Gastroesophageal pH step-up inaccurately locates proximal border of lower esophageal sphincter

Limiting the widespread use of 24-hr pH monitoring is the necessity of manometrically placing the pH probe 5 cm above the proximal lower esophageal sphincter (LES) border. Therefore, we prospectively compared LES localization by gastroesophageal pH step-up with manometry in 71 patients and 14 asymptomatic volunteers. The gastroesophageal pH step-up significantly correlated with the proximal LES border in patients (r=0.53, P<0.0001) and volunteers (r=0.91, P<0.0001). Based on previously published criteria, the pH step-up value was considered acceptably accurate if it was within ±3 cm (6 cm total span) of the manometrically determined proximal LES border. In 58% of patients and 29% of volunteers the pH step-up occurred outside this accuracy range. Esophagitis (P=0.015) and abnormal reflux parameters (P=0.002) were variables contributing to this error. Subsequent analysis found that the pH step-up overestimated the proximal LES border and occurred at the midportion of the sphincter. The pH step-up still inaccurately located the mid LES in 34% of patients. Therefore, manometry should remain the standard for accurate LES localization prior to placing the pH probe.     

Distinct electrophysiological signatures of task-unrelated and dynamic thoughts

Humans spend much of their lives engaging with their internal train of thoughts. Traditionally, research focused on whether or not these thoughts are related to ongoing tasks, and has identified reliable and distinct behavioral and neural correlates of task-unrelated and task-related thought. A recent theoretical framework highlighted a different aspect of thinking—how it dynamically moves between topics. However, the neural correlates of such thought dynamics are unknown. The current study aimed to determine the electrophysiological signatures of these dynamics by recording electroencephalogram (EEG) while participants performed an attention task and periodically answered thought-sampling questions about whether their thoughts were 1) task-unrelated, 2) freely moving, 3) deliberately constrained, and 4) automatically constrained. We examined three EEG measures across different time windows as a function of each thought type: stimulus-evoked P3 event-related potentials and non–stimulus-evoked alpha power and variability. Parietal P3 was larger for task-related relative to task-unrelated thoughts, whereas frontal P3 was increased for deliberately constrained compared with unconstrained thoughts. Frontal electrodes showed enhanced alpha power for freely moving thoughts relative to non-freely moving thoughts. Alpha-power variability was increased for task-unrelated, freely moving, and unconstrained thoughts. Our findings indicate distinct electrophysiological patterns associated with task-unrelated and dynamic thoughts, suggesting these neural measures capture the heterogeneity of our ongoing thoughts.

Cognitive neuroscience has reached a consensus that the brain is not idle at rest (1). This rings intuitively true: When left alone, our minds rarely stay still. Moreover, recent evidence suggests that rest is not a homogeneous state (2), nor is the brain truly “at rest” as it fluctuates across time and contexts (3–6). This too is intuitive: What is striking is not just that we move from thought to thought unprompted but also the diverse ways that trains of thought unfold over time. Sometimes, our thoughts freely wander between topics. You might remember this morning’s run, then imagine gardening, then think about the dinner you’ll cook tonight. Other times, we deliberately constrain our thoughts and work diligently toward a goal. In a quiet moment, you might methodically contemplate the results of your latest experiment. Still other times, our thoughts get stuck on an affectively salient topic, from which it is difficult to break free. You might worry, over and over, about your niece who is going through major surgery next week.Research has traditionally examined the internal train of thought in the context of mind wandering. This field has expanded at such a rapid pace that some have dubbed this the “era of the wandering mind” (7). To date, the vast majority of mind-wandering research has focused on the static content of individual thoughts. In particular, mind-wandering studies have primarily focused on task-unrelated thought (8)—that is, thoughts that are unrelated to an ongoing, typically externally oriented, task (8–10). In the laboratory, subjects’ thoughts are often unrelated to the experimental task (9). Task-unrelated thought is also frequent in everyday life (11), as when a student becomes distracted during a lecture or while driving.Recent theories are less task-centric and instead focus on the dynamics of mind wandering—that is, how internal trains of thoughts unfold over time (12–17). In particular, the “dynamic framework” of spontaneous thought distinguishes three subtypes within the train of thoughts: 1) deliberately constrained, 2) automatically constrained, and 3) freely moving thoughts (12, 14). Constraints on the train of thoughts serve to focus internal attention on a topic for extended periods of time. For example, deliberately constrained thoughts occur when a person actively directs her thoughts to goal-relevant information (e.g., when you contemplate your latest experiment). This type of constraint is implemented through cognitive control. Automatically constrained thoughts focus on affectively or personally salient information that is difficult to disengage from (e.g., when you worry about your niece who will have surgery). This type of constraint is automatic in nature and thought to operate largely outside of cognitive control. In contrast, freely moving thoughts occur when both of these constraints are weak, allowing the mind to wander with no overarching purpose and direction (e.g., when your thoughts drift from a movie, to gardening, to dinner). Notably, the dynamic framework purports that these three subtypes of thoughts are independent of task relatedness. In other words, task-related and task-unrelated thoughts can both be deliberately constrained, automatically constrained, or freely moving. See SI Appendix for further details about the relationship between dynamic categories.Empirical research on the dynamics of thought is in its infancy. Behavioral research has focused on contrasting task-unrelated thoughts with the other three subtypes of thoughts, with a particular emphasis on freely moving thoughts. These findings suggest that self-reported freely moving and task-unrelated thoughts have distinct behavioral markers. For example, studies of mind wandering in everyday life found that self-reports of freely moving and task-unrelated thought fluctuate at different rates throughout the day (11). Consistent with predictions of the dynamic framework, these studies reported that task-unrelated and freely moving thoughts are only modestly correlated (r < 0.3) and they occurred independent of each other (8, 11). Specifically, although task-related thoughts are often deliberately constrained and task-unrelated thoughts sometimes move freely, the dynamic framework predicts that this is not always the case. In fact, task-related thoughts can move freely (e.g., when a graphic designer freely associate ideas for her new website design) or be automatically constrained (e.g., when someone obsesses over a problem at work). Task-unrelated thoughts can be deliberately or automatically constrained (e.g., when you construct a grocery list or worry about your niece’s surgery during a lecture). The only two empirical studies to date have focused explicitly on freely moving thought (8, 11). Although this provides some initial evidence that task-unrelated thought is different from dynamic thoughts, no studies have assessed the neural correlates of dynamic thought types. The identification of different electrophysiological signatures of these thought types would thus provide important validation that these categories reflect distinct entities.In the current study, we examined the electrophysiological signatures of the four types of thought by recording an electroencephalogram (EEG) while participants performed an attention task. Participants occasionally answered thought-sampling questions about the nature of their thoughts throughout the task. Thought sampling is the standard method in mind-wandering research: Participants are randomly interrupted as they perform a laboratory task and answer questions about their immediately preceding thoughts (9, 10). In line with previous studies, we ask the standard question about whether participants’ thoughts were task-unrelated (see ref. 8 for a review). In addition, we asked whether subjects’ trains of thought were freely moving, deliberately constrained, and automatically constrained.We used electroencephalography because this method has the temporal resolution necessary to capture the transient changes in neural activity corresponding to our trains of thoughts, including stimulus-evoked, task-dependent activity and stimulus-independent, intrinsic activity. We first examined event-related potentials (ERPs), which index the electrophysiological response evoked by task-relevant stimuli. Previous research suggests that task-unrelated thought attenuates the magnitude of ERP components associated with sensory (18–20) and cognitive (21–24) processing of task-relevant stimuli. ERPs therefore provide an electrophysiological signature of when a participant has disengaged from task-relevant stimuli. We predicted that task-unrelated thoughts would be associated with a reduced P3 ERP component.To index stimulus-independent, intrinsic neural activity, we examined spectral power in the alpha band (8 to 14 Hz) during a time window after the offset of ERPs, which is unlikely to be impacted by stimulus-evoked responses. This segregation of the poststimulus time window allowed us to disentangle stimulus-evoked, task-dependent responses captured by ERP components in the earlier window and stimulus-independent activity likely associated with the subject’s ongoing thoughts as captured by alpha power in the later time window (as illustrated in Fig. 1). Alpha-power increases recorded over posterior sites have been associated with internal attention (23, 25) as well as spontaneous brain activity recorded at rest that is not elicited by external stimuli (26, 27). In contrast, frontal alpha has been linked to creative, divergent thinking (28, 29). Accordingly, we hypothesized that task-unrelated thoughts would be associated with enhanced posterior alpha power, whereas freely moving thoughts would be associated with increased frontal alpha power. Given that our dynamic thought-sampling questions address variability within the train of thought over time, we examined the neural correlates of these thought dynamics by capturing momentary changes in alpha power (i.e., alpha-power variability) over the same ERP-free time window. We predicted that freely moving thought would be associated with increased alpha-power variability, whereas constrained thought would show reduced alpha-power variability.Open in a separate windowFig. 1.EEG measures across the poststimulus time window. We examined three EEG measures. Stimulus-evoked activity as captured by P3 ERP components was examined during the 0- to 0.6-s poststimulus time window. Alpha power and variability index intrinsic neural activity not impacted by an external stimulus examined after the offset of P3s during the 0.6- to 1.8-s poststimulus time window.     

Permeability measurements with closed vesicles from rat liver nuclear envelopes.

Closed nuclear envelope ghosts in the physiological orientation were prepared from rat liver and nuclei as previously described. Here we report transport measurements of various proteins and ribonucleic acids across the envelope of these vesicles. Histones were accumulated rapidly in the ghosts, in contrast to other, nonnuclear, proteins. Triton X-100 removal of the external nuclear membrane from loaded vesicles, as well as comparative studies with open vesicles, excluded the effects of external adsorption. The exchange rate of histones across the nuclear envelope is strongly depressed in the presence of GTP and GDP. The vesicles contain the translocation mechanism for poly(A)-containing RNA. The translocation of poly(A), messenger RNA, and ribosomal RNA was investigated after entrapment of these nucleic acids during the preparation of vesicles. Our data show that the complete export of only poly(A)-containing RNA from the vesicles is enhanced in the presence of 2 mM ATP. This RNA, as well as poly(A), is transported unidirectionally.     

Liver involvement in multiple myeloma

One hundred twenty-eight records of patients with multiple myeloma were reviewed to assess the incidence and manifestations of liver involvement. Histologic study of the liver was available in 21 patients. Diffuse infiltration of the liver by plasma cells was observed in 10 patients, myeloid metaplasia in four, amyloidosis in two, toxic hepatitis in two, and extrahepatic cholestasis secondary to infiltration of the peripancreatic tissue by plasma cells in one. The clinical signs of plasma cell infiltration of the liver consisted of hepatomegaly in seven patients, mild elevation of liver enzymes in five, and portal hypertension in two. Jaundice was only observed in patients with hepatitis or extrahepatic cholestasis. Liver infiltration by plasma cells did not appear to have a major prognostic significance.     

Semirational design of active tumor suppressor p53 DNA binding domain with enhanced stability

We have designed a p53 DNA binding domain that has virtually the same binding affinity for the gadd45 promoter as does wild-type protein but is considerably more stable. The design strategy was based on molecular evolution of the protein domain. Naturally occurring amino acid substitutions were identified by comparing the sequences of p53 homologues from 23 species, introducing them into wild-type human p53, and measuring the changes in stability. The most stable substitutions were combined in a multiple mutant. The advantage of this strategy is that, by substituting with naturally occurring residues, the function is likely to be unimpaired. All point mutants bind the consensus DNA sequence. The changes in stability ranged from +1.27 (less stable Q165K) to −1.49 (more stable N239Y) kcal mol⁻¹, respectively. The changes in free energy of unfolding on mutation are additive. Of interest, the two most stable mutants (N239Y and N268D) have been known to act as suppressors and restored the activity of two of the most common tumorigenic mutants. Of the 20 single mutants, 10 are cancer-associated, though their frequency of occurrence is extremely low: A129D, Q165K, Q167E, and D148E are less stable and M133L, V203A and N239Y are more stable whereas the rest are neutral. The quadruple mutant (M133LV203AN239YN268D), which is stabilized by 2.65 kcal mol⁻¹ and T_m raised by 5.6°C is of potential interest for trials in vivo.     

Cytokeratin immunoreactivity patterns in the diagnosis of short-segment Barrett's esophagus

BACKGROUND & AIMS: The origin of intestinal metaplasia in short segments of columnar mucosa at the esophagogastric junction has clinical importance but can be difficult to determine at endoscopy. Cytokeratin (CK) 7 and 20 patterns are specific for long-segment Barrett's esophagus; however, their utility in short-segment Barrett's esophagus has not been assessed. METHODS: Endoscopic biopsy specimens from patients with long-segment Barrett's esophagus (n = 49), suspected short-segment Barrett's esophagus (n = 43), and gastric intestinal metaplasia (n = 26) were immunostained for CK7 and CK20. Comprehensive clinical data were obtained, including age, gender, and hiatal hernia and Helicobacter pylori status. RESULTS: A Barrett's CK7/20 pattern was present in 48 (98%) of 49 patients with long-segment Barrett's esophagus, 35 (82%) of 43 with suspected short-segment Barrett's esophagus, and 0 (0%) of 26 patients with gastric intestinal metaplasia. Patients with suspected short-segment Barrett's esophagus with a Barrett's CK7/20 pattern were clinically similar to those with long-segment Barrett's esophagus. In contrast, patients with suspected short-segment Barrett's esophagus with no Barrett's CK7/20 pattern were clinically similar to those with gastric intestinal metaplasia. CONCLUSIONS: A Barrett's CK7/20 pattern identifies a subset of patients with suspected short-segment Barrett's esophagus who have a patient profile similar to that seen in long-segment Barrett's esophagus. A Barrett's CK7/20 pattern is an objective marker of Barrett's mucosa that in conjunction with appropriate clinical and endoscopic data can be used by clinicians to better define patients with short-segment Barrett's esophagus.