Michael Pourdehnad

The measurement of regional cerebral blood flow during the complex cognitive task of meditation: a preliminary SPECT study

This study measured changes in regional cerebral blood flow (rCBF) during the complex cognitive task of meditation using single photon emission computed tomography. Eight experienced Tibetan Buddhist meditators were injected at baseline with 7 mCi HMPAO and scanned 20 min later for 45 min. The subjects then meditated for 1 h at which time they were injected with 25 mCi HMPAO and scanned 20 min later for 30 min. Values were obtained for regions of interest in major brain structures and normalized to whole brain activity. The percentage change between meditation and baseline was compared. Correlations between structures were also determined. Significantly increased rCBF (P<0.05) was observed in the cingulate gyrus, inferior and orbital frontal cortex, dorsolateral prefrontal cortex (DLPFC), and thalamus. The change in rCBF in the left DLPFC correlated negatively (P<0.05) with that in the left superior parietal lobe. Increased frontal rCBF may reflect focused concentration and thalamic increases overall increased cortical activity during meditation. The correlation between the DLPFC and the superior parietal lobe may reflect an altered sense of space experienced during meditation. These results suggest a complex rCBF pattern during the task of meditation.

Cerebral Blood Flow during Meditative Prayer: Preliminary Findings and Methodological Issues:

Meditative practices typically require several coordinated cognitive activities. This study measured changes in cerebral blood flow during “verbal” based meditation by Franciscan nuns involving the internal repetition of a particular phrase. These results are compared with those we previously described in eight Buddhist meditators who use a type of “visualization” technique. Three experienced practitioners of verbal meditation were injected via IV at rest with 260MBq of Tc-99m HMPAO and scanned 30 min. later on a triple head SPECT camera for 45 min. Following the baseline scan, subjects meditated for approximately 40 min. at which time they were injected with 925MBq of HMPAO while they continued to meditate for 10 min. more (total of 50 min. of meditation). The injection during meditation was designed not to disturb practice. Subjects were scanned 20 min. later for 30 min. Counts were obtained for regions of interest for major brain structures and normalized to whole-brain blood flow Compared to baseline, mean verbal meditation scans showed increased blood flow in the prefrontal cortex (7.1%), inferior parietal lobes (6.8%), and inferior frontal lobes (9.0%). There was a strong inverse correlation between the blood flow change in the prefrontal cortex and in the ipsilateral superior parietal lobe (p<.01). This study on a limited number of subjects demonstrated the feasibility of studying different types of meditation with neuroimaging techniques, suggested that several coordinated cognitive processes occur during meditation, and also raised important methodological issues.

Myc and mTOR converge on a common node in protein synthesis control that confers synthetic lethality in Myc-driven cancers

Myc is one of the most commonly deregulated oncogenes in human cancer, yet therapies directly targeting Myc hyperactivation are not presently available in the clinic. The evolutionarily conserved function of Myc in modulating protein synthesis control is critical to the Myc oncogenic program. Indeed, enhancing the protein synthesis capacity of cancer cells directly contributes to their survival, proliferation, and genome instability. Therefore, inhibiting enhanced protein synthesis may represent a highly relevant strategy for the treatment of Myc-dependent human cancers. However, components of the translation machinery that can be exploited as therapeutic targets for Myc-driven cancers remain poorly defined. Here, we uncover a surprising and important functional link between Myc and mammalian target of rapamycin (mTOR)-dependent phosphorylation of eukaryotic translation initiation factor 4E binding protein-1 (4EBP1), a master regulator of protein synthesis control. Using a pharmacogenetic approach, we find that mTOR-dependent phosphorylation of 4EBP1 is required for cancer cell survival in Myc-dependent tumor initiation and maintenance. We further show that a clinical mTOR active site inhibitor, which is capable of blocking mTOR-dependent 4EBP1 phosphorylation, has remarkable therapeutic efficacy in Myc-driven hematological cancers. Additionally, we demonstrate the clinical implications of these results by delineating a significant link between Myc and mTOR-dependent phosphorylation of 4EBP1 and therapeutic response in human lymphomas. Together, these findings reveal that an important mTOR substrate is found hyperactivated downstream of Myc oncogenic activity to promote tumor survival and confers synthetic lethality, thereby revealing a unique therapeutic approach to render Myc druggable in the clinic.

Do high glucose levels have differential effect on FDG uptake in inflammatory and malignant disorders

Background The association of hyperglycaemia with reduced fluorodeoxyglucose (FDG) uptake by tumour cells is well established. Therefore, it is standard practice that all patients must fast for at least several hours prior to FDG positron emission tomography (PET) imaging. However, the effect of hyperglycaemia on FDG uptake by inflammatory and infectious lesions is unknown. The aim of this study was to investigate this important issue. Methods For in vitro studies human mononuclear cells were isolated from 12 normal volunteers and FDG uptake was determined in medium containing differing concentrations of glucose. FDG uptake by human mesothelioma cells was also measured for comparison. For studies involving patients, 416 FDG PET scans of patients with confirmed malignancy (n = 321) or benign lesions (n = 95) were reviewed retrospectively. The relationship between serum glucose level and FDG uptake by the lesions was assessed utilizing the standardized uptake value (SUV) technique. Results In the in vitro studies, while FDG uptake by mesothelioma cells decreased as glucose concentration increased, there was no differential uptake of FDG uptake by mononuclear cells at glucose concentrations less than 250 mg·dl−1. In clinical patients, FDG uptake by malignant lesions was slightly, but negatively affected by serum glucose level (r = −0.21, P<0.01) (glucose range 49-187 mg·dl−1). In contrast, FDG uptake by inflammatory lesions was positively associated with serum glucose level (r = 0.43, P<0.01) (glucose range 54-215 mg·dl−1). Discussion and conclusion While the degree of FDG uptake is primarily influenced by the nature of the underlying lesion, serum glucose concentration appears to have a small effect on FDG uptake, which differs between malignant disorders and inflammatory processes. Our data suggest that below a certain level, elevated glucose concentration might not have a negative effect on FDG uptake in inflammatory cells, contrary to that observed in malignant disorders.

The role of positron emission tomography with fluorine-18-deoxyglucose in identifying colorectal cancer metastases to liver.

Liver metastasis is a common consequence of colorectal carcinoma. Early and accurate detection of liver metastasis is crucial for a decision about partial hepatectomy, which is considered a standard and potentially curative therapy in such a setting. The presence of extrahepatic metastases will exclude surgical resection as a therapeutic option. Positron emission tomography with fluorine-18-deoxyglucose (FDG-PET) has been successful in detecting and staging a variety of malignancies. The purpose of this study was to assess the utility of FDG-PET in the accurate detection of liver and distal metastases from colorectal cancer. The results of 80 PET and computed tomography (CT) scans were compared with surgical pathology and clinical outcome. FDG-PET detected liver metastases in 28 patients, with a sensitivity of 100%. CT detected metastasis in 20 patients, giving a sensitivity of 71.4%. In addition, in one patient with negative CT findings, PET detected a focus of hypermetabolism in the region adjacent to liver, which was proven to be a second focus of primary colon carcinoma. In six patients with liver metastases, PET correctly detected extrahepatic lesions, while CT only detected hepatic lesions. In conclusion, FDG-PET is an excellent imaging modality for the detection and staging of liver metastases in patients with colorectal carcinomas.

Muscarinic blockade inhibits gastric emptying of mixed-nutrient meal: effects of weight and gender.

We compared the vagal contribution to gastric emptying in lean and obese subjects by monitoring gastric emptying of a meal during muscarinic blockade. Lean (n = 6) and obese subjects (n = 6) underwent two treatments: 1) saline infusion and 2) atropine infusion [0.4 mg/m2 bolus, 0.4 mg. (m2)-1. h-1] for 2 h, initiated 30 min before ingestion of a 600-kcal breakfast (64% carbohydrate, 23% fat, 13% protein) composed of orange juice (labeled with Indium-111), egg sandwich (labeled with Technetium-99m), cereal, milk, and banana. Anterior and posterior images were taken every 90 s for 90 min using a dual-headed camera. Atropine significantly delayed emptying of both solid (P < 0.007) and liquid (P < 0.002). Obese subjects exhibited a greater delay in liquid emptying during muscarinic blockade compared with lean subjects (P < 0.02). Female subjects exhibited a slower rate of gastric emptying and were less sensitive to atropine. These data suggest that obese subjects exhibit altered gastric cholinergic activity compared with lean subjects and that gender differences in gastric emptying rate may be due to differences in autonomic tone.We compared the vagal contribution to gastric emptying in lean and obese subjects by monitoring gastric emptying of a meal during muscarinic blockade. Lean ( n = 6) and obese subjects ( n = 6) underwent two treatments: 1) saline infusion and 2) atropine infusion [0.4 mg/m2 bolus, 0.4 mg ⋅ (m2)-1 ⋅ h-1] for 2 h, initiated 30 min before ingestion of a 600-kcal breakfast (64% carbohydrate, 23% fat, 13% protein) composed of orange juice (labeled with Indium-111), egg sandwich (labeled with Technetium-99m), cereal, milk, and banana. Anterior and posterior images were taken every 90 s for 90 min using a dual-headed camera. Atropine significantly delayed emptying of both solid ( P < 0.007) and liquid ( P < 0.002). Obese subjects exhibited a greater delay in liquid emptying during muscarinic blockade compared with lean subjects ( P < 0.02). Female subjects exhibited a slower rate of gastric emptying and were less sensitive to atropine. These data suggest that obese subjects exhibit altered gastric cholinergic activity compared with lean subjects and that gender differences in gastric emptying rate may be due to differences in autonomic tone.

CC-122, a pleiotropic pathway modifier, mimics an interferon response and has antitumor activity in DLBCL

Cereblon (CRBN), a substrate receptor of the Cullin 4 RING E3 ubiquitin ligase complex, is the target of the immunomodulatory drugs lenalidomide and pomalidomide. Recently, it was demonstrated that binding of these drugs to CRBN promotes the ubiquitination and subsequent degradation of 2 common substrates, transcription factors Aiolos and Ikaros. Here we report that CC-122, a new chemical entity termed pleiotropic pathway modifier, binds CRBN and promotes degradation of Aiolos and Ikaros in diffuse large B-cell lymphoma (DLBCL) and T cells in vitro, in vivo, and in patients, resulting in both cell autonomous as well as immunostimulatory effects. In DLBCL cell lines, CC-122-induced degradation or short hairpin RNA-mediated knockdown of Aiolos and Ikaros correlates with increased transcription of interferon (IFN)-stimulated genes independent of IFN-α, -β, and -γ production and/or secretion and results in apoptosis in both activated B-cell (ABC) and germinal center B-cell DLBCL cell lines. Our results provide mechanistic insight into the cell-of-origin independent antilymphoma activity of CC-122, in contrast to the ABC subtype selective activity of lenalidomide.

Standardized uptake value as an unreliable index of renal disease on fluorodeoxyglucose PET imaging

Fluorine-18 2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography has been used extensively in the diagnosis of malignant conditions with high rates of sensitivity and specificity. However, increased FDG uptake is not limited to malignant tissue. In general, lesions with a mild degree of FDG uptake as measured by standardized uptake values less than 2.0 are considered benign, whereas those with values greater than 2.5 are usually regarded as malignant. Standardized uptake values in the kidney can be as high as 22 as a result of excretion of FDG through urine. Two cases are reported in which renal abnormalities could not be distinguished from urine based on standard uptake values alone.

Inter-modality comparisons of seizure focus lateralization in complex partial seizures.

Abstract. Anterior temporal lobectomy offers a high chance of seizure-free outcome in patients suffering from drug-refractory complex partial seizure (CPS) originating from the temporal lobe. Other than EEG, several functional and morphologic imaging methods are used to define the spatial seizure origin. The present study was undertaken to compare the merits of fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET), magnetic resonance imaging (MRI) and single-voxel proton MR spectroscopy (MRS) for the lateralization of temporal lobe seizure foci. The clinical charts and imaging data of 43 consecutive CPS patients were reviewed. Based on surface EEG, 31 patients were classified with temporal lobe epilepsy (TLE; 25 lateralized, 6 not lateralized) and 12 with non-temporal lobe epilepsy. All were examined by FDG-PET, MRS and MRI within 6 weeks. FDG-PET and MRI were interpreted visually, while the N-acetyl-aspartate to creatine ratio was used for MRS interpretation. One FDG-PET scan was invalid due to seizure activity post injection. The MR spectra could not be evaluated in five cases bilaterally and three cases unilaterally for technical reasons. A total of 15 patients underwent anterior temporal lobectomy. All showed a beneficial postoperative outcome. When the proportions of agreement between FDG-PET (0.77), MRI (0.58) and MRS (0.56) and surface EEG in TLE cases were compared, there were no significant differences (P>0.10). However, FDG-PET showed a significantly higher agreement (0.93) than MRI (0.60; P=0.03) with the side of successful temporal lobectomy. The concordance of MRS with the side of successful temporal lobectomy was intermediate (0.75). When the results of functional and morphologic imaging were combined, no significant differences were found between the rates of agreement of FDG-PET/MRI and MRS/MRI with EEG (0.80 vs 0.68; P=0.50) and with the side of successful temporal lobectomy (0.87 vs 0.92; P=0.50) in TLE cases. However, MRS/MRI showed significantly more lateralized temporal lobe abnormalities in non-temporal lobe epilepsy cases than FDG-PET/MRI (0.90 vs. 0.17; P<0.01). Although FDG-PET seems to be the most reliable and stable method for this purpose, we conclude that in TLE cases it may be justified to perform MRS, which is less expensive, faster and has no radiation exposure, in combination with MRI before FDG-PET, since FDG-PET offers little additional diagnostic information if MRS and MRI indicate the same seizure focus lateralization.

Gastric emptying of solids: estimates of lag phase and constant emptying times.

There is no consensus regarding the best way to estimate the lag phase time (Tlag) and the constant emptying time (TRE) of the gastric emptying of solids. Furthermore, biphasic gastric emptying is usually described by the modified power exponential function of either Elashoff or Siegel. In an attempt to test the validity of the power exponential functions and to identify relevant parameters of biphasic gastric emptying, we followed an approach which consists of describing the power exponential function by two straight lines. The first line is horizontal and represents Tlag. The second line is tangential to the constant emptying [tangent at the maximum slope (MS) or at the half-emptying value]. Scintigraphic data of 132 patients and 15 controls were fitted by both power exponential functions. Each corresponding half-emptying time, Tlag and TRE estimated from the Elashof and Siegel power exponential functions were strongly correlated (0.93<r<1, P<0.0001). The Bland and Altman statistical method demonstrated good agreement (<5% outliers). The half-emptying tangent method sometimes gave negative Tlag and should be abandoned. Tlag(MS) and TRE(MS) did not correlate and therefore were independent parameters. We conclude that the Elashoff and Siegel functions are equivalent and that the maximum slope tangent method allows a reliable description of the two independent phases of gastric emptying.