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Biomedical subjects

M Kraut

Publications and source records attributed to M Kraut.

At least 19 recordsLinked to original sources

Advanced bronchioloalveolar carcinoma: a phase II trial of paclitaxel by 96-hour infusion (SWOG 9714): a Southwest Oncology Group study.

BACKGROUND: There are no published prospective trials of chemotherapy for advanced bronchioloalveolar carcinoma (BAC), a subtype of non-small-cell lung cancer for which there is no current standard therapy. This phase II study assesses the efficacy and toxicity of 96-h paclitaxel in chemotherapy-naive patients with advanced BAC. PATIENTS AND METHODS: Patients with histologically confirmed stage IIIB (with pleural effusion) or stage IV BAC were eligible. Treatment consisted of paclitaxel 35 mg/m2/24 h continuously infused over 96 h (days 1-4) every 21 days for up to six courses. RESULTS: A total of 58 eligible patients were enrolled. The objective response rate was 14% (all partial responses, 9% confirmed); 40% of patients demonstrated stable disease. The median progression-free and overall survivals were 5 and 12 months, respectively. Grade 3 or greater toxicities included neutropenia/granulocytopenia (43%), febrile neutropenia (12%), infection (22%), and stomatitis/pharyngitis (10%); there were five treatment-related deaths. CONCLUSIONS: S9714 represents the first prospective multi-institutional cooperative group trial focusing on treatment outcomes in BAC. Studies targeting this population are feasible, and while first-line paclitaxel administered as a prolonged infusion is active in this setting, toxicities limits the utility of this regimen. S9714 serves as a historical control for BAC patients against which future therapeutic approaches can be compared.

Adenocarcinoma, Bronchiolo-Alveolar↗

Inverse T(2) contrast at 1.5 Tesla between gray matter and white matter in the occipital lobe of normal adult human brain.

T(2) of cortical gray matter is generally assumed to be longer than that of white matter. It is shown here that this is not the case in the occipital lobe, but that this effect is often obscured at lower resolution and concealed in standard T(2)-weighted images. Using a high-resolution (1 x 1.3 x 2 mm(3)) segmented EPI Carr-Purcell-Meiboom-Gill sequence, T(2) relaxation times of the brain were measured at 1.5 T for eight healthy adult volunteers. The average T(2) values of cortical gray and white matter were found to be 88 +/- 2 and 84 +/- 3 msec in the frontal lobe, 84 +/- 2 and 83 +/- 3 msec in the parietal lobe, and 79 +/- 1 and 87 +/- 3 msec in the occipital lobe, respectively. This unexpected occipital T(2) contrast between gray and white matter is attributed to regional differences in iron concentration.

Adult↗

White matter hyperintensity volume in late-onset and early-onset schizophrenia.

BACKGROUND: Late life onset schizophrenia (sometimes termed "late paraphrenia") has been theorized to be due to neuro-degenerative processes affecting individuals with latent vulnerability to schizophrenia. However, neuro-imaging studies using computed tomography (CT) and magnetic resonance imaging (MRI) investigating possible degenerative anatomic correlates (atrophy, white matter disease, and strokes) to late onset psychoses have yielded conflicting findings. The variation in these findings may be due to differences in study design, case ascertainment, and measurement methods. OBJECTIVE: The present study compares a continuous measure of total volume of white matter hyperintensities (WMHs) in age, race, and gender-ratio matched groups of late-onset schizophrenic, elderly, early-onset schizophrenic and control subjects. METHOD: Our method of WMH measurement yielded an explicit volume and is an alternative to frequently used ordinal measures. RESULTS: We found no significant differences in the WMH volumes between these three groups. This finding is consistent with a prior study (Symonds et al., 1997. J Neuropsychiat Clin Neurosci 9: 251 - 258), that used ordinal measures.

Age of Onset↗

A weighted least-squares algorithm for estimation and visualization of relative latencies in event-related functional MRI.

The properties of the hemodynamic latencies in functional maps have been relatively unexplored. Accurate methods of estimating hemodynamic latencies are needed to take advantage of this feature of fMRI. A fully automated, weighted least-squares (WLS) method for estimating temporal latencies is reported. Using a weighted linear model, the optimal latency and amplitude of the fMRI response can be determined for those voxels that pass a detection threshold. There is evidence from previous studies that the hemodynamic response may be time-locked to the stimulus within certain limits, less variable earlier in its evolution, and able to resolve information about relative hemodynamic timing. This information can be used to test hypotheses about the sequence and spatial distribution of neural activity. The method can be used to weight the earliest evolution of the hemodynamic response more heavily and decrease bias resulting from the hemodynamic response function. Additionally, the WLS method can control for varying response shapes across the brain and improve latency comparisons between brain regions. The WLS method was developed to study the properties of hemodynamic latencies, which may be increasingly important as event-related fMRI continues to be advanced.

Algorithms↗

Phase II trial of gemcitabine in patients with previously untreated metastatic cancer of the esophagus or gastroesophageal junction.

BACKGROUND: There were approximately 12,500 cases of esophageal carcinoma diagnosed in the US in 1992 and 12,200 deaths. The impact of chemotherapy on patients with metastatic disease is marginal with a median survival of only five months. Gemcitabine (LY188011,2,2,-difluorodeoxycytidine: dFdC), an analog of cytosine arabinoside (ara-C), is a pyrimidine antimetabolite. Gemcitabine has shown interesting clinical activity in initial phase II clinical trials in a variety of malignancies, including the aerodigestive malignancies, squamous-cell carcinoma of the head/neck and both non-small-cell and small-cell lung cancer. PATIENTS AND METHODS: A total of 21 patients with chemotherapy-naïve metastatic esophageal carcinoma were entered. Nineteen patients were evaluable for toxicity and seventeen patients were evaluable for response. Gemcitabine was administered intravenously at 1250 mg/m2 over 30-60 minutes on days 1, 8, and 15 followed by 1 week of rest. This four-week schedule defined a cycle of treatment. Patients may have received a maximum of six cycles. RESULTS: Gemcitabine was well tolerated with minimal non-hematologic toxicity and grade 3-4 anemia, granulocytopenia, and thrombocytopenia occurring in 10.5%, 21%, and 0% of patients, respectively. No responses were seen in the seventeen evaluable patients. CONCLUSIONS: At the dose and schedule studied it would appear that gemcitabine has no activity in patients with chemotherapy-naïve esophageal carcinoma.

Adenocarcinoma↗

Estrogen replacement therapy and MRI-demonstrated cerebral infarcts, white matter changes, and brain atrophy in older women: the Cardiovascular Health Study.

OBJECTIVE: We studied the relationship between the use of estrogen replacement therapy (ERT) and cerebral magnetic resonance imaging (MRI) abnormalities among older women. DESIGN: A population-based prospective study (Cardiovascular Health Study). SETTING: Four regions in the United States. PARTICIPANTS: A total of 2133 (62.9% of the eligible) women aged 65 to 95 years (mean age 74.8), on whom MRI was performed in 1992-1994. MEASUREMENTS: Presence of global brain atrophy, white matter changes, small infarct-like lesion (ILL) (<3 mm), MRI infarcts (> or =3 mm, mostly small and asymptomatic), and cognitive function as measured by Mini-Mental State Exam (MMSE), and by ERT use (current/past/never), adjusted for a number of socioeconomic, lifestyle, and reproductive covariates. RESULTS: Current use of ERT was reported by 15% and past use by another 23% of participants; 35% of all women had MRI infarcts. The prevalence of MRI infarcts did not differ in current or past users from those who had never used ERT (nonusers). Bifrontal distance, the largest distance between frontal horns, and the size of ventricles were larger among current ERT users compared to past users or nonusers (P (trend) = .01), adjusted for all other covariates, but no dose-response relationship to current or past ERT use was found. Duration of estrogen use was not associated with any atrophy measure. Cortical atrophy measure, sulcal widening, or white matter disease did not differ significantly by ERT use or duration of use. Central measures of atrophy, bifrontal distance, and ventricular size were significantly associated with cognition as measured by MMSE. CONCLUSIONS: Current ERT users had much more clinically significant central atrophy than nonusers, but the implications remained unclear.

Aged↗

Current opinions for the treatment of syringomyelia and chiari malformations: survey of the Pediatric Section of the American Association of Neurological Surgeons.

INTRODUCTION: A variety of surgical interventions have been recommended for patients with syringomyelia and Chiari malformation. To obtain a better understanding of currently used management strategies and surgical interventions, this study evaluates current opinions in the treatment of these entities. METHODS: Members of the Pediatric Section of the American Association of Neurological Surgeons (AANS) were surveyed in July of 1998. A questionnaire was designed to assess (1) management of asymptomatic and symptomatic cases; (2) signs and symptoms that warrant surgical intervention, and (3) surgical strategies. Seventy-seven of 234 surveys (33%) were returned. Responses were entered in a Microsoft Excel spreadsheet for data analysis. RESULTS: Each year, respondents evaluated on average 10 patients with confirmed syringomyelia and operated on 7. There was substantial agreement to operate on patients with syringomyelia who had progressive scoliosis or progressive motor/sensory loss. For isolated syringomyelia without a Chiari malformation, the majority of respondents recommended shunting of the syrinx. Opinion was mixed concerning physical restrictions for asymptomatic patients with syringomyelia and Chiari malformations. For Chiari malformations, the majority of respondents recommended a minimum cervicomedullary decompression with dural patch grafting. No consensus was obtained on whether dural patch grafting should be done alone or in combination with intradural dissection or manipulation of the tonsils. CONCLUSION: Although many respondents agreed on the management and surgical treatment of symptomatic patients with syringomyelia and/or Chiari malformations, there was disagreement with regard to the optimal surgical procedure. Respondents rejected prophylactic surgery for their asymptomatic patients, choosing to follow them conservatively with serial imaging and neurological examinations.

Arnold-Chiari Malformation↗

Asymptomatic Chiari Type I malformations identified on magnetic resonance imaging.

OBJECT: Chiari Type I malformation (CMI) is a congenital disorder recognized by caudal displacement of the cerebellar tonsils through the foramen magnum and into the cervical canal. Frequently, associated findings include abnormalities of nearby bony and neural elements as well as syringomyelia. Cerebellar tonsillar ectopia is generally considered pathological when greater than 5 mm below the foramen magnum. However, asymptomatic tonsillar ectopia is an increasingly recognized phenomenon, the significance of which is poorly understood. METHODS: The authors retrospectively reviewed the records of all brain magnetic resonance (MR) images obtained at our hospital over a 43-month period in an attempt to ascertain the relative prevalence and MR imaging characteristics of asymptomatic CMIs. Of 22,591 patients who underwent MR imaging of the head and cervical spine, 175 were found to have CMIs with tonsillar herniation extending more than 5 mm below the foramen magnum. Of these, 25 (14%) were found to be clinically asymptomatic. The average extent of ectopia in this population was 11.4 +/- 4.86 mm, and was significantly associated with a smaller cisterna magna. Syringomyelia and osseous anomalies were found in only one asymptomatic patient. CONCLUSIONS: The authors suggest that the isolated finding of tonsillar herniation is of limited prognostic utility and must be considered in the context of all available clinical and radiographic data. Strategies for treating patients with asymptomatic CMIs are discussed.

Adult↗

Neural pathways in tactile object recognition.

OBJECTIVE: To define further the brain regions involved in tactile object recognition using functional MRI (fMRI) techniques. BACKGROUND: The neural substrates involved in tactile object recognition (TOR) have not been elucidated. Studies of nonhuman primates and humans suggest that basic motor and somatosensory mechanisms are involved at a peripheral level; however, the mechanisms of higher order object recognition have not been determined. METHODS: The authors investigated 11 normal volunteers utilizing fMRI techniques in an attempt to determine the neural pathways involved in TOR. Each individual performed a behavioral paradigm with the activated condition involving identification of objects by touch, with identification of rough/smooth as the control. RESULTS: Data suggest that in a majority of individuals, TOR involves the calcarine and extrastriatal cortex, inferior parietal lobule, inferior frontal gyrus, and superior frontal gyrus-polar region. CONCLUSIONS: TOR may utilize visual systems to access an internal object representation. The parietal cortices and inferior frontal regions may be involved in a concomitant lexical strategy of naming the object being examined. Frontal polar activation likely serves a role in visuospatial working memory or in recognizing unusual representations of objects. Overall, these findings suggest that TOR could involve a network of cortical regions subserving somatosensory, motor, visual, and, at times, lexical processing. The primary finding suggests that in this normal study population, the visual cortices may be involved in the topographic spatial processing of TOR.

Adult↗

Venous blood effects in spin-echo fMRI of human brain.

The spin-echo response to visual activation was studied as a function of spatial resolution at a field of 1.5 T. The results showed that the increase in absolute T(2) upon activation was as large as 22.8 +/- 3.1% (P < 0.05) at the highest resolution (5.3 mm(3)), while it was as small as 3.5 +/- 0.2% (P < 0.05) at the lowest resolution (42.2 mm(3)). In addition, upon increasing resolution, the spin-echo signal decay as a function of echo time changed from monoexponential to nonexponential. These data indicate that, when using the standard resolution for fMRI studies at 1.5 T, the effects of spin-echo changes in the draining veins are of major contribution to the total blood oxygenation level-dependent (BOLD) signal changes measured in voxels encompassing the activated brain areas. The data can be quantitatively accounted for using a model based on the intravascular origin of the spin-echo effect including both macrovascular and microvascular effects. Existing theories for the spin-echo BOLD effect based on diffusion through field gradients predict negligible spin-echo effects inside the large vessels and are therefore incompatible with the data. Magn Reson Med 42:617-626, 1999.

Brain↗

Kinetic analysis of [11C]McN5652: a serotonin transporter radioligand.

The impulse response function of a radioligand is the most fundamental way to describe its pharmacokinetics and to assess its tissue uptake and retention pattern. This study investigates the impulse response function of [11C](+)McN5652, a radioligand used for positron emission tomography (PET) imaging of the serotonin transporter (SERT) in the brain. Dynamic PET studies were performed in eight healthy volunteers injected with [11C](+)McN5652 and subsequently with its pharmacologically inactive enantiomer [11C](-)McN5652. The impulse response function was calculated by deconvolution analysis of regional time-activity curves, and its peak value (f(max)), its retention value at 75 minutes (fT), and its normalized retention (f(rel) = fT/f(max)) were obtained. Alternatively, compartmental models were applied to calculate the apparent total distribution volume (DV(T)) and its specific binding component (DV(S)). Both the noncompartmental (fT,f(rel)) and the compartmental parameters (DV) were investigated with and without correction for nonspecific binding by simple subtraction of the corresponding value obtained with [11C](-)McN5652. The impulse response function obtained by deconvolution analysis demonstrated high tracer extraction followed by a slow decline in the form of a monoexponential function. Statistical analysis revealed that the best compartmental model in terms of analysis of variance F and condition number of the parameter variance-covariance matrix was the one that was based on a single tissue compartment with parameters k1 and k2 and that also included the parameter of regional cerebral blood volume (BV). The parameter f(rel) demonstrated low between-subject variance (coefficient of variation [CV] = 19%), a midbrain to cerebellum ratio of 1.85, and high correlation with the known density of SERT (r = 0.787 where r is the coefficient of linear correlation between the parameter and the known density of SERT). After correction for nonspecific binding, f(rel) demonstrated further improvement in correlation (r = 0.814) and midbrain to cerebellum ratio (3.09). The variance of the distribution volumes was acceptable when the logarithmic transform lnDV was used instead of DV (17% for the three-parameter model), but correlation of this compartmental parameter was slightly less (r = 0.652 for the three-parameter model) than the correlation of the noncompartmental f(rel) with the known density of SERT, and the midbrain to cerebellum ratio was only 1.5 (uncorrected) and 1.8 (corrected). At the expense of increasing variance, the correlation was increased after correction for nonspecific binding using the inactive enantiomer (r = 0.694; CV = 22%). These results indicate that the kinetics of [11C](+)McN5652 can best be described by a one-tissue compartment model with three parameters (k1, k2, and BV), and that both the noncompartmental parameter f(rel) and the compartmental distribution volumes have the potential for quantitative estimation of the density of SERT. Further validation of the radioligand in experimental and clinical situations is warranted.

Adult↗

Determination of oxygen extraction ratios by magnetic resonance imaging.

The oxygen extraction ratio (OER) of a tissue describes the interplay between oxygen delivery and consumption and, as such, directly reflects the viability and activity of any organ. It is shown that OER can be quantified using a single magnetic resonance imaging observable, namely the relaxation time T2 of venous blood draining from the tissue. This principle is applied to study local OER changes in the brain on visual stimulation in humans, unambiguously demonstrating a mismatch between changes in blood flow and oxygen metabolism on activation.

Brain↗

Randomized study of CODE versus alternating CAV/EP for extensive-stage small-cell lung cancer: an Intergroup Study of the National Cancer Institute of Canada Clinical Trials Group and the Southwest Oncology Group.

PURPOSE: To determine whether an intensive weekly chemotherapy regimen plus thoracic irradiation is superior to standard chemotherapy in the treatment of extensive-stage small-cell lung cancer (ESCLC). PATIENTS AND METHODS: Patients with ESCLC were considered eligible for the study if they were younger than 68 years, had a performance status of 0 to 2, and were free of brain metastases. Patients were randomized to receive cisplatin, vincristine, doxorubicin, and etoposide (CODE) or alternating cyclophosphamide, doxorubicin, vincristine/etoposide and cisplatin (CAV/EP). Consolidative thoracic irradiation and prophylactic cranial irradiation were given to patients responding to CODE and according to investigator discretion on the CAV/EP arm. RESULTS: The fidelity of drug delivery on both drug regimens was equal, and more than 70% of all patients received the intended protocol chemotherapy. Although rates of neutropenic fever were similar, nine (8.2%) of 110 patients on the CODE arm died during chemotherapy, whereas one (0.9%) of 109 patients died on the CAV/EP arm. Response rates after chemotherapy were higher (P =.006) with CODE (87%) than with CAV/EP (70%). However, progression-free survival (median of 0.66 years on both arms) and overall survival (median, 0.98 years for CODE and 0. 91 years for CAV/EP) were not statistically different. CONCLUSION: The CODE regimen increased two-fold the received dose-intensity of four of the most active drugs in small-cell lung cancer compared with the standard CAV/EP regimen while maintaining an approximately equal total dose. Despite supportive care (but not routine prophylactic use of granulocyte colony-stimulating factor), there was excessive toxic mortality with the CODE regimen. The response rate with CODE was higher than that of CAV/EP, but progression-free and overall survival were not significantly improved. In view of increased toxicity and similar efficacy, the CODE chemotherapy regimen is not recommended for treatment of ESCLC.

Antineoplastic Combined Chemotherapy Protocols↗

Evaluation of pyrazoloacridine in patients with advanced pancreatic carcinoma.

PURPOSE: Pyrazoloacridine (PZA) is an acridine derivative selected for clinical development because of broad pre-clinical antitumor activity and solid tumor selectivity. Phase I evaluations with PZA have demonstrated predictable toxicity and suggested clinical efficacy. A phase II trial in patients with previously untreated advanced pancreatic cancer was conducted. METHODS: PZA was administered at a dose of 750 mg/m2 intravenously over 3 hours every 21 days. Seventeen patients were treated receiving a total of 46 courses of PZA. RESULTS: Of the 15 patients evaluable for response, no responses were observed (0% response rate, 95% confidence interval 0-22%). Major toxicities directly attributable to PZA included moderate neutropenia and mild neurotoxicity. CONCLUSION: PZA at this dose and schedule of administration was inactive in patients with pancreatic carcinoma.

Acridines↗

Genistein-induced G2-M arrest, p21WAF1 upregulation, and apoptosis in a non-small-cell lung cancer cell line.

Lung cancer is the leading cause of cancer-related death in the world, with increasing incidence in many developed countries. Epidemiological data suggest that consumption of soy products (the isoflavone genistein) may be associated with a decreased risk of breast and prostate cancer; however, such studies are not available for lung cancer. We investigated cell growth inhibition, modulation in gene expression, and induction of apoptosis by genistein in H460 non-small lung cancer cells. Genistein inhibited H460 cell growth in a dose-dependent manner. Flow-cytometric analysis showed that 30 microM genistein arrested cell cycle progression at the G2-M phase. 4,6-Diamidino-2-phenylindole staining, flow-cytometric analysis, and DNA laddering were used to investigate apoptotic cell death, and the results show that 30 microM genistein can cause typical DNA laddering, a hallmark for apoptosis. In addition, flow cytometry and 4,6-diamidino-2-phenylindole staining showed induction of apoptosis by genistein. Our investigation also demonstrated the modulation of p21WAF1 by Western blot analysis of cell lysates obtained from cultured cells treated with 30 and 50 microM genistein for 24, 48, and 72 hours. Simultaneously, immunocytochemical staining was conducted for the expression of p21WAF1 protein. Our results showed that genistein can upregulate p21WAF1 expression in genistein-treated cells. From these results, we conclude that genistein may act as an anticancer agent, and further studies may prove its efficacy in non-small lung cancer cells. Thus the biological effects of genistein may, indeed, be due to the modulation of cell growth, cell death, and cell cycle regulatory molecules.

Anticarcinogenic Agents↗

Clinicopathologic analysis of k-ras, p53, and ERBB-2 gene alterations in pulmonary adenocarcinoma.

We compared PCR-SSCP detected mutations of k-ras (codon 12) and p53 (exons 5-8) to ERBB-2 immunostaining and clinicopathologic features in 31 pulmonary adenocarcinomas. There were nine tumors (29%) with mutations of ras, 13 tumors (42%) with mutations of p53, and three tumors (10%) with mutations of both. Neither k-ras nor p53 mutation alone was significantly correlated with stage, grade, or survival. However, tumors with k-ras mutation were more frequently associated with an invasive growth pattern, defined as > 30% tumor volume composed of infiltrative nests of cells within desmoplastic, scar-like stroma [< 30% volume invasive--1/13 (8%) with k-ras mutation vs. > 30% volume invasive--8/18 (44%) with k-ras mutation, p = 0.02]. Accordingly, k-ras mutations were observed in only 1/9 (15%) predominantly bronchoalveolar or papillary tumors versus 6/22 (28%) acinar or scar carcinoma tumors. All three patients with combined k-ras/p53 mutation had advanced stage (III/IV) at presentation and died of the disease. In contrast to k-ras, staining for ERBB-2 was more frequently observed in tumors exhibiting < 30% invasive growth pattern (12/13, 92%) than in tumors with > 30% invasive growth pattern (10/18, 56%, p = 0.03). ERBB-2 immunoreactivity was more frequent in Stage I (14/15, 93%) versus Stage II-IV (8/16, 50%) cases, but it did not correlate with survival. There was a reciprocal relationship between k-ras mutation and ERBB-2 staining; only 4/9 (44%) k-ras mutated cases were ERBB-2 positive versus 18/22 (82%) cases without k-ras mutation (p = 0.005). In contrast, 8/13 cases with p53 mutation were ERBB-2 positive. We conclude that well-differentiated and less invasive papillary and bronchoalveolar tumors are more often ERBB-2 positive/k-ras negative (i.e. at codon 12), whereas less well differentiated acinar or scar carcinomas are more often ERBB-2 negative/k-ras mutated at codon 12. These findings imply that the divergent histogenesis of pulmonary adenocarcinoma may reflect specific differences in genetic pathology.

Adenocarcinoma↗

Visual activation in alpha-chloralose-anaesthetized cats does not cause lactate accumulation in the visual cortex as detected by [1H]NMR difference spectroscopy.

The hypothesis that neuronal activation results in lactate accumulation due to mismatch between glucose and oxygen consumption was tested in the cat model of visual activation by monitoring cerebral metabolism with localized 1H nuclear magnetic resonance spectroscopy (MRS). Adult cats were anaesthetized with alpha-chloralose, paralysed and mechanically ventilated. Visual evoked potentials measured over the occipital cortex showed maximal amplitude at 2 Hz stimulation, but the latencies of the early cortical potentials, N1 and P1, were independent of stimulation frequency. High signal-to-noise ratio, short echo time volume-selected [1H]MRS was used to monitor cerebral lactate with a temporal resolution of 70 s. Difference proton spectroscopy unambiguously showed no lactate peak in the visual cortex during visual activation at stimulation frequencies ranging from 1 to 16 Hz. Absence of change in lactate concentration during visual stimulation was confirmed by averaging all the spectra acquired during activation and subtracting them from reference spectra collected in darkness, a procedure that had a calculated lactate detection limit of 0.17 mM. We also reduced the O2 in the inspired air to 13%, which decreased pO2 from 94.5 +/- 8.9 to 47.0 +/- 6.8 mmHg, during visual stimulation at 2 or 4 Hz. At this low PO2 level, visual stimulation did not cause lactate accumulation in the visual cortex, however. The present data show that neuronal activation to this degree in the cat brain is not associated with aerobic lactate production to an extent that can be detected with 1H MRS.

Anesthesia, Intravenous↗