Context: Subclinical hypothyroidism (SCH) is associated with cardiovascular (CV) risk factors, an... more Context: Subclinical hypothyroidism (SCH) is associated with cardiovascular (CV) risk factors, and possibly CV disease. However, its management remains controversial. Endothelial progenitor cells (EPC), expressing both endothelial and stem cell markers, are known to offer a novel CV risk marker. Objective: The aim of the study was to ascertain whether EPC count or function is reduced in SCH and whether it improves with T 4 therapy. Design and Intervention: EPC were studied in peripheral blood by fluorescence-activated cell sorter and following in vitro cultures before and after T 4 together with CV risk factors in 20 SCH and healthy controls (HC).
Introduction: This paper reports work undertaken to design two new conditionspecific questionnair... more Introduction: This paper reports work undertaken to design two new conditionspecific questionnaires for use in hypothyroidism: the Underactive Thyroid-Dependent Quality of Life Questionnaire (ThyDQoL) and the Underactive Thyroid Treatment Satisfaction Questionnaire (ThyTSQ). Methods: Semi-structured interviews exploring quality of life (QoL) and experiences of treatment were conducted with 30 women and 8 men with hypothyroidism, (mean age 51.9, range 29-79 years), 37/38 treated with thyroxine, recruited from hospital clinics and primary care. Results: Despite thyroxine treatment, most interviewees reported negative impact of hypothyroidism on QoL, particularly on energy, physical capabilities, motivation, physical appearance and weight. The newly designed ThyDQoL has 18 domains covering these and other aspects of life affected by hypothyroidism. It is an individualised measure of patients' perceived impact of hypothyroidism on their QoL, which takes into account the importance of personally applicable life domains to the patient. A 7-item measure of satisfaction with current treatment was designed (ThyTSQ-Present) but interviews also indicated the need for a separate 4-item section measuring satisfaction with past treatment around the time of diagnosis (ThyTSQ-Past). Conclusions: The ThyDQoL and ThyTSQ questionnaires have good face validity and content validity for adults with hypothyroidism. They are now ready for use in clinical research and psychometric evaluation.
Background Type 1 diabetes (T1DM) is associated with premature cardiovascular disease (CVD) and a... more Background Type 1 diabetes (T1DM) is associated with premature cardiovascular disease (CVD) and a pro-inflammatory state whilst the proangiogenic miR-126-3p/-5p may play a role in CVD. Animal studies established miR-126 to be pro-angiogenic. We hypothesised miR-126-3p/-5p are reduced in T1DM whilst pro-inflammatory cytokines are increased. Methods 29 well controlled, T1DM patients without CVD and 20 healthy controls (HCs) were studied. MiR-126-3p/-5p were assayed in plasma and peripheral blood mononuclear cells (PBMCs) whilst Chemokine C-X-C Receptor 1/2 (CXCR1/2) mRNA in PBMCs by real-time quantitative PCR. Cytokines were assayed by the Mesoscale Discovery. Ingenuity Pathway Analysis (IPA) was used to predict target genes, cellular functions and pathological states regulated by miR-126-3p/-5p. IPA generated both direct and indirect causations between different targets and analysed whether these effects would be inhibitory or stimulatory based on the published evidence. Results T1DM...
Background In spite of clinical progress, cardiovascular disease (CVD) remains the predominant ca... more Background In spite of clinical progress, cardiovascular disease (CVD) remains the predominant cause of mortality worldwide. Overexpression studies in animals have proven miR-424-5p to have anti-angiogenic properties. As type 1 diabetes mellitus (T1DM) without CVD displays endothelial dysfunction and reduced circulating endothelial progenitor cells (cEPCs), it offers a model of subclinical CVD. Therefore, we explored miR-424-5p, cytokines and vascular health in T1DM. Methods Twenty-nine well-controlled T1DM patients with no CVD and 20-matched controls were studied. Cytokines IL8, TNF-α, IL7, VEGF-C, cEPCs/CD45dimCD34+CD133+ cells and ex-vivo proangiogenic cells (PACs)/fibronectin adhesion assay (FAA) were measured. MiR-424-5p in plasma and peripheral blood mononuclear cells (PBMC) along with mRNAs in PBMC was evaluated. Results We found an elevation of IL7 (p = 0.008), IL8 (p = 0.003), TNF-α (p = 0.041), VEGF-C (p = 0.013), upregulation of mRNA CXCR1 (p = 0.009), CXCR2 (p
Cardiovascular disease (CVD) correlates with inflammation and a reduction in circulating endothel... more Cardiovascular disease (CVD) correlates with inflammation and a reduction in circulating endothelial progenitor cells (cEPCs). Recently, CVD was shown to be the main cause of mortality in individuals with type 1 diabetes (T1DM). In animals, miR-342 was shown to exert an anti-inflammatory effect in CVD. Hypothesis: miR-342-3p/-5p are downregulated in subclinical CVD (T1DM), whereas inflammatory cytokines are upregulated. We studied miR -342 -3p/5p in plasma/peripheral blood mononuclear cells (PBMCs) in 29 T1DM and 20 controls (HC). Vascular health was measured by fibronectin adhesion assay (FAA), cEPCs (CD45dimCD34+133+ cells) and by assessing inflammation and tissue inhibition of metalloproteases (TIMP-1). In T1DM IL-7, IL-8, TNFα and VEGF-C were increased in plasma. MiR-342-3p/-5p were downregulated in PBMCs in T1DM, but not in plasma. PANX2, chemokine receptors CXCR1/2 mRNAs, were increased in PBMCs in T1DM. MiR-342-3p was negatively correlated with TIMP-1, IL-6, IL-8, TNF-α, HbA1...
AIMS To assess the impact of periodontal treatment on systemic inflammation in type 2 diabetes. M... more AIMS To assess the impact of periodontal treatment on systemic inflammation in type 2 diabetes. MATERIALS AND METHODS Adults with type 2 diabetes (n=83) and without diabetes (controls, n=75) were recruited, and participants with periodontitis received periodontal treatment and 12 months' follow-up. Biomarkers for periodontal inflammation (gingival crevicular fluid interleukin-6, tumour necrosis factor-α, interleukin-1β, interferon-γ, matrix metalloproteinase-8, matrix metalloproteinase-9, adiponectin) and serum markers of inflammation and diabetes control (glycated haemoglobin, high sensitivity C-reactive protein, interleukin-6, tumour necrosis factor-α, interleukin-1β, interferon-γ, leptin, adiponectin) were measured. Structural equation modelling was used to evaluate periodontal treatment effects on oral and systemic inflammation. RESULTS Periodontal treatment resulted in significant improvements in clinical status and reductions in gingival crevicular fluid biomarkers from baseline to month 12. Structural equation modelling identified that, at baseline, individuals with diabetes and periodontitis had significantly higher systemic inflammation than non-diabetic controls with periodontitis (Δ=0.20, p=0.002), with no significant differences between groups for oral inflammation. There was a greater reduction in systemic inflammation following periodontal treatment in individuals with diabetes and periodontitis compared to those with periodontitis but not diabetes (Δ=-0.25, p=0.01). CONCLUSIONS Diabetes and periodontitis together appear to increase systemic inflammation, with evidence of reductions following periodontal treatment.
The Journal of Clinical Endocrinology & Metabolism
Context: Thyrotropin receptor antibodies (TRAbs) play a crucial role in the pathogenesis of Grave... more Context: Thyrotropin receptor antibodies (TRAbs) play a crucial role in the pathogenesis of Graves disease (GD). However, factors that influence the association of TRAbs with thyroid hormones and relapse risk in GD remain unclear. Objective: We investigated the associations of TRAbs at diagnosis with thyroid hormones and relapse risk and potential factors that can influence these associations in GD. Design and Setting: A prospective study in an endocrine center in England. Patients and Main Outcome Measures: Three hundred eighty-four consecutive patients with GD who had measurements of TRAbs and thyroid hormones at diagnosis. The association of TRAbs with thyroid hormones and relapse risk was assessed through linear regression and Cox proportional hazard models, adjusted for confounders. Results: TRAbs were nonlinearly associated with thyroid hormones, following a curve with an initial positive slope and a subsequent flattening (P , 0.0001). Higher TRAbs were associated with greater relapse risk [hazard ratio (HR), 1.05 (95% CI, 1.02 to 1.08) per 1-U/L increase]. These associations were modified by age, but not by sex, race, smoking, or thyroid peroxidase antibody levels. In younger participants, increasing TRAbs were associated with higher thyroid hormones and greater relapse risk [HR, 1.13 (95% CI, 1.04 to 1.23) per 1-U/L increase]. In older participants, TRAbs were not associated with thyroid hormones or relapse risk [HR, 0.99 (95% CI, 0.93 to 1.05) per 1-U/L increase. Conclusions: In GD, age can influence the effect of TRAbs on thyroid function and relapse risk. TRAbs at diagnosis have better predictive value in younger patients with GD.
International journal of molecular sciences, Jan 19, 2018
Type 1 diabetes (T1DM) is associated with increased cardiovascular disease (CVD) and reduced life... more Type 1 diabetes (T1DM) is associated with increased cardiovascular disease (CVD) and reduced life expectancy. We thus hypothesized that anti-angiogenic miRs are increased in T1DM, and the cardioprotective effect of metformin is mediated via reducing those miRs. In an open label, case-controlled study, 23 T1DM patients without CVD were treated with metformin for eight weeks (TG), matched with nine T1DM patients on standard treatment (SG) and 23 controls (CG). Plasma miR-222, miR-195, miR-21a and miR-126 were assayed by real-time RT-qPCR. The results were correlated with: endothelial function (RHI), circulating endothelial progenitor cells (cEPCs) (vascular repair marker, CD45CD34⁺VEGFR2⁺ cells) and circulating endothelial cells (cECs) (vascular injury marker, CD45CD34⁺CD133⁻CD144⁺ cells). miR-222, miR-195 and miR-21a were higher in T1DM than CG; = 0.009, < 0.0001, = 0.0001, respectively. There was an inverse correlation between logmiR-222 and logRHI ( < 0.05) and a direct corre...
International journal of molecular sciences, Jan 19, 2018
Cardiovascular disease is the leading cause of morbidity/mortality worldwide. Metformin is the fi... more Cardiovascular disease is the leading cause of morbidity/mortality worldwide. Metformin is the first therapy offering cardioprotection in type 2 diabetes and non-diabetic animals with unknown mechanism. We have shown that metformin improves angiogenesis via affecting expression of growth factors/angiogenic inhibitors in CD34⁺ cells under hyperglycemia-hypoxia. Now we studied the direct effect of physiological dose of metformin on human umbilical vein endothelial cells (HUVEC) under conditions mimicking hypoxia-hyperglycemia. HUVEC migration and apoptosis were studied after induction with euglycemia or hyperglycemia and/or CoCl₂ induced hypoxia in the presence or absence of metformin. HUVEC mRNA was assayed by whole transcript microarrays. Genes were confirmed by qRT-PCR, proteins by western blot, ELISA or flow cytometry. Metformin promoted HUVEC migration and inhibited apoptosis via upregulation of vascular endothelial growth factor (VEGF) receptors (VEGFR1/R2), fatty acid binding p...
Results: The records of 2970 patients were analysed. The prevalence of hypothyroidism, thyrotoxic... more Results: The records of 2970 patients were analysed. The prevalence of hypothyroidism, thyrotoxicosis, SCH, and SCT was 0.2%, 0.3%, 6.8%, and 1.7% respectively. There were 575 patients with IHD (69% men, median age 63 years) and 795 without (33% men, median ...
Objective: To evaluate the psychometric properties of two new condition-specific questionnaires: ... more Objective: To evaluate the psychometric properties of two new condition-specific questionnaires: (1) the 18-item ThyDQoL, an individualised patient-centred measure of perceived impact of hypothyroidism on QoL, and (2) the 15-item ThySC symptom checklist in which patients provide "bother" ratings for common hypothyroid symptoms.
Locomotor disease was present in 75% of diabetics with the upper limb the commonest site for abno... more Locomotor disease was present in 75% of diabetics with the upper limb the commonest site for abnormalities. This prevalence was significantly higher than that seen in the controls (53%) [p = 0.02]. Shoulder capsulitis (25%), carpal tunnel syndrome (20%), tenosynovitis (29%), ...
Results: 41 patients (92.7% female) mean age 64 years, range 2785, presented with SCHT due to ei... more Results: 41 patients (92.7% female) mean age 64 years, range 2785, presented with SCHT due to either multinodular enlargement (70.7%), toxic nodule (9.8%), autoimmune (7.3%). 51.2% of patients were symptomatic, 39% patients either had bone or heart disease. ...
Context: Subclinical hypothyroidism (SCH) is associated with cardiovascular (CV) risk factors, an... more Context: Subclinical hypothyroidism (SCH) is associated with cardiovascular (CV) risk factors, and possibly CV disease. However, its management remains controversial. Endothelial progenitor cells (EPC), expressing both endothelial and stem cell markers, are known to offer a novel CV risk marker. Objective: The aim of the study was to ascertain whether EPC count or function is reduced in SCH and whether it improves with T 4 therapy. Design and Intervention: EPC were studied in peripheral blood by fluorescence-activated cell sorter and following in vitro cultures before and after T 4 together with CV risk factors in 20 SCH and healthy controls (HC).
Introduction: This paper reports work undertaken to design two new conditionspecific questionnair... more Introduction: This paper reports work undertaken to design two new conditionspecific questionnaires for use in hypothyroidism: the Underactive Thyroid-Dependent Quality of Life Questionnaire (ThyDQoL) and the Underactive Thyroid Treatment Satisfaction Questionnaire (ThyTSQ). Methods: Semi-structured interviews exploring quality of life (QoL) and experiences of treatment were conducted with 30 women and 8 men with hypothyroidism, (mean age 51.9, range 29-79 years), 37/38 treated with thyroxine, recruited from hospital clinics and primary care. Results: Despite thyroxine treatment, most interviewees reported negative impact of hypothyroidism on QoL, particularly on energy, physical capabilities, motivation, physical appearance and weight. The newly designed ThyDQoL has 18 domains covering these and other aspects of life affected by hypothyroidism. It is an individualised measure of patients' perceived impact of hypothyroidism on their QoL, which takes into account the importance of personally applicable life domains to the patient. A 7-item measure of satisfaction with current treatment was designed (ThyTSQ-Present) but interviews also indicated the need for a separate 4-item section measuring satisfaction with past treatment around the time of diagnosis (ThyTSQ-Past). Conclusions: The ThyDQoL and ThyTSQ questionnaires have good face validity and content validity for adults with hypothyroidism. They are now ready for use in clinical research and psychometric evaluation.
Background Type 1 diabetes (T1DM) is associated with premature cardiovascular disease (CVD) and a... more Background Type 1 diabetes (T1DM) is associated with premature cardiovascular disease (CVD) and a pro-inflammatory state whilst the proangiogenic miR-126-3p/-5p may play a role in CVD. Animal studies established miR-126 to be pro-angiogenic. We hypothesised miR-126-3p/-5p are reduced in T1DM whilst pro-inflammatory cytokines are increased. Methods 29 well controlled, T1DM patients without CVD and 20 healthy controls (HCs) were studied. MiR-126-3p/-5p were assayed in plasma and peripheral blood mononuclear cells (PBMCs) whilst Chemokine C-X-C Receptor 1/2 (CXCR1/2) mRNA in PBMCs by real-time quantitative PCR. Cytokines were assayed by the Mesoscale Discovery. Ingenuity Pathway Analysis (IPA) was used to predict target genes, cellular functions and pathological states regulated by miR-126-3p/-5p. IPA generated both direct and indirect causations between different targets and analysed whether these effects would be inhibitory or stimulatory based on the published evidence. Results T1DM...
Background In spite of clinical progress, cardiovascular disease (CVD) remains the predominant ca... more Background In spite of clinical progress, cardiovascular disease (CVD) remains the predominant cause of mortality worldwide. Overexpression studies in animals have proven miR-424-5p to have anti-angiogenic properties. As type 1 diabetes mellitus (T1DM) without CVD displays endothelial dysfunction and reduced circulating endothelial progenitor cells (cEPCs), it offers a model of subclinical CVD. Therefore, we explored miR-424-5p, cytokines and vascular health in T1DM. Methods Twenty-nine well-controlled T1DM patients with no CVD and 20-matched controls were studied. Cytokines IL8, TNF-α, IL7, VEGF-C, cEPCs/CD45dimCD34+CD133+ cells and ex-vivo proangiogenic cells (PACs)/fibronectin adhesion assay (FAA) were measured. MiR-424-5p in plasma and peripheral blood mononuclear cells (PBMC) along with mRNAs in PBMC was evaluated. Results We found an elevation of IL7 (p = 0.008), IL8 (p = 0.003), TNF-α (p = 0.041), VEGF-C (p = 0.013), upregulation of mRNA CXCR1 (p = 0.009), CXCR2 (p
Cardiovascular disease (CVD) correlates with inflammation and a reduction in circulating endothel... more Cardiovascular disease (CVD) correlates with inflammation and a reduction in circulating endothelial progenitor cells (cEPCs). Recently, CVD was shown to be the main cause of mortality in individuals with type 1 diabetes (T1DM). In animals, miR-342 was shown to exert an anti-inflammatory effect in CVD. Hypothesis: miR-342-3p/-5p are downregulated in subclinical CVD (T1DM), whereas inflammatory cytokines are upregulated. We studied miR -342 -3p/5p in plasma/peripheral blood mononuclear cells (PBMCs) in 29 T1DM and 20 controls (HC). Vascular health was measured by fibronectin adhesion assay (FAA), cEPCs (CD45dimCD34+133+ cells) and by assessing inflammation and tissue inhibition of metalloproteases (TIMP-1). In T1DM IL-7, IL-8, TNFα and VEGF-C were increased in plasma. MiR-342-3p/-5p were downregulated in PBMCs in T1DM, but not in plasma. PANX2, chemokine receptors CXCR1/2 mRNAs, were increased in PBMCs in T1DM. MiR-342-3p was negatively correlated with TIMP-1, IL-6, IL-8, TNF-α, HbA1...
AIMS To assess the impact of periodontal treatment on systemic inflammation in type 2 diabetes. M... more AIMS To assess the impact of periodontal treatment on systemic inflammation in type 2 diabetes. MATERIALS AND METHODS Adults with type 2 diabetes (n=83) and without diabetes (controls, n=75) were recruited, and participants with periodontitis received periodontal treatment and 12 months' follow-up. Biomarkers for periodontal inflammation (gingival crevicular fluid interleukin-6, tumour necrosis factor-α, interleukin-1β, interferon-γ, matrix metalloproteinase-8, matrix metalloproteinase-9, adiponectin) and serum markers of inflammation and diabetes control (glycated haemoglobin, high sensitivity C-reactive protein, interleukin-6, tumour necrosis factor-α, interleukin-1β, interferon-γ, leptin, adiponectin) were measured. Structural equation modelling was used to evaluate periodontal treatment effects on oral and systemic inflammation. RESULTS Periodontal treatment resulted in significant improvements in clinical status and reductions in gingival crevicular fluid biomarkers from baseline to month 12. Structural equation modelling identified that, at baseline, individuals with diabetes and periodontitis had significantly higher systemic inflammation than non-diabetic controls with periodontitis (Δ=0.20, p=0.002), with no significant differences between groups for oral inflammation. There was a greater reduction in systemic inflammation following periodontal treatment in individuals with diabetes and periodontitis compared to those with periodontitis but not diabetes (Δ=-0.25, p=0.01). CONCLUSIONS Diabetes and periodontitis together appear to increase systemic inflammation, with evidence of reductions following periodontal treatment.
The Journal of Clinical Endocrinology & Metabolism
Context: Thyrotropin receptor antibodies (TRAbs) play a crucial role in the pathogenesis of Grave... more Context: Thyrotropin receptor antibodies (TRAbs) play a crucial role in the pathogenesis of Graves disease (GD). However, factors that influence the association of TRAbs with thyroid hormones and relapse risk in GD remain unclear. Objective: We investigated the associations of TRAbs at diagnosis with thyroid hormones and relapse risk and potential factors that can influence these associations in GD. Design and Setting: A prospective study in an endocrine center in England. Patients and Main Outcome Measures: Three hundred eighty-four consecutive patients with GD who had measurements of TRAbs and thyroid hormones at diagnosis. The association of TRAbs with thyroid hormones and relapse risk was assessed through linear regression and Cox proportional hazard models, adjusted for confounders. Results: TRAbs were nonlinearly associated with thyroid hormones, following a curve with an initial positive slope and a subsequent flattening (P , 0.0001). Higher TRAbs were associated with greater relapse risk [hazard ratio (HR), 1.05 (95% CI, 1.02 to 1.08) per 1-U/L increase]. These associations were modified by age, but not by sex, race, smoking, or thyroid peroxidase antibody levels. In younger participants, increasing TRAbs were associated with higher thyroid hormones and greater relapse risk [HR, 1.13 (95% CI, 1.04 to 1.23) per 1-U/L increase]. In older participants, TRAbs were not associated with thyroid hormones or relapse risk [HR, 0.99 (95% CI, 0.93 to 1.05) per 1-U/L increase. Conclusions: In GD, age can influence the effect of TRAbs on thyroid function and relapse risk. TRAbs at diagnosis have better predictive value in younger patients with GD.
International journal of molecular sciences, Jan 19, 2018
Type 1 diabetes (T1DM) is associated with increased cardiovascular disease (CVD) and reduced life... more Type 1 diabetes (T1DM) is associated with increased cardiovascular disease (CVD) and reduced life expectancy. We thus hypothesized that anti-angiogenic miRs are increased in T1DM, and the cardioprotective effect of metformin is mediated via reducing those miRs. In an open label, case-controlled study, 23 T1DM patients without CVD were treated with metformin for eight weeks (TG), matched with nine T1DM patients on standard treatment (SG) and 23 controls (CG). Plasma miR-222, miR-195, miR-21a and miR-126 were assayed by real-time RT-qPCR. The results were correlated with: endothelial function (RHI), circulating endothelial progenitor cells (cEPCs) (vascular repair marker, CD45CD34⁺VEGFR2⁺ cells) and circulating endothelial cells (cECs) (vascular injury marker, CD45CD34⁺CD133⁻CD144⁺ cells). miR-222, miR-195 and miR-21a were higher in T1DM than CG; = 0.009, < 0.0001, = 0.0001, respectively. There was an inverse correlation between logmiR-222 and logRHI ( < 0.05) and a direct corre...
International journal of molecular sciences, Jan 19, 2018
Cardiovascular disease is the leading cause of morbidity/mortality worldwide. Metformin is the fi... more Cardiovascular disease is the leading cause of morbidity/mortality worldwide. Metformin is the first therapy offering cardioprotection in type 2 diabetes and non-diabetic animals with unknown mechanism. We have shown that metformin improves angiogenesis via affecting expression of growth factors/angiogenic inhibitors in CD34⁺ cells under hyperglycemia-hypoxia. Now we studied the direct effect of physiological dose of metformin on human umbilical vein endothelial cells (HUVEC) under conditions mimicking hypoxia-hyperglycemia. HUVEC migration and apoptosis were studied after induction with euglycemia or hyperglycemia and/or CoCl₂ induced hypoxia in the presence or absence of metformin. HUVEC mRNA was assayed by whole transcript microarrays. Genes were confirmed by qRT-PCR, proteins by western blot, ELISA or flow cytometry. Metformin promoted HUVEC migration and inhibited apoptosis via upregulation of vascular endothelial growth factor (VEGF) receptors (VEGFR1/R2), fatty acid binding p...
Results: The records of 2970 patients were analysed. The prevalence of hypothyroidism, thyrotoxic... more Results: The records of 2970 patients were analysed. The prevalence of hypothyroidism, thyrotoxicosis, SCH, and SCT was 0.2%, 0.3%, 6.8%, and 1.7% respectively. There were 575 patients with IHD (69% men, median age 63 years) and 795 without (33% men, median ...
Objective: To evaluate the psychometric properties of two new condition-specific questionnaires: ... more Objective: To evaluate the psychometric properties of two new condition-specific questionnaires: (1) the 18-item ThyDQoL, an individualised patient-centred measure of perceived impact of hypothyroidism on QoL, and (2) the 15-item ThySC symptom checklist in which patients provide "bother" ratings for common hypothyroid symptoms.
Locomotor disease was present in 75% of diabetics with the upper limb the commonest site for abno... more Locomotor disease was present in 75% of diabetics with the upper limb the commonest site for abnormalities. This prevalence was significantly higher than that seen in the controls (53%) [p = 0.02]. Shoulder capsulitis (25%), carpal tunnel syndrome (20%), tenosynovitis (29%), ...
Results: 41 patients (92.7% female) mean age 64 years, range 2785, presented with SCHT due to ei... more Results: 41 patients (92.7% female) mean age 64 years, range 2785, presented with SCHT due to either multinodular enlargement (70.7%), toxic nodule (9.8%), autoimmune (7.3%). 51.2% of patients were symptomatic, 39% patients either had bone or heart disease. ...
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Papers by Jolanta Weaver