Emotion dysregulation, impulsivity and anger rumination in borderline personality disorder: the role of amygdala and insula.

Borderline Personality Disorder (BPD) is a severe mental disorder, characterized by deficits in emotion regulation, interpersonal dysfunctions, dissociation and impulsivity. Brain abnormalities have been generally explored; however, the specific contribution of different limbic structures to BPD symptomatology is not described. The aim of this study is to cover this gap, exploring functional and structural alterations of amygdala and insula and to highlight their contribution to neuropsychiatric symptoms. Twenty-eight BPD patients (23.7 ± 3.42 years; 6 M/22F) and twenty-eight matched healthy controls underwent a brain MR protocol (1.5 T, including a 3D T1-weighted sequence and resting-state fMRI) and a complete neuropsychiatric assessment. Volumetry, cortical thickness and functional connectivity of amygdala and insula were evaluated, along with correlations with the neuropsychiatric scales. BPD patients showed a lower cortical thickness of the left insula (p = 0.027) that negatively correlated with the Anger Rumination Scale (p = 0.019; r = - 0.450). A focused analysis on female patients showed a significant reduction of right amygdala volumes in BPD (p = 0.037), that correlate with Difficulties in Emotion Regulation Scale (p = 0.031; r = - 0.415), Beck Depression Inventory (p = 0.009; r = - 0.50) and Ruminative Response Scale (p = 0.045; r = - 0.389). Reduced functional connectivity was found in BPD between amygdala and frontal pole, precuneus and temporal pole. This functional connectivity alterations correlated with Anger Rumination Scale (p = .009; r = - 0.491) and Barratt Impulsiveness Scale (p = 0.020; r = - 0.447). Amygdala and insula are altered in BPD patients, and these two limbic structures are implicated in specific neuropsychiatric symptoms, such as difficulty in emotion regulation, depression, anger and depressive rumination.

Correction to: Does this lung nodule need urgent review? A discrete choice experiment of Australian general practitioners.

Following publication of the original article [1], the authors flagged that the article had gone to publishing with errors in Tables 1-3.

Does this lung nodule need urgent review? A discrete choice experiment of Australian general practitioners.

BACKGROUND: Lung cancer is the leading cause of cancer mortality in Australia. Guidelines suggest that patients with suspected lung cancer on thoracic imaging be referred for urgent specialist review. However, the term "suspected" is broad and includes the common finding of lung nodules, which often require periodic surveillance rather than urgent invasive investigation. The British Thoracic Society recommends that a lung nodule with a PanCan risk > 10% be considered for invasive investigation. This study aimed to assess which factors influence general practitioners (GPs) to request urgent review for a lung nodule and if these factors concur with PanCan risk prediction model variables. METHODS: A discrete choice experiment was developed that produced 32 individual case vignettes. Each vignette contained eight variables, four of which form the parsimonious PanCan risk prediction model. Two additional vignettes were created that addressed haemoptysis with a normal chest computed tomography (CT) scan and isolated mediastinal lymphadenopathy. The survey was distributed to 4160 randomly selected Australian GPs and they were asked if the patients in the vignettes required urgent (less than two weeks) specialist review. Multivariate logistic regression identified factors associated with request for urgent review. RESULTS: Completed surveys were received from 3.7% of participants, providing 152 surveys (1216 case vignettes) for analysis. The factors associated with request for urgent review were nodule spiculation (adj-OR 5.57, 95% CI 3.88-7.99, p < 0.0001), larger nodule size, presentation with haemoptysis (adj-OR 4.79, 95% CI 3.05-7.52, p < 0.0001) or weight loss (adj-OR 4.87, 95% CI 3.13-7.59, p < 0.0001), recommendation for urgent review by the reporting radiologist (adj-OR 4.68, 95% CI 2.86-7.65, p < 0.0001) and female GP gender (adj-OR 1.87, 95% CI 1.36-2.56, p 0.0001). In low risk lung nodules (PanCan risk < 10%), there was significant variability in perceived sense of urgency. Most GPs (83%) felt that a patient with haemoptysis and a normal chest CT scan did not require urgent specialist review but that a patient with isolated mediastinal lymphadenopathy did (75%). CONCLUSION: Future lung cancer investigation pathways may benefit from the addition of a risk prediction model to reduce variations in referral behavior for low risk lung nodules.

Prognostic value of brain proton MR spectroscopy and diffusion tensor imaging in newborns with hypoxic-ischemic encephalopathy treated by brain cooling.

INTRODUCTION: MRI, proton magnetic resonance spectroscopy (¹H-MRS), and diffusion tensor imaging (DTI) have been shown to be of great prognostic value in term newborns with moderate-severe hypoxic-ischemic encephalopathy (HIE). Currently, no data are available on ¹H-MRS and DTI performed in the subacute phase after hypothermic treatment. The aim of the present study was to assess their prognostic value in newborns affected by moderate-severe HIE and treated with selective brain cooling (BC). METHODS: Twenty infants treated with BC underwent conventional MRI and (1)H-MRS at a mean (SD) age of 8.3 (2.8) days; 15 also underwent DTI. Peak area ratios of metabolites and DTI variables, namely mean diffusivity (MD), axial and radial diffusivity, and fractional anisotropy (FA), were calculated. Clinical outcome was monitored until 2 years of age. RESULTS: Adverse outcome was observed in 6/20 newborns. Both ¹H-MRS and DTI variables showed higher prognostic accuracy than conventional MRI. N-acetylaspartate/creatine at a basal ganglia localisation showed 100% PPV and 93% NPV for outcome. MD showed significantly decreased values in many regions of white and gray matter, axial diffusivity showed the best predictive value (PPV and NPV) in the genu of corpus callosum (100 and 91%, respectively), and radial diffusivity was significantly decreased in fronto white matter (FWM) and fronto parietal (FP) WM. The decrement of FA showed the best AUC (0.94) in the FPWM. CONCLUSION: Selective BC in HIE neonates does not affect the early and accurate prognostic value of ¹H-MRS and DTI, which outperform conventional MRI.

The role of pH on the thermodynamics and kinetics of muscle biochemistry: an in vivo study by (31)P-MRS in patients with myo-phosphorylase deficiency.

In this study we assessed ΔG'(ATP) hydrolysis, cytosolic [ADP], and the rate of phosphocreatine recovery using Phosphorus Magnetic Resonance Spectroscopy in the calf muscle of a group of patients affected by glycogen myo-phosphorylase deficiency (McArdle disease). The goal was to ascertain whether and to what extent the deficit of the glycogenolytic pathway would affect the muscle energy balance. A typical feature of this pathology is the lack of intracellular acidosis. Therefore we posed the question of whether, in the absence of pH decrease, the rate of phosphocreatine recovery depends on the amount of phosphocreatine consumed during exercise. Results showed that at the end of exercise both [ADP] and ΔG'(ATP) of patients were significantly higher than those of matched control groups reaching comparable levels of phosphocreatine concentration. Furthermore, in these patients we found that the rate of phosphocreatine recovery is not influenced by the amount of phosphocreatine consumed during exercise. These outcomes provide experimental evidence that: i) the intracellular acidification occurring in exercising skeletal muscle is a protective factor for the energy consumption; and ii) the influence of pH on the phosphocreatine recovery rate is at least in part related to the kinetic mechanisms of mitochondrial creatine kinase enzyme.

Combined brain voxel-based morphometry and diffusion tensor imaging study in idiopathic restless legs syndrome patients.

BACKGROUND AND PURPOSE: The aim of this study was to evaluate the presence of abnormalities in the brain of patients with restless legs syndrome (RLS) using voxel-based morphometry and diffusion tensor imaging (DTI). METHODS: Twenty patients and twenty controls were studied. Voxel-based morphometry analysis was performed using statistical parametric mapping (SPM8) and FSL-VBM software tools. For voxel-wise analysis of DTI, tract-based spatial statistics (TBSS) and SPM8 were used. RESULTS: Applying an appropriate threshold of probability, no significant results were found either in comparison or in correlation analyses. CONCLUSIONS: Our data argue against clear structural or microstructural abnormalities in the brain of patients with idiopathic RLS, suggesting a prevalent role of functional or metabolic impairment.

Pitfalls and advantages of different strategies for the absolute quantification of N-acetyl aspartate, creatine and choline in white and grey matter by 1H-MRS.

This study extensively investigates different strategies for the absolute quantitation of N-acetyl aspartate, creatine and choline in white and grey matter by (1)H-MRS at 1.5 T. The main focus of this study was to reliably estimate metabolite concentrations while reducing the scan time, which remains as one of the main problems in clinical MRS. Absolute quantitation was based on the water-unsuppressed concentration as the internal standard. We compared strategies based on various experimental protocols and post-processing strategies. Data were obtained from 30 control subjects using a PRESS sequence at several TE to estimate the transverse relaxation time, T(2), of the metabolites. Quantitation was performed with the algorithm QUEST using two different metabolite signal basis sets: a whole-metabolite basis set (WhoM) and a basis set in which the singlet signals were split from the coupled signals (MSM). The basis sets were simulated in vivo for each TE used. Metabolites' T(2)s were then determined by fitting the estimated signal amplitudes of the metabolites obtained at different TEs. Then the absolute concentrations (mM) of the metabolites were assessed for each subject using the estimated signal amplitudes and either the mean estimated relaxation times of all subjects (mean protocol, MP) or the T(2) estimated from the spectra derived from the same subject (individual protocol, IP). Results showed that MP represents a less time-consuming alternative to IP in the quantitation of brain metabolites by (1)H-MRS in both grey and white matter, with a comparable accuracy when performed by MSM. It was also shown that the acquisition time might be further reduced by using a variant of MP, although with reduced accuracy. In this variant, only one water-suppressed and one water-unsuppressed spectra were acquired, drastically reducing the duration of the entire MRS examination. However, statistical analysis highlights the reduced accuracy of MP when performed using WhoM, particularly at longer echo times.

Cerebral Mitochondrial Microangiopathy Leads to Leukoencephalopathy in Mitochondrial Neurogastrointestinal Encephalopathy.

BACKGROUND AND PURPOSE: Mitochondrial neurogastrointestinal encephalopathy is a rare disorder due to recessive mutations in the thymidine phosphorylase gene, encoding thymidine phosphorylase protein required for mitochondrial DNA replication. Clinical manifestations include gastrointestinal dysmotility and diffuse asymptomatic leukoencephalopathy. This study aimed to elucidate the mechanisms underlying brain leukoencephalopathy in patients with mitochondrial neurogastrointestinal encephalopathy by correlating multimodal neuroradiologic features to postmortem pathology. MATERIALS AND METHODS: Seven patients underwent brain MR imaging, including single-voxel proton MR spectroscopy and diffusion imaging. Absolute concentrations of metabolites calculated by acquiring unsuppressed water spectra at multiple TEs, along with diffusion metrics based on the tensor model, were compared with those of healthy controls using unpaired t tests in multiple white matters regions. Brain postmortem histologic, immunohistochemical, and molecular analyses were performed in 1 patient. RESULTS: All patients showed bilateral and nearly symmetric cerebral white matter hyperintensities on T2-weighted images, extending to the cerebellar white matter and brain stem in 4. White matter, N-acetylaspartate, creatine, and choline concentrations were significantly reduced compared with those in controls, with a prominent increase in the radial water diffusivity component. At postmortem examination, severe fibrosis of brain vessel smooth muscle was evident, along with mitochondrial DNA replication depletion in brain and vascular smooth-muscle and endothelial cells, without neuronal loss, myelin damage, or gliosis. Prominent periependymal cytochrome C oxidase deficiency was also observed. CONCLUSIONS: Vascular functional and histologic alterations account for leukoencephalopathy in mitochondrial neurogastrointestinal encephalopathy. Thymidine toxicity and mitochondrial DNA replication depletion may induce microangiopathy and blood-brain-barrier dysfunction, leading to increased water content in the white matter. Periependymal cytochrome C oxidase deficiency could explain prominent periventricular impairment.

Diffusion Tensor Imaging Mapping of Brain White Matter Pathology in Mitochondrial Optic Neuropathies.

BACKGROUND AND PURPOSE: Brain white matter is frequently affected in mitochondrial diseases; optic atrophy gene 1-autosomal dominant optic atrophy and Leber hereditary optic neuropathy are the most frequent mitochondrial monosymptomatic optic neuropathies. In this observational study, brain white matter microstructure was characterized by DTI in patients with optic atrophy gene 1-autosomal dominant optic atrophy and Leber hereditary optic neuropathy, in relation to clinical and genetic features. MATERIALS AND METHODS: Nineteen patients with optic atrophy gene 1-autosomal dominant optic atrophy and 17 with Leber hereditary optic neuropathy older than 18 years of age, all genetically diagnosed, and 19 healthy volunteers underwent DTI by using a 1.5T MR imaging scanner and neurologic and ophthalmologic assessments. Brain white matter DTI metrics were calculated for all participants, and, in patients, their correlations with genetics and clinical findings were calculated. RESULTS: Compared with controls, patients with optic atrophy gene 1-autosomal dominant optic atrophy had an increased mean diffusivity in 29.2% of voxels analyzed within major white matter tracts distributed throughout the brain, while fractional anisotropy was reduced in 30.3% of voxels. For patients with Leber hereditary optic neuropathy, the proportion of altered voxels was only 0.5% and 5.5%, respectively, of which half was found within the optic radiation and 3.5%, in the smaller acoustic radiation. In almost all regions, fractional anisotropy diminished with age in patients with optic atrophy gene 1-autosomal dominant optic atrophy and correlated with average retinal nerve fiber layer thickness in several areas. Mean diffusivity increased in those with a missense mutation. Patients with Leber hereditary optic neuropathy taking idebenone had slightly milder changes. CONCLUSIONS: Patients with Leber hereditary optic neuropathy had preferential involvement of the optic and acoustic radiations, consistent with trans-synaptic degeneration, whereas patients with optic atrophy gene 1-autosomal dominant optic atrophy presented with widespread involvement suggestive of a multisystemic, possibly a congenital/developmental, disorder. White matter changes in Leber hereditary optic neuropathy and optic atrophy gene 1-autosomal dominant optic atrophy may be exploitable as biomarkers.

The VO(2)-on kinetics in constant load exercise sub-anaerobic threshold reflects endothelial function and dysfunction in muscle microcirculation.

To propose a test to evaluate endothelial function, based on VO(2) on-transition kinetics in sub-anaerobic threshold (AT) constant load exercise, we tested healthy subjects and patients with ischemic-hypertensive cardiopathy by two cardiopulmonary tests on a cycle ergometer endowed with an electric motor to overcome initial inertia: a pre-test and, after at least 24 h, one 6 min constant load exercise at 90 % AT. We measured net phase 3 VO(2)-on kinetics and, by phase 2 time constant (tau), valued endothelial dysfunction. We found shorter tau in repeated tests, shorter time between first and second test, by persisting endothelium-dependent arteriolar vasodilatation and/or several other mechanisms. Reducing load to 80 % and 90 % AT did not produce significant changes in tau of healthy volunteers, while in heart patients an AT load of 70 %, compared to 80 % AT, shortened tau (delta=4.38+/-1.65 s, p=0.013). In heart patients, no correlation was found between NYHA class, ejection fraction (EF), and the two variables derived from incremental cycle cardio-pulmonary exercise, as well as between EF and tau; while NYHA class groups were well correlated with tau duration (r=0.92, p=0.0001). Doxazosin and tadalafil also significantly reduced tau. In conclusion, the O(2) consumption kinetics during the on-transition of constant load exercise below the anaerobic threshold are highly sensitive to endothelial function in muscular microcirculation, and constitute a marker for the evaluation of endothelial dysfunction.

No correlation between muscle A3243G mutation load and mitochondrial function in vivo.

The authors studied the relationship between the percentage level of A3243G mitochondrial DNA mutation and the degree of mitochondrial dysfunction in vivo in nine individuals from four pedigrees using phosphorus MRS in muscle. There was no significant correlation between mutation load and maximum rate of adenosine triphosphate production (V(max)). V(max) was normal in a subject with 32% A3243G in muscle, which is in contrast with a previous observation of markedly reduced V(max) in a patient with only 6% A3243G in muscle. Factors besides mutation load, such as nuclear genes, influence expression of the A3243G mutation in vivo.

Altered cellular metabolism following traumatic brain injury: a magnetic resonance spectroscopy study.

Experimental studies have reported early reductions in pH, phosphocreatine, and free intracellular magnesium following traumatic brain injury using phosphorus magnetic resonance spectroscopy. Paradoxically, in clinical studies there is some evidence for an increase in the pH in the subacute stage following traumatic brain injury. We therefore performed phosphorus magnetic resonance spectroscopy on seven patients in the subacute stage (mean 9 days postinjury) following traumatic brain injury to assess cellular metabolism. In areas of normal-appearing white matter, the pH was significantly alkaline (patients 7.09 +/- 0.04 [mean +/- SD], controls 7.01 +/- 0.04, p = 0.008), the phosphocreatine to inorganic phosphate ratio (PCr/Pi) was significantly increased (patients 4.03 +/- 1.18, controls 2.64 +/- 0.71, p = 0.03), the inorganic phosphate to adenosine triphosphate ratio (Pi/ATP) was significantly reduced (patients 0.37 +/- 0.10, controls 0.56 +/- 0.19, p = 0.04), and the PCr/ATP ratio was nonsignificantly increased (patients 1.53 +/- 0.29, controls 1.34 +/- 0.19, p = 0.14) in patients compared to controls. Furthermore, the calculated free intracellular magnesium was significantly increased in the patients compared to the controls (patients 0.33 +/- 0.09 mM, controls 0.22 +/- 0.09 mM, p = 0.03)). Proton spectra, acquired from similar regions showed a significant reduction in N-acetylaspartate (patients 9.64 +/- 2.49 units, controls 12.84 +/- 2.35 units, p = 0.03) and a significant increase in choline compounds (patients 7.96 +/- 1.02, controls 6.67 +/- 1.01 units, p = 0.03). No lactate was visible in any patient or control spectrum. The alterations in metabolism observed in these patients could not be explained by ongoing ischemia but might be secondary to a loss of normal cellular homeostasis or a relative alteration in the cellular population, in particular an increase in the glial cell density, in these regions.

Mitochondrial dysfunction in Friedreich's ataxia: from pathogenesis to treatment perspectives.

Friedreich's ataxia (FRDA), the most common inherited ataxia, is an autosomal recessive degenerative disorder caused by a GAA triplet expansion or point mutations in the FRDA gene on chromosome 9q13. The FRDA gene product, frataxin, is a widely expressed mitochondrial protein, which is severely reduced in FRDA patients. The demonstration that deficit of frataxin in FRDA is associated with mitochondrial iron accumulation, increased sensitivity to oxidative stress, deficit of respiratory chain complex activities and in vivo impairment of cardiac and skeletal muscle tissue energy metabolism, has established FRDA as a "new" nuclear encoded mitochondrial disease. Pilot studies have shown the potential effect of antioxidant therapy based on idebenone or coenzyme Q10 plus Vitamin E administration in this condition and provide a strong rationale for designing larger randomized clinical trials.

The limit dextrinases from ungerminated oats (Avena sativa L.) and ungerminated rice (Oryza sativa L.).

The limit dextrinases from ungerminated oats and rice have been purified, and their substrate specificity compared with a bacterial isoamylase preparation. Both cereal enzymes could hydrolyse (1 yields6)-alpha-D-glucosidic linkages in oligosaccharide alpha-dextrins, pullulan, amylopectin, and the beta-limit dextrins of amylopectin and glycogen. However, under comparable conditions, they were unable to attack glycogens.

Purification of malted-barley endo-beta-D-glucanases by ion-exchange chromatography: some properties of an endo-barley-beta-D-glucanase.

Two endo-beta-D-glucanases which act, respectively, on (1 leads to 3)-beta-D-glucans and barley beta-D-glucan have been isolated from malted barley, and purified by ion-exchange chromatography. The latter enzyme is highly specific for barley beta-D-glucan, and has no action on either (1 leads to 3)- or (1 leads to 4)-beta-D-glucans. It will also act on dyed barley-beta-D-glucan. Certain group-specific reagents inhibit the endo-barley-beta-D-glucanase and the endo-(1 leads to 3)-beta-D-glucanase to similar extents.

The limit dextrinase from malted sorghum (Sorghum vulgare).

A limit dextrinase, free from contaminating carbohydrases, has been purified from malted sorghum flour. The enzyme readily hydrolysed alpha-limit dextrins having maltosyl or maltotriosyl side-chains, pullulan, and amylopectin beta-limit dextrin. Glycogen beta-limit dextrin and amylopectin were more slowly hydrolysed, the detection of the hydrolysis of amylopectin being dependent on enzyme concentration. No significant debranching of glycogen could be detected.

Partial purification and properties of a bacterial isoamylase.

Isoamylase has been prepared by affinity chromatography of a commercial enzyme-preparation from a strain of Cytophaga (also known as a Flavobacterium or Polyangium). The enzyme was not very stable, but the stability could be improved by calcium ions. The enzyme had a very low but significant activity on pullulan and on alpha-dextrins having maltosyl side-chains. This observation, which is contrary to previous reports, has been related to the specificity of isoamylase and other bacterial debranching-enzymes.

Some properties of a fungal beta-D-glucanase preparation.

A commercial enzyme preparation, of fungal origin, contained a mixture of beta-D-glucanases which were fractionated by ion-exchange chromatography to give a mixture of an endo-(1 leads to 4)- and an exo-(1 leads to 3)-beta-D-glucanase. These two enzymes were then separated by molecular-sieve chromatography on Sephadex G-150. The purified exo-(1 leads to 3)-beta-D-glucanase has a relatively high specificity for (1 leads to 3)-beta-D-glucosidic linkages, and has no action on lichenin.

The iodine-staining properties and fine structure of some mammalian and invertebrate glycogens.

Glycogens from mammalian and invertebrate sources have been compared by measuring the iodine-staining spectra of the debranched polymers and the debranched beta-amylase limit dextrins. From the results, it is concluded that, whereas the interior chains of each group of glycogen are very similar, the exterior chains of the mammalian glycogens generally contain a small number of longer chains which are not found in the invertebrate glycogens.