Comparative studies of glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1: evidence for a eutherian mammalian origin for the GPIHBP1 gene from an LY6-like gene

Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) functions as a platform and transport agent for lipoprotein lipase (LPL) which functions in the hydrolysis of chylomicrons, principally in heart, skeletal muscle and adipose tissue capillary endothelial cells. Previous reports of genetic deficiency for this protein have described severe chylomicronemia. Comparative GPIHBP1 amino acid sequences and structures and GPIHBP1 gene locations were examined using data from several mammalian genome projects. Mammalian GPIHBP1 genes usually contain four coding exons on the positive strand. Mammalian GPIHBP1 sequences shared 41–96% identities as compared with 9–32% sequence identities with other LY6-domain-containing human proteins (LY6-like). The human N-glycosylation site was predominantly conserved among other mammalian GPIHBP1 proteins except cow, dog and pig. Sequence alignments, key amino acid residues and conserved predicted secondary structures were also examined, including the N-terminal signal peptide, the acidic amino acid sequence region which binds LPL, the glycosylphosphatidylinositol linkage group, the Ly6 domain and the C-terminal α-helix. Comparative and phylogenetic studies of mammalian GPIHBP1 suggested that it originated in eutherian mammals from a gene duplication event of an ancestral LY6-like gene and subsequent integration of exon 2, which may have been derived from BCL11A (B-cell CLL/lymphoma 11A gene) encoding an extended acidic amino acid sequence

Maintenance N-acetyl cysteine treatment for bipolar disorder : a double-blind randomised placebo controlled trial

Background N-acetyl cysteine (NAC) is a glutathione precursor that has been shown to have antidepressant efficacy in a placebo-controlled trial. The current study aimed to investigate the maintenance effects of NAC following eight weeks of open-label treatment for bipolar disorder.Method The efficacy of a double blind randomized placebo controlled trial of 2 g/day NAC as adjunct maintenance treatment for bipolar disorder was examined. Participants (n = 149) had a Montgomery Asberg Depression Rating Score of [greater than or equal to]12 at trial entry and, after eight weeks of open-label NAC treatment, were randomized to adjunctive NAC or placebo, in addition to treatment as usual. Participants (primarily outpatients) were recruited through public and private services and through newspaper advertisements. Time to intervention for a mood episode was the primary endpoint of the study, and changes in mood symptoms, functionality and quality of life measures were secondary outcomes.Results There was a substantial decrease in symptoms during the eight-week open-label NAC treatment phase. During the subsequent double-blind phase, there was minimal further change in outcome measures with scores remaining low. Consequently, from this low plateau, between-group differences did not emerge on recurrence, clinical functioning or quality of life measures.Conclusions There were no significant between-group differences in recurrence or symptomatic outcomes during the maintenance phase of the trial; however, these findings may be confounded by limitations. Trial Registration The trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12607000074493)

Disentangling manual muscle testing and Applied Kinesiology: critique and reinterpretation of a literature review

Cuthbert and Goodheart recently published a narrative review on the reliability and validity of manual muscle testing (MMT) in the Journal. The authors should be recognized for their effort to synthesize this vast body of literature. However, the review contains critical errors in the search methods, inclusion criteria, quality assessment, validity definitions, study interpretation, literature synthesis, generalizability of study findings, and conclusion formulation that merit a reconsideration of the authors' findings. Most importantly, a misunderstanding of the review could easily arise because the authors did not distinguish the general use of muscle strength testing from the specific applications that distinguish the Applied Kinesiology (AK) chiropractic technique. The article makes the fundamental error of implying that the reliability and validity of manual muscle testing lends some degree of credibility to the unique diagnostic procedures of AK. The purpose of this commentary is to provide a critical appraisal of the review, suggest conclusions consistent with the literature both reviewed and omitted, and extricate conclusions that can be made about AK in particular from those that can be made about MMT. When AK is disentangled from standard orthopedic muscle testing, the few studies evaluating unique AK procedures either refute or cannot support the validity of AK procedures as diagnostic tests. The evidence to date does not support the use of MMT for the diagnosis of organic disease or pre/subclinical conditions

SUDOSCAN: A Simple, Rapid, and Objective Method with Potential for Screening for Diabetic Peripheral Neuropathy.

Clinical methods of detecting diabetic peripheral neuropathy (DPN) are not objective and reproducible. We therefore evaluated if SUDOSCAN, a new method developed to provide a quick, non-invasive and quantitative assessment of sudomotor function can reliably screen for DPN. 70 subjects (45 with type 1 diabetes and 25 healthy volunteers [HV]) underwent detailed assessments including clinical, neurophysiological and 5 standard cardiovascular reflex tests (CARTs). Using the American Academy of Neurology criteria subjects were classified into DPN and No-DPN groups. Based on CARTs subjects were also divided into CAN, subclinical-CAN and no-CAN. Sudomotor function was assessed with measurement of hand and foot Electrochemical Skin Conductance (ESC) and calculation of the CAN risk score. Foot ESC (μS) was significantly lower in subjects with DPN [n = 24; 53.5(25.1)] compared to the No-DPN [77.0(7.9)] and HV [77.1(14.3)] groups (ANCOVA p<0.001). Sensitivity and specificity of foot ESC for classifying DPN were 87.5% and 76.2%, respectively. The area under the ROC curve (AUC) was 0.85. Subjects with CAN had significantly lower foot [55.0(28.2)] and hand [53.5(19.6)] ESC compared to No-CAN [foot ESC, 72.1(12.2); hand ESC 64.9(14.4)] and HV groups (ANCOVA p<0.001 and 0.001, respectively). ROC analysis of CAN risk score to correctly classify CAN revealed a sensitivity of 65.0% and specificity of 80.0%. AUC was 0.75. Both foot and hand ESC demonstrated strong correlation with individual parameters and composite scores of nerve conduction and CAN. SUDOSCAN, a non-invasive and quick test, could be used as an objective screening test for DPN in busy diabetic clinics, insuring adherence to current recommendation of annual assessments for all diabetic patients that remains unfulfilled

Quantitative Analysis of the Ellipsoid Zone Intensity in Phenotypic Variations of Intermediate Age-Related Macular Degeneration

Purpose: Reduction of the ellipsoid zone (EZ) intensity has been reported in eyes with age-related macular degeneration (AMD). This study determined whether overall EZ intensity, in retinal locations undisturbed by pathologic features, is associated with the presence of clinical features, which are known important phenotypic risk factors for disease progression, large drusen, reticular pseudodrusen (RPD), and pigmentary abnormalities. Methods: A horizontal B-scan through the foveola on spectral-domain optical coherence tomography (SD-OCT) was performed in both eyes of 75 participants with bilateral intermediate AMD and 10 age-similar control participants. Eyes with AMD were classified as per the presence of large drusen, RPD, and hyperpigmentary changes. The relative EZ intensity profile, up to an eccentricity of 3400 μm, was averaged over seven 1000-μm retinal segments. The association between relative EZ intensity profile over seven retinal segments and AMD pathologic features was analyzed. Results: The average relative EZ intensities were significantly reduced in eyes with intermediate AMD compared to normal eyes (P ≤ 0.025) and with increasing age (P ≤ 0.020). On multivariate analyses, only the presence of hyperpigmentary changes and increasing age were significantly associated with reduced overall relative intensities (P ≤ 0.024), but not the presence of large drusen or RPD (P ≥ 0.115). Conclusions: The presence of hyperpigmentary change in the macula in association with large drusen, not large drusen alone, nor large drusen with RPD, was significantly associated with a generalised reduction in EZ intensity. Quantitative assessment of the relative EZ intensity may serve as an effective biomarker of disease severity and progression

Assessing mechanisms of GPIHBP1 and lipoprotein lipase movement across endothelial cells.

Lipoprotein lipase (LPL) is secreted into the interstitial spaces by adipocytes and myocytes but then must be transported to the capillary lumen by GPIHBP1, a glycosylphosphatidylinositol-anchored protein of capillary endothelial cells. The mechanism by which GPIHBP1 and LPL move across endothelial cells remains unclear. We asked whether the transport of GPIHBP1 and LPL across endothelial cells was uni- or bidirectional. We also asked whether GPIHBP1 and LPL are transported across cells in vesicles and whether this transport process requires caveolin-1. The movement of GPIHBP1 and LPL across cultured endothelial cells was bidirectional. Also, GPIHBP1 moved bidirectionally across capillary endothelial cells in live mice. The transport of LPL across endothelial cells was inhibited by dynasore and genistein, consistent with a vesicular transport process. Also, transmission electron microscopy (EM) and dual-axis EM tomography revealed GPIHBP1 and LPL in invaginations of the plasma membrane and in vesicles. The movement of GPIHBP1 across capillary endothelial cells was efficient in the absence of caveolin-1, and there was no defect in the internalization of LPL by caveolin-1-deficient endothelial cells in culture. Our studies show that GPIHBP1 and LPL move bidirectionally across endothelial cells in vesicles and that transport is efficient even when caveolin-1 is absent