Decoupling the role of stress and corrosion in the intergranular cracking of noble-metal alloys.

Intergranular stress-corrosion cracking (IGSCC) is a form of environmentally induced crack propagation causing premature failure of elemental metals and alloys. It is believed to require the simultaneous presence of tensile stress and corrosion; however, the exact nature of this synergy has eluded experimental identification. For noble metal alloys such as Ag-Au, IGSCC is a consequence of dealloying corrosion, forming a nanoporous gold layer that is believed to have the ability to transmit cracks into grain boundaries in un-dealloyed parent phase via a pure mechanical process. Here using atomic-scale techniques and statistical characterizations for this alloy system, we show that the separate roles of stress and anodic dissolution can be decoupled and that the apparent synergy exists owing to rapid time-dependent morphology changes at the dealloyed layer/parent phase interface. We discuss the applicability of our findings to the IGSCC of important engineering Fe- and Ni-based alloys in critical applications.

[Magneto-encephalographic (MEG) brain recordings during traumatic memory recall in women with post-traumatic stress disorder: A pilot study]. / Enregistrement magnéto-encéphalographique (MEG) de réminiscences du trauma chez des femmes souffrant de stress post-traumatique : une étude pilote.

AIM OF THE STUDY: The experiment studied the effects of a short duration exposure to traumatic memories using magneto-encephalography (MEG). PATIENTS: Nine right-handed DSM-4 PTSD patients were recruited from a unit for anxiety disorders and an organisation supporting victims of violence. In order to have a homogeneous sample, we included only women who suffered from civilian PTSD. Exclusion criteria were co-morbid major medical illness, metallic dental prostheses that would interfere in the magnetic measurement, and current drug treatment. All participants were free from neurological disease and had normal hearing. They signed a written informed consent form. An ethics committee accepted the study. METHOD: A tape-recorded voice administered a script-driven imagery. The patients had to imagine, successively, a neutral image, a traumatic memory and rest, while MEG measured brain activities across delta, theta, alpha and beta bands. Each condition lasted three minutes. Heart rate (HR), anxiety and the vividness of mental images were recorded at the end of each phase. MEG power analysis was carried out with Statistical Parametric Mapping (SPM) 8. The signals were averaged for each of the three conditions of threeminutes duration. The dependent variable was a subtracted value: (trauma - rest) - (neutral - rest). The significance threshold was set at P<0.01. RESULTS: Anxiety and HR significantly increased during the trauma condition and returned to the neutral level during rest. The vividness of the mental imagery remained stable across the three conditions. The left-brain demonstrated a statistically significant power decrease in the secondary visual cortex (BA 18-19) in the delta band, the insula (BA13) in the beta band, the insula (BA13), premotor cortex (BA 6), Broca area (BA 44), and BA 43, in the alpha band. DISCUSSION: The symptom provocation protocol was successful in eliciting subjective anxiety and HR response in relation to traumatic memories. Our MEG results are in keeping with previous neuro-imagery studies showing decreased activities in the insula and Broca area during PTSD symptom provocation. However, we did not replicate the activation in the amygdala and the cingulate and prefrontal cortex found in some studies. Moreover, the within-group design, the small sample, and the inclusion of only female patients with milder dissociative symptoms limit our conclusions. The MEG protocol we used may also explain some partial discrepancies with previous MEG studies. However, our aim was to provoke a specific autobiographic recall of a traumatic event unfolding several sequential mental images along three minutes as in exposure therapy for PTSD. CONCLUSION: Despite its limitations, this pilot study is the first to provide MEG data during trauma recall. It suggests that recalling a specific traumatic event along three minutes results in hypo-activations of the brain regions regulating language and emotions. This paves the way to recording whole sessions of specific therapies for PTSD, with MEG using the millisecond resolution. MEG might be of interest to study the suppression of traumatic memories and their activation and habituation through prolonged graduated exposure in imagination across several sessions. MEG could also be used to study the effects of medication on PTSD symptoms. A controlled replication in a larger sample including male and female patients with various traumatic experiences is needed.

Examinations of oxidation and sulfidation of grain boundaries in alloy 600 exposed to simulated pressurized water reactor primary water.

High-resolution characterizations of intergranular attack in alloy 600 (Ni-17Cr-9Fe) exposed to 325°C simulated pressurized water reactor primary water have been conducted using a combination of scanning electron microscopy, NanoSIMS, analytical transmission electron microscopy, and atom probe tomography. The intergranular attack exhibited a two-stage microstructure that consisted of continuous corrosion/oxidation to a depth of ~200 nm from the surface followed by discrete Cr-rich sulfides to a further depth of ~500 nm. The continuous oxidation region contained primarily nanocrystalline MO-structure oxide particles and ended at Ni-rich, Cr-depleted grain boundaries with spaced CrS precipitates. Three-dimensional characterization of the sulfidized region using site-specific atom probe tomography revealed extraordinary grain boundary composition changes, including total depletion of Cr across a several nm wide dealloyed zone as a result of grain boundary migration.

A new in vivo model for luteolysis using systemic pulsatile infusions of PGF(2α).

A new in vivo model for studying luteolysis was developed in sheep to provide a convenient method for collecting corpora lutea for molecular, biochemical, and histological analysis during a procedure that mimics natural luteolysis. It was found that the infusion of prostaglandin F(2α) (PGF(2α)) at 20 µg/min/h into the systemic circulation during the mid luteal phase of the cycle allowed sufficient PGF(2α) to escape across the lungs and thus mimic the transient 40% decline in the concentration of progesterone in peripheral plasma seen at the onset of natural luteolysis in sheep. Additional 1h-long systemic infusions of PGF(2α), given at physiological intervals, indicated that two infusions were not sufficient to induce luteolysis. However, an early onset of luteolysis and estrus was induced in one out of three sheep with three infusions, two out of three sheep with four infusions, and three out of three sheep with five infusions. Reducing the duration of each systemic infusion of PGF(2α) from 1h to 30 min failed to induce luteolysis and estrus even after six systemic infusions indicating that, not only are the amplitude and frequency of PGF(2α) pulses essential for luteolysis, but the actual duration of each pulse is also critical. We conclude that a minimum of five systemic pulses of PGF(2α), given in an appropriate amount and at a physiological frequency and duration, are required to mimic luteolysis consistently in all sheep. The five pulse regimen thus provides a new accurate in vivo model for studying molecular mechanisms of luteolysis.

Caprylic acid reduces Salmonella Enteritidis populations in various segments of digestive tract and internal organs of 3- and 6-week-old broiler chickens, therapeutically.

We investigated the efficacy of feed supplemented with caprylic acid (CA), a natural, 8-carbon fatty acid for reducing Salmonella enterica serovar Enteritidis colonization in commercial broiler chickens. In separate 3- and 6-wk trials, 1-d-old straight-run broiler chicks (n = 70 birds/trial) were assigned to a control group (challenged with Salmonella Enteritidis, no CA) and 2 replicates of 0.7 and 1% CA (n = 14 birds/group). Water and feed were provided ad libitum. On d 1, birds were tested for any inherent Salmonella (n = 2 birds/group). For the 3-wk trial, on d 5, birds were challenged with 8 log(10) cfu of Salmonella Enteritidis of a 4-strain mixture by crop gavage, and after 5 d postchallenge, birds (n = 2 birds/group) were euthanized to ensure Salmonella Enteritidis colonization. Caprylic acid was supplemented the last 5 d before tissue collection (n = 10 birds/group). For the 6-wk trial, on d 25, birds were challenged and confirmed for Salmonella Enteritidis colonization. The birds (n = 10 birds/group) were euthanized for tissue samples after CA supplementation for the last 5 d. Caprylic acid at 0.7 or 1% decreased Salmonella Enteritidis populations in cecum, small intestine, cloaca, liver, and spleen in both 3- and 6-wk trials. Body weight of birds did not differ between the groups (P ≥ 0.05). Further, to elucidate a potential antibacterial mechanism of action of CA, we investigated if CA could reduce Salmonella Enteritidis invasion of an avian epithelial cell line and expression of invasion genes hilA and hilD. The cell invasion study revealed that CA reduced invasive abilities of all Salmonella Enteritidis strains by ~80% (P < 0.05). Gene expression studies indicated that CA downregulated (P < 0.001) Salmonella invasion genes hilA and hilD. These results suggest that supplementation of CA through feed could reduce Salmonella Enteritidis colonization in broiler chicken and potentially reduces the pathogen's ability to invade intestinal epithelial cells by downregulating key invasion genes, hilA and hilD.

The intracellular signal transduction mechanism of interleukin 5 in eosinophils: the involvement of lyn tyrosine kinase and the Ras-Raf-1-MEK-microtubule-associated protein kinase pathway.

Interleukin 5 (IL-5) regulates the growth and function of eosinophils. The objective of this study was to investigate the intracellular signal transduction mechanism of IL-5 in eosinophils. Purified eosinophils were stimulated with IL-5, and the involvement of various kinases was investigated by immunoblotting, immune complex kinase assay, and in situ denatured/renatured kinase assay. We found that IL-5 induced tyrosine phosphorylation and activation of a number of kinases. Two species of lyn kinases (53 and 56 kD) were present in eosinophils. Both forms were Tyr-phosphorylated and activated rapidly within 1 min. Further, lyn kinase was physically associated with the IL-5 beta receptor in eosinophils. Ras was studied by immunoprecipitation followed by thin-layer chromatography. Ras bound higher quantities of [alpha-32P]guanosine 5'triphosphate upon stimulation with IL-5. Raf-1 kinase showed increased Tyr phosphorylation on immunoblotting and increased activity in the immune complex kinase assay. Two species of MEK (MAP or Erk kinase) (41 and 45 kD) were identified in eosinophils, which underwent autophosphorylation upon stimulation. Microtubule-associated protein (MAP) kinase (p44) was Tyr-phosphorylated on immunoblotting and had increased activity in the immune-complex kinase assay. MAP kinases were also studied after metabolic radiolabeling of the cells with [32P]orthophosphates. IL-5 stimulated phosphorylation of MAP kinases in situ. Thus, we have delineated major components of an important signaling pathway in eosinophils. We believe that one of the signals generated by IL-5 receptor activation is propagated through the lyn-Ras-Raf-1-MEK-MAP kinase pathway.

Radiotherapy dose and survival outcomes in human papillomavirus positive oropharyngeal cancer.

OBJECTIVE: To evaluate the effect of definitive radiotherapy dose on survival in patients with human papillomavirus positive oropharyngeal carcinoma. METHODS: Human papillomavirus positive oropharyngeal carcinoma patients staged T1-3 and N0-2c, who received definitive radiotherapy (fraction sizes of 180 cGy to less than 220 cGy), were identified from the National Cancer Database 2010-2014 and stratified by radiation dose (50 Gy to less than 66 Gy, or 66 Gy or more). RESULTS: A total of 2173 patients were included, of whom 124 (6 per cent) received a radiation dose of 50 Gy to less than 66 Gy. With a median follow up of 33.8 months, patients had a 3-year overall survival rate of 88.6 per cent (95 per cent confidence interval = 87.1-90.1 per cent). On multivariate Cox analysis, a radiotherapy dose of 50 Gy to less than 66 Gy (hazard ratio = 0.95, 95 per cent confidence interval = 0.52-1.74, p = 0.86) was not a predictor of increased mortality risk. CONCLUSION: Human papillomavirus positive oropharyngeal carcinoma patients had excellent outcomes with definitive radiotherapy doses of 50 Gy to less than 66 Gy. These results further support patients enrolling into clinical trials for radiation dose de-escalation.

Independent protein-profiling studies show a decrease in apolipoprotein A1 levels in schizophrenia CSF, brain and peripheral tissues.

Although some insights into the etiology of schizophrenia have been gained, an understanding of the illness at the molecular level remains elusive. Recent advances in proteomic profiling offer great promise for the discovery of markers underlying pathophysiology of diseases. In the present study, we employed two high-throughput proteomic techniques together with traditional methods to investigate cerebrospinal fluid (CSF), brain and peripheral tissues (liver, red blood cells and serum) of schizophrenia patients in an attempt to identify peripheral/surrogate disease markers. The cohorts used to investigate each tissue were largely independent, although some CSF and serum samples were collected from the same patient. To address the major confounding factor of antipsychotic drug treatment, we also included a large cohort of first-onset drug-naive patients. Apolipoprotein A1 (apoA1) showed a significant decrease in expression in schizophrenia patients compared to controls in all five tissues examined. Specifically, using SELDI-TOF mass spectrometry, apoA1 was found decreased in CSF from schizophrenia patients (-35%, P=0.00001) and, using 2D-DIGE, apoA1 was also found downregulated in liver (-30%, P=0.02) and RBCs (-60%, P=0.003). Furthermore, we found a significant reduction of apoA1 in sera of first-onset drug-naive schizophrenia patients using enzyme-linked immunosorbent assay (-18%, P=0.00008) and in two investigations of post-mortem brain tissue using western blot analysis (-35%, P=0.05; -51%, P=0.05). These results show that apoA1 is consistently downregulated in the central nervous system as well as peripheral tissues of schizophrenia patients and may be linked to the underlying disease mechanism.

A network model of catecholamine effects: gain, signal-to-noise ratio, and behavior.

At the level of individual neurons, catecholamine release increases the responsivity of cells to excitatory and inhibitory inputs. A model of catecholamine effects in a network of neural-like elements is presented, which shows that (i) changes in the responsivity of individual elements do not affect their ability to detect a signal and ignore noise but (ii) the same changes in cell responsivity in a network of such elements do improve the signal detection performance of the network as a whole. The second result is used in a computer simulation based on principles of parallel distributed processing to account for the effect of central nervous system stimulants on the signal detection performance of human subjects.

The role of locus coeruleus in the regulation of cognitive performance.

Noradrenergic locus coeruleus (LC) neurons were recorded in monkeys performing a visual discrimination task, and a computational model was developed addressing the role of the LC brain system in cognitive performance. Changes in spontaneous and stimulus-induced patterns of LC activity correlated closely with fluctuations in behavioral performance. The model explains these fluctuations in terms of changes in electrotonic coupling among LC neurons and predicts improved performance during epochs of high coupling and synchronized LC firing. Cross correlations of simultaneously recorded LC neurons confirmed this prediction, indicating that electrotonic coupling in LC may play an important role in attentional modulation and the regulation of goal-directed versus exploratory behaviors.

Aircraft soot from conventional fuels and biofuels during ground idle and climb-out conditions: Electron microscopy and X-ray micro-spectroscopy.

Aircraft soot has a significant impact on global and local air pollution and is of particular concern for the population working at airports and living nearby. The morphology and chemistry of soot are related to its reactivity and depend mainly on engine operating conditions and fuel-type. We investigated the morphology (by transmission electron microscopy) and chemistry (by X-ray micro-spectroscopy) of soot from the exhaust of a CFM 56-7B26 turbofan engine, currently the most common engine in aviation fleet, operated in the test cell of SR Technics, Zurich airport. Standard kerosene (Jet A-1) and a biofuel blend (Jet A-1 with 32% HEFA) were used at ground idle and climb-out engine thrust, as these conditions highly influence air quality at airport areas. The results indicate that soot reactivity decreases from ground idle to climb-out conditions for both fuel types. Nearly one third of the primary soot particles generated by the blended fuel at climb-out engine thrust bear an outer amorphous shell implying higher reactivity. This characteristic referring to soot reactivity needs to be taken into account when evaluating the advantage of HEFA blending at high engine thrust. The soot type that is most prone to react with its surrounding is generated by Jet A-1 fuel at ground idle. Biofuel blending slightly lowers soot reactivity at ground idle but does the opposite at climb-out conditions. As far as soot reactivity is concerned, biofuels can prove beneficial for airports where ground idle is a common situation; the benefit of biofuels for climb-out conditions is uncertain.

A method for site-specific and cryogenic specimen fabrication of liquid/solid interfaces for atom probe tomography.

A site-specific, cryogenic, focused ion beam (FIB) method is presented for the preparation of atom probe tomography (APT) specimens from a frozen liquid/solid interface. As a practical example, the interface between water and a corroded boroaluminosilicate glass has been characterized by APT for the first time. The water/glass interface is preserved throughout specimen preparation by plunge freezing the corroding glass particles with the corrosion solution into slush nitrogen. Site-specific specimen preparation is enabled through a new approach to extract and mount a small volume of material using a cryogenically cooled FIB stage and micromanipulator. The prepared APT specimens are subsequently transferred from the FIB to APT under cryogenic and high-vacuum conditions using a novel FIB/APT transfer shuttle and home-built environmental transfer hub attached to the APT system. Particular focus is given to the technical methods for specimen fabrication under cryogenic conditions. Persistent challenges are discussed in addition to future opportunities for this new specimen preparation method.

Bedside multimarker testing for risk stratification in chest pain units: The chest pain evaluation by creatine kinase-MB, myoglobin, and troponin I (CHECKMATE) study.

BACKGROUND: Earlier, rapid evaluation in chest pain units may make patient care more efficient. A multimarker strategy (MMS) testing for several markers of myocardial necrosis with different time-to-positivity profiles also may offer clinical advantages. METHODS AND RESULTS: We prospectively compared bedside quantitative multimarker testing versus local laboratory results (LL) in 1005 patients in 6 chest pain units. Myoglobin, creatine kinase-MB, and troponin I were measured at 0, 3, 6, 9 to 12, and 16 to 24 hours after admission. Two MMS were defined: MMS-1 (all 3 markers) and MMS-2 (creatine kinase-MB and troponin I only). The primary assessment was to relate marker status with 30-day death or infarction. More patients were positive by 24 hours with MMS than with LL (MMS-1, 23.9%; MMS-2, 18.8%; LL, 8.8%; P=0.001, all comparisons), and they became positive sooner with MMS-1 (2.5 hours, P=0.023 versus LL) versus MMS-2 (2.8 hours, P=0.026 versus LL) or LL (3.4 hours). The relation between baseline MMS status and 30-day death or infarction was stronger (MMS-1: positive, 18.8% event rate versus negative, 3.0%, P=0.001; MMS-2: 21.9% versus 3.2%, P=0.001) than that for LL (13.6% versus 5.5%, P=0.038). MMS-1 discriminated 30-day death better (positive, 2.0% versus negative, 0.0%, P=0.007) than MMS-2 (positive, 1.8% versus negative, 0.2%; P=0.055) or LL (positive, 0.0% versus negative, 0.5%; P=1.000). CONCLUSIONS: Rapid multimarker analysis identifies positive patients earlier and provides better risk stratification for mortality than a local laboratory-based, single-marker approach.

Detecting compensatory covariation signals in protein evolution using reconstructed ancestral sequences.

When protein sequences divergently evolve under functional constraints, some individual amino acid replacements that reverse the charge (e.g. Lys to Asp) may be compensated by a replacement at a second position that reverses the charge in the opposite direction (e.g. Glu to Arg). When these side-chains are near in space (proximal), such double replacements might be driven by natural selection, if either is selectively disadvantageous, but both together restore fully the ability of the protein to contribute to fitness (are together "neutral"). Accordingly, many have sought to identify pairs of positions in a protein sequence that suffer compensatory replacements, often as a way to identify positions near in space in the folded structure. A "charge compensatory signal" might manifest itself in two ways. First, proximal charge compensatory replacements may occur more frequently than predicted from the product of the probabilities of individual positions suffering charge reversing replacements independently. Conversely, charge compensatory pairs of changes may be observed to occur more frequently in proximal pairs of sites than in the average pair. Normally, charge compensatory covariation is detected by comparing the sequences of extant proteins at the "leaves" of phylogenetic trees. We show here that the charge compensatory signal is more evident when it is sought by examining individual branches in the tree between reconstructed ancestral sequences at nodes in the tree. Here, we find that the signal is especially strong when the positions pairs are in a single secondary structural unit (e.g. alpha helix or beta strand) that brings the side-chains suffering charge compensatory covariation near in space, and may be useful in secondary structure prediction. Also, "node-node" and "node-leaf" compensatory covariation may be useful to identify the better of two equally parsimonious trees, in a way that is independent of the mathematical formalism used to construct the tree itself. Further, compensatory covariation may provide a signal that indicates whether an episode of sequence evolution contains more or less divergence in functional behavior. Compensatory covariation analysis on reconstructed evolutionary trees may become a valuable tool to analyze genome sequences, and use these analyses to extract biomedically useful information from proteome databases.

Computational modeling of emotion: explorations through the anatomy and physiology of fear conditioning.

Recent discoveries about the neural system and cellular mechanisms in pathways mediating classical fear conditioning have provided a foundation for pursuing concurrent connectionist models of this form of emotional learning. The models described are constrained by the known anatomy underlying the behavior being simulated. To date, implementations capture salient features of fear learning, both at the level of behavior and at the level of single cells, and additionally make use of generic biophysical constraints to mimic fundamental excitatory and inhibitory transmission properties. Owing to the modular nature of the systems model, biophysical modeling can be carried out in a single region, in this case the amygdala. Future directions include application of the biophysical model to questions about temporal summation in the two sensory input paths to amygdala, and modeling of an attentional interrupt signal that will extend the emotional processing model to interactions with cognitive systems.

Schizophrenic deficits in the processing of context. A test of a theoretical model.

BACKGROUND: Schizophrenic patients show various deficits in cognitive functions that have been difficult to understand in terms of a common unifying hypothesis. Previously described neural network models of cognitive tasks suggest that several schizophrenic performance deficits may be related to a single function-an impairment in maintaining contextual information over time and in using that information to inhibit inappropriate responses. METHODS: We tested first-episode schizophrenic patients and patients later in the course of their illness on a new variant of the Continuous Performance Test designed specifically to elicit deficits in the processing of contextual information. RESULTS: Unmedicated schizophrenic patients showed a deterioration of their signal detection performance that followed the pattern predicted by the context hypothesis, ie, they responded inappropriately when correct responding required the maintenance of context information over time to inhibit the expression of a habitual response. This deficit correlated with positive symptoms. The results also suggested that the deficit may be worse in unmedicated patients who have had a longer course of illness. Medicated patients showed a more diffuse performance deficit. CONCLUSIONS: These results support the view that a single deficit in the processing of context information may underlie various cognitive impairments observed in schizophrenia. They also suggest that such an impairment is associated with positive rather than negative symptoms, and that it may worsen with the course of the illness as in the kraepelinian view of schizophrenia.

May 1999--16 year old male with an unexpected MRI finding.

Four years after resection of a supratentorial pilocytic astrocytoma this 16-year-old boy displayed widespread leptomeningeal seeding. Although the primary tumor lacked contrast enhancement, the multiple metastatic nodules were markedly contrast enhancing. Both the initial and disseminated tumor were consistent with a pilocytic astrocytoma. He was treated with vincristin and carboplatinum and the tumor was stable up to Dec. 1998. Dissemination of low-grade intracranial astrocytoma in children occurs in only 4%. It is not a sign of malignancy. The present case is similar to previously published cases. The prognosis of these patients might be quite favorable when treated with radiotherapy and/or chemotherapy.

Dopamine and the mechanisms of cognition: Part I. A neural network model predicting dopamine effects on selective attention.

BACKGROUND: Dopamine affects neural information processing, cognition, and behavior; however, the mechanisms through which these three levels of function are affected have remained unspecified. We present a parallel-distributed processing model of dopamine effects on neural ensembles that accounts for effects on human performance in a selective attention task. METHODS: Task performance is stimulated using principles and mechanisms that capture salient aspects of information processing in neural ensembles. Dopamine effects are simulated as a change in gain of neural assemblies in the area of release. RESULTS: The model leads to different predictions as a function of the hypothesized location of dopamine effects. Motor system effects are simulated as a change in gain over the response layer of the model. This induces speeding of reaction times but an impairment of accuracy. Cognitive attentional effects are simulated as a change in gain over the attention layer. This induces a speeding of reaction times and an improvement of accuracy, especially at very fast reaction times and when processing of the stimulus requires selective attention. CONCLUSIONS: A computer simulation using widely accepted principles of processing in neural ensembles can account for reaction time distributions and time-accuracy curves in a selective attention task. The simulation can be used to generate predictions about the effects of dopamine agonists on performance. An empirical study evaluating these predictions is described in a companion paper.

Dopamine and the mechanisms of cognition: Part II. D-amphetamine effects in human subjects performing a selective attention task.

BACKGROUND: A neural network computer model described in a companion paper predicted the effects of increased dopamine transmission on selective attention under two different hypotheses. METHODS: To evaluate these predictions we conducted an empirical study in human subjects of D-amphetamine effects on performance of the Eriksen response competition task. Ten healthy volunteers were tested before and after placebo or D-amphetamine in a double-blind cross-over design. RESULTS: D-amphetamine induced a speeding of reaction time overall and an improvement of accuracy at fast reaction times but only in the task condition requiring selective attention. CONCLUSIONS: This pattern of results conforms to the prediction of the model under the hypothesis that D-amphetamine primarily affects dopamine transmission in cognitive rather than motor networks. This suggests that the principles embodied in parallel distributed processing models of task performance may be sufficient to predict and explain specific behavioral effects of some drug actions in the central nervous system.

Interstitial hyperthermia and iridium-192 treatment alone vs. interstitial iridium-192 treatment/hyperthermia and low dose cisplatinum infusion in the treatment of locally advanced head and neck malignancies.

PURPOSE: To determine whether the addition of low dose platinum infusional chemotherapy adds to the effectiveness of interstitial hyperthermia/iridium-192 management of locally advanced head and neck malignancies. METHODS AND MATERIALS: From 1987 to 1993, 36 patients with locally advanced head and neck malignancies were treated locally with interstitial hyperthermia and iridium-192 as part or all of their management. Twenty-two of the above-mentioned patients also received low dose infusional cisplatinum chemotherapy at 20 mg/M2 per day during the time of the implant. No patient received greater than 100 mg/M2 total dose. Implant times ranged from 38.5 to 134 h and total doses delivered with the radiation implants ranged from 15 to 39.9 Gy. Average implant volume was 50 cc. Twenty-three patients received external beam irradiation supplementation in a dose range from 25.2 to 64 Gy. RESULTS: Median follow-up for the entire group was 8, months with 7 months for the chemotherapy group vs. 12 months for the no-chemotherapy group. Freedom from relapse rates for the chemotherapy group vs. the no-chemotherapy group were 70% at 41 months vs. 63% at 60 months, p = not significant (p = NS). Overall survival by Life Table Analysis was 28% for the chemotherapy group at 41 months vs. 31% for the no-chemotherapy group at 60 months (p = NS). Complete response (CR) rates were 93% for the chemotherapy group vs. 86% for the no-chemotherapy group. Seven patients in the chemotherapy group had recurrent disease and four patients in the no-chemotherapy group were being treated for recurrent disease. Complication rates were similar in both groups, with two patients in the chemotherapy arm requiring hyperbaric oxygen treatments and one patient in the no-chemotherapy arm requiring hyperbaric oxygen treatments (for soft tissue necrosis). CONCLUSION: It appears that low dose platinum infusional chemotherapy can be added safely to patients receiving interstitial iridium-192 implants along with interstitial hyperthermia for head and neck malignancies. Although there appears to be a trend toward better freedom from relapse by adding chemotherapy, a larger trial and longer follow-up will be necessary to prove statistical significance. Further research in these areas is recommended in the form of a randomized prospective study.