Glucagon-like Peptide-1 Receptor Agonists and Diabetic Osteopathy: Another Positive Effect of Incretines? A 12 Months Longitudinal Study.

Diabetic osteopathy is a frequent complication in patients with type 2 diabetes mellitus (T2DM). The association between T2DM and increased fracture risk has led to study the impact of new antidiabetic drugs on bone metabolism. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are incretin mimetic drugs which have many pleiotropic properties. The relationship between GLP-1RAs and bone is very complex: while in vitro and animal studies have demonstrated a protective effect on bone, human studies are scarce. We led a 12 months longitudinal study evaluating bone changes in 65 patients withT2DM for whom a therapy with GLP-1RAs had been planned. Fifty-four T2DM patients completed the 12-month study period; of them, 30 had been treated with weekly dulaglutide and 24 with weekly semaglutide. One-year therapy with GLP-1RAs resulted in a significant reduction in weight and BMI. Bone mineral density (BMD), bone metabolism, trabecular bone score (TBS), adiponectin, and myostatin were evaluated before and after 12 months of GLP-1RAs therapy. After 12 months of therapy bone turnover markers and adiponectin showed a significant increase, while myostatin values showed a modest but significant reduction. BMD-LS by DXA presented a significant reduction while the reduction in BMD-LS by REMS was not significant and TBS values showed a marginal increase. Both DXA and REMS techniques showed a modest but significant reduction in femoral BMD. In conclusion, the use of GLP-1RAs for 12 months preserves bone quality and reactivates bone turnover. Further studies are needed to confirm whether GLP-1RAs could represent a useful therapeutic option for patients with T2DM and osteoporosis.

Ability of radiofrequency echographic multispectrometry to identify osteoporosis status in elderly women with type 2 diabetes.

BACKGROUND: Patients with type 2 diabetes (T2DM) have an increased or normal BMD; however fragility fractures represent one of the most important complications of T2DM. AIMS: This study aimed to evaluate whether the use of the Radiofrequency Echographic multi spectrometry (REMS) technique may improve the identification of osteoporosis in T2DM patients. METHODS: In a cohort of 90 consecutive postmenopausal elderly (70.5 ± 7.6 years) women with T2DM and in 90 healthy controls we measured BMD at the lumbar spine (LS-BMD), at femoral neck (FN-BMD) and total hip (TH-BMD) using a dual-energy X-ray absorptiometry device; moreover, REMS scans were also carried out at the same axial sites. RESULTS: DXA measurements were all higher in T2DM than in non-T2DM women; instead, all REMS measurements were lower in T2DM than in non T2DM women. Moreover, the percentage of T2DM women classified as "osteoporotic", on the basis of BMD by REMS was markedly higher with respect to those classified by DXA (47.0% vs 28.0%, respectively). On the contrary, the percentage of T2DM women classified as osteopenic or normal by DXA was higher with respect to that by REMS (48.8% and 23.2% vs 38.6% and 14.5%, respectively). T2DM women with fragility fractures presented lower values of both BMD-LS by DXA and BMD-LS by REMS with respect to those without fractures; however, the difference was significant only for BMD-LS by REMS (p < 0.05). CONCLUSIONS: Our data suggest that REMS technology may represent a useful approach to enhance the diagnosis of osteoporosis in patients with T2DM.

Clinical impact of oral antidiabetic medications in heart failure patients.

Heart failure (HF) is a common complication in patients with type 2 diabetes and it is closely associated with high morbidity and mortality rate. The incidence of cardiovascular events in patients with diabetes is related to high levels of glycemia, expressed by increase of HbA1c levels. However, there is little evidence to indicate that glycemic control can reduce the incidence of HF events in this population. Recently, several new antidiabetic drugs have been proposed although the exact clinical impact on heart failure occurrence and deterioration is under debate. Most common oral antidiabetic medication such as SGLT2, GLP-1 receptor agonist, metformin, and DPP4 inhibitor revealed peculiar metabolic and biomolecular signal effects. Moreover, the negative effects of thiazolidinediones on HF prognosis, on cardiac function, and exercise tolerance is of great interest. Conversely, several studies on GLP-1RA have highlighted many positive effects on cardiac myocytes, reducing apoptosis through cAMP/PKA/CRCB-mediated pathways protecting against oxidative stress. DPP-4 inhibitors have a controversial effect: saxagliptin and alogliptin may increase the risk of HF as opposed to vildagliptin and sitagliptin. Metformin increases myocardial ATP levels due to activation of 5-AMPK and this could explain the positive link between the drug and events rate reduction in diabetic patients with HF. The more interesting class of new drugs is SGLT2 inhibitors, that seems to have a positive effect on cardiac function by 38% reduction of HF incidence and mortality with empagliflozin treatment. In this review, we would analyze the specific effects of each class so as to better elucidate the clinical impact of antidiabetic drug on HF for guiding the clinicians in the choice of a best individualized therapy.

Role of Advanced Glycation End-Products and Oxidative Stress in Type-2-Diabetes-Induced Bone Fragility and Implications on Fracture Risk Stratification.

Type 2 diabetes (T2D) and osteoporosis (OP) are major causes of morbidity and mortality that have arelevant health and economic burden. Recent epidemiological evidence suggests that both of these disorders are often associated with each other and that T2D patients have an increased risk of fracture, making bone an additional target of diabetes. As occurs for other diabetic complications, the increased accumulation of advanced glycation end-products (AGEs) and oxidative stress represent the major mechanisms explaining bone fragility in T2D. Both of these conditions directly and indirectly (through the promotion of microvascular complications) impair the structural ductility of bone and negatively affect bone turnover, leading to impaired bone quality, rather than decreased bone density. This makes diabetes-induced bone fragility remarkably different from other forms of OP and represents a major challenge for fracture risk stratification, since either the measurement of BMD or the use of common diagnostic algorithms for OP have a poor predictive value. We review and discuss the role of AGEs and oxidative stress on the pathophysiology of bone fragility in T2D, providing some indications on how to improve fracture risk prediction in T2D patients.

G-protein-coupled receptors (GPCRs) in the treatment of diabetes: Current view and future perspectives.

G-protein coupled receptors (GPCRs) represent the largest receptor family in the genome and are of great interest for the design of novel drugs in a wide variety of diseases including neurologic disorders, obesity and Type 2 diabetes mellitus. The latter is a chronic disease characterized by insulin resistance and impaired insulin secretion, affecting >400 million patients worldwide. Here we provide an overview on: a) The molecular basis of GPCR signalling and of its involvement in the regulation of insulin secretion and of glucose homeostasis; b) the role of GPCRs in type 2 diabetes pathophysiology and as therapeutic targets of current and future glucose-lowering drugs.

Circulating MicroRNAs as Biomarkers of Gestational Diabetes Mellitus: Updates and Perspectives.

Gestational diabetes mellitus (GDM) is defined as any degree of carbohydrate intolerance, with onset or first recognition during second or third trimester of gestation. It is estimated that approximately 7% of all pregnancies are complicated by GDM and that its prevalence is rising all over the world. Thus, the screening for abnormal glucose levels is generally recommended as a routine component of care for pregnant women. However, additional biomarkers are needed in order to predict the onset or accurately monitor the status of gestational diabetes. Recently, microRNAs, a class of small noncoding RNAs demonstrated to modulate gene expression, have been proven to be secreted by cells of origin and can be found in many biological fluids such as serum or plasma. Such feature renders microRNAs as optimal biomarkers and sensors of in situ tissue alterations. Furthermore, secretion of microRNAs via exosomes has been reported to contribute to tissue cross talk, thus potentially represents, if disrupted, a mechanistic cause of tissue/cell dysfunction in a specific disease. In this review, we summarized the recent findings on circulating microRNAs and gestational diabetes mellitus with particular focus on the potential use of microRNAs as putative biomarkers of disease as well as a potential cause of GDM complications and ß cell dysfunction.

Serum Levels of miR-148a and miR-21-5p Are Increased in Type 1 Diabetic Patients and Correlated with Markers of Bone Strength and Metabolism.

Type 1 diabetes (T1D) is characterized by bone loss and altered bone remodeling, resulting into reduction of bone mineral density (BMD) and increased risk of fractures. Identification of specific biomarkers and/or causative factors of diabetic bone fragility is of fundamental importance for an early detection of such alterations and to envisage appropriate therapeutic interventions. MicroRNAs (miRNAs) are small non-coding RNAs which negatively regulate genes expression. Of note, miRNAs can be secreted in biological fluids through their association with different cellular components and, in such context, they may represent both candidate biomarkers and/or mediators of bone metabolism alterations. Here, we aimed at identifying miRNAs differentially expressed in serum of T1D patients and potentially involved in bone loss in type 1 diabetes. We selected six miRNAs previously associated with T1D and bone metabolism: miR-21; miR-24; miR-27a; miR-148a; miR-214; and miR-375. Selected miRNAs were analyzed in sera of 15 T1D patients (age: 33.57 ± 8.17; BMI: 21.4 ± 1.65) and 14 non-diabetic subjects (age: 31.7 ± 8.2; BMI: 24.6 ± 4.34). Calcium, osteocalcin, parathormone (PTH), bone ALkaline Phoshatase (bALP), and Vitamin D (VitD) as well as main parameters of bone health were measured in each patient. We observed an increased expression of miR-148a (p = 0.012) and miR-21-5p (p = 0.034) in sera of T1D patients vs non-diabetic subjects. The correlation analysis between miRNAs expression and the main parameters of bone metabolism, showed a correlation between miR-148a and Bone Mineral Density (BMD) total body (TB) values (p = 0.042) and PTH circulating levels (p = 0.033) and the association of miR-21-5p to Bone Mineral Content-Femur (BMC-FEM). Finally, miR-148a and miR-21-5p target genes prediction analysis revealed several factors involved in bone development and remodeling, such as MAFB, WNT1, TGFB2, STAT3, or PDCD4, and the co-modulation of common pathways involved in bone homeostasis thus potentially assigning a role to both miR-148a and miR-21-5p in bone metabolism alterations. In conclusion, these results lead us to hypothesize a potential role for miR-148a and miR-21-5p in bone remodeling, thus representing potential biomarkers of bone fragility in T1D.

Circulating microRNA (miRNA) Expression Profiling in Plasma of Patients with Gestational Diabetes Mellitus Reveals Upregulation of miRNA miR-330-3p.

Gestational diabetes mellitus (GDM) is characterized by insulin resistance accompanied by low/absent beta-cell compensatory adaptation to the increased insulin demand. Although the molecular mechanisms and factors acting on beta-cell compensatory response during pregnancy have been partially elucidated and reported, those inducing an impaired beta-cell compensation and function, thus evolving in GDM, have yet to be fully addressed. MicroRNAs (miRNAs) are a class of small endogenous non-coding RNAs, which negatively modulate gene expression through their sequence-specific binding to 3'UTR of mRNA target. They have been described as potent modulators of cell survival and proliferation and, furthermore, as orchestrating molecules of beta-cell compensatory response and function in diabetes. Moreover, it has been reported that miRNAs can be actively secreted by cells and found in many biological fluids (e.g., serum/plasma), thus representing both optimal candidate disease biomarkers and mediators of tissues crosstalk(s). Here, we analyzed the expression profiles of circulating miRNAs in plasma samples obtained from n = 21 GDM patients and from n = 10 non-diabetic control pregnant women (24-33 weeks of gestation) using TaqMan array microfluidics cards followed by RT-real-time PCR single assay validation. The results highlighted the upregulation of miR-330-3p in plasma of GDM vs non-diabetics. Furthermore, the analysis of miR-330-3p expression levels revealed a bimodally distributed GDM patients group characterized by high or low circulating miR-330 expression and identified as GDM-miR-330high and GDM-miR-330low. Interestingly, GDM-miR-330high subgroup retained lower levels of insulinemia, inversely correlated to miR-330-3p expression levels, and a significant higher rate of primary cesarean sections. Finally, miR-330-3p target genes analysis revealed major modulators of beta-cell proliferation and of insulin secretion, such as the experimentally validated genes E2F1 and CDC42 as well as AGT2R2, a gene involved in the differentiation of mature beta-cells. In conclusion, we demonstrated that plasma miR-330-3p could be of help in identifying GDM patients with potential worse gestational diabetes outcome; in GDM, miR-330-3p may directly be transferred from plasma to beta-cells thus modulating key target genes involved in proliferation, differentiation, and insulin secretion.

Characteristics and familial aggregation of Paget's disease of bone in Italy.

UNLABELLED: This study examined the characteristics of 147 PDB cases from Italy. Our data showed a reduced clinical severity of PDB with respect to other populations and provided further support of the importance of environmental factors (rural area of residence and animal contact) in the pathogenesis of PDB. Familial aggregation was observed in 15% of cases. INTRODUCTION: The etiology of Paget's disease of bone (PDB) remains unknown. Current evidence suggests that interactions among genetic or exogenous factors seem to be necessary for disease expression. Major epidemiological studies were performed in the United Kingdom and in other populations of British descent. To date, there are no reliable data on PDB characteristics among the Italian population, and its frequency in different areas of the country remains unknown. MATERIALS AND METHODS: In an attempt to evaluate clinical characteristics, the proportion of familial cases and the influence of environmental features on the occurrence of the disease, we studied 147 consecutive PDB patients. For all subjects, a detailed medical history was obtained, and constitutional features were recorded. Characteristics of PDB patients were compared with those obtained from 323 consecutive non-Pagetic outpatient control subjects. RESULTS AND CONCLUSIONS: Of the 147 PDB patients, 22 (15%) had at least one other family member affected, 19 (13%) reported one family member with suspected features of PDB, and 106 (72%) were classified as sporadic PDB. Even though we observed a reduced clinical severity of PDB with respect to other populations (mean number of affected sites, 2.2 +/- 1.6), we did not find any evidence of a decreased severity of the disease over time. We also found an association of PDB with animal contact (odds ratio [OR], 2.22; p < 0.0005) and a significant prevalence of PDB in rural versus urban districts (OR, 2.42; p < 0.0005). Osteoarthritis (45%), fractures (14%), hearing loss (14%), and valvular calcifications (15%) were the most observed complications. Interestingly, the geographical distribution of PDB showed a concentration of cases in rural areas of Campania and Tuscany. These areas may indicate local clustering of PDB cases in Italy, similar to that observed in other countries.

Evaluation of C-reactive protein measurement for assessing the risk and prognosis in ischemic stroke: a statement for health care professionals from the CRP Pooling Project members.

BACKGROUND AND PURPOSE: Several studies have shown, in different populations, that modest elevation of plasma C-reactive protein (CRP) in the range seen in apparently healthy individuals is a strong predictor of future vascular events. Elevated plasma CRP concentrations are also associated with an increased risk of cerebrovascular events and an increased risk of fatal and nonfatal cardiovascular events in ischemic stroke patients. These epidemiological and clinical observations suggest that determination of plasma CRP concentrations could be used as an adjunct for risk assessment in primary and secondary prevention of cerebrovascular disease and be of prognostic value. The aim of this review is to summarize the evidence for CRP as an independent predictor of cerebrovascular events in at-risk individuals and ischemic stroke patients and to consider its usefulness in evaluating prognosis after stroke. SUMMARY OF REVIEW: CRP fulfils most of the requirements of a new risk and prognostic predictor, but several issues await further confirmation and clarification before this marker can be included in the routine evaluation of stroke patients and subjects at risk for cerebrovascular disease. Potentially important associations have been established between elevated plasma CRP concentrations and increased efficacy of established therapies, particularly lipid-lowering therapy with statins. CONCLUSIONS: At present, there is not sufficient evidence to recommend measurement of CRP in the routine evaluation of cerebrovascular disease risk in primary prevention, because there is insufficient evidence as to whether early detection, or intervention based on detection, improves health outcomes, although shared risk of cardiovascular disease indicates this may be of value. In secondary prevention of stroke, elevated CRP adds to existing prognostic markers, but it remains to be established whether specific therapeutic options can be derived from this.

MicroRNA-124a is hyperexpressed in type 2 diabetic human pancreatic islets and negatively regulates insulin secretion.

AIMS: MicroRNAs are a class of negative regulators of gene expression, which have been shown to be involved in the development of endocrine pancreas and in the regulation of insulin secretion. Since type 2 diabetes (T2D) is characterized by beta cell dysfunction, we aimed at evaluating expression levels of miR-124a and miR-375, both involved in the control of beta cell function, in human pancreatic islets obtained from T2D and from age-matched non-diabetic organ donors. METHODS: We analyzed miR-124a and miR-375 expression by real-time qRT-PCR in human pancreatic islets and evaluated the potential role of miR-124a by overexpressing or silencing such miRNA in MIN6 pseudoislets. RESULTS: We identified a major miR-124a hyperexpression in T2D human pancreatic islets with no differential expression of miR-375. Of note, miR-124a overexpression in MIN6 pseudoislets resulted in an impaired glucose-induced insulin secretion. In addition, miR-124a silencing in MIN6 pseudoislets resulted in increased expression of predicted target genes (Mtpn, Foxa2, Flot2, Akt3, Sirt1 and NeuroD1) involved in beta cell function. For Mtpn and Foxa2, we further demonstrated the actual binding of miR-124a to their 3UTR sequences by luciferase assay. CONCLUSIONS: We uncovered a major hyperexpression of miR-124a in T2D islets, whose silencing resulted in increased expression of target genes of major importance for beta cell function and whose overexpression impaired glucose-stimulated insulin secretion, leading to the hypothesis that an altered miR-124a expression may contribute to beta cell dysfunction in type 2 diabetes.

[Diagnostic and therapeutic features of pulmonary embolism in elderly patients]. / Aspetti diagnostici e terapeutici dell'embolia polmonare nel paziente anziano.

BACKGROUND: Pulmonary embolism (PE) is often underdiagnosed in the elderly for nonspecificity and atypicity of presentation. The aim of this study was to evidence, retrospectively, the clinical, instrumental and laboratory aspects in the diagnosis of elderly patients with suspected PE and to observe the antithrombotic primary prophylaxis, acute antithrombotic treatment and its hemorrhagic side effects in patients with confirmed PE (CPE). METHODS: We conducted an observational, retrospective, study on 118 hospitalized patients > or = 65 years (49 males and 69 females, mean age 77.76 +/- 7.17 years) during a 5-year period who underwent a scintigraphic lung scan for suspected PE. Clinical, instrumental and laboratory findings of 75 patients with CPE were compared with 43 patients with unconfirmed PE (UCPE). RESULTS: Symptoms of dyspnea and chest pain and all the considered signs, except tachycardia, were significantly more frequent in the CPE group. Bed rest > 4 days, venous insufficiency, deep vein thrombosis, obesity and stroke were the risk factors significantly more frequent in the CPE group. Sinus tachycardia, incomplete right bundle branch block, ST-T alterations were significantly more present in the CPE group. Cardiomegaly was the only significant more frequent chest X-ray finding in the CPE group, while echocardiography showed a significant involvement of the right ventricle in the CPE group. Plasma D-dimer levels were significantly higher in the CPE group but the mean values were > 500 micrograms/l in both groups. In arterial blood gas analysis we found more severe hypoxemia, arterial hyposaturation and higher alveolar-oxygen gradient in the CPE group, while we did not find a more frequent respiratory alkalosis in this group. Heart failure, ischemic heart disease and chronic obstructive pulmonary disease were the more frequent diagnoses in the UCPE group. None of the patients received thrombolysis. Seventy percent of the CPE patients received intravenous heparin; 9 hemorrhagic side effects occurred, 3 of them being major with one fatal in one patient treated with subcutaneous unfractionated heparin. CONCLUSIONS: Our study shows the diagnostic difficulties of PE in the elderly because of nonspecifcity of clinical, instrumental and laboratory aspects. Although many of these aspects are significantly more frequent in the CPE group, the same are often the main aspects also in the UCPE group. Moreover, our study reveals the low utilization of antithrombotic primary prophylaxis and high risk of hemorrhagic side effects of heparin in this subgroup of patients.

Beyond glycemic control in diabetes mellitus: effects of incretin-based therapies on bone metabolism.

Diabetes mellitus (DM) and osteoporosis (OP) are common disorders with a significant health burden, and an increase in fracture risk has been described both in type 1 (T1DM) and in type 2 (T2DM) diabetes. The pathogenic mechanisms of impaired skeletal strength in diabetes remain to be clarified in details and they are only in part reflected by a variation in bone mineral density. In T2DM, the occurrence of low bone turnover together with a decreased osteoblast activity and compromised bone quality has been shown. Of note, some antidiabetic drugs (e.g., thiazolidinediones, insulin) may deeply affect bone metabolism. In addition, the recently introduced class of incretin-based drugs (i.e., GLP-1 receptor agonists and DPP-4 inhibitors) is expected to exert potentially beneficial effects on bone health, possibly due to a bone anabolic activity of GLP-1, that can be either direct or indirect through the involvement of thyroid C cells. Here we will review the established as well as the putative effects of incretin hormones and of incretin-based drugs on bone metabolism, both in preclinical models and in man, taking into account that such therapeutic strategy may be effective not only to achieve a good glycemic control, but also to improve bone health in diabetic patients.

Choreoathetosis associated with non-chetotic hyperglycemia.

Choreoathetosis is a rare neurologic complication of the diabetic disease. The purpose of this case report is to increase the knowledge of such occurrence by describing the case of an elderly woman who was admitted to our institution for an over 20-day history of choreic movement in the left side of the body. She had a 6-year history of type 2 diabetes mellitus with a poor metabolic control including a glycosylated hemoglobin of 13%. Unenhanced computed tomography of the brain was negative. At magnetic resonance imaging, the right putamen showed high signal intensity on T1-weighted images and an area of high signal intensity on T2-weighted images, diffusion-weighted images and apparent diffusion coefficient maps. During the hospitalization, an adequate diet therapy was performed, and insulin therapy was gradually adjusted using regular insulin at main meals associated with basal insulin (glargine) "bed time". This resulted in progressive normalization of blood glucose values and an improvement of dyskinesia. There is a deep correlation between non-chetotic hyperglycemia and neurologic lesions leading to choreoathetosis. The etiopathogenesis seems multifactorial, and include hyperosmolar damage on cortical cells, alteration in GABA neurotransmission and in cerebral vascular self-regulation mechanism. Notably, in DM type 2 choreoathetosis may be related to both vascular and neuro-metabolic alterations in the basal nucleus due to inadequate glycemic control continuing in the time. This rare complication of DM type 2 is a pathological entity to be considered benign, since it is generally transient and reversible with the attainment of an adequate metabolic compensation.

Circulating sclerostin levels and bone turnover in type 1 and type 2 diabetes.

CONTEXT: Previous observations showed a condition of low bone turnover and decreased osteoblast activity in both type 1 and 2 diabetes mellitus (DM1 and DM2). Sclerostin is a secreted Wnt antagonist produced by osteocytes that regulates osteoblast activity and thus bone turnover. Its levels increase with age and are regulated by PTH. OBJECTIVES: The aim of the present study was to evaluate circulating sclerostin levels in patients with DM1 or DM2 with normal renal function and to analyze its relationship with PTH, 25-hydroxyvitamin D, and bone turnover markers. DESIGN, AND SETTING: This was a cross-sectional study conducted at a clinical research center. PARTICIPANTS: Forty DM2 and 43 DM1 patients were studied and compared with a reference control group (n = 83). RESULTS: In the overall cohort, sclerostin levels were higher in males than in females and significantly increased with age in both genders. The positive correlation between sclerostin and age was maintained in DM1 but not in DM2 patients. Moreover, sclerostin levels were higher in DM2 than in controls or DM1 patients, and this difference persisted when adjustments were made for age and body mass index. Consistent with previous clinical and experimental observations, sclerostin was negatively associated with PTH in nondiabetic patients (r = -0.30; P < 0.01), independently of age and gender. Conversely, an opposite but nonsignificant trend between PTH and sclerostin was observed in both DM1 (r = 0.26; P = 0.09) and DM2 (r = 0.32; P = 0.07) cohorts. CONCLUSIONS: These findings suggest that sclerostin is increased in DM2. Moreover, the transcriptional suppression of sclerostin production by PTH might be impaired in both DM1 and DM2.

The relationship between plasma homocysteine levels and bone mineral density in post-menopausal women.

BACKGROUND: Whether or not mild hyperhomocysteinemia and low serum levels of folates or vitamin B12 are risk factors for osteoporosis in the elderly is controversial. AIMS AND METHODS: To investigate whether or not plasma levels of total homocysteine (tHcy) and serum levels of folates and vitamin B12 are associated with bone mineral density (BMD), we carried out a cross-sectional study on 446 post-menopausal women (mean age: 65.1+/-9.4 years), consecutively seen at the Siena Unit (Tuscany region, Central Italy) for BMD evaluation over a two-year period. BMD of the total femur, femoral neck and lumbar spine was detected by dual-energy X-ray absorptiometry. RESULTS: The age-adjusted geometric mean of plasma tHcy levels (micromol/L) was 9.96+/-1.29 in women with normal BMD, 11.06+/-1.32 in those with osteopenia and 11.88+/-1.35 in those with osteoporosis (p<0.0001). On multiple linear regression analysis, adjusting for age, body mass index, folates, vitamin B12, creatinine clearance, smoking habit and alcohol intake, tHcy was negatively related to BMD of the total femur [beta estimate for log-homocysteine: -0.050 (95% CI: -0.100 to -0.001, p=0.048; R(2)=0.02)], but not of femoral neck or lumbar spine. There was no significant association between BMD and serum levels of folates and vitamin B12. CONCLUSIONS: tHcy is negatively associated with BMD of the total femur. The contribution of tHcy to explain the variance of BMD is small (2% of the total variance) but clinically relevant, considering the high prevalence of osteoporosis among post-menopausal women and the possibility to lower tHcy by vitamin supplementation.

Pulmonary embolism in very old patients.

BACKGROUND AND AIMS: Diagnosis of pulmonary embolism (PE) in the elderly remains difficult and is often late, although its incidence increases steadily with age. Since few studies have reported the clinical picture of this disease in very old patients, the aim of our study was to focus on clinical, instrumental and laboratory aspects in patients 75 years of age and over with suspected PE. METHODS: Symptoms, signs, risk factors for venous thromboembolic diseases, 12-lead electrocardiograms, B-mode echocardiograms, chest X-rays, leg compression venous ultrasonography, latex-assay quantitative D-dimer, and arterial blood gas analyses were collected for 96 elderly patients of 75 years and over (mean age 81.22 +/- 4.81) with suspected PE, admitted to our acute geriatric ward from 1997 to 2000. Patients were divided into two groups: 59 patients with PE (PE+) confirmed by pulmonary angiography, scintigraphic lung scan or necropsy, and 37 patients with normal lung scan or without PE at necropsy (PE-). RESULTS: Dyspnea and chest pain were the most common symptoms in both groups, but significantly more frequent in the PE+ group. Tachycardia, fever, cyanosis, and tachypnea were the most common objective signs in both groups; tachycardia and tachypnea were not significantly different between the two groups. Bed rest, venous insufficiency and leg deep vein thrombosis were the most common venous risk factors in PE+ and significantly different with respect to PE-. Sinus tachycardia, ST-T abnormalities and right bundle branch block were the most common electrocardiographic aspects in PE+; echocardiograms showed significantly more frequent acute involvement of right heart in PE+, whereas chest X-rays were rarely compatible with PE and did not reveal differences between the two groups. D-Dimer was significantly higher in PE+ but was below 500 ng/mL only in 25% of cases in PE-. More severe hypoxemla, oxy-hemoglobin hyposaturation and increased alveolar-arterial oxygen gradients were found at arterial blood gas analysis in PE+. CONCLUSIONS: Although many analyzed clinical, instrumental and laboratory aspects were significantly more frequent in the PE+ group, they were all non-specific and not conclusive for diagnosis of PE. Our retrospective study focus may add information about the picture and diagnostic difficulties of PE in very old patients.