A global call to action to improve the care of people with fragility fractures.

The ageing of society is driving an enormous increase in fragility fracture incidence and imposing a massive burden on patients, their families, health systems and societies globally. Disrupting the status quo has therefore become an obligation and a necessity. Initiated by the Fragility Fracture Network (FFN) at a "Presidents' Roundtable" during the 5th FFN Global Congress in 2016 several leading organisations agreed that a global multidisciplinary and multiprofessional collaboration, resulting in a Global Call to Action (CtA), would be the right step forward to improve the care of people presenting with fragility fractures. So far global and regional organisations in geriatrics/internal medicine, orthopaedics, osteoporosis/metabolic bone disease, rehabilitation and rheumatology were contacted as well as national organisations in five highly populated countries (Brazil, China, India, Japan and the United States), resulting in 81societies endorsing the CtA. We call for implementation of a systematic approach to fragility fracture care with the goal of restoring function and preventing subsequent fractures without further delay. There is an urgent need to improve: To address this fragility fracture crisis, the undersigned organisations pledge to intensify their efforts to improve the current management of all fragility fractures, prevent subsequent fractures, and strive to restore functional abilities and quality of life.

Evidence of linkage to loci for both asthma and allergic rhinitis on chromosome 12q 14.3-q24.1

As many as 80 percent of asthmatics have atopy and between 60 and 80 percent of allergic asthmatic have coexisting rhinitis. It has been proposed that asthma and allergic rhinitis are essentially the same inflammatory disease of human airways. Previously, we provided the first evidence for linkage of asthma and "high" total serum IgE concentration to chromosome 12q markers among families from Barbados and the US. To identify loci in this chromosome 12q region contributing to the distinct clinical phenotypes of asthma and allergic rhinitis, we conducted linkage analyses among 33 multiplex Barbadian families using densely-spaced microsatellite markers in the 12q14.3-q24.1 region. Maximal evidence for linkage to asthma and allergic rhinitis occurred at markers separated by 4.5 cM. D12S326 and D12S1052 = (NPL = 3.52, p = 0.001 and 1.72, p = 0.039, respectively), these two markers lie 9.13 cM downstream from IFNG. There was no evidence of linkage to either phenotype at markers flanking STAT6. These results suggest that a common gene on the long arm of chromosome 12 is important for both asthma and allergic rhinitis.(AU)

Linkage analysis of asthma, allergic rhinitis and atrophy to markers on chromosome 12q in families from Barbados - abstract

Findings from numerous studies have demonstrated that there is a strong heritable component to asthma and atrophy, although the genetic pathophysiology of these traits is poorly understood. To identify loci in chromosome 12q1s-q24.1 contributing to asthma and asthma-associated traits, we conducted linkage analyses among 29 multiples Barbadian families. Sib-pair analysis of 10 polymorphic micro satellite markers in 345 full and 219 half-sib pairs from Barbados revealed evidence for linkage of certain markers with a gene(s) controlling asthma (D12S379,p=0.001; D12S311,p=0.010; D12S95,p=0.010; D12S360,p=0.018), allergic rhinitis (D12S1052,p=0.040; D12S311,p=0.005; D12S95,p0.021), total serum IgE concentration (D12S1052,p=0.016; D12S311,p=0.007; D12S360,p=0.013; D12S78,p=0.002), and specific IgE antibodies (Alec) to the storage mite Blomia tropicalis (Blot M; D12S311,p=0.006; D12S360,p=0.007; D12S78,p=0.003). Significant evidence of transmission disequilibrium was observe for certain alleles at these loci in addition to high multi allergen IgE Ab. These findings suggest that a gene(s) in the 12q 15-q24.1 region, which contains several candidate genes, including interferon-y (IFNG), is important for asthma and the associated traits of allergic rhinitis, "high" total IgE, and "high" specific IgE (AU).

Nucleotide sequence analysis of a complementary DNA coding for a Blomia tropicalis allergen.

Blomia tropicalis is a mite of allergenic importance in tropical and subtropical areas. A clone (Bt11a) from a B. tropicalis complementary DNA library was expressed in lambda phage and analyzed by plaque radioimmunoassay. The recombinant allergen produced by this clone was bound by IgE in 16 of 32 sera from individuals with asthma with a positive RAST response and none of 3 control sera from healthy individuals with negative RAST response to B. tropicalis. The cDNA insert was amplified by polymerase chain reaction with use of universal primers. A 582-base-pair (bp) fragment was cloned into a pCR II vector. The complete sequence of both strands was determined by using T7, SP6, and internal primers. The sequence shows a 432 bp reading frame with a 34 bp 5' untranslated region and a 116 bp 3' untranslated region with a poly A tail. Analysis of the sequence suggests that it encodes a putative signal peptide of 20 residues and a 124-residue mature protein allergen of 14,206 Da. The nucleotide and the inferred amino acid sequences did not show homology to any known sequence. No potential N-linked glycosylation site was found. The recombinant protein appears to represent a major allergen of the mite B. tropicalis.

Linkage of asthma and total serum IgE concentration to markers on chromosome 12q: evidence from Afro-Caribbean and Caucasian populations.

To identify genes potentially relevant in atopic asthma, we analyzed markers in chromosome 12q15-q24.1 for linkage to asthma and total serum IgE concentration. Sib-pair analyses of 10 markers in 345 full- and 219 half-sib pairs from 29 multiplex Afro-Caribbean families provided evidence for linkage to this region for both asthma and total serum IgE. Certain alleles at these loci showed significant evidence of transmission disequilibrium with both asthma and high IgE. Using 6 of these markers and 11 additional markers, evidence for linkage of total IgE to 12q was also found in 12 Caucasian Amish kindreds (24 nuclear families) by both sib-pair and transmission disequilibrium analyses. These findings suggest that the 12q15-q24.1 region may contain a gene(s) controlling asthma and the associated "high total IgE" trait.

Linkage of asthma and total serum IgE concentration to markers on chromosome 12q: evidence from Afro-Caribbean and Caucasian population

To identify genes potentially relevant in atopic asthma, we analyzed markers in chromosome 12q15-q24.1 for linkage to asthma and total serum Ige concentration. Sib-pair analyses of 10 markers in 345 full- and 219 half-sib pairs from 29 multiplex Afro-Caribbean families provided evidence for linkage to his region for both asthma and total serum IgE. Certain alleles at these loci showed significant evidence of transmission disequilibrium with both asthma and high IgE. Using 6 of these markers and 11 additional markers, evidence for linkage of total IgE to 12q was also found in 12 Caucasian Amish kindreds (24 nuclear families) by both sib-pair and transmission disequilibrium analyses. These findings suggest that the 12q15-q24.1 region may contain a gene(s) contolling asthma and the associated high total IgE. trait.(AU)

Cloning and expression of complementary DNA coding for an allergen with common antibody-binding specificities with three allergens of the house dust mite Blomia tropicalis.

The mite Blomia tropicalis is a potent source of allergens in tropical and subtropical regions. So far, most of these allergens have only been studied by immunoblotting. To characterize them at the molecular level, a lambda gt11 complementary DNA library was constructed from messenger RNA isolated from whole B. tropicalis mites. This library was screened by using pooled sera from patients allergic to B. tropicalis in a plaque IgE radioimmunoassay. A B. tropicalis IgE-positive clone (Bt-M) was selected for immunologic studies. After subcloning into pBluescript (Stratagene, La Jolla, Calif.), it produced a sequence of 310 bp, with a probable amino acid sequence of 72 residues for the expressed peptide. The recombinant protein was transferred to nitrocellulose filters and probed with 100 sera from patients allergic to B. tropicalis. Forty-seven percent of sera reacted with the recombinant allergen. Immunoblottings performed with allergic serum and B. tropicalis-affinity-purified IgE demonstrated that the recombinant protein shares allergenic epitopes with the 11-13, 14, and 16 kd native allergens of B. tropicalis, which are known to be important allergens of this mite.

Membrane assembly studied by spin-label electron spin resonance.

Conventional electron spin resonance (ESR) of spin-labelled lipids and saturation transfer ESR of spin-labelled proteins are used to study lipid-protein interactions and the mobility of integral proteins, respectively, both in biological membranes and in reconstituted lipid-protein systems. Conventional ESR spectra reveal two spin-labelled lipid populations, the mobility of one of which is hindered by direct interaction with the integral membrane proteins. The proportion of the latter component increases with increasing protein content and with increasing selectivity of the lipid species for the protein. The two-component spectra are quantitated by spectral subtraction and addition, and by simulation using the exchange-coupled Bloch equations. Lipid exchange rates at the protein interface obtained by simulation are found to be consistent with fast exchange found by 2H NMR on similar systems and to reflect the lipid selectivity observed by ESR. Protein-reactive covalent spin labels have been used to study the rotational diffusion and aggregation states of membrane proteins via saturation transfer ESR. The integral protein rotation is uniaxial to the first approximation and the anisotropic motion is analyzed to obtain the principal component of the diffusion tensor. The latter is sensitively dependent on the cross-sectional dimensions of the protein in the membrane, and hence on its state of assembly. A variety of new experiments based on the power saturation properties of the spin-labelled components are also used to determine lipid exchange rates, protein translational diffusion rates, and the location and penetration of proteins in membranes.

The role of total IgE as a predictor of asthma in Barbadian subjects - abstract

Assessment of the epidemiology of asthma requires that the asthma phenotype be characterized. A study was conducted in Barbados among 24 families (n = 175 persons). The geometric mean serum total IgE (tIgE) was 559.8 ng/ml, and was significantly higher in asthmatic subjects (n = 88; means = 1352.1) than in non-asthmatic subjects (n = 87; means = 229.6; t-test, p < 0.001). Asthma subjects reported shortness of breath (80.7 percent), cough (77.3 percent), wheezing (72.7 percent). An index of asthma severity was created based on questionnaire data. Shortness of breath, cough and wheeze were similarly correlated with the index of severity; however, none of the symptoms were significantly correlated with tIgE. Similarly, tIgE was not correlated with the severity score of any of the individual variables that comprised the severity score. The findings in this study of Afro-Caribbean subjects living in a tropical setting concur with those of Caucasian subjects living in developed, temperate locales, whereby tIgE is a good means of classifying the presence or absence of asthma. The poor association between tIgE and severity of asthma and asthma symptoms warrants further investigation into the validation of the severity scale, but raises the question regarding the absence of a relationship between tIgE and asthma severity (AU)

Fetal methylmercury study in a Peruvian fish-eating population.

Maternal consumption during pregnancy of methylmercury (MeHg)-contaminated fish in Japan and of MeHg-contaminated bread in Iraq caused psychomotor retardation in the offspring. Studies in Iraq suggested adverse fetal effects when maternal hair mercury concentrations were as low as 20 ppm. This prospective study involved 131 infant-mother pairs in Mancora, Peru with peak maternal hair MeHg levels during pregnancy from 1.2 ppm to 30.0 ppm, geometric mean 8.3. The MeHg was believed to be derived from marine fish in the diet. There was no increase in the frequency of neurodevelopmental abnormalities in early childhood. The possible role of selenium or other protective mechanisms in marine fish is discussed. This previously unpublished study was conducted between 1981 and 1984. Our report of August 1985 to the funding agencies has been circulated, and the data were presented at the Twelfth International Neurotoxicology Conference in Hot Spring, Arkansas, October 30 to November 2, 1994. The current account has not been modified or updated since 1985. For reference to interim publications on fetal MeHg studies in Iraq and New Zealand see Marsh et al., 1995.

IgE antibodies to four mite allergens in atopics and non-atopics living in Barbados - abstract

The prevalence of specific IgE (RAST) to Blomia tropicalis (Bt) was evaluated for 64 individuals from four families residing in Barbados, with self-reported atopic asthma (AA) and/or self-reported allergic rhinitis (AR) or individuals with no reported atopic disease (NA). The presence of specific IgE antibodies that reacted with components of Chortoglyphus arcuatus (Ca), Dermatophagoides pteronyssinus (Dp) and Euroglyphus maynei (Em) was also evaluated; components from Ca, Dp and Em were separated by SDS-PAGE, transferred to nitrocellulose membranes and screened with sera from the 22 AAs, 17 ARs and 25 NAs. Total serum IgE was significantly higher in individuals with self-reported AA (logIgE = 977 ng/ml) than in individuals reporting no AA (logIgE = 323 ng/ml). There was a significant difference between the number of AAs who were Bt-positive according to RAST (68 percent) and the number of individuals without AA(p=0.002). IgE antibodies to Ch and Em were significantly higher in individuals with AA than in those without AA (p = 0.001 and p = 0.005, respectively), and there was a weak correlation between IgE antibodies to Dp and self-reported AA (p=0.05). A significant pattern of conversion of response to certain bands within families was observed (AU)

Sensitivity to blomia tropicalis among allergic individuals in Barbados - abstract

The prevalence of specific IgE (RAST) to tropical house dust mite Blomia tropicalis (Bt) was studied in 126 related individuals with self-reported atopic asthma (AA) and/or self-reported allergic rhinitis (AR) and individuals with no reported atopic disease. RAST results were considered positive when a serum bound > 5 percent of the total counts (percent TCB) added; 17 (65.4 percent) AA were positive to Bt, 7 (29.2 percent) AR without AA were positive to Bt, and 16 (21.9 percent) individuals reporting no AA or AR were positive to Bt. Total serum IgE was significantly higher in individuals with self-reported AA (750 ng/ml) than in individuals reporting no AA (282 ng/ml; Student's t test, p = 0.02). There was no association between total serum IgE and self-reported AR. Additionally, total IgE was weakly correlated with RAST (Bt) for all individuals (r=0.349, p=0.001). Subjects with self-reported AA had a significantly higher mean percentage TCB (19 + 17) than individuals without self-reported AA (10 + 14; Student's test, p<0.05). This study suggests that sensitivity to Bt is common in individuals with atopic asthma living in Barbados (AU)

Gangliosides in acetylcholine receptor-rich membranes from Torpedo marmorata and Discopyge tschudii.

The ganglioside composition of membranes enriched in nicotinic acetylcholine receptor (AChR) from the electric rays Discopyge tschudii and Torpedo marmorata has been determined, and compared to that of total electric organ. A ganglioside having the chromatographic mobility of GM2 constitutes the major ganglioside (approximately 60%) in total D. tschudii electric organ, followed by a component with the mobility of GD3 (approximately 10%), and a component running just below GD1a (about 12%). Minor constituents running as GM3 (2%) and as polysialogangliosides (comprising 8-15%) were also observed. Purified native membranes of D. tschudii and T. marmorata displayed a similar profile, except that they were richer in a GM1-like component, and the proportion of GM2-like gangliosides was lower than that in total electric organ. Using a 125I-cholera toxin overlay assay on neuraminidase-treated high-performance thin layer chromatograms, the presence of GM1, GD1a and trace amounts of GD1b and GT1 (or GQ) were detected in D. Tschudii total membranes. Immunocytochemical trechniques showed the co-localization of gangliosides GQ1c/GT1c/GP1c, recognized by the monoclonal antibody Q211, and the AChR at the ventral, innervated face of the electrocyte.

Effect of local anaesthetics on steroid-nicotinic acetylcholine receptor interactions in native membranes of Torpedo marmorata electric organ.

Interactions between steroids and the nicotinic acetylcholine receptor (AChR) have been studied in native membrane vesicles from Torpedo marmorata electric organ by electron spin resonance (ESR) and fluorescence techniques. ESR spectra of spin-labelled cholestane (CSL) revealed that this steroid probe was incorporated into the AChR-rich membrane vesicles in regions which were to a certain extent enriched preferentially in the steroid, both in the presence and in the absence of local anaesthetics. Since the nitroxide group present in CSL is also a paramagnetic quencher of the intrinsic protein fluorescence, this property was used to characterize the AChR-steroid interactions. The quenching induced by CSL was sensitive both to AChR concentration and to the action of cholinergic agonists. In competition experiments, the ability of CSL to quench the AChR intrinsic fluorescence was markedly inhibited by benzocaine, tetracaine and QX-222 (a quaternary trimethylammonium derivative of lidocaine), and was totally inhibited by procaine. The effectiveness of local anaesthetics in inhibiting CSL-induced quenching followed the order: procaine much greater than benzocaine approximately greater than tetracaine greater than QX-222. This inhibition effect was shown not to be charge-dependent. The data can be interpreted in terms of a model requiring specific association sites for local anaesthetics on the hydrophobic surface of the AChR which at least partially overlap with those for steroids.

Methylmercury in populations eating large quantities of marine fish.

A Peruvian population was identified that was chronically exposed to methylmercury from the long-term consumption of ocean fish. The weekly fish intake averaged 10.1 kg per average family of 6.2 persons. Blood methylmercury concentrations ranged from 11 to 275 ng/ml, with a mean of 82 ng/ml. Paresthesias were reported by 29.5% of the population. In contrast, a nearby control population had a mean weekly fish consumption of 1.9 kg per average family of 6.4 persons. Their blood methylmercury levels were 3.3-25.1 ng/ml, with a mean of 9.9 ng/ml. Paresthesias were reported by 49.5% of this control group. No individual was identified with symptoms or signs that could be attributed to methylmercury intoxication.