess deaths associated with CT poverty reaches 25-30%. We recommend that these methods be incorporated into routine analyses of public health surveillance data to highlight continuing social disparities in premature mortality.

Adolescent↗

Proteomics and diabetic nephropathy.

Diabetes mellitus is acknowledged to be a group of metabolic diseases and heterogeneous in natural history, pathogenesis, response to treatment, and disease progression and remission. Diabetic nephropathy (DN) accounts for approximately 40% of all newly diagnosed cases of end-stage renal disease. The complexity of diabetes and its complications requires a broad-based, unbiased, scientific approach such as proteomics. Recently, proteomics (the systematic analysis of protein identity, quantity, and function) has been applied to the study of DN. Proteomic investigations into diabetic kidney disease have identified new mechanisms of diabetic renal pathology, as well as potential urinary markers of DN. Other current proteomic advances in understanding DN include identifying the role of advanced glycation end products in decreased mitochondrial respiration and also the rapid development of mass spectrometric methods for protein and peptide markers of DN development and markers to pharmacologic therapies. Proteomic analysis has only recently been applied to the study of DN, yet it has shown substantial potential.

Animals↗

Conversion of induced ventricular tachycardia by single and serial chest thumps: a study in domestic pigs 1 week after experimental myocardial infarction.

A single chest thump (CT) is widely accepted in the emergency treatment of ventricular asystole, whereas there exists controversy about this method for the interruption of ventricular tachycardia (VT). Hitherto, delivering serial chest thumps (SCTs) has been described only once for the treatment of VT. A systematic analysis for interruption of VT by CT or SCTs (or both) is lacking. We have therefore investigated this subject in five domestic pigs after experimental myocardial infarction. Manual conversion was attempted in 20 induced VTs. Six VTs were converted by CT, seven VTs were converted by the first SCTs, and six VTs were converted by the last of multiple (two to seven) SCTs. The overall success was 95%. There were no serious complications. The rate of successful SCTs exceeded the rate of VT by 10% to 126%. The technique of SCTs, the mechanisms of manual conversion, and the controversial opinions regarding the value of precordial thumping in asystole, VT, and ventricular fibrillation are discussed. SCTs should be practiced only very cautiously in patients until further experience is available.

Animals↗

Clinical success, complications and restenosis rates with excimer laser coronary angioplasty. The Percutaneous Excimer Laser Coronary Angioplasty Registry.

The role of excimer laser angioplasty in treating complex coronary artery disease remains uncertain. A randomized trial comparing this new technology with balloon angioplasty cannot be designed until systematic analysis identifies the lesion types that are likely to benefit from treatment with excimer laser angioplasty. In a cohort of 764 patients who had 858 coronary stenoses treated with excimer laser-facilitated angioplasty, relative risk analysis was used to examine acute success, complications and restenosis rates, and the results were compared with those of balloon angioplasty to identify the lesion types that show the greatest benefit with the new treatment. Clinical success was achieved in 657 patients (86%), as indicated by < or = 50% residual stenosis and no in-hospital complication. A major in-hospital complication (death, bypass surgery, or Q-wave or non-Q-wave myocardial infarction) occurred in 58 patients (7.6%). Follow-up angiography was obtained in 70% of eligible patients. Combining angiographic and noninvasive restenosis rates yielded an overall restenosis rate of 46%. Relative risk analysis showed that major complications occurred frequently in lesions at an arterial bifurcation (odds ratio [OR] 5.96 [2.76, 12.6]; p = 0.001). However, certain complex lesions that are difficult to treat with balloon angioplasty (saphenous vein graft lesions, lesions > 10 mm, ostial lesions, calcified stenoses, total occlusions and unsuccessful balloon dilatations), analyzed together as a group, had lower complication rates by univariate (OR 0.59 [0.35, 1.00]; p = 0.051) and multivariate logistic regression (p = 0.006) analyses.(ABSTRACT TRUNCATED AT 250 WORDS)

Angioplasty, Balloon, Coronary↗

The bimodal mortality pattern of systemic lupus erythematosus.

The changing pattern of mortality in systemic lupus erythematosus (SLE) led to an examination of the deaths in a long-term systematic analysis of 81 patients followed for five years at the University of Toronto Rheumatic Disease Unit. During the follow-up 11 patients died; six patients died within the first year after diagnosis (group I) and five patients died an average of 8.6 years (from 2.5 to 19.5 years) after diagnosis (group II). In those who died early, the SLE was active clinically and serologically, and nephritis was present in four. Their mean prednisone dose was 53.3 mg/day. In four patients a major septic episode contributed to their death. In those who died late in the course of the disease, only one patient had active lupus and none had active lupus nephritis. Their mean prednisone dose was 10.1 mg/day taken for a mean of 7.2 years. In none was sepsis a contributing factor to their death. All five of these patients had had a recent myocardial infarction at the time of death; in four, ti was the primary cause of death. Mortality in SLE follows a bimodal pattern. Patients who die early in the course of their disease, die with active lupus, receive large doses of steroids and have a remarkable incidence of infection. In those who die late in the course of the disease, death is associated with inactive lupus, long duration of steroid therapy and a striking incidence of myocardial infarction due to atherosclerotic heart disease.

Adult↗

Issues in the treatment of noncardiac chest pain.

Evaluation of therapy for noncardiac chest pain calls for a systematic analysis of all relevant factors. Central chest pain is often experienced as a threat to life. Fear and anxiety concerning heart disease or cancer can increase pain and hamper therapy. The relief of pain can result from factors other than the actual treatment employed (i.e., placebo effects, relief of anxiety, spontaneous improvement, changes in life-style not related to treatment, or other, concomitant therapies prescribed). Therapeutic failure may be explained by diagnostic error, incorrect treatment, insufficient duration of therapy, incorrect dosage regimen, individual response to pharmacologic agents, poor drug absorption, drug interactions, poor compliance, poor surgical technique, and, finally, lack of effective therapeutic options. The rational evaluation of therapy for noncardiac chest pain is also hampered by its multifactorial etiology and the difficulty of selecting study patients with identical pain etiology. Controversies in the treatment of noncardiac chest pain reflect the uncertainty regarding pathophysiology. A primary issue is whether to treat patients medically with life-style modifications and pharmacologic agents, or surgically. A variety of pharmacologic agents and surgical techniques have been used to treat noncardiac chest pain. Treatment includes psychosocial considerations in addition to medical or surgical therapy. The most important role for the physician of a patient with noncardiac chest pain is to listen well, to be confirming and understanding, and to treat the patient not just as an apparatus that needs repair but as a socially integrated human being.

Chest Pain↗

Doppler ultrasonography in high-risk pregnancies: systematic review with meta-analysis.

OBJECTIVE: Our objective was to review all available (published and unpublished) randomized controlled trials of Doppler ultrasonography of the umbilical artery in high-risk pregnancies. STUDY DESIGN: Only completed randomized controlled trials were included and reviewed according to the prespecified protocol. Data were sought for 24 prespecified perinatal outcomes. All meta-analyses were based on the "intention to treat." Primary outcome was defined as perinatal death (any death in utero or postnatally recorded during duration of individual randomized controlled trial). Reported perinatal outcomes that were not prespecified were meta-analyzed on a post hoc basis. RESULTS: Twenty randomized controlled trials of Doppler ultrasonography were identified; 12 fulfilled the prespecified criteria. Meta-analysis shows a significant reduction in the number of antenatal admissions (44%, 95% confidence interval 28% to 57%), inductions of labor (20%, 95% confidence interval 10% to 28%), and cesarean sections for fetal distress (52%, 95% confidence interval 24% to 69%) in the Doppler group and that the clinical action guided by Doppler ultrasonography reduces the odds of perinatal death by 38% (95% confidence interval 15% to 55%). The reduction in perinatal deaths was also observed in five mortality subgroups (i.e., stillbirths, neonatal deaths, deaths of normally formed babies, normally formed stillbirths, and deaths of normally formed neonates). Post hoc analyses revealed a statistically significant reduction in elective delivery, intrapartum fetal distress, and hypoxic encephalopathy in the Doppler group. CONCLUSION: There is now compelling evidence that women with high-risk pregnancies, including preeclampsia and suspected intrauterine growth retardation, should have access to Doppler ultrasonographic study of umbilical artery waveforms.

Delivery, Obstetric↗

Management of laryngotracheal trauma.

Blunt trauma to the neck requires a systematic analysis of the laryngotrachea, the esophagus and the cervical spine in addition to general trauma considerations. Acute airway decompensation is best managed by tracheotomy, although if the situation permits, an orderly physical examination including indirect laryngoscopy and selected roentgenographic studies will yield an appropriate picture of the injury. Although broad guidelines are helpful, each case may dictate an individual therapeutic modification.

Accidents, Occupational↗

Cycled DNA immunoprecipitation procedure to enrich the target sequences for DNA binding proteins with the fold purification monitored.

Using centromere DNA binding protein (CENP-B) expressed as a fusion to beta-galactosidase in Escherichia coli, we established a cycled DNA immunoprecipitation procedure for enriching CENP-B binding sequences and monitoring the enrichment process. Degenerated synthetic oligonucleotides for an authentic CENP-B binding sequence, inserted into a pUC-derived vector, were incubated with the crude CENP-B extract. DNA-protein complexes formed in vitro were immunologically precipitated utilizing the beta-galactosidase moiety as a tagged antigen. The effectiveness of repeating cycles of immunoprecipitation was demonstrated by the color selection method designed for pUC-derived plasmids, after introducing the precipitated plasmids into Escherichia coli. After three cycles of DNA immunoprecipitation, only a few kinds of sequences constituted the majority. By repeating two more cycles, the most predominant sequence was finally enriched until homogeneous, indicating the enrichment of the binding sequences in a hierarchical order. Further application to human genomic DNA showed that two EcoRI DNA fragments, 0.49 and 0.78 kb in size, were exclusively identified. This procedure can be applied to the systematic analysis of binding sequences for any other DNA binding proteins without production of any specific antibodies or further purification.

Antibodies↗

Effects of antidiuretic hormone on kinetic and energetic determinants of active sodium transport in frog skin.

The effects of antidiuretic hormone (ADH) on the rate of transepithelial active Na transport JaNa and the rate of suprabasal O2 consumption of Jsbr were studied in paired hemiskins of frog. Within some 30 min following administration of ADH both JaNa and Jsbr increased to near-maximal levels and then remained stable for at least an hour. On symmetric perturbation of the transepithelial electrical potential delta psi at 6-min intervals, the dependence of JaNa and Jsbr on delta psi was near-linear, both in control and experimental hemi-skins. The stability and near-linearity of the system permitted systematic analysis of the parameters of linear non-equilibrium thermodynamic (NET) and electrical equivalent circuit (EC) formulations. ADH (100 mU/ml) stimulated two of the three NET phenomenological L coefficients, as well as A, the affinity (negative Gibbs free energy) of a metabolic reaction driving transport. Observations at partially depressed levels of transport indicated that the effects of kinetic and energetic factors are to some extent discrete. EC analysis showed stimulation of the amiloride-sensitive conductance Ka, but not of the apparent electromitive force of Na transport 'ENa'. Similar effects were produced by 10 mU/ml of ADH or by 10 mM dibutyryl cyclic AMP, although less marked effects on the L coefficients were noted with the lower concentration of hormone. It is suggested that, in contrast to EC analysis, the NET formulation distinguishes between kinetic and energetic determinants of transport, supporting a dual mechanism of action of ADH.

Animals↗

Further studies on substituted quinazolines and triazines as inhibitors of a methotrexate-insensitive murine dihydrofolate reductase.

Data are presented on the systematic analysis of thirty-five quinazoline and substituted triazine compounds as inhibitors of a methotrexate-insensitive form of dihydrofolate reductase purified from methotrexate-resistant L5178Y murine leukemia cells. Several of the compounds were found to be more potent inhibitors of this enzyme activity than was methotrexate. Two of the triazine compounds had IC50 values approaching 10nM, which is close to that of methotrexate for the normal drug-sensitive dihydrofolate reductase. In addition, some of these compounds, especially the triazines, exhibit a specificity of inhibition for the methotrexate-insensitive enzyme as compared to the normal methotrexate-sensitive dihydrofolate reductase derived from the same cell line. These compounds may, therefore, be potentially useful in the treatment of those methotrexate-resistant tumours which express an altered, methotrexate-insensitive dihydrofolate reductase.

Animals↗

Afferent connections to the bed nucleus of the stria terminalis.

A systematic analysis of the distribution of cells containing horseradish peroxidase (HRP) end-product following HRP injections in the bed nucleus of the stria terminalis (BNST) revealed a topographic distribution of input from the amygdala. The appearance of HRP cells in the medial amygdaloid nucleus was associated with HRP injections in all parts of the amygdala except its most lateral portion. Injections of HRP confined to the anterolateral portion of the BNST resulted in extensive HRP labeling of cells in the basolateral amygdala, the central nucleus, and the amygdala hippocampal area. Labeling of the amygdala hippocampal area was also associated with HRP injections in the caudodorsal BNST or the supracommissural portion of the stria terminalis. Injections that labeled the commissural division of the stria terminalis produced labeling of cells in the anterior basolateral amygdala and in the nucleus of the lateral olfactory tract. The cortical and basomedial amygdaloid nuclei appear to project only weakly to the BNST. Several other regions that provide afferents to the BNST are described although their input is minor relative to that of the amygdala.

Afferent Pathways↗

Are ventromedial medulla neuronal properties modified by chronic peripheral inflammation? A single-unit study in the awake, freely moving polyarthritic rat.

In the present work, we recorded the neuronal properties of the ventromedial medulla, a brainstem structure involved in the descending spinal control systems related to nociception, in awake, freely moving healthy and polyarthritic rats. These animals were rendered polyarthritic with a subcutaneous administration of the Freund's adjuvant into the tail, and studied at 20 and 30 days post-inoculation. At the ventromedial medulla level, the single-unit activities were recorded by means of a chronically implanted device supporting a 50 microns platinum-iridium wire as the recording electrode. With a total of 308 recorded neurons, we determined that in both healthy rats, i.e. animals having received mineral oil only and arthritic rats, there were ventromedial medulla units with common physiological properties, but also changes. In agreement with the results from anesthetized arthritic rats at spinal and thalamic levels, the systematic analysis of the responses to light touch and mechanical shock revealed that the 'multimodal, multireceptive' units, excited by innocuous and noxious stimuli, were much more responsive to both modalities in arthritic rats. Approximately 7% of these neurons displayed a 'paroxysmal' spontaneous activity, also reported in the literature for other structures. In addition, we recorded a significant number of neurons inhibited or excited-inhibited by innocuous and noxious cutaneous stimulations, and a few with a regular spontaneous activity, also responding, which has never been the case in healthy rats. We conclude that a peripheral chronic inflammation, such as arthritis, can produce changes of the ventromedial medulla neuronal properties, as compared to healthy animals. Consequently, in addition to its classical role in the spinal control of nociception, the ventromedial medulla is able to develop some form of plasticity in the case of persistent pain of peripheral origin.

Animals↗

Hypothalamic neuropeptide Y, its gene expression and receptor activity: relation to circulating corticosterone in adrenalectomized rats.

Previous evidence has suggested a possible relationship between the adrenal steroid, corticosterone (CORT) and neuropeptide Y (NPY) in the brain. To provide a more systematic analysis of this interaction, the present study employed a variety of techniques, including in situ hybridization to measure NPY gene expression, radioimmunoassay to examine peptide levels and radioligand [125I]peptide YY (PYY) binding for analysis of peptide receptors. The results show that adrenalectomy (ADX), which caused a decline in CORT to levels < 0.3 micrograms %, has generally little impact on the hypothalamic NPY projection system under normal, basal conditions. This includes peptide gene expression or content in the area of its cell bodies (arcuate nucleus, ARC), in addition to peptide binding at its receptor sites. While it also includes peptide content at most hypothalamic terminal sites, there are three notable exceptions, namely, the medial paraventricular (PVN) and dorsomedial nuclei and medial preoptic area, where NPY nerve terminals and glucocorticoid receptors are particularly dense and the decline in CORT through ADX markedly reduces NPY content. In contrast, evidence obtained from CORT replacement in ADX rats shows that this steroid has profound impact on all components of the hypothalamic NPY system. This peptide-steroid interaction is apparent at the level of the cell body (ARC), as well as at the nerve terminal or receptor site (PVN and ARC), where CORT levels > 10 micrograms % strongly potentiate NPY gene expression, peptide content and radioligand binding. These and other findings suggest that this CORT-NPY interaction in the hypothalamus occurs physiologically under conditions, e.g., at the onset of the active feeding cycle, when circulating CORT normally rises.

Adrenalectomy↗

A computer model of re-entry in cardiac tissue.

This paper describes the use of a computer model to investigate the nature of impulse propagation and the mechanisms of electrical instability which precipitate ventricular arrhythmias. The model provides the opportunity for a systematic analysis of the conditions of cardiac conduction under controlled conditions. From the simulation studies performed it is found that the most critical parameter which influences re-entry circuit formation is the ratio of exited to refractory duration.

Arrhythmias, Cardiac↗

Subcortical correlates of the somatic, auditory and visual vertex activities. II. Referential EEG responses.

A systematic analysis of polarity, amplitude and latency of the referential EEG responses correlated to surface somatic (SVA), auditory (AVA) and visual (VVA) vertex activities (VA) was done in various subcortical structures of a non-specific system of the same group of patients with electrodes implanted and reported in a previous work. These structures included the caudal and rostral mesencephalic reticular formations (cttc and rttc), the subthalamic region (Sth), the centro-median (Ce), parafascicular (Pf), ventrolateral (VL), dorsolateral (DL) and reticularis (Rt) thalamic nuclei; the orbito-frontal cortex (GO), the anterior commissure (Acm), the pallidum medialis and lateralis (Pm and Pl), the putamen (Pt) and the amygdala (Am). Subcortical SVA, AVA and VVA were formed by 4 consecutive components O, A, B and C correlated to components P1, N1, P2 and N2 of the surface VA. Components A and B of the subcortical SVA reversed polarity 4 times when recorded in structures arranged in a caudo-rostral order: between rttc-Ce and VL, between Rt and GO, between GO and Acm and between Acm and Am. Components A and B of subcortical AVA and VVA reversed polarity two times each: AVA between cttc and rttc and between GO and Acm; while VVA between GO and Acm and between Acm and Pm. Components A and B of SVA and VVA attained maximal amplitudes and minimal latencies at GO. From here, their amplitude decreased and latency increased with distance along other structures rostrally and caudally located. Components A and B of AVA attained maximal amplitudes and minimal latencies at cttc.(ABSTRACT TRUNCATED AT 250 WORDS)

Brain↗