Pediatric joint hypermobility: a diagnostic framework and narrative review

BACKGROUND: Hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) are debilitating conditions. Diagnosis is currently clinical in the absence of biomarkers, and criteria developed for adults are difficult to use in children and biologically immature adolescents. Generalized joint hypermobility (GJH) is a prerequisite for hEDS and generalized HSD. Current literature identifies a large proportion of children as hypermobile using a Beighton score ≥ 4 or 5/9, the cut off for GJH in adults. Other phenotypic features from the 2017 hEDS criteria can arise over time. Finally, many comorbidities described in hEDS/HSD are also seen in the general pediatric and adolescent population. Therefore, pediatric specific criteria are needed. The Paediatric Working Group of the International Consortium on EDS and HSD has developed a pediatric diagnostic framework presented here. The work was informed by a review of the published evidence. OBSERVATIONS: The framework has 4 components, GJH, skin and tissue abnormalities, musculoskeletal complications, and core comorbidities. A Beighton score of ≥ 6/9 best identifies children with GJH at 2 standard deviations above average, based on published general population data. Skin and soft tissue changes include soft skin, stretchy skin, atrophic scars, stretch marks, piezogenic papules, and recurrent hernias. Two symptomatic groups were agreed: musculoskeletal and systemic. Emerging comorbid relationships are discussed. The framework generates 8 subgroups, 4 pediatric GJH, and 4 pediatric generalized hypermobility spectrum disorders. hEDS is reserved for biologically mature adolescents who meet the 2017 criteria, which also covers even rarer types of Ehlers-Danlos syndrome at any age. CONCLUSIONS: This framework allows hypermobile children to be categorized into a group describing their phenotypic and symptomatic presentation. It clarifies the recommendation that comorbidities should be defined using their current internationally accepted frameworks. This provides a foundation for improving clinical care and research quality in this population

Implementation of population screening for colorectal cancer by repeated fecal occult blood test in the Netherlands

<p>Abstract</p> <p>Background</p> <p>Colorectal cancer (CRC) is the third most prevalent type of cancer in the world. Its prognosis is closely related to the disease stage at the time of diagnosis. Early detection of symptomless CRC or precursor lesions through population screening could reduce CRC mortality. However, screening programs are only effective if enough people are willing to participate. This study aims to asses the uptake of a second round of fecal occult blood test (FOBt) based screening and to explore factors that could potentially increase this uptake.</p> <p>Methods and design</p> <p>Two years after the first screening round, 10.000 average risk persons, aged 50 to 75, will again receive an invitation to participate in immunohistochemical FOBt (iFOBt) based screening. Eligible persons will be recruited through a city population database. Invitees will be randomized to receive either an iFOBt with a faeces collection paper or an iFOBt without a collection paper. The iFOBts will be analyzed in a specialized laboratory at the Academic Medical Centre. Positive iFOBts will be followed by a consultation at our outpatient clinic and, in the absence of contra-indications and after informed consent, by a colonoscopy. The primary outcome measure is the participation rate. Secondary outcome measures are the effect of the addition of a collection paper on the participation rate, reasons for participation and non-participation, measures of informed choice and psychological consequences of screening and measures of psychological and physical burden associated with the iFOBt and the colonoscopy. Another secondary outcome measure is the diagnostic yield of the program.</p> <p>Discussion</p> <p>In order to implement population screening for colorectal cancer in the Netherlands, information is needed on the uptake of repeated rounds of FOBt-based screening and on factors that could potentially increase this uptake in the future since effectiveness of such a program depends on the willingness of persons to participate. This study will provide information on the actual uptake and perception of a second round of iFOBt-based screening. The results of this study will contribute to the future implementation of a national colorectal screening program in the Netherlands.</p> <p>Trial registration</p> <p>Dutch Trial register: NTR1327</p

Solid-state NMR applied to photosynthetic light-harvesting complexes

This short review describes how solid-state NMR has provided a mechanistic and electronic picture of pigment–protein and pigment–pigment interactions in photosynthetic antenna complexes. NMR results on purple bacterial antenna complexes show how the packing of the protein and the pigments inside the light-harvesting oligomers induces mutual conformational stress. The protein scaffold produces deformation and electrostatic polarization of the BChl macrocycles and leads to a partial electronic charge transfer between the BChls and their coordinating histidines, which can tune the light-harvesting function. In chlorosome antennae assemblies, the NMR template structure reveals how the chromophores can direct their self-assembly into higher macrostructures which, in turn, tune the light-harvesting properties of the individual molecules by controlling their disorder, structural deformation, and electronic polarization without the need for a protein scaffold. These results pave the way for addressing the next challenge, which is to resolve the functional conformational dynamics of the lhc antennae of oxygenic species that allows them to switch between light-emitting and light-energy dissipating states

The effect of Tai Chi Chuan in reducing falls among elderly people: design of a randomized clinical trial in the Netherlands [ISRCTN98840266]

BACKGROUND: Falls are a significant public health problem. Thirty to fifty percent of the elderly of 65 years and older fall each year. Falls are the most common type of accident in this age group and can result in fractures and subsequent disabilities, increased fear of falling, social isolation, decreased mobility, and even an increased mortality. Several forms of exercise have been associated with a reduced risk of falling and with a wide range of physiological as well as psychosocial health benefits. Tai Chi Chuan seems to be the most promising form of exercise in the elderly, but the evidence is still controversial. In this article the design of a randomized clinical trial is presented. The trial evaluates the effect of Tai Chi Chuan on fall prevention and physical and psychological function in older adults. METHODS/DESIGN: 270 people of seventy years and older living at home will be identified in the files of the participating general practitioners. People will be asked to participate when meeting the following inclusion criteria: have experienced a fall in the preceding year or suffer from two of the following risk factors: disturbed balance, mobility problems, dizziness, or the use of benzodiazepines or diuretics. People will be randomly allocated to either the Tai Chi Chuan group (13 weeks, twice a week) or the no treatment control group. The primary outcome measure is the number of new falls, measured with a diary. The secondary outcome measures are balance, fear of falling, blood pressure, heart rate, lung function parameters, physical activity, functional status, quality of life, mental health, use of walking devices, medication, use of health care services, adjustments to the house, severity of fall incidents and subsequent injuries. Process parameters will be measured to evaluate the Tai Chi Chuan intervention. A cost-effectiveness analysis will be carried out alongside the evaluation of the clinical results. Follow-up measurements will be collected at 3, 6 and 12 months after randomization. DISCUSSION: As far as we know this is the first trial in Europe considering Tai Chi Chuan and fall prevention. This project will answer a pragmatic research question regarding the efficacy of Tai Chi Chuan regarding fall reduction

State based model of long-term potentiation and synaptic tagging and capture

Recent data indicate that plasticity protocols have not only synapse-specific but also more widespread effects. In particular, in synaptic tagging and capture (STC), tagged synapses can capture plasticity-related proteins, synthesized in response to strong stimulation of other synapses. This leads to long-lasting modification of only weakly stimulated synapses. Here we present a biophysical model of synaptic plasticity in the hippocampus that incorporates several key results from experiments on STC. The model specifies a set of physical states in which a synapse can exist, together with transition rates that are affected by high- and low-frequency stimulation protocols. In contrast to most standard plasticity models, the model exhibits both early- and late-phase LTP/D, de-potentiation, and STC. As such, it provides a useful starting point for further theoretical work on the role of STC in learning and memory

Effects of deletion of the Streptococcus pneumoniae lipoprotein diacylglyceryl transferase gene lgt on ABC transporter function and on growth in vivo

Lipoproteins are an important class of surface associated proteins that have diverse roles and frequently are involved in the virulence of bacterial pathogens. As prolipoproteins are attached to the cell membrane by a single enzyme, prolipoprotein diacylglyceryl transferase (Lgt), deletion of the corresponding gene potentially allows the characterisation of the overall importance of lipoproteins for specific bacterial functions. We have used a Δlgt mutant strain of Streptococcus pneumoniae to investigate the effects of loss of lipoprotein attachment on cation acquisition, growth in media containing specific carbon sources, and virulence in different infection models. Immunoblots of triton X-114 extracts, flow cytometry and immuno-fluorescence microscopy confirmed the Δlgt mutant had markedly reduced lipoprotein expression on the cell surface. The Δlgt mutant had reduced growth in cation depleted medium, increased sensitivity to oxidative stress, reduced zinc uptake, and reduced intracellular levels of several cations. Doubling time of the Δlgt mutant was also increased slightly when grown in medium with glucose, raffinose and maltotriose as sole carbon sources. These multiple defects in cation and sugar ABC transporter function for the Δlgt mutant were associated with only slightly delayed growth in complete medium. However the Δlgt mutant had significantly reduced growth in blood or bronchoalveolar lavage fluid and a marked impairment in virulence in mouse models of nasopharyngeal colonisation, sepsis and pneumonia. These data suggest that for S. pneumoniae loss of surface localisation of lipoproteins has widespread effects on ABC transporter functions that collectively prevent the Δlgt mutant from establishing invasive infection

Glucocorticoid Receptor 1B and 1C mRNA Transcript Alterations in Schizophrenia and Bipolar Disorder, and Their Possible Regulation by GR Gene Variants

Abnormal patterns of HPA axis activation, under basal conditions and in response to stress, are found in individuals with schizophrenia and bipolar disorder. Altered glucocorticoid receptor (GR) mRNA and protein expression in the dorsolateral prefrontal cortex (DLPFC) in psychiatric illness have also been reported, but the cause of these abnormalities is not known. We quantified expression of GR mRNA transcript variants which employ different 5′ promoters, in 35 schizophrenia cases, 31 bipolar disorder cases and 34 controls. We also explored whether sequence variation within the NR3C1 (GR) gene is related to GR mRNA variant expression. Total GR mRNA was decreased in the DLPFC in schizophrenia cases relative to controls (15.1%, p<0.0005) and also relative to bipolar disorder cases (8.9%, p<0.05). GR-1B mRNA was decreased in schizophrenia cases relative to controls (20.2%, p<0.05), while GR-1C mRNA was decreased in both schizophrenia and bipolar disorder cases relative to controls (16.1% and 17.2% respectively, both p<0.005). A dose-dependent effect of rs10052957 genotype on GR-1B mRNA expression was observed, where CC homozygotes displayed 18.4% lower expression than TC heterozygotes (p<0.05), and 31.8% lower expression than TT homozygotes (p<0.005). Similarly, a relationship between rs6190 (R23K) genotype and GR-1C expression was seen, with 24.8% lower expression in GG homozygotes than GA heterozygotes (p<0.01). We also observed an effect of rs41423247 (Bcl1) SNP on expression of 67 kDa GRα isoform, the most abundant GRα isoform in the DLPFC. These findings suggest possible roles for the GR-1B and GR-1C promoter regions in mediating GR gene expression changes in psychotic illness, and highlight the potential importance of sequence variation within the NR3C1 gene in modulating GR mRNA expression in the DLPFC