Vogt–Koyanagi–Harada syndrome

Objectives

The objectives of this study are to review our current knowledge of the aetiopathogenesis of Vogt–Koyanagi–Harada syndrome, including viral infection, genetic factors and immunomediated mechanisms, and to discuss pathogenesis and its relevance to pharmacotherapy.

Systematic review methodology

Relevant publications from 1965 to 2012 on the aetiopathogenesis and pharmacotherapy of VKHS were analysed.

Results and conclusion

Vogt–Koyanagi–Harada syndrome (VKHS) is a rare multisystemic autoimmune disease that affects tissues containing melanin, including the eye, inner ear, meninges, and skin. The disease is characterised by bilateral uveitis associated with a varying constellation of auditory, neurological and cutaneous manifestations.The disease occurs more frequently among people with darker skin pigmentation. Asians, Native Americans, and Hispanics are most frequently affected. It predominates in patients aged between 20 and 50 years, and females are affected more frequently, with a female:male ratio of 2:1.The classic clinical course is characterised by bilateral panuveitis, hypoacusis, and meningitis, in addition to cutaneous involvement with poliosis, vitiligo, and alopecia.Although the exact cause of VKH disease remains unknown, it is thought to be a T-cell-mediated autoimmune process directed against melanocytes.VKHS classically begins with vague systemic symptoms suggestive of a viral infection, although a clear association between a specific viral agent and the disease has not been established.Genetic factors may play an important role in the loss of self-tolerance in VKHS. The HLA-DRB1*0405 allele is the main susceptibility allele for VKHS.Early and aggressive systemic corticosteroids are still the primary initial therapy for VKHS. Ocular complications may require an intravitreous injection of corticosteroids. Despite proper treatment with steroids, a number of patients experience recurrent attacks or steroid-associated complications. Thus, non steroid immunomodulatory therapy (IMT) has become necessary for the treatment of VKHS.     

Density–property relationships in collagen–glycosaminoglycan scaffolds

Collagen–glycosaminoglycan scaffolds for the regeneration of skin have previously been fabricated by freeze-drying a slurry containing a co-precipitate of collagen and glycosaminoglycan. The mechanical properties of the scaffold are low (e.g. the dry compressive Young’s modulus is roughly 30 kPa and the dry compressive strength is roughly 5 kPa). There is interest in using these scaffolds for tendon and ligament regeneration where there is a need for improved mechanical properties. Previous attempts to increase the mechanical properties of the scaffold by increasing the solid volume fraction of the scaffolds were limited by the increasing viscosity of the slurry, making it more difficult to mix and giving inhomogeneous scaffolds. Our recent work on mineralized collagen–glycosaminoglycan scaffolds used a vacuum filtration technique to increase the volume fraction of solids in the slurry, thereby increasing the density and mechanical properties of the scaffolds. In this work, we used this technique to fabricate collagen–glycosaminoglycan scaffolds with dry densities between 0.0076 and 0.0311 g cm^?3 and pore sizes between 250 and 350 μm, values appropriate for soft tissue growth. The compressive Young’s modulus and strength in the dry state increased from 32 to 127 kPa and from 5 to 19 kPa, respectively, with increasing density. The tensile Young’s modulus in the dry state increased from 295 to 3.1 MPa with increasing density. Finally, we showed that the attachment of cells onto the scaffold was directly proportional to the specific surface area of the scaffold, which defines the total internal surface area per volume of scaffold.     

Infant–mother and infant–sibling attachment in Zambia

This study, the first in Zambia using the Strange Situation Procedure (SSP) to observe attachment relationships and the “very first” observational study of infant–sibling attachment, examined patterns of infant–mother and infant–sibling attachment, and tested their association. We included siblings who were substantially involved in caregiving activities with their younger siblings. We hypothesized that infants would develop attachment relationships to both mothers and siblings; the majority of infants would be classified as securely attached to both caregivers, and infant–mother and infant–sibling attachment would be unrelated. The sample included 88 low-income families in Lusaka, Zambia (average of 3.5 children; SD = 1.5). The SSP distributions (infant–mother) were 59% secure, 24% avoidant and 17% resistant, and 46% secure, 20% avoidant, 5% resistant and 29% disorganized for three- and four-way classifications, respectively. The infant–sibling classifications were 42% secure, 23% avoidant and 35% resistant, and 35% secure, 23% avoidant, 9% resistant and 33% disorganized for three- and four-way classifications, respectively. Infant–mother and infant–sibling attachment relationships were not associated.     

Effect of countermovement on power–force–velocity profile

Purpose

To study the effect of a countermovement on the lower limb force–velocity (F–v) mechanical profile and to experimentally test the influence of F–v mechanical profile on countermovement jump (CMJ) performance, independently from the effect of maximal power output (P _max).

Methods

Fifty-four high-level sprinters and jumpers performed vertical maximal CMJ and squat jump (SJ) against five to eight additional loads ranging from 17 to 87 kg. Vertical ground reaction force data were recorded (1,000 Hz) and used to compute center of mass vertical displacement. For each condition, mean force, velocity, and power output were determined over the entire push-off phase of the best trial, and used to determine individual linear F–v relationships and P _max. From a previously validated biomechanical model, the optimal F–v profile maximizing jumping performance was determined for each subject and used to compute the individual mechanical F–v imbalance (Fv _IMB) as the difference between actual and optimal F–v profiles.

Results

A multiple regression analysis clearly showed (r ² = 0.952, P < 0.001, SEE 0.011 m) that P _max, Fv _IMB and lower limb extension range (h _PO) explained a significant part of the interindividual differences in CMJ performance (P < 0.001) with positive regression coefficients for P _max and h _PO and a negative one for Fv _IMB.

Conclusion

Compared to SJ, F–v relationships were shifted to the right in CMJ, with higher P _max, maximal theoretical force and velocity (+35.8, 20.6 and 13.3 %, respectively). As in SJ, CMJ performance depends on Fv _IMB, independently from the effect of P _max, with the existence of an individual optimal F–v profile (Fv _IMB having an even larger influence in CMJ).     

Methamphetamine-associated dysregulation of the hypothalamic–pituitary–thyroid axis

Methamphetamine and HIV impair thyroid function, but few studies have investigated their combined effects on thyroid dysregulation. This study examined the associations of methamphetamine use alone and in combination with HIV on thyroid function among men in South Florida. Measures of thyroid function in methamphetamine-using, HIV-infected (METH+HIV+; n?=?127) and HIV-negative (METH+HIV?; n?=?46) men who have sex with men (MSM) were compared to non-methamphetamine-using, HIV-negative men (METH?HIV?; n?=?136). Thyroid function was dysregulated in methamphetamine-using MSM, irrespective of HIV status. Both meth-using groups had greater odds of abnormal thyroid stimulating hormone levels and significantly higher mean free triiodothyronine (T3) levels. Elevated free T3 was associated with greater depressive symptoms. Overall, outcomes have important implications for assessment of thyroid function in methamphetamine users, particularly among those presenting with depression.     

Density–property relationships in mineralized collagen–glycosaminoglycan scaffolds

Mineralized collagen–glycosminoglycan scaffolds have previously been fabricated by freeze-drying a slurry containing a co-precipitate of calcium phosphate, collagen and glycosaminoglycan. The mechanical properties of the scaffold are low (e.g. the dry Young’s modulus for a 50 wt.% mineralized scaffold is roughly 780 kPa). Our previous attempt to increase the mechanical properties of the scaffold by increasing the mineralization (from 50 to 75 wt.%) was unsuccessful due to defects in the more mineralized scaffold. In this paper, we describe a new technique to improve the mechanical properties by increasing the relative density of the scaffolds. The volume fraction of solids in the slurry was increased by vacuum-filtration. The slurry was then freeze-dried in the conventional manner to produce scaffolds with relative densities between 0.045 and 0.187 and pore sizes of about 100–350 μm, values appropriate for bone growth. The uniaxial compressive stress–strain curves of the scaffolds indicated that the Young’s modulus in the dry state increased from 780 to 6500 kPa and that the crushing strength increased from 39 to 275 kPa with increasing relative density. In the hydrated state, the Young’s modulus increased from 6.44 to 34.8 kPa and the crushing strength increased from 0.55 to 2.12 kPa; the properties were further increased by cross-linking. The modulus and strength were well described by models for cellular solids.     

Emergence and evolution of the renin–angiotensin–aldosterone system

The renin-angiotensin-aldosterone system (RAAS) is not the sole, but perhaps the most important volume regulator in vertebrates. To gain insights into the function and evolution of its components, we conducted a phylogenetic analysis of its main related genes. We found that important parts of the system began to appear with primitive chordates and tunicates and that all major components were present at the divergence of bony fish, with the exception of the Mas receptor. The Mas receptor first appears after the bony-fish/tetrapod divergence. This phase of evolutionary innovation happened about 400 million years ago. We found solid evidence that angiotensinogen made its appearance in cartilage fish. The presence of several RAAS genes in organisms that lack all the components shows that these genes have had other ancestral functions outside of their current role. Our analysis underscores the utility of sequence comparisons in the study of evolution. Such analyses may provide new hypotheses as to how and why in today's population an increased activity of the RAAS frequently leads to faulty salt and volume regulation, hypertension, and cardiovascular diseases, opening up new and clinically important research areas for evolutionary medicine.     

Inhibition of return in cue–target and target–target tasks

Inhibition of return (IOR), the term given for the slowing of a response to a target that appeared at the same location as a previously presented stimulus, has been studied with both target–target (TT; participants respond to each successive event) and cue–target (CT; participants only respond to the second of two events) tasks. Although both tasks have been used to examine the processes and characteristics of IOR, few studies have been conducted to understand if there are any differences in the processes that underlie the IOR that results from ignoring (CT paradigm) or responding to (TT paradigm) the first stimulus. The purpose of the present study was to examine the notion that IOR found in TT tasks represents “true” IOR whereas IOR found in CT tasks consist of both “true” IOR and response inhibition (Coward et al. in Exp Brain Res 155:124–128, 2004). Consistent with the pattern of effects found by Coward et al. (Exp Brain Res 155:124–128, 2004), IOR was larger in the CT task than in the TT task when a single detection response was required (Experiment 1). However, when participants completed one of two spatially-directed responses (rapid aiming movement to the location of the target stimulus), IOR effects from the CT and TT tasks were equal in magnitude (Experiment 2). Rather than CT tasks having an additional response inhibition component, these results suggest that TT tasks may show less of an inhibitory effect because of a facilitatory response repetition effect.     

Deformation-induced ω phase in modified Ti–29Nb–13Ta–4.6Zr alloy by Cr addition

For spinal-fixation applications, implants should have a high Young’s modulus to reduce springback during operations, though a low Young’s modulus is required to prevent stress shielding for patients after surgeries. In the present study, Ti–29Nb–13Ta–4.6Zr alloy (TNTZ) with a low Young’s modulus was modified by adding Cr to obtain a higher deformation-induced Young’s modulus in order to satisfy these contradictory requirements. Two newly designed alloys, TNTZ–8Ti–2Cr and TNTZ–16Ti–4Cr, possess more stable β phases than TNTZ. These alloys consist of single β phases and exhibit relatively low Young’s moduli of <65 GPa after solution treatment. However, after cold rolling, they exhibit higher Young’s moduli owing to a deformation-induced ω-phase transformation. These modified TNTZ alloys show significantly less springback than the original TNTZ alloy based on tensile and bending loading–unloading tests. Thus, the Cr-added TNTZ alloys are beneficial for spinal-fixation applications.     

The cerebello-hypothalamic–pituitary–adrenal axis dysregulation hypothesis in depressive disorder

Depressive disorder can be viewed as an adaptive defense mechanism in response to excessive stress that has gone awry. The hypothalamic–pituitary–adrenal (HPA) axis is an important node in the brain’s stress circuit and suggested to play a role in several subtypes of depression. While the hippocampus, amygdala and prefrontal cortex are considered important regions implicated in stress regulation and depressive disorder, the existence of reciprocal monosynaptic cerebello-hypothalamic connections and the presence of dense glucocorticoid binding sites point towards the view that the cerebellum plays a functional role in the regulation of HPA-axis as well. The present hypothesis may further contribute to contemporary neurobiological views on stress regulation and depressive disorder, and may offer a potential biological basis for developing novel neurosomatic treatment protocols.     

Conformational changes in actin–myosin isoforms probed by Ni(II)·Gly–Gly–His reactivity

Crucial information concerning conformational changes that occur during the mechanochemical cycle of actin–myosin complexes is lacking due to the difficulties encountered in obtaining their three-dimensional structures. To obtain such information, we employed a solution-based approach through the reaction of Ni(II)·tripeptide chelates which are able to induce protein cleavage and cross-linking reactions. Three different myosin motor domain isoforms in the presence of actin and nucleotides were treated with a library of Ni(II)·tripeptide chelates and two reactivities were observed: (1) muscle motor domains were cross-linked to actin, as also observed for the skeletal muscle isoform, while (2) the Dictyostelium discoideum motor domain was cleaved at a single locus. All Ni(II)·tripeptide chelates tested generated identical reaction products, with Ni(II)·Gly–Gly–His, containing a C-terminal carboxylate, exhibiting the highest reactivity. Mass spectrometric analysis showed that protein cleavage occurred within segment 242–265 of the Dictyostelium discoideum myosin heavy chain sequence, while the skeletal myosin cross-linking site was as localized previously within segment 506–561. Using a fusion protein consisting of the yellow and cyan variants of green fluorescent protein linked by Dictyostelium discoideum myosin segment 242–265, we demonstrated that the primary sequence of this segment alone is not a sufficient substrate for Ni(II)·Gly–Gly–His-induced cleavage. Importantly, the cross-linking and cleavage reactions both exhibited specific structural sensitivities to the nature of the nucleotide bound to the active site, validating the conformational changes suggested from crystallographic data of the actin-free myosin motor domain.