Summary
High bone mineral density on routine dual energy X-ray absorptiometry (DXA) may indicate an underlying skeletal dysplasia. Two hundred fifty-eight individuals with unexplained high bone mass ...(HBM), 236 relatives (41% with HBM) and 58 spouses were studied. Cases could not float, had mandible enlargement, extra bone, broad frames, larger shoe sizes and increased body mass index (BMI). HBM cases may harbour an underlying genetic disorder.
Introduction
High bone mineral density is a sporadic incidental finding on routine DXA scanning of apparently asymptomatic individuals. Such individuals may have an underlying skeletal dysplasia, as seen in
LRP5
mutations. We aimed to characterize unexplained HBM and determine the potential for an underlying skeletal dysplasia.
Methods
Two hundred fifty-eight individuals with unexplained HBM (defined as L1 Z-score ≥ +3.2 plus total hip Z-score ≥ +1.2, or total hip Z-score ≥ +3.2) were recruited from 15 UK centres, by screening 335,115 DXA scans. Unexplained HBM affected 0.181% of DXA scans. Next 236 relatives were recruited of whom 94 (41%) had HBM (defined as L1 Z-score + total hip Z-score ≥ +3.2). Fifty-eight spouses were also recruited together with the unaffected relatives as controls. Phenotypes of cases and controls, obtained from clinical assessment, were compared using random-effects linear and logistic regression models, clustered by family, adjusted for confounders, including age and sex.
Results
Individuals with unexplained HBM had an excess of sinking when swimming (7.11 3.65, 13.84,
p
< 0.001; adjusted odds ratio with 95% confidence interval shown), mandible enlargement (4.16 2.34, 7.39,
p
< 0.001), extra bone at tendon/ligament insertions (2.07 1.13, 3.78,
p
= 0.018) and broad frame (3.55 2.12, 5.95,
p
< 0.001). HBM cases also had a larger shoe size (mean difference 0.4 0.1, 0.7 UK sizes,
p
= 0.009) and increased BMI (mean difference 2.2 1.3, 3.1 kg/m
2
,
p
< 0.001).
Conclusion
Individuals with unexplained HBM have an excess of clinical characteristics associated with skeletal dysplasia and their relatives are commonly affected, suggesting many may harbour an underlying genetic disorder affecting bone mass.
Bacterial infections are known to alter glucose metabolism within tissues via mechanisms of inflammation. We conducted this study to examine whether insulin response genes are differentially ...expressed in gingival tissues, comparing samples from experimental gingivitis and periodontitis subjects to those from healthy individuals. Total RNA was extracted from gingival biopsies from 26 participants: 8 periodontally healthy, 9 experimental gingivitis, and 9 periodontitis subjects. Gene expression patterns were evaluated with a polymerase chain reaction array panel to examine 84 candidate genes involved with glucose metabolism, insulin resistance, and obesity. Array data were evaluated with a t test adjusted by the false discover rate (P < 0.05), and ingenuity pathway analysis was performed for statistical testing of pathways. Although tissue samples were not sufficient to enable protein quantification, we confirmed the upregulation of the key gene using lipopolysaccharide-stimulated primary gingival epithelial cells by Western blot. The mRNA expression patterns of genes that are associated with insulin response and glucose metabolism are markedly different in experimental gingivitis subjects compared with healthy controls. Thirty-two genes are upregulated significantly by at least 2-fold, adjusted for false discover rate (P < 0.05). Periodontitis subjects show similar but attenuated changes in gene expression patterns, and no genes meet the significance criteria. Ingenuity pathway analysis demonstrates significant activation of the carbohydrate metabolism network in experimental gingivitis but not in periodontitis. G6PD protein increases in response to lipopolysaccharide stimulation in primary gingival epithelial cells, which is in the same direction as upregulated mRNA in tissues. Acute gingival inflammation may be associated with tissue metabolism changes, but these changes are not evident in chronic periodontitis. This study suggests that acute gingival inflammation may induce localized changes that modify tissue insulin/glucose metabolism.
Background
Fast diagnosis and delivery of treatment to patients experiencing acute stroke can reduce subsequent disability. While telemedicine can improve rural community access to specialists and ...facilitate timely diagnosis and treatment decisions, it is not widely used for stroke in Australia.
Aim
Identifying the barriers and facilitators to clinician engagement with, and utilisation of, telemedicine consultations could expedite implementation in rural and remote locations.
Methods
Purposive sampling was used to identify and recruit medical and nursing staff varying in telemedicine experience across one hospital department. Twenty‐four in‐depth, face‐to‐face interviews were conducted examining aspects surrounding stroke telemedicine uptake. Inductive qualitative thematic analysis was undertaken, and two further researchers verified coding.
Results
The main barriers identified were contrasting opinions about the utility of thrombolysis for treating acute stroke, lack of confidence in the telemedicine system, perceived limited need for specialist advice and concerns about receiving advice from an unfamiliar doctor. Facilitators included assistance with diagnosis and treatment, the need for a user‐friendly system and access to specialists for complex cases.
Conclusions
Acceptability of telemedicine for acute stroke was multifaceted and closely aligned with regional clinician beliefs about the value of thrombolysis for stroke, highlighting an important area for education. Addressing beliefs about treatment efficacy and other perceived barriers is important for establishing a stroke telemedicine programme.
During apoptosis, the interphase microtubule network is dismantled then later replaced by a novel, non-centrosomal microtubule array. These microtubules assist in the peripheral redistribution of ...nuclear fragments in the apoptotic cell; however, the regulation of apoptotic microtubule assembly is not understood. Here, we demonstrate that microtubule assembly depends upon the release of nuclear RanGTP into the apoptotic cytoplasm because this process is blocked in apoptotic cells overexpressing dominant-negative GDP-locked Ran (T24N). Actin-myosin-II contractility provides the impetus for Ran release and, consequently, microtubule assembly is blocked in blebbistatin- and Y27632-treated apoptotic cells. Importantly, the spindle-assembly factor TPX2 (targeting protein for Xklp2), colocalises with apoptotic microtubules, and siRNA silencing of TPX2, but not of the microtubule motors Mklp1 and Kid, abrogates apoptotic microtubule assembly. These data provide a molecular explanation for the assembly of the apoptotic microtubule network, and suggest important similarities with the process of RanGTP- and TPX2-mediated mitotic spindle formation.
Uridine diphosphate (UDP) is a proinflammatory nucleotide implicated in inflammatory bowel disease. Intestinal alkaline phosphatase (IAP) is a gut mucosal defense factor capable of inhibiting ...intestinal inflammation. We used the malachite green assay to show that IAP dephosphorylates UDP. To study the anti-inflammatory effect of IAP, UDP or other proinflammatory ligands (LPS, flagellin, Pam3Cys, or TNF-α) in the presence or absence of IAP were applied to cell cultures, and IL-8 was measured. UDP caused dose-dependent increase in IL-8 release by immune cells and two gut epithelial cell lines, and IAP treatment abrogated IL-8 release. Costimulation with UDP and other inflammatory ligands resulted in a synergistic increase in IL-8 release, which was prevented by IAP treatment. In vivo, UDP in the presence or absence of IAP was instilled into a small intestinal loop model in wild-type and IAP-knockout mice. Luminal contents were applied to cell culture, and cytokine levels were measured in culture supernatant and intestinal tissue. UDP-treated luminal contents induced more inflammation on target cells, with a greater inflammatory response to contents from IAP-KO mice treated with UDP than from WT mice. Additionally, UDP treatment increased TNF-α levels in intestinal tissue of IAP-KO mice, and cotreatment with IAP reduced inflammation to control levels. Taken together, these studies show that IAP prevents inflammation caused by UDP alone and in combination with other ligands, and the anti-inflammatory effect of IAP against UDP persists in mouse small intestine. The benefits of IAP in intestinal disease may be partly due to inhibition of the proinflammatory activity of UDP.
•A simple method to perform flow cytometry on bone marrow trephines suspensions.•This method is a powerful tool when no other material is available for diagnosis.•Excellent correlation with bone ...marrow aspirates and blood has been demonstrated.
An adequate bone marrow aspirate is essential for a rapid diagnosis of acute leukaemia by multicolour flow cytometry enabling the simultaneous assessment of multiple antigens on the cell surface as well as intracellular or nuclear ones.
In the context of acute leukaemia, it is important to have a diagnosis of the blasts lineage as soon as possible to decide the appropriate treatment. This is sometimes delayed due to difficulties in obtaining a bone marrow aspirate due to a “dry tap”.
In this study we evaluated retrospectively cell markers results by flow cytometry of unfixed bone marrow trephines of 65 patients with leukaemia at diagnosis and including a few after treatment.
Our aims were:
1) To compare cell markers results between bone marrow trephine (BMT) and bone marrow aspirate (BMA) 24 cases and BMT with peripheral blood (PB) 14 cases in paired samples to establish if they were reproducible with results of the unfixed bone marrow trephine biopsies.
2) To ascertain a precise diagnosis in 27 (42%) of the cases in which only a bone marrow trephine was available.
We demonstrated that unfixed bone marrow trephine provides an adequate and representative cell suspension for flow cytometry and it is a powerful tool when no other material (bone marrow aspirate or peripheral blood) is available to make a rapid diagnosis.
Furthermore when marrow aspirate or peripheral blood paired samples were available, flow cytometry results obtained were identical across all the sample types.
Applicability to the clinical laboratory:
We described a method to obtain a cell suspension from core biopsies that can easily be implemented routinely in a laboratory that performs diagnostic flow cytometry immunophenotyping. This method is simple, inexpensive and it doesn’t require extra equipment.
Objective
To evaluate the prevalence of elevations of anti‐cyclic citrullinated peptide‐3 (anti‐CCP3) antibody, rheumatoid factor IgM (RF‐IgM) and serum calprotectin (sCP) in pre–rheumatoid arthritis ...(RA) as well as the diagnostic accuracies of these biomarkers for the timing of diagnosis of future RA.
Methods
A total of 215 RA cases, each with approximately three pre‐RA diagnoses and one post–RA diagnosis serum sample, and controls were identified from the Department of Defense Serum Repository. All case samples and a single sample from each control subject were tested for anti‐CCP3 (IgG), RF‐IgM, and sCP. The diagnostic accuracies of biomarkers for future RA were evaluated.
Results
Anti‐CCP3, RF‐IgM, and sCP were elevated in pre‐RA, with anti‐CCP3 and sCP significantly elevated compared with RF‐IgM at the earliest time points. Within the cases, the combination of anti‐CCP3 and RF‐IgM positivity had a positive predictive value (PPV) of 35.6% for a diagnosis of RA in 3 years or less, which is significantly higher than the PPV of 18.7% for anti‐CCP3 positivity alone (P < 0.001). A combination of anti‐CCP3, RF‐IgM, and sCP had the highest PPV (53.0%) for a diagnosis of RA in 3 years or less; however, this was not significantly higher than the PPV for anti‐CCP3 and RF‐IgM positivity (P = 0.248).
Conclusion
Anti‐CCP3, RF‐IgM, and sCP are elevated in pre‐RA; furthermore, combinations of elevations of these biomarkers are more commonly seen in the period of less than or equal to 3 years to diagnosis. This may be considered in creating inclusion criteria in prevention trials in RA. In addition, the biologic relationships of these biomarkers in pre‐RA need exploration.
The observational relationship between obesity and periodontitis is widely known, yet causal evidence is lacking. Our objective was to investigate causal associations between periodontitis and body ...mass index (BMI).
We performed Mendelian randomization analyses with BMI-associated loci combined in a genetic risk score (GRS) as the instrument for BMI. All analyses were conducted within the Gene-Lifestyle Interactions and Dental Endpoints (GLIDE) Consortium in 13 studies from Europe and the USA, including 49,066 participants with clinically assessed (seven studies, 42.1% of participants) and self-reported (six studies, 57.9% of participants) periodontitis and genotype data (17,672/31,394 with/without periodontitis); 68,761 participants with BMI and genotype data; and 57,871 participants (18,881/38,990 with/without periodontitis) with data on BMI and periodontitis.
In the observational meta-analysis of all participants, the pooled crude observational odds ratio (OR) for periodontitis was 1.13 95% confidence interval (CI): 1.03, 1.24 per standard deviation increase of BMI. Controlling for potential confounders attenuated this estimate (OR = 1.08; 95% CI:1.03, 1.12). For clinically assessed periodontitis, corresponding ORs were 1.25 (95% CI: 1.10, 1.42) and 1.13 (95% CI: 1.10, 1.17), respectively. In the genetic association meta-analysis, the OR for periodontitis was 1.01 (95% CI: 0.99, 1.03) per GRS unit (per one effect allele) in all participants and 1.00 (95% CI: 0.97, 1.03) in participants with clinically assessed periodontitis. The instrumental variable meta-analysis of all participants yielded an OR of 1.05 (95% CI: 0.80, 1.38) per BMI standard deviation, and 0.90 (95% CI: 0.56, 1.46) in participants with clinical data.
Our study does not support total adiposity as a causal risk factor for periodontitis, as the point estimate is very close to the null in the causal inference analysis, with wide confidence intervals.
There is increasing support for HPV vaccination in the pharmacy setting, but the availability of the HPV vaccine is not well known. Additionally, little is known about perceptions of medical ...providers regarding referring patients to community pharmacies for HPV vaccination. The purpose of this study was to determine HPV vaccine availability in community pharmacies and to understand, among family medicine and obstetrics-gynecology providers, the willingness of and perceived barriers to referring patients for HPV vaccination in a pharmacy setting. HPV vaccine availability data were collected from pharmacies in a southern region of the United States. Family medicine and obstetrics-gynecology providers were surveyed regarding vaccine referral practices and perceived barriers to HPV vaccination in a community pharmacy. Results indicated the HPV vaccine was available in most pharmacies. Providers were willing to refer patients to a community pharmacy for HPV vaccination, despite this not being a common practice, likely due to numerous barriers reported. Pharmacist-administered HPV vaccination continues to be a commonly reported strategy for increasing HPV vaccination coverage. However, coordinated efforts to increase collaboration among vaccinators in different settings and to overcome systematic and legislative barriers to increasing HPV vaccination rates are still needed.
Many workers have recognised the link between Nuclear Magnetic Resonance (NMR) derived T2 distributions and pore size distributions in reservoir rocks. This property has been used to develop models ...to obtain primary drainage capillary pressure curves from T2 distributions. These models often assume that the rocks pore space resembles a simple bundle of capillary tubes. They do not consider the existence of multiple pore body connections and pore body restrictions/throats. The most successful models utilise variable scaling factors to convert T2 times to pore diameters and hence capillary pressure. The variable scaling factor approach recognises the existence of variable surface relaxivity throughout the pore space due to variations in mineralogy and pore topography. This investigation uses SCAL data from the ART NMR Sandstone Rock Catalogue to obtain core calibrated variable scaling factors for 174 reservoir sandstone samples. The depositional environments for these samples include; aeolian, fluvial, coastal and shallow and deep marine. The samples used have a wide variety of mineralogy, diagenetic overprints and cover six orders of magnitude in absolute permeability. Three different methods for obtaining the scaling factors are presented and the relative merits of each discussed. A global model to predict capillary pressure from NMR T2 distributions in reservoir sandstones has been developed using correlations between the variable scaling factors and permeability.
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