Identification of biomarkers in patients with rheumatoid arthritis responsive to DMARDs but with progressive bone erosion.

Introduction: Rheumatoid arthritis (RA) is an inflammatory autoimmune disease that may cause joint destruction and disability. The pharmacological treatment of RA aims at obtaining disease remission by effectively ceasing joint inflammation and arresting progressive bone erosions. Some patients present bone lesions accrual even after controlling joint inflammation with current therapies. Our study aimed to analyze lymphocyte subsets and levels of circulating cytokines in patients with RA with progressive bone erosions. Methods: We enrolled 20 patients with a diagnosis of RA and 12 healthy donors (HD). Patients with RA were divided into patients with bone erosions (RA-BE+) and without bone erosions (RA-BE-). Lymphocyte subsets in peripheral blood were evaluated by flow cytometry. Circulating cytokines levels were evaluated by protein array. Results: The distribution of lymphocyte subsets was not able to separate HD from AR patients and RA-BE+ and RA-BE- in cluster analysis. We observed a significant expansion of CXCR5- PD1+ T peripheral helper cells (Tph cells) and a reduction in both total memory B cells and switched memory B cells in RA patients compared to HD. We observed an expansion in the frequency of total B cells in RA-BE+ patients compared to RA-BE- patients. Unsupervised hierarchical clustering analysis of 39 cytokines resulted in a fairly good separation of HD from RA patients but not of RA-BE+ patients from RA-BE- patients. RA-BE+ patients showed significantly higher levels of IL-11 and IL-17A than RA-BE- patients. Conclusion: We show that patients with progressive erosive disease are characterized by abnormalities in B cells and in cytokines with a proven role in bone reabsorption. Understanding the role played by B cells and the cytokine IL-11 and IL-17A in progressive erosive disease can help identify novel biomarkers of erosive disease and design treatment approaches aimed at halting joint damage in RA.

Efficacy of switching from teriparatide to zoledronic acid or denosumab on bone mineral density and biochemical markers of bone turnover in older patients with severe osteoporosis: a real-life study.

PURPOSE: Osteoporosis is characterized by loss of bone mass and susceptibility to fracture. Skeletal effects of teriparatide (TPT) are not persistent after drug withdrawal and sequential therapy with bisphosphonates or denosumab (Dmab) after TPT discontinuation represents a valid option. Here, the two sequential strategies were evaluated in severe osteoporotic patients. METHODS: The study retrospectively enrolled 56 severe osteoporotic patients who received TPT for 24 months followed by 24 months of zoledronic acid (ZOL) (TPT + ZOL) or Dmab (TPT+Dmab). Clinical features, incident fractures, bone mineral density (BMD) measurements, and bone marker profiles were collected. One-way ANOVA analyzed the difference between mean T-scores at baseline, after 24 months of TPT, and after 2 doses of ZOL or after at least 3 doses of Dmab. RESULTS: Twenty-three patients received TPT + ZOL (19 females, 4 males; median [IR] age, 74.3 [66.9, 78.6] years) and 33 patients received TPT+Dmab (31 females, 2 males; mean [IR] age, 66.6 ± 11.3 years). Mean lumbar and hip T-scores were increased after both TPT + ZOL and TPT+Dmab (all p < 0.05 vs baseline). The size effects induced by TPT + ZOL on the lumbar and hip BMD T-scores were similar to those observed with TPT+Dmab with mean T-scores increases of about 1 and 0.4 SD, respectively. No significant between-group differences were identified. Incident fragility fractures occurred in 3 (13%) patients treated with TPT + ZOL and in 5 (15%) patients treated with TPT+Dmab. CONCLUSIONS: Sequential TPT + ZOL therapy is likely to increase bone mineralization at the lumbar level and to stabilize it at the femoral level, similarly to what obtained with the sequential TPT+Dmab. Both ZOL and Dmab are suggested to be effective sequential treatments after TPT.

Hypercalciuria in Postmenopausal Women With Reduced Bone Mineral Density Is Associated With Different Mineral Metabolic Profiles: Effects of Treatment With Thiazides and Anti-resorptives.

Hypercalciuria may represent a challenge during the workup for osteoporosis management. The present study aimed: (1) to describe the phenotype associated with hypercalciuria in vitamin D-sufficient (serum 25 hydroxyvitamin D (25OHD) > 20 ng/ml) patients with osteopenia/osteoporosis; (2) to analyze the effects of thiazides and anti-resorptive drugs on urine calcium excretion (UCa), mineral metabolic markers, and bone mineral density. Seventy-seven postmenopausal women with hypercalciuria (Uca > 4.0 mg/kg body weight/24 h on two determinations) were retrospectively evaluated in a real-life setting. Median UCa was 5.39 (4.75-6.70) mg/kg/24 h. Kidney stones occurred in 32.9% of patients, who had median UCa similar to that of patients without kidney stones. Clustering analysis considering the three variables, such as serum calcium, phosphate, and parathormone (PTH), identified two main clusters of hypercalciuric patients. Cluster 1 (n = 13) included patients with a primary hyperparathyroidism-like profile, suggesting a certain degree of autonomous PTH secretion from parathyroid glands. Within cluster 2 (n = 61), two subgroups were recognized, cluster 2A (n = 18) that included patients with relatively increased PTH and normophosphatemia, and cluster 2B (n = 43) that included patients with the normal mineral profile. After a follow-up of 33.4 ± 19.6 months, 49 patients treated with thiazidic diuretics (TZD) were reevaluated; 20 patients were treated with hydrochlorothiazide (HCT; 12.5-37.5 mg/day), 29 with indapamide (IND; 1.50-3.75 mg/day). Any significant difference could be detected in all the parameters both basal and treated conditions between patients treated with HCT or IND. TZD induced a mean 39% reduction in UCa and 63.3% of patients obtained Uca < 4.0 mg/kg/24 h, independent of their mineral metabolic profile. Moreover, TZD induced a significant decrease in PTH levels. TZD-treated patients normalizing UCa experienced an increase in bone mineral densities when concomitantly treated with anti-resorptives, while any gain could be observed in TZD-treated patients with persistent hypercalciuria. Finally, multiple regression analysis showed that UCa reduction was at least in part related to denosumab treatment. In conclusion, in postmenopausal osteoporotic women, hypercalciuria is associated with kidney stones in about one-third of patients and with a wide range of impaired PTH secretion, determining a diagnostic challenge. TZD efficiently reduces UCa and normalization contributes to increasing anti-resorptives positive effect on bone mineral density.

Management of psoriatic arthritis in rheumatology and dermatology settings: sub-analysis of the Italian population from the international LOOP study.

Psoriatic arthritis (PsA) patients are often treated by dermatology and rheumatology specialities and may receive different treatments. To evaluate the impact of dermatology/rheumatology specialist settings on diagnosis and therapeutic approach in PsA patients. This cross-sectional multicounty study in Italy involved twenty-eight rheumatology or dermatology clinics. Patients with suspected or confirmed PsA were examined by both a dermatologist and a rheumatologist. A total of 413 patients were enrolled and 347 (84%) were diagnosed with PsA. The majority of patients were enrolled from a rheumatology setting (N = 224, 64.6%). Patients with PsA in the dermatology settings had significantly higher disease activity, including skin involvement and musculoskeletal symptoms. Time from PsA onset to diagnosis was 22.3 ± 53.8 vs. 39.4 ± 77.5 months (p = 0.63) in rheumatology and dermatology settings; time from diagnosis to initiation of csDMARD was 7.3 ± 27.5 vs. 19.5 ± 50.6 months, respectively (p < 0.001). In contrast, time from diagnosis to bDMARD use was shorter in dermatology settings (54.9 ± 69 vs. 44.2 ± 65.6 months, p = 0.09, rheumatology vs. dermatology), similar to the time taken from first csDMARDs and bDMARDs (48.7 ± 67.9 vs. 35.3 ± 51.9 months, p = 0.34). The choice to visit a rheumatologist over a dermatologist was positively associated with female gender and swollen joints and negatively associated with delay in time from musculoskeletal symptom onset to PsA diagnosis. This study highlights a diagnostic delay emerging from both settings with significantly different therapeutic approaches. Our data reinforce the importance of implementing efficient strategies to improve early identification of PsA that can benefit from the integrated management of PsA patients. Key Points • A diagnostic delay was observed from both dermatology and rheumatology settings with significantly different therapeutic approaches. • Shared dermatology and rheumatology clinics offer the combined expertise to improve in the early identification and management of PsA.

Hypertryptasemia and Mast Cell-Related Disorders in Severe Osteoporotic Patients.

PURPOSE: Systemic mastocytosis (SM) is characterized by a clonal proliferation of neoplastic mast cells (MCs) in one or more extracutaneous organs including the bone marrow (BM). SM is often associated with osteoporosis (OP) and fractures. Hypertryptasemia usually occurs in SM. We investigated the prevalence of hypertryptasemia in a series of severe osteoporotic patients, the performance of the tryptase test in diagnosing SM in these patients, and their bone features. METHODS: The medical records of 232 patients (168 females and 64 males) with a diagnosis of OP (50.4% with fractures) and a serum tryptase assessment were reviewed. BM assessment was performed in a subset of hypertryptasemic patients; clinical, biochemical, and radiographic data were collected. RESULTS: Hypertryptasemia was detected in 33 patients. BM assessment (n = 16) was normal in 8 hypertryptasemic patients, while BM criteria for the diagnosis of SM were met in 3 patients, MC alterations were detected in 4 patients, and one patient presented a polycythemia vera. Serum tryptase levels were higher than 11.4 ng/ml in all patients with BM alterations. The best cut-off of tryptase level related to BM alterations was 17.9 ng/ml, with a sensibility and sensitivity of 75% (AUC = 0.797 and P = 0.015 by ROC analysis). All osteoporotic patients with hypertryptasemia experienced at least one vertebral fracture associated with a severe reduction of the lumbar bone mineral density. CONCLUSIONS: The prevalence of MC-related disorders in severe OP was 3.0%, accounting for the 7.4% of the secondary causes of OP. MC-related disorders may be involved in bone fragility and assessment of serum tryptase is useful to detect MC-related disorders.

Bone Features of Unaffected Skeletal Sites in Melorheostosis: A Case Report.

BACKGROUND: Melorheostosis is a rare sporadic sclerosing bone dysplasia, which commonly affects appendicular skeleton with bone hyperostosis and soft tissues sclerosis; fragility fractures are rare in melorheostotic patients. We investigated bone features at unaffected sites in a postmenopausal woman with melorheostosis of the right lower limb and with a fracture of the melorheostosis-free T11 vertebral. METHODOLOGY: Melorheostotic lesions were evaluated by plain radiography, magnetic resonance of the right lower limb, and whole-body bone scintigraphy. Dual X-ray absorptiometry, trabecular bone score, and quantitative computed tomography were performed to investigate unaffected bone sites. Biochemical assessment of bone metabolism was obtained. RESULTS: Dual X-ray absorptiometry was indicative of normal mineralization at femoral sites and osteopenia at lumbar spine (T-score -1.1), which was confirmed by spinal quantitative computed tomography (volumetric bone mineral density 89 mg/cm3). Trabecular bone score suggested only mildly altered bone microarchitecture (1.304, normal values >1.350). Bone markers were consistent with high bone turnover. Causes of secondary osteoporosis or alterations in bone metabolism were excluded. Zoledronic acid induced a reduction in bone turnover markers after 6 months without significant changes in clinical features. CONCLUSIONS: Fragility fractures at apparently unaffected sites may occur in adults with melorheostosis, in absence of significant demineralization diagnosed by dual X-ray absorptiometry, trabecular bone score, and quantitative computed tomography, which may underestimate the fracture risk in this set of patients. Treatment with zoledronate could be considered also to prevent fragility fractures.

Planning and Endograft Related Variables Predisposing to Late Distal Type I Endoleaks.

OBJECTIVE: Late distal type I endoleak (ELIB) hampers the outcome of endovascular repair (EVAR) for abdominal aortic aneurysm (AAA); however, only few dedicated experiences have been reported in the literature. The aim of the study was to evaluate the incidence, presentation and treatment of late ELIB and to identify possible anatomical and technical predictors. METHODS: All patients undergoing elective EVAR between 2008 and 2013 were collected prospectively. Follow up was by post-operative computed tomography angiography (CTA) performed within 30 days and CTA and/or duplex ultrasound (DUS) at six or 12 months and yearly thereafter. Patients with late ELIB, defined as distal type I endoleak detected more than six months after the primary intervention without endoleak on the intra-operative completion angiogram and on the post-operative CTA, were retrospectively selected (G1) and compared with a control group with no ELIB (G2) homogeneous for clinical conditions, endograft implanted, and timing of follow up. The minimum follow up required for inclusion in the study was 24 months. Pre-operative morphological aorto-iliac features and EVAR implant details were evaluated, and measurements performed after centre lumen line reconstructions using dedicated software. The differences between G1 and G2 were analysed using the chi-square test, the Student t test, and logistic regression. RESULTS: Six hundred and sixteen patients were submitted to EVAR. ELIB was detected in 14 cases (2.3%) (G1) at a median follow up of 32.8 (IQR 48) months. In three of the 14 cases ELIB was symptomatic (AAA rupture, 2; pain, 1); in the remaining 11 cases it was asymptomatic and found incidentally at routine follow up. Treatment was by open repair in one case and by endovascular iliac leg extension in 13 cases. Hypogastric exclusion was necessary in two of 14 cases. Thirty patients were included in G2, with a median follow up of 41.2 (25) months. Common iliac artery length <4 cm (OR 5.3, 95% CI 1.1-29.5, p = .05), diameter > 15 mm (OR 3.5, 95% CI 1.2-10.9, p = .03), and severe thrombotic apposition (>50% of circumference) (OR 5, 95% CI 1.2-19.2, p = .02), at the iliac sealing zone were significant predictors of ELIB, on univariable analysis; oversizing of the iliac leg diameter < 10% and distal sealing > 1 cm above the hypogastric origin were independently associated with ELIB (OR 5.4, 95% CI 1.3-21.5, p = .01 and OR 6.6, 95% CI 1.1-39.3, p = .03, respectively), on multivariable analysis. CONCLUSION: The present data underline that ELIB is a non-negligible occurrence during long term EVAR follow up and requires further interventions, most often by endovascular solutions. According to the ELIB risk factors identified in this study, an iliac leg diameter oversize >10% and extensive common iliac artery coverage (<1 cm above the hypogastric origin) would be suggested to prevent this complication.

Increased frequency of activated CD8+ T cell effectors in patients with psoriatic arthritis.

The aim of this study is to identify subsets of T cells differentially represented in the circulation of patients with psoriatic arthritis and to evaluate the possibility that they can recirculate between peripheral blood and the inflamed joints. We analyzed the phenotype and cytokine expression in circulating CD8+ and CD4+ T cells in 69 subjects: 28 with cutaneous psoriasis, 15 patients with psoriatic arthritis, and 26 healthy subjects. In the circulation, the percentage of each subset was compared among the groups and correlation was calculated with the serum concentration of C-reactive protein. To investigate the migration of T cells towards the inflamed joints, we performed a transwell migration assay towards patient serum and synovial fluid. In selected patients we analyzed in parallel T cells from peripheral blood and from synovial fluid. In the circulation, we found increased percentage of CD8+ CCR6+ T cell effectors expressing CD69 and of IL-17-producing T cells in patients with psoriatic arthritis. CD8+ effector/effector memory T cells showed increased migration towards synovial fluid. Finally, in synovial fluid we found accumulation of CXCR3+ CD8+ T cells and CD69+ cells. CD4+ T cells in the two compartments shared many similarities with CD8+ T cells. The results indicate a role for memory T cell effectors in systemic and joint manifestations of psoriatic arthritis.

Evaluation of Amides, Carbamates, Sulfonamides, and Ureas of 4-Prop-2-ynylidenecycloalkylamine as Potent, Selective, and Bioavailable Negative Allosteric Modulators of Metabotropic Glutamate Receptor 5.

Negative allosteric modulators (NAMs) of the metabotropic glutamate receptor 5 (mGlu5) hold great promise for the treatment of a variety of central nervous system disorders. We have recently reported that prop-2-ynylidenecycloalkylamine derivatives are potent and selective NAMs of the mGlu5 receptor. In this work, we explored the amide, carbamate, sulfonamide, and urea derivatives of prop-2-ynylidenecycloalkylamine compounds with the aim of improving solubility and metabolic stability. In silico and experimental analyses were performed on the synthesized series of compounds to investigate structure-activity relationships. Compounds 12, 32, and 49 of the carbamate, urea, and amide classes, respectively, showed the most suitable cytochrome inhibition and metabolic stability profiles. Among them, compound 12 showed excellent selectivity, solubility, and stability profiles as well as suitable in vitro and in vivo pharmacokinetic properties. It was highly absorbed in rats and dogs and was active in anxiety, neuropathic pain, and lower urinary tract models.

Hybrid Foot Vein Arterialization in No-Option Patients With Critical Limb Ischemia: A Preliminary Report.

PURPOSE: To describe a preliminary experience in treating no-option critical limb ischemia (CLI) patients with a hybrid foot vein arterialization (HFVA) technique combining open plus endovascular approaches. MATERIALS AND METHODS: Between May 2016 and January 2018, 35 consecutive patients (mean age 68±12 years; 28 men) with 36 no-option CLI limbs underwent HFVA in our center. All limbs had grade 3 WIfI (Wound, Ischemia, and foot Infection) ischemia, and the wound classification was grade 1 in 4 (11%) limbs, grade 2 in 4 (11%), and grade 3 in 28 (78%). Surgical bypass was done on the medial marginal vein or a posterior tibial vein, followed by endovascular removal of foot vein valves and embolization of foot vein collaterals. A "tension-free" surgical approach was used to treat foot lesions. RESULTS: At a mean follow-up of 10.8±2 months, limb salvage was achieved in 25 (69%) limbs and wound healing in 16 (44%); 9 patients presented an unhealed wound. Eleven (31%) patients underwent a major amputation (2 below the knee and 9 thigh). One patient with an unhealed wound and open bypass died of myocardial infarction. CONCLUSION: HFVA is a promising technique able to achieve acceptable rates of limb salvage and wound healing in no-option patients generally considered candidates for an impending major amputation. Further studies are needed to standardize the technique and better identify patients who can benefit from this approach.

The Value of Carotid Endarterectomy as a Learning Tool for Trainees.

BACKGROUND: Carotid endarterectomy (CEA) intervention needs a specific training and a sufficient learning curve to obtain optimal results in terms of outcome. A formative program was settled up in a single academic center to optimize training of standard CEA procedures. This study aims to evaluate the 11-year results of the teaching CEA program. METHODS: The trainees CEA teaching program is carried on during the 5-year vascular surgery residency period, and it is stratified as follows: learning theory and intervention assistance (minimum 50 procedures per year) in the first and second residency year; performing CEA as second operator in the third and fourth residency year (minimum 50 procedures per year); CEA execution as first operator with attending supervision in the last residency year. All CEA procedures from 2005 to 2015 were retrospectively collected and the 30-day results were compared according to the expertise of the first operator: experienced vascular surgeons (EVSs) versus trainees. All CEA procedures were performed in general anesthesia, with routine shunting and patching. RESULTS: In the study period, 1,379 (361 [26.2%] symptomatic; 1,018 [73.8%] asymptomatic) CEAs were performed. Trainees performed 199 (14.4%) CEAs as first operator. Patients submitted to CEA by trainees were similar in terms of preoperative clinical characteristics except for the patients' age (trainees 72.4 years versus EVS 70.8 years, P = 0.02) and smoking history (trainees 30.7% versus EVS 24.1%, P = 0.04). The 30-day complication rates were similar in CEA performed by trainees versus EVS: stroke 0.5% vs. 1.1%, P = 0.5; death 0.0% vs. 0.5%, P = 0.6; stroke/death 0.5% vs. 1.7%, P = 0.24; hematoma 3.0% vs. 2.2%, P = 0.48; and cranial nerve injury 9.0% vs. 7.8%, P = 0.47, respectively. The intervention time was significantly longer in CEAs performed by trainees compared with EVS: 104 ± 1.9 min versus 98 ± 1.0 min, P = 0.02. CONCLUSIONS: With a defined CEA teaching program, trainees can obtain results similar to those of more experienced surgeons in terms of clinical outcome at the price of an increased intervention time.

Relationship between Calcification and Vulnerability of the Carotid Plaques.

BACKGROUND: Carotid plaques with a high degree of calcification are usually considered at low embolic risk. However, since a precise evaluation of the extent of calcification is not possible preoperatively through duplex ultrasound and postoperatively by conventional histological examination due to the decalcification process, the relationship between the amount of calcium involvement and plaque vulnerability has not been evaluated yet. This study aims to correlate the extent of carotid plaque calcification with clinical, radiological, and histological complications. METHODS: Symptomatic and asymptomatic consecutive patients submitted to carotid endarterectomy between January to December 2014 were included in the study. The amount of carotid calcification was assessed at preoperative computed tomography (CT) through measurement of thickness and circumferential calcium extension and graded from 1 to 8 accordingly (Babiarz classification). Patients were then categorized into 2 groups (low-level group: grade 1-5; high-level group: grade 6-8) and correlated with clinical characteristics and ipsilateral cerebral ischemic lesions at CT. Vulnerability of the plaque was assessed histologically according with American Heart Association (AHA) Classification. Results were overall blindly correlated. RESULTS: One hundred five patients (81% male; age: 73 ± 8 years) were enrolled in the study. Forty (38%) were symptomatic and 43 (40%) had an ipsilateral focal lesion at preoperative cerebral CT. Thirty-six (38%) patients had high-level carotid calcification degree at CT scan. At histological analysis, 56 (56%) plaques were considered complicated (AHA type VI). Patients with high-level and low-level carotid calcification had similar epidemiological risk factors, preoperative neurological symptoms, and histological complications (17% vs. 15%, P = 0.76 and 50% vs. 55%, P = 0.62, respectively). The high-level calcification group showed a significantly higher incidence of ipsilateral cerebral lesions at preoperative CT (56% vs. 32%, P = 0.01). CONCLUSIONS: A high level of calcification of the carotid plaque is not necessarily associated with lower vulnerability: the incidence of preoperative neurological symptoms and histological complications is similar in patients with and without extensive carotid plaque calcification. Cerebral ischemic lesions may be even more frequent in the presence of highly calcified plaques.

Impact of acute cerebral ischemic lesions and their volume on the revascularization outcome of symptomatic carotid stenosis.

BACKGROUND: The influence of acute cerebral ischemic lesions (CILs) on the revascularization outcome of symptomatic carotid stenosis has been scarcely investigated in the literature. This study evaluated the effect of CILs and their volume on the results of carotid revascularization in symptomatic patients. METHODS: All patients with symptomatic carotid artery stenosis who underwent carotid endarterectomy (CEA) or carotid artery stenting (CAS) between 2005 and 2014 were considered. CILs ipsilateral to the stenosis were identified in the preoperative cerebral computed tomography. The volume was quantified in mm3 and correlated with 30-day rates of stroke and stroke/death by χ2, multivariate analysis, Pearson correlation, and receiver operating characteristic curves. RESULTS: A total of 489 symptomatic patients were treated by CEA (327 [67%]) or CAS (162 [33%]), 186 (38%) ≤2 weeks and 303 (62%) >2 weeks from symptom onset. CEA and CAS patients had statistically similar rates of stroke (3.3% vs 5.5%; P = .27) and stroke/death (3.8% vs 5.9%; P = .22). CILs were identified in 251 patients (53%) and were associated with similar stroke and stroke/death rate compared with patients without CIL (12 [4.8%] vs 8 [3.5%], P = .46; and 14 [5.6%] vs 8 [3.5%]; P = .26, respectively). The median CIL volume was 1000 mm3 (interquartile range [IQR], 7000 mm3). Patients with postoperative stroke and stroke/death had a significantly higher preoperative CIL volume of 5100 mm3 (IQR, 31,000 mm3) vs 1000 mm3 (IQR, 7000 mm3; P = .01) and 4500 mm3 (IQR, 17,450 mm3) vs 1000 mm3 (IQR, 7000 mm3; P = .03), respectively. The receiver operating characteristic curve analysis showed a volume of 4000 mm3 was predictive of postoperative stroke with 75% sensitivity and 63% specificity. A CIL volume ≥4000 mm3 was an independent risk factor for postoperative stroke, with a stroke rate of 9.3% (n = 9) vs 1.9% (n = 3) for a CIL volume of <4000 mm3 (odds ratio, 4.6; 95% confidence interval, 1.1-19.1; P = .03). CONCLUSIONS: CIL volume in symptomatic carotid stenosis seems to influence the 30-day outcome independently from the timing of carotid revascularization. A CIL volume of ≥4000 mm3 could be considered a significant predictor for postoperative stroke after carotid revascularization.

The detrimental impact of silent cerebral infarcts on asymptomatic carotid endarterectomy outcome.

BACKGROUND: Silent cerebral infarctions (SCIs) can be identified by preoperative computed tomography (CT) scans in patients with severe carotid stenosis being considered for carotid endarterectomy (CEA). It is unknown whether this finding has any effect on perioperative complications or long-term outcome. This study investigates the influence of SCI on early and late complications in asymptomatic patients undergoing CEA. METHODS: All consecutive CEAs undertaken for asymptomatic severe carotid stenosis from 2005 to 2013 were retrospectively evaluated for clinical and anatomic characteristics. SCI was defined as cerebral embolic infarcts in the anterior or middle cerebral artery territory, ipsilateral to the target carotid stenosis, identified on preoperative CT. The end points of the study were to compare the 30-day and long-term stroke and death rate after CEA in patients with and without SCI. All patients were followed yearly through duplex ultrasonography and clinical assessment. Statistical methods used were Cox regression (hazard ratio) and Kaplan-Meier for life-table analysis. RESULTS: A total of 743 CEAs were performed in asymptomatic patients during the study period of which all had CT scans, and 97 (13.1%) demonstrated SCI. All patient stroke and death outcomes at 30 days were 0.5% and 0.7%, respectively. Patients with SCI had a significantly higher 30-day stroke outcome (3.1% vs 0.2%; P = .001; odds ratio, 16.39; 95% confidence interval, 1.33-201.4; P = .02) but not death or stroke/death outcome (0% vs 0.8%; P = .19 and 3.1% vs 0.9%, P = .06, respectively) compared with those without SCI. In addition, at a mean follow-up of 44.3 ± 23.9 months, the patients with SCI had a significantly worse 5-year ipsilateral stroke or any stroke-/death-free survival compared with patients without SCI (86.7% vs 99.0%; P = .001; and 76.9% vs 87.7%; P = .004). SCI was confirmed as an independent predictor of late any stroke/death by Cox regression (hazard ratio, 2.45; 95% confidence interval, 1.29-4.67; P = .006). CONCLUSIONS: Patients who have SCI in the presence of severe carotid stenosis and undergo CEA have significantly worse perioperative stroke and long-term stroke/death outcomes. This data would suggest that asymptomatic patients undergoing CEA who have CT scan evidence of a cerebral infarct have worse prognosis than those with normal CT scans.

Insights into the interaction of negative allosteric modulators with the metabotropic glutamate receptor 5: discovery and computational modeling of a new series of ligands with nanomolar affinity.

Metabotropic glutamate receptor 5 (mGlu5) is a biological target implicated in major neurological and psychiatric disorders. In the present study, we have investigated structural determinants of the interaction of negative allosteric modulators (NAMs) with the seven-transmembrane (7TM) domain of mGlu5. A homology model of the 7TM receptor domain built on the crystal structure of the mGlu1 template was obtained, and the binding modes of known NAMs, namely MPEP and fenobam, were investigated by docking and molecular dynamics simulations. The results were validated by comparison with mutagenesis data available in the literature for these two ligands, and subsequently corroborated by the recently described mGlu5 crystal structure. Moreover, a new series of NAMs was synthesized and tested, providing compounds with nanomolar affinity. Several structural modifications were sequentially introduced with the aim of identifying structural features important for receptor binding. The synthesized NAMs were docked in the validated homology model and binding modes were used to interpret and discuss structure-activity relationships within this new series of compounds. Finally, the models of the interaction of NAMs with mGlu5 were extended to include important non-aryl alkyne mGlu5 NAMs taken from the literature. Overall, the results provide useful insights into the molecular interaction of negative allosteric modulators with mGlu5 and may facilitate the design of new modulators for this class of receptors.

Endovascular treatment of late coronary-subclavian steal syndrome.

OBJECTIVE: Coronary-subclavian steal syndrome (CSSS) is a rare cause of myocardial ischemia subsequent to stenosis or occlusion of the subclavian artery (SA) proximal to internal thoracic artery (ITA) coronary bypass. Only single cases have been reported in published studies to date. We report a significant series of patients with late CSSS treated through an endovascular approach. METHODS: We reviewed a series of consecutive patients treated for CSSS. The clinical, anatomic, and technical characteristics of the procedures were considered. Follow-up was performed through clinical and laboratory (electrocardiography, echocardiography, duplex ultrasonography) evaluations. RESULTS: From January 2005 to March 2013, 10 patients with CSSS were treated; 7 had stable and 3 unstable angina. Of the 10 patients, 8 had left SA stenosis (6 ostial to the origin and 2 in the middle segment), 1 had proximal occlusion of the left SA, and 1 had stenosis in the innominate artery (proximally to a right internal thoracic artery). Arterial access was at the brachial artery through surgical exposure (n=6), or radial artery percutaneously (n=3). In 1 case of proximal occlusion of the left SA, simultaneous femoral and percutaneous radial access was necessary. Predilatation of the stenotic lesion was performed in 6. Balloon expandable stents were used in 7 patients with proximal ostial stenosis or occlusion and self-expandable stents in 2 with nonostial lesions. In 1 other patient with proximal heavy calcified stenosis, cutting-balloon predilatation was performed, resulting in dissection of the SA and occlusion of the ITA graft; blood flow was restored in the left upper arm and myocardium by adjunctive dilatation of the SA and endovascular coronary revascularization. No patients developed angina during the follow-up period (15±7 months). CONCLUSIONS: A tailored endovascular approach can be used to treat CSSS. However, the occurrence of potentially lethal complications is possible and needs prompt correction.

The influence of study design on the evaluation of ruptured abdominal aortic aneurysm treatment.

BACKGROUND: The best strategy in the treatment for ruptured abdominal aortic aneurysm (RAAA) is an ongoing matter of debate. Differently from several retrospective studies, recent randomized controlled trials (RCTs) failed to demonstrate the superiority of endovascular repair (EVAR) over open repair (OPEN). The aim of the present study was to compare 30-day mortality of EVAR and OPEN in RAAA according to different study designs through a systematic review and meta-analysis. METHODS: A systematic literature search of all series comparing the outcome of EVAR and OPEN in RAAA was performed. Studies on symptomatic aneurysms without frank ruptures were excluded. The analyses evaluated the effect of the study design on EVAR versus OPEN 30-day mortality. The pooled mortality risk was expressed as odds ratio (OR) with a 95% confidence interval (CI) by random effect model. RESULTS: Four different study designs were evaluated. 1) Patients allocation in EVAR or OPEN was "unbiased" (3 studies, 2 RCTs): there was no superiority treatment in EVAR versus OPEN (OR, 1.58; 95% CI, 0.82-3.06; P = 0.17). 2) Patients submitted to EVAR were compared with a historical OPEN group (2 studies): no difference between EVAR and OPEN (OR, 3.55; 95% CI, 0.47-26.62; P = 0.22). 3) EVAR was the preferential treatment and OPEN was confined to patients with unsuitable anatomy for endovascular procedures (18 studies): in this type of study OPEN had a higher risk of 30-day mortality (OR, 2.18; 95% CI, 1.61-2.96; P < 0.00001). 4) The 30-day mortality after EVAR introduction in centers using both EVAR and OPEN was compared with the only OPEN treatment (7 studies): the latter had higher mortality compared with the protocol with both EVAR and OPEN options (OR, 2.26; 95% CI, 1.41-3.63; P = 0.0007). CONCLUSIONS: Only few studies are available to compare EVAR and OPEN in an "unbiased" cohort, with no significant differences between the 2 treatments. However, after the introduction of EVAR and OPEN protocols, the overall mortality for RAAA was reduced compared with the only OPEN option, suggesting a beneficial effect of EVAR in selected cases.

Impact of postoperative transient ischemic attack on survival after carotid revascularization.

OBJECTIVE: Major postoperative complications such as stroke and myocardial infarction are usually carefully evaluated in the analysis of carotid revascularization performance. Although transient ischemic attacks (TIAs) are often left unreported, they also may influence long-term outcome. The aim of our study was to evaluate the influence of postoperative TIA in the long-term survival of patients submitted to carotid revascularization. METHODS: All consecutive patients submitted to either carotid artery stenting or carotid endarterectomy for symptomatic or asymptomatic carotid stenosis from 2005 to 2012 were retrospectively analyzed. Patients were stratified according to their postoperative (30-day) neurologic course (no symptoms, TIA, or stroke). Kaplan-Maier with log-rank analysis was performed to compare the 5-year survival of patients with postoperative TIA, stroke, or neither; factors affecting the 5-year mortality were evaluated by multivariable Cox proportional hazards models. RESULTS: Over a total of 1390 carotid revascularizations (carotid endarterectomy, n = 868 [62.4%]; carotid artery stenting, n = 522 [37.6%]), neurological perioperative complications occurred in 67 (4.7%) cases (38, 2.7% TIA; 29, 2.0% stroke). At 5-year follow-up, overall survival was significantly lower in patients with postoperative TIA (78.4 ± 8.0% vs 97.4 ± 0.6%; P < .001) and postoperative stroke (68.2 ± 14.4% vs 97.4 ± 0.6%; P = .03) compared with patients without neurological complications. By means of multivariate Cox analysis, postoperative TIA and stroke were independent predictors of decreased survival (hazard ratio [HR], 3.10; 95% confidence interval [CI], 1.01-9.72; P = .04, and HR, 3.87; 95% CI, 1.13-13.19; P = .03, respectively), other than age >80 years, postoperative myocardial infarction, and chronic renal failure (HR, 2.07; 95% CI, 1.41-4.90; P = .01; HR, 4.33; 95% CI, 2.74-23.79; P = .04; HR, 2.54; 95% CI, 1.04-6.19; P = .04, respectively). CONCLUSIONS: TIAs are significant events, possibly determined by a wider extent of atherosclerotic disease, with important effects on long-term mortality similar to that in strokes. Different from most trials evaluating the outcomes of revascularization techniques, the incidence of perioperative TIA should be accurately considered in the analysis.

Recognition of morphometric vertebral fractures by artificial neural networks: analysis from GISMO Lombardia Database.

BACKGROUND: It is known that bone mineral density (BMD) predicts the fracture's risk only partially and the severity and number of vertebral fractures are predictive of subsequent osteoporotic fractures (OF). Spinal deformity index (SDI) integrates the severity and number of morphometric vertebral fractures. Nowadays, there is interest in developing algorithms that use traditional statistics for predicting OF. Some studies suggest their poor sensitivity. Artificial Neural Networks (ANNs) could represent an alternative. So far, no study investigated ANNs ability in predicting OF and SDI. The aim of the present study is to compare ANNs and Logistic Regression (LR) in recognising, on the basis of osteoporotic risk-factors and other clinical information, patients with SDI≥1 and SDI≥5 from those with SDI = 0. METHODOLOGY: We compared ANNs prognostic performance with that of LR in identifying SDI≥1/SDI≥5 in 372 women with postmenopausal-osteoporosis (SDI≥1, n = 176; SDI = 0, n = 196; SDI≥5, n = 51), using 45 variables (44 clinical parameters plus BMD). ANNs were allowed to choose relevant input data automatically (TWIST-system-Semeion). Among 45 variables, 17 and 25 were selected by TWIST-system-Semeion, in SDI≥1 vs SDI = 0 (first) and SDI≥5 vs SDI = 0 (second) analysis. In the first analysis sensitivity of LR and ANNs was 35.8% and 72.5%, specificity 76.5% and 78.5% and accuracy 56.2% and 75.5%, respectively. In the second analysis, sensitivity of LR and ANNs was 37.3% and 74.8%, specificity 90.3% and 87.8%, and accuracy 63.8% and 81.3%, respectively. CONCLUSIONS: ANNs showed a better performance in identifying both SDI≥1 and SDI≥5, with a higher sensitivity, suggesting its promising role in the development of algorithm for predicting OF.

Non-invasive assessment of coronary flow reserve and ADMA levels: a case-control study of early rheumatoid arthritis patients.

OBJECTIVE: Plasma concentration of asymmetric dimethylarginine (ADMA), a major endogenous inhibitor of nitric oxide synthase, is considered a novel risk factor for endothelial dysfunction associated with enhanced atherosclerosis. Coronary microcirculation abnormalities have been demonstrated in patients with early rheumatoid arthritis (ERA) without any signs or symptoms of coronary artery disease (CAD). The aim of the study was to compare the ERA and control groups with ADMA, intima-media thickness (IMT) and coronary flow reserve (CFR) levels. It assessed whether ERA patients have more cardiovascular risk (endothelial dysfunction and coronary microvascular abnormalities), and evaluated whether any difference in IMT/CFR between ERA and controls can be explained by any difference in ADMA levels between the groups. METHODS: The study involved 25 ERA patients (female/male 21/4; mean age 52.04 +/- 14.05 years; disease duration