Intracellular pH Measurements of the Whole Head and the Basal Ganglia in Chronic Liver Disease: A Phosphorus-31 MR Spectroscopy Study

The purpose of this study was to determine the intracellular pH of the whole head and in voxels localized to the basal ganglia in patients with chronic liver disease using phosphorus-31 magnetic resonance spectroscopy (³¹P MRS). The study group compromised 82 patients with biopsy-proven cirrhosis (43 Child's grade A, 25 Child's grade B and 14 Child's grade C). Eleven subjects showed no evidence of neuropsychiatric impairment on clinical, psychometric and electrophysiological testing, 37 showed evidence of minimal hepatic encephalopathy and 34 had overt hepatic encephalopathy. Unlocalized³¹P MRS of the whole head was performed in 48 patients and 10 healthy volunteers. Localized³¹P MRS of the basal ganglia was performed in the 34 patients and in 20 healthy volunteers. The intracellular pH values were calculated from the chemical shift difference between the inorganic phosphate (P_i) and phosphocreatine (PCr) resonances. The percentage inorganic phosphate (%P_i), phosphocreatine (%PCr) and βNTP signals, relative to the total³¹P signal, and peak area ratios of inorganic phosphate and phosphocreatine, relative to βNTP were also measured. There were no differences between patients and volunteers in intracellular pH in³¹P MR spectra measured from the whole head or the basal ganglia. There was no correlation between the severity of encephalopathy (West Haven criteria) or liver dysfunction (Child score) and intracellular pH values. There was also no significant change in the inorganic phosphate, phosphocreatine or βNTP resonances in spectra acquired from the whole head. However, in spectra localized to the basal ganglia, there was a significant increase in mean P_i/NTP (p=0.02) and PCr/NTP (p=0.009). The mean %P_i and mean %PCr were also increased (p=0.06; p=0.05, respectively), but there was no significant change in mean %βNTP. When the patient population was classified according to the severity of encephalopathy, those with overt disease had a higher mean P_i/NTP and %P_i (p=0.03; p=0.01), compared to the reference population. Our results suggest that there are detectable bioenergetic abnormalities in patients with minimal hepatic encephalopathy or stable, overt chronic hepatic encephalopathy, but any associated intracellular pH change is probably a secondary, rather than a primary phenomenon.     

Validation of computed tomography image integration into the EnSite NavX mapping system to perform catheter ablation of atrial fibrillation

Introduction: The complex anatomy of the left atrium (LA) makes location of ablation catheters difficult using fluoroscopy alone, and therefore 3D mapping systems are now routinely used. We describe the integration of a CT image into the EnSite NavX System with Fusion and its validation in patients undergoing atrial fibrillation (AF) or left atrial tachycardia (AT) catheter ablation. Methods and Results: Twenty‐three patients (61 ± 9.2 years, 16 male) with paroxysmal (14) and persistent (8) AF and persistent (1) AT underwent ablation using CT image integration into the EnSite NavX mapping system with the EnSite Fusion Dynamic Registration software module. In all cases, segmentation of the CT data was accomplished using the EnSite Verismo segmentation tool, although repeat segmentation attempts were required in seven cases. The CT was registered with the NavX‐created geometry using an average of 24 user‐defined fiducial pairs (range 9 to 48). The average distance from NavX‐measured lesion positions to the CT surface was 3.2 ± 0.9 mm (median 2.4 mm). A large, automated, retrospective test using registrations with random subsets of each patient's fiducial pairs showed this average distance decreasing as the number of fiducial pairs increased, although the improvement ceased to be significant beyond 15 pairs. In confirmation, those studies which had used 16 or more pairs had a smaller average lesion‐to‐surface distance (2.9 ± 0.7 mm) than those using 15 or fewer (4.3 ± 0.8 mm, P < 0.02). Finally, for the 13 patients who underwent left atrial circumferential ablation (LACA), there was no significant difference between the circumference computed using NavX‐measured positions and CT surface positions for either the left pulmonary veins (178 ± 64 vs. 177 ± 60 mm; P = 0.81) or the right pulmonary veins (218 ± 86 vs. 207 ± 81 mm; P = 0.08). Conclusion: CT image integration into the EnSite NavX Fusion system was successful in all patients undergoing catheter ablation. A learning curve exists for the Verismo segmentation tool; but once the 3D model was created, the registration process was easily accomplished, with a registration error that is comparable with registration errors using other mapping systems with CT image integration. All patients went on to have subsequent successful ablation procedures. Where LACA was performed (13 patients), only four patients required segmental ostial lesions to achieve electrical isolation.     

Object identification in simultanagnosia: When wholes are not the sum of their parts

Abstract

We examined object identification in two simultanagnosic patients, ES and GK. We show that the patients tended to identify animate objects more accurately than inanimate objects (Experiments 1 and 4). The patients also showed relatively good identification of objects that could be recognised from their global shape, but not objects whose recognition depended on their internal detail (Experiment 2). Indeed, the presence of local segmentation cues disrupted global identification (Experiment 3). Identification was aided, though, by the presence of surface colour and texture (Experiment 4). We suggest that the patients could derive global representations of objects that served to recognise animate items. In contrast, they were impaired at coding parts-based representations for the identification of inanimate objects.     

Action naming with impaired semantics: Neuropsychological evidencecontrasting naming and reading for objects and verbs

We contrast naming from pictures, and reading words, for objects and verbs (actions relating to the objects) in a patient with a large, posterior left-hemisphere lesion. We present evidence for spared picture naming for verbs relative to objects, whilst the opposite pattern of sparing occurred in reading. Objects were also spared relative to verbs in tasks requiring that written words be matched to either pictures or auditory words, in the presence of semantically related or unrelated distractors. We conclude that verb semantics were more impaired than semantic knowledge for objects, and that the better semantic knowledge for object names supported word reading. With pictures, however, action verb retrieval was maintained through a nonsemantic route from vision to action, or though preserved right-hemisphere “action semantics.”     

Life Change Events,Ballistocardiography and Coronary Death

Abstract

Thirty-six men and women who experienced a documented myocardial infarction, half of whom ultimately died from their disease and half of whom survived over a six-year period, provided longitudinal recent life changes and ballistocardiographic data. The 18 patients who died from their coronary disease indicated a significant buildup in life changes which peaked approximately one year prior to death; their serial ballistocardiograms indicated a significant buildup in average force of contraction which was seen to peak approximately six months prior to death. The 18 post-infarction patients who survived the six-year follow-up showed neither a buildup in life change nor a buildup in the ballistocardiographic index of cardiac contraction force. These findings of a life change peak preceding ballistocardiographic evidence of an “overworked” heart are discussed in terms of their possible medical and psychophysiological significances.     

Mitochondrial Abnormality Associates with Type-Specific Neuronal Loss and Cell Morphology Changes in the Pedunculopontine Nucleus in Parkinson Disease

Cholinergic neuronal loss in the pedunculopontine nucleus (PPN) associates with abnormal functions, including certain motor and nonmotor symptoms. This realization has led to low-frequency stimulation of the PPN for treating patients with Parkinson disease (PD) who are refractory to other treatment modalities. However, the molecular mechanisms underlying PPN neuronal loss and the therapeutic substrate for the clinical benefits following PPN stimulation remain poorly characterized, hampering progress toward designing more efficient therapies aimed at restoring the PPN''s normal functions during progressive parkinsonism. Here, we investigated postmortem pathological changes in the PPN of PD cases. Our study detected a loss of neurons producing gamma-aminobutyric acid (GABA) as their output and glycinergic neurons, along with the pronounced loss of cholinergic neurons. These losses were accompanied by altered somatic cell size that affected the remaining neurons of all neuronal subtypes studied here. Because studies showed that mitochondrial dysfunction exists in sporadic PD and in PD animal models, we investigated whether altered mitochondrial composition exists in the PPN. A significant up-regulation of several mitochondrial proteins was seen in GABAergic and glycinergic neurons; however, cholinergic neurons indicated down-regulation of the same proteins. Our findings suggest an imbalance in the activity of key neuronal subgroups of the PPN in PD, potentially because of abnormal inhibitory activity and altered cholinergic outflow.CME Accreditation Statement: This activity (“ASIP 2013 AJP CME Program in Pathogenesis”) has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Society for Clinical Pathology (ASCP) and the American Society for Investigative Pathology (ASIP). ASCP is accredited by the ACCME to provide continuing medical education for physicians.The ASCP designates this journal-based CME activity (“ASIP 2013 AJP CME Program in Pathogenesis”) for a maximum of 48 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.CME Disclosures: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose.Patients with Parkinson disease (PD) present with a multitude of motor-related disabilities, including progressive resting tremor, rigidity, bradykinesia/akinesia, gait disturbances, and postural instability. In addition, it is recognized increasingly that various nonmotor functions are also left impaired, including mood, cognition, sleep, autonomic nervous system functions, and sensory functions.¹ A neuropathological signature of PD is the progressive deterioration of dopamine-producing neurons in the substantia nigra pars compacta (SNpc).² Although the precise cellular and molecular mechanisms underlying this neuronal death remain unknown, several reports implicate an underlying mitochondrial dysfunction, relating to energy deficits, enhanced production of free-radical species with concomitant oxidative stress,³ proteasomal deregulation,⁴ and neuronal excitotoxicity.⁵Evidence for a mitochondrial-related cause in PD stems from studies reporting on the use of human postmortem brains of patients with PD, which found a deficiency of complex I of the mitochondrial respiratory chain in the SNpc.⁶ Furthermore, outside the central nervous system a mitochondrial respiratory chain complex I deficiency has also been detected in the blood platelets of patients with PD, with some patients who also displayed defects of mitochondrial respiratory chain complexes II and III.⁷ In this regard, Gu et al⁸ found that a mitochondrial DNA (mtDNA) abnormality may underlie this mitochondrial defect in at least a proportion of patients with PD. By contrast, data reporting on mitochondrial respiratory chain defects in skeletal muscle cells of patients with PD remain somewhat more controversial. In this regard, Penn et al⁹ performed 31P magnetic resonance spectroscopy on the resting muscles of patients with PD, to report detecting defects in oxidative phosphorylation in the patients'' musculature, compared with healthy control cases. However, a study by Taylor et al¹⁰ was unable to validate this result. It has been proposed that the conflicting results that report on skeletal mitochondrial defects in patients with PD may relate to either methodological variation for assessing this biochemical defect or may be a reflection of the heterogeneity of the disease.¹¹Further evidence for an association between PD and a mitochondrial defect was obtained from the use of experimental neurotoxins such as rotenone and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Use of such toxins mimic parkinsonism in animals to a remarkably accurate extent, with studies showing that the pathological substrate for this defect may be due to the ability of such toxins to inhibit complex I of the mitochondrial respiratory chain.^12,13 Finally, disordered mitochondrial function, including defects in oxidative phosphorylation, are also seen in rare, young-onset genetic forms of PD, such as in patients who harbor mutations in genes such as Parkinson protein 2, E3 ubiquitin protein ligase [parkin (official symbol, PARK2)], parkinson protein 7 [DJ-1, (official symbol, PARK7)], and PTEN (phosphatase and tensin homologue) induced putative kinase 1 (PINK1), where loss of function of the respective protein products associate with deregulation of the mitochondrial quality control pathways of the cells.¹⁴Although the principal motor features of PD stem from reduced dopaminergic innervation of the striatum because of a substantial loss of SNpc dopaminergic neurons, recognition is growing that PD symptoms could result from disruption to multiple neural regions and systems.¹⁵ Although the loss of neurons is most conspicuous in the SNpc, neuronal loss and the presence of intracytoplasmic Lewy bodies (LBs) and Lewy neurites (LNs), composed of aggregation-prone proteins such as α-synuclein (αSYN) form an additional neuropathological hallmark of PD¹⁶ and have been observed in brain regions as diverse as the dorsal motor nucleus of vagus of the medulla, the locus ceruleus in the pons, the raphe nucleus, the basal forebrain, and allocortical regions such as the hippocampus and amygdala.¹⁷ Such widespread distribution of PD pathology could correlate with the variety of motor and nonmotor symptoms observed in patients with PD.¹⁸ PD-related pathologies that affect regions other than the dopaminergic-rich SNpc suggest that, although treatments that target only the nigrostriatal dopaminergic system could substantially benefit patients with PD, they are unlikely to completely resolve the PD-related deficit.¹⁹One particular brain region, the pedunculopontine nucleus (PPN), located within the lateral tegmental region and spanning the pontine midbrain isthmus, has been deemed critically important for regulating some of the physiological functions that fail during progressive PD. Such functions include regulating the activity of the reticular activating system for controlling rapid eye movement (REM) sleep.²⁰ Interestingly, patients with PD frequently present with abnormal REM muscle tone and concomitant REM sleep behavior disorder (RBD),²¹ which may be due to a loss of PPN cells and their concomitant functions during progressive PD. Moreover, PPN axons project toward and receive input from a variety of brain regions, including the thalamus, SN (both the compacta and reticular part), cortical regions, and spinal cord, all of which are involved in regulating aspects of voluntary motor function.^22–30 The PPN was assigned a role in the onset and progression of PD because of reports that the nucleus undergoes degenerative changes, principally affecting the resident cholinergic neurons.^31,32 The loss of these cells is believed to provide the cellular basis for the gait and postural deficits that patients with PD experience³³ and nonhuman primates rendered parkinsonian via cytotoxic lesions.^34,35 In addition, LBs and LNs are seen within the remaining PPN neurons in the postmortem brains of patients with PD.³⁶ Such findings provided the rationale for the commencement of therapeutic trials of deep brain stimulation of the PPN, with trial results reporting a reduction in gait and postural dysfunction in patients with PD after receiving PPN deep brain stimulation.^37,38Here, we used serially cut sections taken from the postmortem PPN of patients with PD and compared this with elderly, healthy control persons, who died without known neurological or psychiatric deficit. After confirming a decreased number of cholinergic neurons in PD-affected PPNs, as previously reported,^31,32 we studied whether the remaining cholinergic neurons undergo somatic cell size alterations. Because it is unknown whether other, noncholinergic neurons are also lost in the PPN of patients with PD, we next determined whether glycinergic and GABAergic neurons in the PPN also degenerate as a result of PD, and whether the remaining neurons undergo structural alterations. In an attempt to explain the altered cell numbers and cellular structural changes seen in the PPN of the present study''s cohort of patients with PD compared with controls, and consistent with the wide amount of literature that suggests an association between PD and mitochondrial dysfunction, we determined whether the loss of different neuronal subpopulations in the PPN is linked to mitochondrial abnormalities.     

How doctors move from generic goals to specific communicative behavior in real practice consultations

Objective

To understand how recommendations for communication can be brought into alignment with clinical communication routines, we explored how doctors select communicative actions during consultations.

Methods

We conducted stimulated recall interviews with 15 GPs (general practitioners), asking them to comment on recordings of two consultations. The data analysis was based on the principles of grounded theory.

Results

A model describing how doctors select communicative actions during consultations was developed. This model illustrates how GPs constantly adapt their selection of communicative actions to their evaluation of the situation. These evaluations culminate in the selection of situation-specific goals. These multiple and often dynamic goals require constant revision and adaptation of communication strategies, leading to constant readjustments of the selection of communicative actions. When selecting consultation goals GPs weigh patients’ needs and preferences as well as the medical situation and its consequences.

Conclusions

GPs’ selection of communicative actions during consultations is situational and goal driven.

Practice implications

To help doctors develop communicative competence tailored to the specific situation of each consultation, holistic communication training courses, which pay attention to the selection of consultation goals and matching communication strategies besides training specific communication skills, seem preferable to current generic communication skills training.     

Option Grids: Shared decision making made easier

Objective

To describe the exploratory use of short decision support tools for patients, called Option Grids. Option Grids are summary tables, using one side of paper to enable rapid comparisons of options, using questions that patients frequently ask (FAQs) and designed for face-to-face clinical encounters. To date, most evidence about ‘patient decision aids’ has been based on tools with high content levels, designed for patients to use independently, either before or after visits.

Methods

We studied the use of Option Grids in a quality improvement project, collecting field notes and conducting interviews with clinical teams.

Results

In the ‘Making Good Decisions in Collaboration’ (MAGIC) program, clinicians found that using Option Grids made it easier to explain the existence of options and reported a ‘handover’ effect, where patient involvement in decision making was enhanced.

Conclusion

Option Grids made options more visible and clinicians found it easier to undertake shared decision making when these tools were available. Used in a collaborative way, they enhance patients’ confidence and voice, increasing their involvement in collaborative dialogs.

Practice implications

Further work to confirm these preliminary findings is required, to measure processes and to assess whether these tools have similar impact in other clinical settings.