Three-dimensional characterisation of the globe position in the orbit

Graefe's Archive for Clinical and Experimental Ophthalmology - Current methods to analyse the globe position, including Hertel exophthalmometry and computed tomography (CT), are limited to the...     

Disturbed Interplay Between Mid- and High-Level Vision in ASD? Evidence from a Contour Identification Task with Everyday Objects

Atypical visual processing in children with autism spectrum disorder (ASD) does not seem to reside in an isolated processing component, such as global or local processing. We therefore developed a paradigm that requires the interaction between different processes—an identification task with Gaborized object outlines—and applied this to two age groups of 6-to-10 and 10-to-14 year old children with and without ASD. Event history analyses demonstrated an identification disadvantage in the ASD group, which remained quite stable during the temporal unfolding of the outline. The typically developing group particularly outperformed the ASD group when more complex contours were shown. Together, our results suggest that the interplay between local and global processes and between bottom-up and top-down processes is disturbed in ASD.     

Oral cladribine for B-cell chronic lymphocytic leukaemia: report of a phase II trial with a 3-d, 3-weekly schedule in untreated and pretreated patients, and a long-term follow-up of 126 previously untreated patients

A phase II study was undertaken to evaluate the efficacy and toxicity of a new schedule of cladribine administration (10 mg/m2 orally daily for 3 d every 3 weeks) in 107 patients with B-cell chronic lymphocytic leukaemia (CLL). To minimize toxicity, treatment withdrawal criteria were defined. The results of the 63 previously untreated patients were retrospectively compared with 63 from an earlier study using a 5-d monthly schedule. The compiled data were analysed for prognostic factors for survival. No significant difference regarding response were seen in the two cohorts of the 126 previously untreated patients. The complete response (CR), nodular partial response (nPR) and partial response (PR) rates were 15%, 21% and 41%. Quality of response had no impact on survival. The 3- and 5-year overall survival for previously untreated patients was 73% and 58%, respectively, with a median follow-up of 54 months. Pretreatment haemoglobin <11.0 g/dl and elevated beta-2-microglobulin had a negative influence on survival. Major infections occurred in 21% of patients in the 3-d study compared with 35% in the 5-d study. The overall response (OR) and CR rates in the 40 previously treated patients were 34% and 5% respectively. Median overall survival was 24 months and median progression-free survival for responding patients was 14 months. Cladribine used as a single agent is an effective treatment with an acceptable safety profile for pretreated and untreated B-CLL. The achievement of complete remission was not a prerequisite for long-term survival.     

Characterization of an orphan G protein-coupled receptor localized in the dorsal root ganglia reveals adenine as a signaling molecule

The cloning of novel G protein-coupled receptors and the search for their natural ligands, a process called reverse pharmacology, is an excellent opportunity to discover novel hormones and neurotransmitters. Based on a degenerate primer approach we have cloned a G protein-coupled receptor whose mRNA expression profile indicates highest expression in the dorsal root ganglia, specifically in the subset of small neurons, suggesting a role in nociception. In addition, moderate expression was found in lung, hypothalamus, peripheral blood leukocytes, and ovaries. Guided by a receptor-activation bioassay, we identified adenine as the endogenous ligand, which activated the receptor potently and with high structural stringency. Therefore, we propose to name this receptor as the adenine receptor. Hormonal functions have already been demonstrated for adenine derivatives like 6-benzylaminopurine in plants and 1-methyladenine in lower animals. Here, we demonstrate that adenine functions as a signaling molecule in mammals. This finding adds a third family besides P1 and P2 receptors to the class of purinergic receptors.     

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.     

Inverse relationship between plasminogen activator inhibitor-I activity and adiponectin in overweight and obese women. Interrelationship with visceral adipose tissue, insulin resistance, HDL-chol and inflammation

Adipose tissue is an active endocrine organ secreting different adipokines such as plasminogen activator inhibitor-1 (PAI-1) and adiponectin, among many others. In this study, we investigated the association between PAI-1 activity and serum adiponectin levels in a group of 444 overweight and obese women and assessed the interrelationship with visceral adipose tissue (VAT; CT-scan L4-L5), insulin resistance (HOMA-IR), HDL cholesterol (HDL-chol) and inflammation (hs-CRP). PAI-1 was inversely related to adiponectin (r = -0.25, p < 0.001; adjusted for age and BMI). After adjustment for age, VAT, HOMA-IR and hs-CRP, the relationship remained significant (r = -0.15; p = 0.001), but disappeared after additional adjustment for HDL-chol (r = -0.09; p = 0.067). Subjects were divided in two groups according to the median levels of adiponectin or PAI-1 levels. PAI-1 activity (19.1 +/- 11.4 vs. 15.8 +/- 8.6 AU/ml; p = 0.003) and adiponectin levels (9.8 +/- 4.6 vs. 8.4 +/- 4.0 microg/ml; p < 0.001) were significantly higher in the low adiponectin/PAI-1 groups. The difference in PAI-1 remained significant after adjustment for age and BMI (p = 0.001), became borderline significant after adjustment for age and VAT (p = 0.052), and disappeared after adjustment for age and HOMA-IR (p = 0.116) or age and HDL-chol (p = 0.443). The difference in adiponectin levels remained significant after adjustment for age, VAT, HOMA-IR and hs-CRP (p = 0.006), but disappeared after additional adjustment for HDL-chol (p = 0.089). Further analyses suggest a contribution of HOMA-IR and/or HDL-chol in the relationship between PAI-1 and adiponectin. HDL-chol was found to be the only factor independently determining both factors. In conclusion, in overweight and obese women, PAI-1 activity was inversely related to serum adiponectin, independent of visceral adipose tissue.