Autoimmune polyglandular syndrome Type 2: the tip of an iceberg?

Autoimmune polyglandular syndromes (APS) are conditions characterized by the association of two or more organ-specific disorders. Type 2 APS is defined by the occurrence of Addison's disease with thyroid autoimmune disease and/or Type 1 diabetes mellitus. Clinically overt disorders are considered only the tip of the autoimmune iceberg, since latent forms are much more frequent. Historical, clinical, genetic, and immunological aspects of Type 2 APS are reviewed. Furthermore, data on 146 personal cases of Type 2 APS are also reported.     

Bridging the transmission gap: an end to an important mystery of attachment research?

The authors provide a context for this special section by arguing that the attachment relationships of infancy fulfil an evolutionary role in ensuring that the brain structures that come to subserve social cognition are appropriately organised and prepared to equip the individual for the collaborative existence with other people for which his or her brain was designed. Processes as fundamental as gene expression or changes in receptor densities can be seen as direct functions of the extent of understanding of mental states provided by the caregiving environment. If the attachment relationship is indeed a major organiser of brain development, it is even more important to understand the processes that underpin the transgenerational transmission of attachment patterns. The contributions of the papers in the special section to understanding the role of reflective function in the development of attachment and social cognition are reviewed, and the implications for the development of both theory and practice are explored.     

Nevo syndrome with an NSD1 deletion: a variant of Sotos syndrome?

A 17-month-old girl with clinical manifestations of Nevo syndrome and NSD1 (nuclear receptor binding SET domain protein 1) deletion is described. Nevo syndrome is a rare overgrowth syndrome showing considerable phenotypic overlap with Sotos syndrome-another, more frequent overgrowth syndrome caused by NSD1 mutations or deletions. About a half of Japanese Sotos syndrome patients carry a 2.2-Mb common deletion encompassing NSD1 and present with frequent brain, cardiovascular, or urinary tract anomalies. The girl we described had the common deletion and showed patent ductus arteriosus, atrial septal defect, vesicoureteral reflux, and bilateral hydronephrosis. It was thus concluded that the clinical manifestations, including the Nevo syndrome phenotype, were caused by the microdeletion.     

Mowat–Wilson syndrome: an underdiagnosed syndrome?

Mowat–Wilson syndrome (MWS) is an autosomal dominant developmental disorder with mental retardation and variable multiple congenital abnormalities due to mutations of the ZEB2 ( ZFHX1B ) gene at 2q22. MWS was first described in 1998 and the causative gene was delineated in 2001. Since then, 115 different mutations of ZEB2 have been published in association with this syndrome in 161 individuals. However, recent reports suggest that due to the variability of the congenital abnormalities, this syndrome may still be underdiagnosed. We report two unrelated patients with MWS where the clinical diagnosis was established only after finding of disruption of the ZEB2 gene by a balanced translocation breakpoint and an interstitial microdeletion, respectively.     

Can an injured discoid lateral meniscus be returned to the correct anatomic position and size of the native lateral meniscus after surgery?

BackgroundNo previous studies have compared the position and size of the remaining discoid lateral meniscus (DLM) with that of a normal lateral meniscus. This study aimed to evaluate the postoperative position and size of DLM compared with that of normal controls using magnetic resonance imaging (MRI).MethodsThis retrospective study involved 52 symptomatic complete type DLMs (discoid group) who underwent arthroscopic surgery and 50 normal controls (control group). Pre- and postoperative MRI evaluations, height, width, and relative percentage of extrusion (RPE) were assessed. Sagittal position parameters, including distances from articular cartilage center to anterior meniscus (CAMD) and from anterior articular cartilage margin to anterior horn (ACMD), were also assessed. Logistic regression analysis was performed to find factors with extrusion of remaining DLM.ResultsThe height of the discoid group was significantly lower than that of the control group (P = 0.000). RPE in the discoid group was significantly larger than in the control group (P = 0.005). Only CAMD and ACMD in the discoid group were different (positioned more anteriorly) from the control group (P = 0.000). Preoperative meniscal shift (odds ratio (OR): 12.448; P = 0.003) and operative technique, especially partial meniscectomy with repair (OR: 19.125; P = 0.000), were the major factors associated with extrusion.ConclusionThe width of remaining DLM was comparable to that of normal controls, but the position was found to be more anterior and lateral than that of normal controls. Preoperative meniscal shift and combined meniscus repair were the major factors for smaller width and greater extrusion; thus, surgeons should address and counsel these factors before surgery.     

Reach adaptation: what determines whether we learn an internal model of the tool or adapt the model of our arm?

We make errors when learning to use a new tool. However, the cause of error may be ambiguous: is it because we misestimated properties of the tool or of our own arm? We considered a well-studied adaptation task in which people made goal-directed reaching movements while holding the handle of a robotic arm. The robot produced viscous forces that perturbed reach trajectories. As reaching improved with practice, did people recalibrate an internal model of their arm, or did they build an internal model of the novel tool (robot), or both? What factors influenced how the brain solved this credit assignment problem? To investigate these questions, we compared transfer of adaptation between three conditions: catch trials in which robot forces were turned off unannounced, robot-null trials in which subjects were told that forces were turned off, and free-space trials in which subjects still held the handle but watched as it was detached from the robot. Transfer to free space was 40% of that observed in unannounced catch trials. We next hypothesized that transfer to free space might increase if the training field changed gradually, rather than abruptly. Indeed, this method increased transfer to free space from 40 to 60%. Therefore although practice with a novel tool resulted in formation of an internal model of the tool, it also appeared to produce a transient change in the internal model of the subject's arm. Gradual changes in the tool's dynamics increased the extent to which the nervous system recalibrated the model of the subject's own arm.     

Behçet’s syndrome as a tool to dissect the mechanisms of thrombo-inflammation: clinical and pathogenetic aspects

Behçet’s syndrome (BS) is a complex disease with different organ involvement. The vascular one is the most intriguing, considering the existence of a specific group of patients suffering from recurrent vascular events involving the venous and, more rarely, the arterial vessels. Several clinical clues suggest the inflammatory nature of thrombosis in BS, especially of the venous involvement, thus BS is considered a model of inflammation-induced thrombosis. Unique among other inflammatory conditions, venous involvement (together with the arterial one) is currently treated with immunosuppressants, rather than with anti-coagulants. Although many in-vitro studies have suggested the different roles of the multiple players involved in clot formation, in-vivo models are crucial to study this process in a physiological context. At present, no clear mechanisms describing the pathophysiology of thrombo-inflammation in BS exist. Recently, we focused our attention on BS patients as a human in-vivo model of inflammation-induced thrombosis to investigate a new mechanism of clot formation. Indeed, fibrinogen displays a critical role not only in inflammatory processes, but also in clot formation, both in the fibrin network and in platelet aggregation. Reactive oxygen species (ROS)-derived modifications represent the main post-translational fibrinogen alterations responsible for structural and functional changes. Recent data have revealed that neutrophils (pivotal in the pathogenetic mechanisms leading to BS damage) promote fibrinogen oxidation and thrombus formation in BS. Altogether, these new findings may help understand the pathogenetic bases of inflammation-induced thrombosis and, more importantly, may suggest potential targets for innovative therapeutic approaches.     

Issues to debate on the Women's Health Initiative: estrogen: an instrument or the conductor of the orchestra?

Although it is well known that cyclic production of sex hormones is essential to establish reproductive function and female characteristics, distant impacts of the activity of the female endocrine system result from a concert of delicate mechanisms. Estrogen is rather an instrument than a conductor in this physiological orchestra of the female. Thus, controversies in the explanation of results from studies on hormone replacement therapy (HRT) and cardiovascular disease (CVD) prevention might be eliminated, if we analyse not only the role of estrogen but a broader spectrum of factors leading to CVD. Authors would like to hypothesize that haemorheological changes in women around menopause, such as increased blood and plasma viscosity, haematocrit and fibrinogen, are largely responsible for the increased mortality in the post-menopausal life period. We believe that a cyclic withdrawal bleeding establishes a more favourable haemorheological condition, thus, sequentially administered estrogen might be protective in post-menopausal women. Nevertheless, other factors, that decrease blood viscosity, such as daily exercise, intake of ample amount of fluids as well as ideal nutrition, are equally important. We are confident that sequential HRT, as well as healthy life style and risk prevention programmes have their proper place in the management of this issue.     

Autosomal dominant microtia and ocular coloboma: new syndrome or an extension of the oculo-auriculo-vertebral spectrum?

The oculo-auriculo-vertebral (OAV) spectrum is an etiologically heterogeneous condition classically consisting of microtia, hemifacial microsomia, epibulbar dermoids, and vertebral anomalies. Other eye findings described in OAV include upper eyelid colobomas, ptosis, and varying degrees of microphthalmia or even anophthalmia. Iris and/or retinal colobomas have rarely been reported. We describe two familial cases of apparent OAV with ocular colobomas. We postulate that iris and/or retinal colobomas associated with OAV may represent a subgroup within the OAV spectrum with autosomal dominant inheritance, as in the families described herein. Since microtia can result from aberrant migration of neural crest cells into the first and second branchial arches during early embryonic development, and concomitant deficient neural crest migration into the developing eye can lead to ocular coloboma and or iris heterochromia, it may be that the altered gene or genes in our familial cases are involved with regulation of neural crest development.     

Sexual differentiation of the brain in man and animals: Of relevance to Klinefelter syndrome?

The developing brain is highly sensitive to the organizing effects of steroids of gonadal origin in a process referred to as sexual differentiation. Early hormone effects prime the brain for adult sensitivity to the appropriate hormonal milieu, maximizing reproductive fitness via coordinated physiology and behavior. Animal models, in particular rodents, have provided insight into general principles and the cellular and molecular mechanisms of brain differentiation. Cellular endpoints influenced by steroids in the developing brain include neurogenesis, migration, apoptosis, dendritic growth, and synaptic patterning. Important roles for prostaglandins, endocanabinoids, and epigenetics are among the many cellular mediators of hormonal organization. Transference of general principles of brain sexual differentiation to humans relies on observations of individuals with genetic anomalies that either increase or decrease hormone exposure and sensitivity. The physiology and behavior of individuals with XXY (Klinefelter syndrome) has not been considered in the context of sexual differentiation of the brain, most likely due to the delay in diagnoses and highly variable presentation. The behavioral phenotype and impairments in the domains of speech and language that are characteristic of individuals with XXY is consistent with the reduced androgen production associated with the syndrome. Hormone replacement appears effective in restoring some deficits and impact may be further improved by increased understanding of the hormonally mediated sexual differentiation of the brain. © 2013 Wiley Periodicals, Inc.     

Oral-gut connection: one step closer to an integrated view of the gastrointestinal tract?

Although an enrichment of orally derived bacteria is reported in the gut microbiota of patients with several diseases, it is mostly unknown whether oral bacteria can colonize and induce intestinal inflammation. In a recent paper in Science, Atarashi et al.¹ from Kenya Honda's laboratory show that a subset of orally derived bacteria colonizes and persists in the gut, leading to activation of the intestinal immune system and subsequent chronic inflammation in a susceptible host. The impact of oral health status as a potential contributor to inflammatory diseases at distal sites of the body deserves consideration.     

Bridging the transmission gap: An end to an important mystery of attachment research?

Abstract

The authors provide a context for this special section by arguing that the attachment relationships of infancy fulfil an evolutionary role in ensuring that the brain structures that come to subserve social cognition are appropriately organised and prepared to equip the individual for the collaborative existence with other people for which his or her brain was designed. Processes as fundamental as gene expression or changes in receptor densities can be seen as direct functions of the extent of understanding of mental states provided by the caregiving environment. If the attachment relationship is indeed a major organiser of brain development, it is even more important to understand the processes that underpin the transgenerational transmission of attachment patterns. The contributions of the papers in the special section to understanding the role of reflective function in the development of attachment and social cognition are reviewed, and the implications for the development of both theory and practice are explored.     

Stepwise enforcement of the notochord and its intersection with the myoseptum: an evolutionary path leading to development of the vertebra?

The notochord constitutes the main axial support during the embryonic and larval stages, and the arrangement of collagen fibrils within the notochord sheath is assumed to play a decisive role in determining its functional properties as a fibre-wound hydrostatic skeleton. We have found that during early ontogeny in Atlantic salmon stepwise changes occur in the configuration of the collagen fibre-winding of the notochord sheath. The sheath consists of a basal lamina, a layer of type II collagen, and an elastica externa that delimits the notochord; and these constituents are secreted in a specific order. Initially, the collagen fibrils are circumferentially arranged perpendicular to the longitudinal axis, and this specific spatial fibril configuration is maintained until hatching when the collagen becomes reorganized into distinct layers or lamellae. Within each lamella, fibrils are parallel to each other, forming helices around the longitudinal axis of the notochord, with a tangent angle of 75-80 degrees to the cranio-caudal axis. The helical geometry shifts between adjacent lamellae, forming enantiomorphous left- and right-handed coils, respectively, thus enforcing the sheath. The observed changes in the fibre-winding configuration may reflect adaptation of the notochord to functional demands related to stage in ontogeny. When the vertebral bodies initially form as chordacentra, the collagen lamellae of the sheath in the vertebral region are fixed by the deposition of minerals; in the intervertebral region, however, they represent a pre-adaptation providing torsional stability to the intervertebral joint. Hence, these modifications of the sheath transform the notochord per se into a functional vertebral column. The elastica externa, encasing the notochord, has serrated surfaces, connected inward to the type II collagen of the sheath, and outward to type I collagen of the mesenchymal connective tissue surrounding the notochord. In a similar manner, the collagen matrix of the neural and haemal arch cartilages is tightly anchored to the outward surface of the elastic membrane. Hence, the elastic membrane may serve as an interface between the notochord and the adjacent structures, with an essential function related to transmission of tensile forces from the musculature. The interconnection between the notochord and the myosepta is discussed in relation to function and to evolution of the arches and the vertebra. Contrary to current understanding, this study also shows that notochord vacuolization does not result in an increased elongation of the embryo, which agrees with the circular arrangement of type II collagen that probably only enables a restricted increase in girth upon vacuolization, not aiding elongation. As the vacuolization occurs during the egg stage, this type of collagen disposition, in combination with an elastica externa, also probably facilitates flexibility and curling of the embryo.     

Telepathology: a diagnostic tool for the millennium?

Many developments in science have their origins in science fiction and telepathology is no exception. The concept was first illustrated in 1924 in the magazine 'Radio News'. It was not until 1980, however, that the first working telepathology system was demonstrated. Although the system was shown to work, it required special hardware, dedicated software and special microwave transmission links to be installed. Little interest was shown worldwide because of the very high cost and the inability of many people to replicate such a system. Ten years later, the personal computer (PC) was able to provide more than adequate performance at low cost for both image display quality and speed, and the development of video technology had resulted in high quality images being produced by television cameras that were now easily affordable. Microscopes were also relatively cheaper. Thus, by 1993 or 1994, all the hardware necessary to produce a telepathology system was available at reasonable cost. Telepathology can now be used for remote primary diagnosis, remote referral to a specialist pathologist, remote teaching, remote presentation of post-mortem or microscopic findings, quality assurance image circulation and feedback, and consensus diagnosis for pathological review in clinical trials. There are two residual problems. The first concerns the speed of data transmission, commonly referred to as the bandwidth. The second is that the software provided by most of the manufacturers and suppliers of these systems is not entirely suitable to the task and the systems are not interoperable. It is clear that the approach of the manufacturers is at present unlikely to produce telepathology systems which pathologists feel comfortable in using. A somewhat different approach is illustrated by the accompanying article in this issue from the Berlin group, where a relatively simple Java-based applet and the Internet are used to allow single or multiple users to view slides on a robotic microscope. This could form the basis for a truly useful system, but still needs modification for some applications.     

Tandem mass spectrometry: the tool of choice for diagnosing inborn errors of metabolism?

The early diagnosis of inborn errors of metabolism (IEM) by laboratory-based mass screening is a prime example of preventive medicine. However, several factors restrict the range of IEM that can be screened for, and the numbers of people to whom it can be made available. Mass screening in the United Kingdom is limited primarily to that for phenylketonuria and congenital hypothyroidism. Ideally, extension of mass screening of neonates for additional clinically significant IEM is a desirable strategy. Tandem mass spectrometry (TMS) is a powerful and effective diagnostic technique and has been proposed as a means to realise this aim. Its main advantages are improved accuracy, sensitivity and specificity over existing methods, and its suitability for cost-effective multidisease IEM mass screening. The evolution, principles and applications of TMS are described, and the practical and clinical implications of extending diagnostic services for IEM using TMS are discussed.