Identifying characteristics of an effective fracture liaison service: systematic literature review.

Fracture liaison services (FLS) have been demonstrated to improve outcomes following osteoporotic fracture. The aim of this systematic literature review (SLR) was to determine the characteristics of an FLS that lead to improved patient outcomes. We conducted a SLR, including articles published between 2000 and February 2017, using global (Medline, EMBASE, PubMed and Cochrane Library) and local databases. Studies including patients aged ≥ 50 years with osteoporotic fractures enrolled in an FLS were assessed. Information extracted from each article included key person coordinating the FLS (physician, nurse or other healthcare professional), setting (hospital vs community), intensity (single vs multiple), duration (long vs short term), fracture type and gender. A meta-analysis of randomised controlled trials was conducted based on the key person coordinating the FLS. Out of 7236 articles, 57 were considered to be high quality and identified for further analysis. The SLR identified several components which contributed to FLS success, including multidisciplinary involvement, driven by a dedicated case manager, regular assessment and follow-up, multifaceted interventions and patient education. Meta-analytic data confirm the effectiveness of an FLS following an osteoporotic fracture: approximate 27% increase in the likelihood of BMD testing and up to 21% increase in the likelihood of treatment initiation compared with usual care. The balance of evidence indicates that the multifaceted FLS and dedicated coordination are important success factors that contribute to effective FLS interventions which reduce fracture-related morbidity and mortality.

Economic impact and cost-effectiveness of fracture liaison services: a systematic review of the literature.

Fracture liaison services (FLS), implemented in different ways and countries, are reported to be a cost-effective or even a cost-saving secondary fracture prevention strategy. This presumed favorable cost-benefit relationship is encouraging and lends support to expanded implementation of FLS per International Osteoporosis Foundation Best Practice Standards. This study summarizes the economic impact and cost-effectiveness of FLS implemented to reduce subsequent fractures in individuals with osteoporosis. This systematic review identified studies reporting economic outcomes for FLS in osteoporotic patients aged 50 and older through a comprehensive search of MEDLINE, EMBASE, Cochrane Central, and PubMed of studies published January, 2000 to December, 2016. Grey literature (e.g., Google scholar, conference abstracts/posters) were also hand searched through February 2017. Two independent reviewers screened titles and abstracts and conducted full-text review on qualified articles. All disagreements were resolved by discussion between reviewers to reach consensus or by a third reviewer. In total, 23 qualified studies that evaluated the economic aspects of FLS were included: 16 cost-effectiveness studies, 2 cost-benefit analyses, and 5 studies of cost savings. Patient populations varied (prior fragility fracture, non-vertebral fracture, hip fracture, wrist fracture), and FLS strategies ranged from mail-based interventions to comprehensive nurse/physician-coordinated programs. Cost-effectiveness studies were conducted in Canada, Australia, USA, UK, Japan, Taiwan, and Sweden. FLS was cost-effective in comparisons with usual care or no treatment, regardless of the program intensity or the country in which the FLS was implemented (cost/QALY from $3023-$28,800 US dollars (USD) in Japan to $14,513-$112,877 USD in USA. Several studies documented cost savings. FLS, implemented in different ways and countries, are reported to be cost-effective or even cost-saving. This presumed favorable cost-benefit relationship is encouraging and lends support to expanded implementation of FLS per International Osteoporosis Foundation Best Practice Standards.

Fracture liaison services for osteoporosis in the Asia-Pacific region: current unmet needs and systematic literature review.

The analysis aimed to identify the treatment gaps in current fracture liaison services (FLS) and to provide recommendations for best practice establishment of future FLS across the Asia-Pacific region. The findings emphasize the unmet need for the implementation of new programs and provide recommendations for the refinement of existing ones. The study's objectives were to evaluate fracture liaison service (FLS) programs in the Asia-Pacific region and provide recommendations for establishment of future FLS programs. A systematic literature review (SLR) of Medline, PubMed, EMBASE, and Cochrane Library (2000-2017 inclusive) was performed using the following keywords: osteoporosis, fractures, liaison, and service. Inclusion criteria included the following: patients ≥ 50 years with osteoporosis-related fractures; randomized controlled trials or observational studies with control groups (prospective or retrospective), pre-post, cross-sectional and economic evaluation studies. Success of direct or indirect interventions was assessed based on patients' understanding of risk, bone mineral density assessment, calcium intake, osteoporosis treatment, re-fracture rates, adherence, and mortality, in addition to cost-effectiveness. Overall, 5663 unique citations were identified and the SLR identified 159 publications, reporting 37 studies in Asia-Pacific. These studies revealed the unmet need for public health education, adequate funding, and staff resourcing, along with greater cooperation between departments and physicians. These actions can help to overcome therapeutic inertia with sufficient follow-up to ensure adherence to recommendations and compliance with treatment. The findings also emphasize the importance of primary care physicians continuing to prescribe treatment and ensure service remains convenient. These findings highlight the limited evidence supporting FLS across the Asia-Pacific region, emphasizing the unmet need for new programs and/or refinement of existing ones to improve outcomes. With the continued increase in burden of fractures in Asia-Pacific, establishment of new FLS and assessment of existing services are warranted to determine the impact of FLS for healthcare professionals, patients, family/caregivers, and society.

Risk factor profiling and study of atherosclerotic coronary plaque burden and morphology with coronary computed tomography angiography in coronary artery disease among young Indians.

BACKGROUND: With a decade earlier manifestation of coronary artery disease (CAD) and paucity of data characterizing coronary plaque with coronary computed tomography angiography (CTA) among CAD patients in India, the study aimed to analyze patient characteristics and coronary plaque burden and morphology in young Indian patients with CAD. METHODS: Serial coronary CTA was performed in 96 CAD patients. Among 60 patients ≤40years, risk factor and coronary plaque analysis done using a 256- slice CT in 33 patients with acute coronary syndrome (ACS) was compared with 27 patients with chronic stable angina (CSA). Univariate and multivariate analysis was performed, for factors predicting ACS as an outcome among young CAD patients. In addition, quantitative and morphologic plaque characteristics were compared among those ≤40years and >40years. RESULTS: Among 60 subjects ≤40years of age, 77% had dyslipidemia, 70% high lipoprotein(a), 53.33% elevated hs-CRP and 73.33% raised homocysteine. hs-CRP (9.33 vs. 3.33, p value=0.01) and serum triglycerides (178.67 vs. 141.42, p value=0.03) were markedly raised in patients with ACS. Statistically significant number of patients in the ACS group had positive remodelling (ACS, 69.7% vs. CSA, 14.8%; p value<0.001), low attenuation plaque (ACS, 63.6% vs. CSA, 11.1%; p value<0.001), spotty calcification (ACS, 36.4% vs. CSA, 3.7%; p=0.002) and non-calcified plaque (ACS, 69.7% vs. CSA, 11.1%; p<0.001). On multivariate analysis, only lipoprotein (a) >30mg/dL and composite vulnerability score maintained a predictive value for ACS in patients ≤40years. Statistically significant number of patients in the younger age group had higher mean total plaque volume (66.17±41.31mm3 vs. 44.94±49.07mm3; p=0.03), remodelling index (1.5±0.27 vs. 1.08±0.38; p=0.0001). Comparing culprit lesion characteristics of ACS patients in the two age groups, positive remodelling (95.8% vs. 70.5%, p=0.02), spotty calcification (50% vs. 11.7%, p=0.01) and non-calcified plaque (95.8% vs. 70.5%, p=0.02) were significantly more frequent in patients ≤40years. CONCLUSION: ACS in young Indians is characterized by a higher prevalence of both conventional and newer risk factors. In addition, culprit lesions in young ACS patients are more frequently characterized by coronary plaques with high risk morphological features. This may have implications in terms of preventive strategies to identify this high-risk group.

Occupation and cancer in Britain.

BACKGROUND: Prioritising control measures for occupationally related cancers should be evidence based. We estimated the current burden of cancer in Britain attributable to past occupational exposures for International Agency for Research on Cancer (IARC) group 1 (established) and 2A (probable) carcinogens. METHODS: We calculated attributable fractions and numbers for cancer mortality and incidence using risk estimates from the literature and national data sources to estimate proportions exposed. RESULTS: 5.3% (8019) cancer deaths were attributable to occupation in 2005 (men, 8.2% (6362); women, 2.3% (1657)). Attributable incidence estimates are 13 679 (4.0%) cancer registrations (men, 10 063 (5.7%); women, 3616 (2.2%)). Occupational attributable fractions are over 2% for mesothelioma, sinonasal, lung, nasopharynx, breast, non-melanoma skin cancer, bladder, oesophagus, soft tissue sarcoma, larynx and stomach cancers. Asbestos, shift work, mineral oils, solar radiation, silica, diesel engine exhaust, coal tars and pitches, occupation as a painter or welder, dioxins, environmental tobacco smoke, radon, tetrachloroethylene, arsenic and strong inorganic mists each contribute 100 or more registrations. Industries and occupations with high cancer registrations include construction, metal working, personal and household services, mining, land transport, printing/publishing, retail/hotels/restaurants, public administration/defence, farming and several manufacturing sectors. 56% of cancer registrations in men are attributable to work in the construction industry (mainly mesotheliomas, lung, stomach, bladder and non-melanoma skin cancers) and 54% of cancer registrations in women are attributable to shift work (breast cancer). CONCLUSION: This project is the first to quantify in detail the burden of cancer and mortality due to occupation specifically for Britain. It highlights the impact of occupational exposures, together with the occupational circumstances and industrial areas where exposures to carcinogenic agents occurred in the past, on population cancer morbidity and mortality; this can be compared with the impact of other causes of cancer. Risk reduction strategies should focus on those workplaces where such exposures are still occurring.

[Dental fluorosis: an epidemiological investigation in the area of Ouardanine in Tunisia]. / La fluorose dentaire: enquête epidémiologique dans la région de ouardanine en Tunisie.

In this work, we carried out a transverse epidemiological investigation about the oral health state of pupils in the Ouardanine area. The investigation concerned 300 fifteen-year-old pupils. An amount of fluoride was administrated within drinking water. Further studies, within few years, will be desirableto follow the fluorosis evolution in this area.

Dentin alteration of deciduous teeth in human hypophosphatemic rickets.

Familial hypophosphatemic rickets is in most cases transmitted as an X-linked dominant trait and results from mutation of the PHEX gene, predominantly expressed in osteoblast and odontoblast. Patients have been reported to display important dentin defects, and therefore, we explored the dentin structure, composition, and distribution of extracellular matrix (ECM) molecules in hypophosphatemic human deciduous teeth. Compared to age-matched controls, the dentin from hypophosphatemic patients exhibited major differences: presence of large interglobular spaces resulting from the lack of fusion of calcospherites in the circumpulpal dentin; defective mineralization in the interglobular spaces contrasting with normal Ca-P levels in the calcospherites on X-ray microanalysis; abnormal presence of low-molecular weight protein complexes recognized on Western blots by antibodies against matrix extracellular phosphoglycoprotein (MEPE), dentin sialoprotein, osteopontin, and reduced osteocalcin (OC) level; and accumulation in the interglobular spaces of immunolabeling with antibodies against DSP, dentin matrix protein, bone sialoprotein, MEPE and OC, while chondroitin/dermatan sulfate glycosaminoglycans were exclusively located inside calcospherites. Alterations of the post-translational processing or partial degradation of some ECM appear as key factors in the formation of the defective hypophosphatemic dentin.

Down regulation of humoral immunity in chickens due to carbendazim.

This study was planned to investigate the effect of very low dose of carbendazim on the humoral immune response in the chicken. Sixteen adult chickens, earlier vaccinated against New Castle Disease were divided in two experimental groups. Chickens of group I served as control, while group II birds were given a feed containing 200 ppm of carbendazim, which is considered no observable effect level (NOEL) dose, for a period of 6 months. The Humoral immune response was measured by the B-lymphocyte blastogenesis assay using lipopolysaccharide as mitogen and the quantitation of IgG, IgA, IgM levels by using respective antichicken conjugates, through an ELISA method. Total serum proteins, serum gamma-globulins and globulins were measured using commercially available kits. Carbendazim significantly (P< or =0.05) reduced both the B-lymphocyte proliferation and serum IgG, IgM and IgA levels, leading to decreased immunocompetence. At the end of experiment percent decrease in B-lymphocyte proliferation was 20.5% and that in serum IgG, IgM and IgA were 11.2, 22.9 and 28.8%, respectively. The percent decrease in total serum protein, serum gamma-globulins and serum globulins were 14.6, 18.5 and 9.7%, respectively. Results clearly indicated down regulation of humoral immunity by carbendazim at NOEL dose.

Mechanism of specific target recognition and RNA hydrolysis by ribonucleolytic toxin restrictocin.

Restrictocin, a member of the fungal ribotoxin family, specifically cleaves a single phosphodiester bond in the 28S rRNA and potently inhibits eukaryotic protein synthesis. Residues Tyr47, His49, Glu95, Phe96, Pro97, Arg120, and His136 have been predicted to form the active site of restrictocin. In this study, we have individually mutated these amino acids to alanine to probe their role in restrictocin structure and function. The role of Tyr47, His49, Arg120, and His136 was further investigated by making additional mutants. Mutating Arg120 or His136 to alanine or the other amino acids rendered the toxin completely inactive, whereas mutating Glu95 to alanine only partially inactivated the toxin. Mutation of Phe96 and Pro97 to Ala had no effect on the activity of restrictocin. The Tyr47 to alanine mutant was inactive in inhibiting protein synthesis, and had a nonspecific ribonuclease activity on 28S rRNA similar to that shown previously for the His49 to Ala mutant. Unlike the His136 to Ala mutant, the double mutants containing Tyr47 or His49 mutated to alanine along with His136 did not compete with restrictocin to cause a significant reduction in the extent of cleavage of 28S rRNA. In a model of restrictocin and a 29-mer RNA substrate complex, residues Tyr47, His49, Glu95, Arg120, and His136 were found to be near the cleavage site on RNA. It is proposed that in restrictocin Glu95 and His136 are directly involved in catalysis, Arg120 is involved in the stabilization of the enzyme-substrate complex, Tyr47 provides structural stability to the active site, and His49 determines the substrate specificity.

Down-regulation of specific members of the glutamine synthetase gene family in alfalfa by antisense RNA technology.

Glutamine synthetase (GS) catalyzes the ATP-dependent condensation of NH3 with glutamate to produce glutamine. In plants GS is an octameric enzyme and is located either in the cytoplasm (GS1) or in the chloroplast (GS2). Two distinct classes of GS1 genes with unique 3'-untranslated region (3'UTR) have been identified in alfalfa. We have demonstrated that the two classes exhibit differential expression pattern in the different plant organs suggesting different functional roles for the different isozymes. To determine the functional significance of the two classes of GS1 genes in alfalfa, we have utilized antisense gene constructs aimed specifically at the 3'UTR of the two GS1 genes and introduced them individually into alfalfa. Our data show that the gene constructs are effective in lowering the corresponding transcript level very effectively though there were organ-specific differences in the level of reduction. No transcript corresponding to the antisense gene construct was detected in any of the alfalfa transformants though they accumulated to significant levels in transgenic tobacco containing the same construct. This suggests that the antisense transcript was not stable in the presence of the homologous target sequence. Transgenic alfalfa with up to 80% reduction in the transcript level corresponding to each gene class, however, showed no reduction in GS activity or GS1 polypeptide level. The results suggest that GS1 mRNA levels are not rate-limiting for GS1 polypeptide synthesis and that GS levels are controlled both at the transcriptional and translational/post-translational level.

Coexpression of the maize delta-zein and beta-zein genes results in stable accumulation of delta-zein in endoplasmic reticulum-derived protein bodies formed by beta-zein.

Zeins, the major seed storage proteins of maize, are of four distinct types: alpha, beta, delta, and gamma. They are synthesized on the rough endoplasmic reticulum (ER) in a sequential manner and deposited in ER-derived protein bodies. We investigated the potential for producing sulfur-rich beta-zein and delta-zein proteins in leaf and seed tissues by expressing the corresponding genes in a constitutive manner in transgenic tobacco. The delta-zein and beta-zein, when synthesized individually, were stable in the vegetative tissues and were deposited in unique, zein-specific ER-derived protein bodies. Coexpression of delta-zein and beta-zein genes, however, showed that delta-zein was colocalized in beta-zein-containing protein bodies and that the level of delta-zein was fivefold higher in delta-/beta-zein plants than in delta-zein plants. We conclude that delta-zein interacts with beta-zein and that the interaction has a stabilizing effect on delta-zein.

Putrescine Aminopropyltransferase Is Responsible for Biosynthesis of Spermidine, Spermine, and Multiple Uncommon Polyamines in Osmotic Stress-Tolerant Alfalfa.

The biosynthesis of polyamines from the diamine putrescine is not fully understood in higher plants. A putrescine aminopropyltransferase (PAPT) enzyme activity was characterized in alfalfa (Medicago sativa L.). This enzyme activity was highly specific for putrescine as the initial substrate and did not recognize another common diamine, 1,3-diaminopropane, or higher-molecular-weight polyamines such as spermidine and spermine as alternative initial substrates. The enzyme activity was inhibited by a general inhibitor of aminopropyltransferases, 5[prime]-methylthioadenosine, and by a specific inhibitor of PAPTs, cyclohexylammonium sulfate. The initial substrate specificity and inhibition characteristics of the enzyme activity suggested that it is a classical example of a PAPT. However, this enzyme activity yielded multiple polyamine products, which is uncharacteristic of PAPTs. The major reaction product of PAPT activity in alfalfa was spermidine. The next most abundant products of the enzyme reaction using putrescine as the initial substrate included the tetramines spermine and thermospermine. These two tetramines were distinguished by thin-layer chromatography to be distinct reaction products exhibiting differential rates of formation. In addition, the uncommon polyamines homocaldopentamine and homocaldohexamine were tentatively identified as minor enzymatic reaction products but only in extracts prepared from osmotic stresstolerant alfalfa cultivars. PAPT activity from alfalfa was highest in meristematic shoot tip and floral bud tissues and was not detected in older, nonmeristematic tissues. Product inhibition of the enzyme activity was observed after spermidine was added into the in vitro assay for alfalfa PAPT activity. A biosynthetic pathway is proposed that accounts for the characteristics of this PAPT activity and accommodates a novel scheme by which certain uncommon polyamines are produced in plants.

Scintigraphic detection of a disseminated synovial lymphoma in a postrenal transplant patient.

Post-transplant lymphoproliferative disease is a recognized complication of immunosuppressive therapy, however, articular lymphomas involving the synovlum are very rare. Disseminated synovial lymphoma of the knee with hepatic involvement in a patient after renal transplant was suggested on bone/gallium scintigraphy and confirmed by synovial biopsy. Gallium scanning thus was instrumental in the evaluation, staging, and proper treatment of this rare condition.

Scintigraphic localization of recurrent anastomotic site bleeding in the gastrointestinal tract.

Scanning with Tc-99m labeled RBC was performed in two patients with recurrent postoperative gastrointestinal bleeding after partial colonic resection. Imaging correctly identified the source of bleeding at the anastomotic site in the large bowel, effectively contributing in the patient's treatment planning. Radionuclide scintigraphy provides a simple, noninvasive modality to diagnose and manage difficult clinical situations such as postoperative bleeding.

Accumulation of 15-Kilodalton Zein in Novel Protein Bodies in Transgenic Tobacco.

Zeins, the seed storage proteins of maize, are a group of alcohol-soluble polypeptides of different molecular masses that share a similar amino acid composition but vary in their sulfur amino acid composition. They are synthesized on the rough endoplasmic reticulum (ER) in the endosperm and are stored in ER-derived protein bodies. Our goal is to balance the amino acid composition of the methionine-deficient forage legumes by expressing the sulfur amino acid-rich 15-kD zeins in their leaves. However, it is crucial to know whether this protein would be stable in nonseed tissues of transgenic plants. The major focus of this paper is to compare the accumulation pattern of the 15-kD zein protein with a vacuolar targeted seed protein, [beta]-phaseolin, in nonseed tissues and to determine the basis for its stability/instability. We have introduced the 15-kD zein and bean [beta]-phaseolin-coding sequences behind the 35S cauliflower mosaic virus promoter into tobacco (Nicotiana tabacum) and analyzed the protein's accumulation pattern in different tissues. Our results demonstrate that the 15-kD seed protein is stable not only in seeds but in all nonseed tissues tested, whereas the [beta]-phaseolin protein accumulated only in mid- and postmaturation seeds. Interestingly, zein accumulates in novel protein bodies both in the seeds and in nonseed tissues. We attribute the instability of the [beta]-phaseolin protein in nonseed tissues to the fact that it is targeted to protease-rich vacuoles. The stability of the 15-kD zein could be attributed to its retention in the ER or to the protease-resistant nature of the protein.

Constitutive expression of the beta-phaseolin gene in different tissues of transgenic alfalfa does not ensure phaseolin accumulation in non-seed tissue.

Phaseolin is a glycoprotein that constitutes the major storage protein in bean seeds. The phaseolin gene promoters function in a seed-specific manner. In an attempt to understand if events following transcription of the gene also contribute to the seed-specific accumulation of the phaseolin protein, we studied the effect of substituting the constitutive CaMV-35S promoter for the beta-phaseolin gene promoter on expression of the phaseolin gene in different plant organs. A chimeric gene consisting of the 35S promoter, the coding sequence of the beta-phaseolin gene (all five introns and six exons) and the 3'-flanking region of the beta-phaseolin gene, was introduced into alfalfa via Agrobacterium tumefaciens. While all organs examined shared high levels of phaseolin transcripts, the only organ that showed significant accumulation of the phaseolin protein were the mature seeds. Co-migration of the major immunoreactive polypeptides from the non-seed organs with the authentic beta-phaseolin polypeptides on SDS-PAGE indicates that the protein in non-seed organs undergoes correct post-translational processing and modification, but are more unstable in a non-seed environment.