Study on a family with anderson--Fabry''s disease and associated familial spastic paraplegia.

A family in the north-east of England with Anderson--Fabry's disease is presented. Alpha-galactosidase activity in plasma and white cells was significantly reduced in three adult male members of the family. One of them had an abnormal chromosome karyotype pattern with an extra Y chromosome (47,XYY) and he was clinically less severely affected than his brothers. Coincidentally five other members of the family suffered from a form of familial spastic paraplegia.     

The International Frontal Sinus Anatomy Classification (IFAC) and Classification of the Extent of Endoscopic Frontal Sinus Surgery (EFSS)

The frontal recess and frontal sinus anatomy can vary from simple to complex. The variations in the anatomy of the frontal recess and frontal sinus are considerable but almost all variations can be classified if the various cell patterns are analyzed. This consensus document was developed to improve the ability of the surgeon to understand these possible variations, plan the surgery, and communicate these complexities when teaching or reporting outcomes. Once the surgeon understands the anatomical pattern of the frontal sinus and recess cells, the extent of surgery can be planned. This document presents a classification of the extent of surgery based on the anatomical classification.     

The international sinonasal microbiome study: A multicentre,multinational characterization of sinonasal bacterial ecology

The sinonasal microbiome remains poorly defined, with our current knowledge based on a few cohort studies whose findings are inconsistent. Furthermore, the variability of the sinus microbiome across geographical divides remains unexplored. We characterize the sinonasal microbiome and its geographical variations in both health and disease using 16S rRNA gene sequencing of 410 individuals from across the world. Although the sinus microbial ecology is highly variable between individuals, we identify a core microbiome comprised of Corynebacterium, Staphylococcus, Streptococcus, Haemophilus and Moraxella species in both healthy and chronic rhinosinusitis (CRS) cohorts. Corynebacterium (mean relative abundance = 44.02%) and Staphylococcus (mean relative abundance = 27.34%) appear particularly dominant in the majority of patients sampled. Amongst patients suffering from CRS with nasal polyps, a statistically significant reduction in relative abundance of Corynebacterium (40.29% vs 50.43%; P = .02) was identified. Despite some measured differences in microbiome composition and diversity between some of the participating centres in our cohort, these differences would not alter the general pattern of core organisms described. Nevertheless, atypical or unusual organisms reported in short-read amplicon sequencing studies and that are not part of the core microbiome should be interpreted with caution. The delineation of the sinonasal microbiome and standardized methodology described within our study will enable further characterization and translational application of the sinus microbiota.     

Local allergic rhinitis: concept, pathophysiology, and management

Local allergic rhinitis (LAR) is a localized nasal allergic response in the absence of systemic atopy characterized by local production of specific IgE (sIgE) antibodies, a T(H)2 pattern of mucosal cell infiltration during natural exposure to aeroallergens, and a positive nasal allergen provocation test response with release of inflammatory mediators (tryptase and eosinophil cationic protein). Although the prevalence remains to be established, a number of patients previously given a diagnosis of nonallergic rhinitis or idiopathic rhinitis are now being classified as having LAR. Culprit allergens responsible include house dust mite, grass and olive pollens, and many others. For the diagnosis of LAR, neither skin prick testing nor determination of the presence of serum sIgE antibodies is useful, and a nasal allergen provocation test is needed to identify the culprit allergen or allergens. In a certain proportion of cases, local sIgE can be detected, and conjunctivitis, asthma, or both can be associated. Whether patients with LAR will have systemic atopy in the future is a matter of debate. Further studies are needed for examine the prevalence of this phenomenon in different areas, to improve the diagnostic methods to better identify these patients, and to develop therapeutic approaches, including the use of immunotherapy.     

Patterns of Child and Adolescent Mental Health Care in Greece

During the last 20 years the mental health care system in Greece underwent a dramatic change; the implementation of the EEC Reg. 815/84 programme contributed to a significant shift towards the extramural care and rehabilitation of patients with long-term mental health problems. The child and adolescent mental health (CAMH) care system was transformed by this change to a lesser degree. Despite bureaucratic obstacles and other difficulties, a substantial number of CAMH outpatient services have been developed in Greece. They are concentrated mainly in the larger cities and they focus on providing assessment and to some extent therapy and counselling; prevention and promotion of CAMH are not yet perceived as priority areas. In addition, there is a lack of specialised day care services for specific populations such as young people with disorders of the autistic spectrum and intellectual disabilities. There have been some recent improvements in education and research in the field of CAMH but these sectors are in need of further investment and development. Unfortunately, the current economic crisis has affected both the development of new services and the optimal functioning of those already in operation. Nevertheless, Greece must invest in CAMH and the rights of the children and young people should be protected.     

Effects of different bleaching methods on shear bond strengths of orthodontic brackets

Objective:To evaluate the effects of different bleaching methods on the shear bond strength (SBS) of orthodontic brackets.Materials and Methods:Forty-five freshly extracted premolars were randomly divided into three groups (n  =  15 per group). In group I, bleaching was performed with the office bleaching method. In group II, bleaching was performed with the home bleaching method. Group III served as the control. Orthodontic brackets were bonded with a light cure composite resin and cured with an LED light. After bonding, the SBS of the brackets were tested with a Universal testing machine.Results:Analysis of variance indicated a significant difference between groups (P < .001). The highest values for SBS were measured in group III (20.99 ± 2.32 MPa). The SBS was significantly lower in groups I and II than in group III (P < .001). The lowest values for SBS were measured in group II (6.42 ± 0.81 MPa). SBS was significantly higher in group I than in group II (P < .001).Conclusions:Both of the bleaching methods significantly affected the SBS of orthodontic brackets on human enamel. Bleaching with the home bleaching method affected SBS more adversely than did bleaching with the office bleaching method.     

Genetic Variation of DKK3 May Modify Renal Disease Severity in ADPKD

Significant variation in the course of autosomal dominant polycystic kidney disease ( ADPKD) within families suggests the presence of effect modifiers. Recent studies of the variation within families harboring PKD1 mutations indicate that genetic background may account for 32 to 42% of the variance in estimated GFR (eGFR) before ESRD and 43 to 78% of the variance in age at ESRD onset, but the genetic modifiers are unknown. Here, we conducted a high-throughput single-nucleotide polymorphism (SNP) genotyping association study of 173 biological candidate genes in 794 white patients from 227 families with PKD1. We analyzed two primary outcomes: (1) eGFR and (2) time to ESRD (renal survival). For both outcomes, we used multidimensional scaling to correct for population structure and generalized estimating equations to account for the relatedness among individuals within the same family. We found suggestive associations between each of 12 SNPs and at least one of the renal outcomes. We genotyped these SNPs in a second set of 472 white patients from 229 families with PKD1 and performed a joint analysis on both cohorts. Three SNPs continued to show suggestive/significant association with eGFR at the Dickkopf 3 (DKK3) gene locus; no SNPs significantly associated with renal survival. DKK3 antagonizes Wnt/β-catenin signaling, which may modulate renal cyst growth. Pending replication, our study suggests that genetic variation of DKK3 may modify severity of ADPKD resulting from PKD1 mutations.Autosomal dominant polycystic kidney disease ( ADPKD) is the most common monogenic kidney disease worldwide, affecting one in 500 to 1000 births.^1,2 It is characterized by focal development of renal cysts in an age-dependent manner. Typically, only a few renal cysts are clinically detectable during the first three decades of life; however, by the fifth decade, tens of thousands of renal cysts of different sizes can be found in most patients.³ Progressive cyst expansion with age leads to massive enlargement and distortion of the normal architecture of both kidneys and, ultimately, ESRD in most patients. ADPKD is also associated with an increased risk for cardiac valvular defects, colonic diverticulosis, hernias, and intracranial arterial aneurysms. Overall, ADPKD accounts for approximately 5% of ESRD in North America.²Mutations of PKD1 and PKD2 respectively account for approximately 85% and approximately 15% of linkage-characterized European families. Polycystin-1 (PC-1) and PC-2, the proteins encoded by PKD1 and PKD2, respectively, function as a macromolecular complex and regulate multiple signaling pathways to maintain the normal tubular structure and function.¹ Monoclonal expansion of individual epithelial cells that have undergone a somatic “second hit” mutation, resulting in biallelic inactivation of either PKD1 or PKD2, seems to provide a major mechanism for focal cyst initiation,⁴ possibly through the loss of polycystin-mediated mechanosensory function in the primary cilium.⁵ In addition, a large prospective, observational study indicated that renal cysts in ADPKD expand exponentially with increasing age, and patients with large polycystic kidneys are at higher risk for developing kidney failure⁶; however, the key factors that modulate renal disease progression in ADPKD remain incompletely understood.Renal disease severity in ADPKD is highly variable, with the age of onset of ESRD ranging from childhood to old age.^7–11 A strong genetic locus effect has been noted in ADPKD. Adjusted for age and gender, patients with PKD1 have larger kidneys and earlier onset at ESRD than patients with PKD2 (mean age at ESRD 53.4 versus 72.7 years, respectively).^8,9 By contrast, a weak allelic effect (based on the 5′ versus 3′ location of the germline mutations) on renal disease severity may be present for PKD1¹⁰ but not PKD2.¹¹ Marked intrafamilial variability in renal disease is well documented in ADPKD and suggests a strong modifier effect.^10–15 In an extreme example, large polycystic kidneys were present in utero in one of a pair of dizygotic twins affected with the same germline PKD1 mutation, whereas the kidneys of the co-twin remained normal at 5 years of age.¹² Several studies have quantified the role of genetic background in the phenotypic expression of ADPKD. In a comparison of monozygotic twins and siblings, greater variance in the age of onset of ESRD in the siblings supported a role for genetic modifiers.¹³ Two other studies of intrafamilial disease variability in PKD1 have estimated that genetic factors may account for 32 to 42% of the variance of creatinine clearance before ESRD and 43 to 78% of the variance in age at ESRD.^14,15 The magnitude of the modifier gene effect from these studies suggests that mapping such factors is feasible. Here, we report the results of an association study of modifier genes for PKD1 renal disease severity.     

Did We Get Sensorimotor Adaptation Wrong? Implicit Adaptation as Direct Policy Updating Rather than Forward-Model-Based Learning

The human motor system can rapidly adapt its motor output in response to errors. The prevailing theory of this process posits that the motor system adapts an internal forward model that predicts the consequences of outgoing motor commands and uses this forward model to plan future movements. However, despite clear evidence that adaptive forward models exist and are used to help track the state of the body, there is no definitive evidence that such models are used in movement planning. An alternative to the forward-model-based theory of adaptation is that movements are generated based on a learned policy that is adjusted over time by movement errors directly (“direct policy learning”). This learning mechanism could act in parallel with, but independent of, any updates to a predictive forward model. Forward-model-based learning and direct policy learning generate very similar predictions about behavior in conventional adaptation paradigms. However, across three experiments with human participants (N = 47, 26 female), we show that these mechanisms can be dissociated based on the properties of implicit adaptation under mirror-reversed visual feedback. Although mirror reversal is an extreme perturbation, it still elicits implicit adaptation; however, this adaptation acts to amplify rather than to reduce errors. We show that the pattern of this adaptation over time and across targets is consistent with direct policy learning but not forward-model-based learning. Our findings suggest that the forward-model-based theory of adaptation needs to be re-examined and that direct policy learning provides a more plausible explanation of implicit adaptation.SIGNIFICANCE STATEMENT The ability of our brain to adapt movements in response to error is one of the most widely studied phenomena in motor learning. Yet, we still do not know the process by which errors eventually result in adaptation. It is known that the brain maintains and updates an internal forward model, which predicts the consequences of motor commands, and the prevailing theory of motor adaptation posits that this updated forward model is responsible for trial-by-trial adaptive changes. Here, we question this view and show instead that adaptation is better explained by a simpler process whereby motor output is directly adjusted by task errors. Our findings cast doubt on long-held beliefs about adaptation.