Association between Neuropsychological Performance and CSF Profile in Subjective Cognitive Decline: Towards the Diagnosis of Preclinical AD.

BACKGROUND: In the perspective of novel treatments with disease-modifying drugs, a timely diagnosis of Alzheimer's' disease (AD) at preclinical phase represents a major issue. To this purpose, in clinical setting, there is the need to detect the earliest cognitive symptoms not yet fulfilling Mild Cognitive Impairment criteria, in order to proceed to biomarker assessment for diagnostic definition. In terms of cognitive performance, Subjective Cognitive Decline (SCD) is still a controversial entity, due to the difficulty of reliably measuring subtle deficits. OBJECTIVE: To evaluate the possibility to predict the presence of AD-like CSF pattern in SCD individuals, according to their neuropsychological performance assessed by means of both traditional and computerized measures. DESIGN: Retrospective study. SETTING: Clinical setting (Centre for Memory Disturbances, Section of Neurology, University Hospital of Perugia, Italy). PARTICIPANTS: 74 consecutive SCD subjects who underwent an in-depth (paper-pencil and computerized) neuropsychological assessment and CSF analysis for AD biomarkers (Aß42/Aß40 ratio, phospho-tau, total tau). MEASUREMENTS: Neuropsychological assessment was composed of traditional tests assessing five cognitive domains (verbal memory, attention, executive functions, language, visuo-spatial abilities) and computerized tasks from CAmbridge Neuropsychological Test Automated Battery (CANTAB) (Pattern Recognition Memory, Paired Associates Learning and Spatial Working Memory). According to their performance at traditional tests, SCD individuals were categorized into cognitively normal (CN) and subtle impaired (SI); with respect to CANTAB, they were defined as CANTAB- in presence of normal performance, and CANTAB+ in presence of at least one pathological score. The subgroup with completely normal performance was defined as CN/CANTAB-, and the subgroup with impairment in both measures as SI/CANTAB+. Differences in prevalence of A/T/N profile according to cognitive profiles were assessed by Fisher's exact text for count data. RESULTS: None of CN/CANTAB- subjects showed A+/T+ status. SI/CANTAB+ subjects showed a significantly high prevalence of A+/T+ profile (14/35, 40%, p=0.03 vs CN/CANTAB-). CONCLUSION: The neuropsychological profile may be of help in identifying SCD subjects requiring biomarker assessment. If confirmed in larger cohorts, the combination of traditional and computerized tests (namely, CANTAB) might represent a feasible strategy in clinical setting for carrying out biomarker assessment in individuals before the MCI stage. Detection of AD in these subjects would give them the highest chances to halt disease progression by means of disease modifying treatments.

A systematic review on the risk of neurodegenerative diseases and neurocognitive disorders in professional and varsity athletes.

OBJECTIVE: The aim of this systematic review (SR) was to gather all available epidemiological evidence on former participation in any type of sport, at a professional and varsity level, as a potential risk factor for neurodegenerative diseases (NDs) and neurocognitive disorders (NCDs). DESIGN: Systematic searches were performed on PubMed, the Cochrane databases, and the ISI Web of Knowledge databases. Included studies were assessed using the NOS checklist. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: All epidemiological studies reporting data on the possible association between a clinical diagnosis of amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND), dementia or mild cognitive impairment (MCI), Parkinson's disease (PD), chronic traumatic encephalopathy (CTE) at any stage and with any clinical pattern and the former participation in any types of sport at a varsity and professional level were included. RESULTS: Data from the 17 included studies showed a higher frequency of NDs and NCDs in former soccer and American football players. Updating the previous SR confirmed a higher frequency of ALS/MND in former soccer players. Data reported a significantly higher risk of dementia/AD in former soccer players, and of MCI in former American football players. Results also showed a significantly higher risk of PD in former soccer and American football players, and a significantly higher risk of CTE in former boxers and American football players. This SR confirmed a higher risk of NDs and NCDs in former professional/varsity athletes. However, the pathological mechanisms underlying this association remain unclear, and further high-quality studies should be performed to clarify whether the association could be sport specific.

Intrathecal kappa free light chains as markers for multiple sclerosis.

Cerebrospinal fluid (CSF) kappa free light chain (KFLC) index has been described as a reliable marker of intrathecal IgG synthesis to diagnose multiple sclerosis (MS). Our aims were: (1) to compare the efficiency of KFLC through different interpretation approaches in diagnosing MS. (2) to evaluate the prognostic value of KFLC in radiologically and clinically isolated syndromes (RIS-CIS). We enrolled 133 MS patients and 240 with other neurological diseases (93 inflammatory including 18 RIS-CIS, 147 non-inflammatory). Albumin, lambda free light chain (LFLC) and KFLC were measured in the CSF and serum by nephelometry. We included two groups of markers: (a) corrected for blood-CSF barrier permeability: immunoglobulin G (IgG), KFLC and LFLC indexes. (b) CSF ratios (not including albumin and serum-correction): CSF KFLC/LFLC, CSF KFLC/IgG, CSF LFLC/IgG. KFLC were significantly higher in MS patients compared to those with other diseases (both inflammatory or not). KFLC index and CSF KFLC/IgG ratio showed high sensitivity (93% and 86.5%) and moderate specificity (85% and 88%) in diagnosing MS. RIS-CIS patients who converted to MS showed greater KFLC index and CSF KFLC/IgG. Despite OB are confirmed to be the gold-standard to detect intrathecal IgG synthesis, the KFLC confirmed their accuracy in MS diagnosis. A "kappa-oriented" response characterizes MS and has a prognostic impact in the RIS-CIS population.

Kappa free light chains could predict early disease course in multiple sclerosis.

BACKGROUND: Cerebrospinal fluid (CSF) kappa free light chains (KFLC) have been suggested as quantitative alternative to oligoclonal bands (OB) in multiple sclerosis (MS) diagnosis. Despite OB have been associated to poor disease prognosis, little is known on KFLC in predicting MS early progression. Our aim is to evaluate the prognostic value of KFLC in a cohort of Italian MS patients. METHODS: 100 patients (64 females) underwent CSF analysis during their diagnostic MS work-up. We collected clinical/paraclinical features (gender, age at onset, clinical course, early MS treatments (within 1 year), gadolinium-enhancing (Gd+) lesions), calculated K index (ratio CSF-serum KFLC and albumin), and MS severity score (MSSS) at last follow up (minimum 1 year). Statistical analysis included Mann-Whitney descriptive analysis, Spearman correlation for independent samples, and linear regression for significant predictors. RESULTS: K index resulted a significant predictor for disability over time being higher in patients who developed greater MSSS. Accordingly, K index was also significantly increased in patients undergoing early versus delayed treatment (N = 50/100, p = 0.046). A similar role in predicting MS disability was confirmed for age at onset. No other factors were retained in our regression model. Of note, K index was not associated to known MS prognostic markers such as gender, age at onset, and Gd+ lesions (N = 31/96). CONCLUSION: Our study suggests KFLC as a CSF quantitative marker to predict early disability in MS (despite not being a substitute for OB).

Resource-theoretic approach to vectorial coherence.

We propose a formal resource-theoretic approach to assess the coherence between partially polarized electromagnetic fields. From this framework, we identify two resource theories for the vectorial coherence: polarization-sensitive coherence and polarization-insensitive coherence. For each theory, we find the set of incoherent states and a class of operations that preserve this set (i.e., the incoherent operations). Both resource theories are endowed with a certain preorder relation that provides a hierarchy among the coherence-polarization states; thus, a necessary condition to consider in deciding whether a quantity is proper to measure the vectorial coherence is that it respects such a hierarchy. Finally, we examine most previously introduced coherence measures from this perspective.

Impact of polymorphism rs7041 and rs4588 of Vitamin D Binding Protein on the extent of coronary artery disease.

BACKGROUND AND AIM: 25-hydroxyvitamin D deficiency represents a widespread social problem but also an emerging risk factor for cardiovascular disease. Genetic variants of the Vitamin D Binding Protein (VDBP), the main transporter of vitamin D in the bloodstream, have been shown to account for a significant variability in the levels and systemic effects of vitamin D. We investigated whether the single nucleotide polymorphisms, rs7041 and rs4588, of VDBP are associated to the prevalence and extent of coronary artery disease. METHODS AND RESULTS: A consecutive cohort of patients undergoing coronary angiography in a single centre were included. Significant CAD was defined as at least 1 stenosis >50%, severe CAD for as left main and/or three-vessel disease. VDBP genetic status was assessed by polymerase chain reaction and restriction fragment length polymorphism technique. We included 1080 patients, 57% carried the mutated G allele of rs7041, whereas 22% carried the A allele of rs4588. Higher levels of C- reactive protein were observed in the carriers of G allele of rs7041 (p = 0.02), whereas 25-hydroxyvitamin D levels were similar across groups. A higher prevalence of lesions in the left anterior descending artery and a longer lesion length were observed in "A" carriers for rs4588 (p = 0.04 and p = 0.03, respectively). On the contrary, a higher prevalence of bifurcation lesions and chronic occlusions was observed in G carriers (p = 0.002 and p = 0.01 respectively). Both polymorphisms of VDBP did not affect the prevalence of CAD (rs7041: 79.1% TT vs 80.3% TG vs 78.5% GG, p = 0.81; rs4588 = 80.3% CC vs 78.5% AC + AA, p = 0.49) and severe CAD, (rs7041: 31.1% TT % vs 31.3% TG vs 30.6% GG, p = 0.88; rs4588: 32.2% CC vs 29.3% AC + AA, p = 0.31). Results were confirmed at multivariate analysis, for both rs7041 and rs4588. However, when including the levels of 25-hydroxyvitamin D in the multivariate model, we observed that 25(OH)D status and not genetic variants of VDBP were significantly associated with CAD (25-hydroxyvitamin D OR [95% CI] = 0.99 [0.97-1.0], p = 0.05; rs7041 TG: OR [95% CI] = 1.26 [0.73-2.19], p = 0.41; rs7041 GG: OR [95% CI] = 1.25 [0.82-1.91], p = 0.30; rs4588 AC + AA: OR [95% CI] = 0.76 [0.51-1.13], p = 0.18). CONCLUSION: This study showed in a large cohort of patients undergoing coronary angiography, that the polymorphisms rs7041 and rs4588 of VDBP are not associated with the levels of 25-hydroxyvitamin D nor with the prevalence and extent of CAD. In fact, 25-hydroxyvitamin D levels but not VDBP genetic status independently predicted the occurrence of coronary lesions at angiography.

A case of false positive Troponin I in a patient affected by cryoglobulinemic vasculitis.

Troponin I (TnI) false positive results have been reported in patients affected by immune disorders. We report the case of a 74-year-old woman affected by cryoglobulinemic vasculitis, admitted to the Emergency Room because of a lipotimic episode. A marked elevation of TnI plasma concentration was confirmed in multiple determinations, despite the absence of symptoms or electrocardiogram findings suggesting myocardial infarction. TnI plasma concentration was reported normal after re-testing with a different commercial kit. A false TnI positivity should be considered in patients with immune disorders, especially if seropositive for rheumatoid factor, when the clinical context does not suggest myocardial infarction.

Impact of neutrophil-to-lymphocyte ratio on periprocedural myocardial infarction in patients undergoing non-urgent percutaneous coronary revascularisation.

BACKGROUND: Pro-thrombotic conditions importantly influence myocardial perfusion and procedural results after percutaneous coronary intervention (PCI). The neutrophil-to-lymphocyte ratio (NLR) has emerged as a predictor of cardiovascular events and of long-term prognosis, especially in ST-elevation myocardial infarction patients undergoing primary PCI. The aim of our study was to evaluate the role of NLR on periprocedural myocardial infarction (MI) in patients undergoing non-urgent PCI. METHODS: In a consecutive cohort of 1542 patients undergoing PCI, myonecrosis biomarkers were determined at 6, 12, 24 and 48 hours post-procedure. Patients were divided into quintiles according to NLR values. Periprocedural myonecrosis was defined as a troponin I increase of 3 times the upper limit of normal or as 50 % of an elevated baseline value, whereas periprocedural MI was defined as a CK-MB increase of 3 times the upper limit of normal or 50 % of baseline. RESULTS: Higher NLR was related to age, established risk factors and cardiovascular history. NLR was associated with severe coronary artery disease (p = 0.009), tighter stenosis (p < 0.001), coronary calcifications (p = 0.005), intracoronary thrombus or thrombectomy use (p < 0.001), TIMI flow pre- and post-PCI (p < 0.001), and inversely to restenosis (p = 0.04) and use of a drug-eluting stent (p = 0.001). NLR did not influence the occurrence of myonecrosis (p = 0.75; adjusted OR (95 % CI) = 0.99 (0.63-1.54), p = 0.96), but was associated with a higher occurrence of periprocedural MI, even after correction for baseline differences (p = 0.03; adjusted OR (95 % CI) = 1.33 (1.02-2.3), p = 0.02), with NLR ≥ 3 best predicting the risk of periprocedural MI at the receiver operating characteristic curve analysis. CONCLUSION: In patients undergoing non-urgent PCI, a higher NLR increases the risk of periprocedural MI, especially for values ≥ 3.

Serum uric acid levels during dual antiplatelet therapy with ticagrelor or clopidogrel: Results from a single-centre study.

BACKGROUND AND AIMS: New antithrombotic therapies have significantly improved the outcomes of patients with acute coronary syndrome (ACS), where the introduction of ticagrelor has provided the greatest mortality benefits. However, ticagrelor treatment has been associated with a potential increase in the serum uric acid (SUA) levels, which may influence endothelial dysfunction and prothrombotic status, thereby affecting the risk of acute cardiovascular events in patients requiring dual antiplatelet therapy (DAPT). The present study aimed to compare the impact of antiplatelet agents such as ticagrelor or clopidogrel on SUA levels and their effect on platelet reactivity. METHODS AND RESULTS: We included patients admitted for ACS or elective percutaneous coronary intervention (PCI) and discharged with ASA (acetylsalicylic acid; 100-160 mg) and clopidogrel (75 mg) or ticagrelor (90 mg twice a day). Chemistry was assessed at admission (baseline) and after a 30-90-day period of DAPT (together with platelet reactivity). The absolute and percentage variations of SUA after DAPT introduction were considered. Multiple-electrode aggregometry was used to assess platelet function. A total of 378 patients were enrolled, with 145 treated with aspirin and clopidogrel (AC) and 233 with aspirin and ticagrelor (AT). The AC patients were older (p = 0.003) and more often showed elective PCI as an indication to DAPT (<0.001); they received chronic therapy with ARB (angiotensin II receptor blocker; p = 0.001), nitrates (p = 0.044), CCB (calcium channel blocker; p = 0.005) and diuretics (p = 0.044). The AT patients displayed a higher percentage of ACS diagnosis (p < 0.001) and received chronic therapy with ACE (angiotensin-converting enzyme) inhibitors (p = 0.001), beta blockers (p = 0.001) and statins (p = 0.013). The AC patients displayed higher platelet reactivity at COL (collagen) test, ASPI test and ADP (adenosine diphosphate) test (p = 0.03, 0.001 and <0.001, respectively) and a higher percentage of HRPR (high residual platelet reactivity) in the ADP test (p = 0.001). No difference was found in the baseline uric acid and creatinine levels between AC and AT patients. At 30-90 days, a significant absolute and percentage increase in the SUA levels was found in AT as compared to AC patients (0.204 mg/dl vs. -0.165 mg/dl, p = 0.034; 6.26% vs. -0.005%, p = 0.018, respectively). Results were not influenced by variations in renal function. At multivariate analysis, in fact, ticagrelor therapy emerged as an independent predictor of increase in the uric acid levels (odds ratio (OR; 95% confidence interval (CI)) = 2.79 (1.66-4.67), p < 0.001). However, the variation in the SUA levels did not affect platelet reactivity or HRPR in both AC and AT patients. CONCLUSION: An increase in the SUA levels at 30-90 days was observed in patients receiving chronic DAPT with ticagrelor, but not clopidogrel treatment. However, the changes in the SUA levels do not influence platelet aggregation.

Uric acid and high-residual platelet reactivity in patients treated with clopidogrel or ticagrelor.

BACKGROUND AND AIM: High residual platelet reactivity (HRPR) is still an important challenge, despite the advent of new potent ADP-antagonists. Therefore it is of extreme importance to identify factors that can influence platelet activation. Serum uric acid (SUA) has been largely addressed in the past as a possible risk factor for coronary artery disease, with a possible association with platelets hyperreactivity. So far no studies have assessed the role of serum uric acid on the response to dual antiplatelet therapy. Therefore, the aim of our study was to evaluate the impact of uric acid levels on platelet function in patients treated with dual antiplatelet therapy (DAPT) with clopidogrel or ticagrelor. METHODS AND RESULTS: We scheduled for platelet function assessment at 30-90 days post-discharge patients treated with DAPT (ASA + clopidogrel or ticagrelor) for an ACS or elective percutaneous coronary intervention (PCI). Platelet function was assessed by whole blood impedance aggregometry (Multiplate(®)-Roche Diagnostics AG), HRPR was considered for ASPI test >862 AU(∗)min (for ASA) and ADP test values ≥417 AU* min (for ADP-antagonists). RESULTS: We included a total of 493 patients (262 were on ASA and clopidogrel and 231 on ASA and ticagrelor). Patients were divided according to quartiles of serum uric acid levels measured at the time of platelet aggregation assessment (Group 1 <4.6 mg/dL, n = 114; Group 2, 4.7-5.8 mg/dL, n = 133; Group 3, 5.9-6.8 mg/dL, n = 124; Group 4, >6.9, n = 122). Patients with higher uric acid levels were older, more often smokers, with history of hypertension and previous coronary artery bypass surgery and renal failure and were more often on therapy with diuretics at admission. Patients with higher SUA had higher triglycerides and fibrinogen. Uric acid levels did not influence ASPI, COL, TRAP and ADP tests. High residual platelet reactivity (HRPR) was observed in 1.5% of patients treated with ASA, with no difference according to SUA quartiles (p = 0.60), confirmed at multivariate analysis after correction for baseline confounders (adjusted OR[95%CI] = 1.05 [0.44-2.52], p = 0.90). HRPR for ADP-antagonists was observed in 23.6% of patients, with no difference according to SUA quartiles (p = 0.47); this result was confirmed also after correction for baseline confounders (adjusted OR[95%CI] = 1.04 [0.84-1.28], p = 0.73). Moreover, no association was found between HRPR and uric acid levels both among patients treated with clopidogrel (p = 0.35) or ticagrelor (p = 0.74), that was confirmed after correction for baseline confounding factors (adjusted OR[95%CI] = 1.18 [0.90-1.55], p = 0.23) and (adjusted OR[95%CI] = 0.96 [0.63-1.47], p = 0.85). The absence of association between SUA and platelet reactivity was confirmed at linear regression analysis both with clopidogrel (r = 0.03, p = 0.55) or ticagrelor (r = -0.01, p = 0.85). CONCLUSION: This is the first large study showing that in patients receiving DAPT, uric acid levels do not influence response to ticagrelor and clopidogrel or the effectiveness of ASA.

Advanced age and high-residual platelet reactivity in patients receiving dual antiplatelet therapy with clopidogrel or ticagrelor.

UNLABELLED: ESSENTIALS: Dual antiplatelet therapy (DAPT) in elderly patients requires balancing bleedings and thrombosis. Impact of age on high residual on-treatment platelet reactivity (HRPR) on DAPT was studied. A reduced effectiveness of adenosine diphosphate antagonists was observed over 70 years of age. The occurrence of HRPR was increased among elderly patients with both clopidogrel and ticagrelor. BACKGROUND: The aim of the present study was to evaluate the impact of age on platelet function and the occurrence of high residual on-treatment platelet reactivity (HRPR) in patients treated with dual antiplatelet therapy (DAPT) using acetylsalicilic acid (ASA) and clopidogrel or ticagrelor. METHODS: Patients treated with DAPT (ASA and clopidogrel or ticagrelor) were scheduled for platelet function assessment at 30-90 days post-discharge. By whole blood impedance aggregometry, HRPR was considered for ASPI test values > 862 AU*min (for ASA) and adenosine diphosphate (ADP) test values > 417 AU*min (for ADP antagonists). Elderly patients were defined as those aged ≥ 70 years. RESULTS: Among 494 patients on DAPT, 224 (45.3%) were ≥ 70 years old. ADP-mediated platelet aggregation increased with decades of age (279.3 ± 148.6 vs. 319.6 ± 171.1 vs. 347.3 ± 190.1 vs. 345.7 ± 169.2), whereas no difference was observed for ASA response. A reduced effectiveness of ADP antagonists was observed among elderly patients; in fact, among the 117 patients displaying HRPR (23.7%), a higher prevalence was observed among patients over 70 years old (30.4% vs. 18.1%; adjusted odds ratio (OR) [95% confidence interval (CI)] = 2.19 [1.29-3.71]). Similar results were obtained among the 266 clopidogrel-treated patients (38.5% vs. 27.9%; adjusted OR [95% CI] = 2.91 [1.46-5.8]) and in the 228 patients receiving ticagrelor (19.1% vs. 8.1%; adjusted OR [95% CI] = 2.55 [1.02-8.59]). CONCLUSION: In patients receiving dual antiplatelet therapy, advanced age is independently associated with a reduced effectiveness of ADP antagonists and a higher rate of HRPR with both clopidogrel and ticagrelor.

Vitamin D status and type 1 diabetes in children: evaluation according to latitude and skin color.

AIM: We aim to investigate vitamin D (25OHD) levels in children with or without type 1 diabetes (T1D) according to latitude and skin color. METHODS: We compared 25OHD levels in children with T1D living in Piedmont, of Caucasian or Moroccan origin, with healthy control subjects matched for age and ethnicity. Data of resident children in Morocco, with and without T1D, were used for comparison. RESULTS: Caucasian (21.4±1.5 vs. 24.0±0.5 ng/mL, P<0.05) and Moroccan children with T1D (12.0±2.6 vs. 17.1±1.7 ng/mL, P<0.05) living in Piedmont had lower 25OHD levels than their counterparts without diabetes. Moroccan children living in Morocco with and without T1D had similar 25OHD levels. Vitamin D deficiency was associated with T1D in Caucasian and Moroccan children living in Piedmont (OR: 1.720, CI95% 1.034-2.860, P<0.03), CONCLUSION: Lower vitamin D levels were associated with T1D in Piedmont. Further studies are necessary to explain a possible relationship between vitamin D and T1D.

Assessing Serum Concentrations of 25-Hydroxy-Vitamin D in North-Western Italy.

OBJECTIVES: Backgound: Most of the published studies on vitamin D levels in Italy have been performed in specific age- or disease- subgroups. Few data are available on the status of vitamin D in the adult general population. OBJECTIVE: We report on vitamin D levels of a large sample of adults from North-Western Italy. Association with age, sex, and season is also evaluated. PARTICIPANTS: 13,110 cases (24% men, 76% women; median age 67 [interquartile range, IQR, 56-77] years old) were collected in the North-Eastern of Piedmont (Italy). MEASUREMENTS: 25-OH-vitamin D levels were measured by chemiluminescent immunoassay. RESULTS: Median total vitamin D level was 19.9 ng/ml (IQR 11.2-28.8 ng/ml) with up to 3,592 (27.4%) and 10,185 (77.7%) subjects respectively below 12 and 30 ng/ml. Vitamin D levels were significantly higher in women than in men (20.5 vs 18.1 ng/ml; p<0.001), in summer than in winter (21.4 vs 18.5 ng/ml; p<0.001), and in individuals aged ≤45years or 46-64 years than in those older than 65 years (20.3 and 21.3 vs 18.8 ng/ml). The lowest mean vitamin D levels were reported during the winter season by men aged ≥65 years (14.7 ng/ml) and 46-64 years (16.8 ng/ml). Multivariate analysis confirmed that age (p<0.001), sex (p=0.002), season (p<0.001) and their interaction (p=0.03) were independently associated to vitamin D concentrations. CONCLUSIONS: This study clearly shows that the majority of adult Italian population, living in a sunny and highly urbanized area of North-Western Italy, have an important deficiency in vitamin D. However, these data must be interpreted with caution if considering the lack of standardization of vitamin D assays.

Renal echo-3D and microalbuminuria in children of diabetic mothers: a preliminary study.

Maternal diabetes has assumed epidemic relevance in recent years and animal studies have provided some evidence that it may cause abnormalities in renal development and a reduction in nephron endowment in the offspring; however, human data are lacking. The renal cortex contains ∼95% of the glomeruli and its volume could be taken as a surrogate measure of glomerular number; based on this assumption, we measured renal cortex volume and in addition, microalbuminuria in a homogeneous sample of 42 children of diabetic (pregestational, n = 13, and gestational, n = 29) mothers, compared with 21 healthy children born of non-diabetic mothers. The offspring of diabetic mothers showed a significant reduction of renal cortex volume and higher albumin excretion compared with controls, possibly attributable to a reduction in the number of nephrons and the difference was statistically significant (P < 0.001). Although further studies on a larger sample are necessary, our preliminary findings suggest that maternal diabetes may affect renal development with sequelae later in life, requiring closer monitoring and follow-up. Furthermore, the importance of strict maternal diabetes management and control must be emphasized.

Role of the laboratory in monitoring patients receiving dual antiplatelet therapy.

INTRODUCTION: The increasing demand for therapeutic monitoring in patients receiving antiplatelet therapy has been paralleled by the development of instruments and tests whose clinical usefulness is still under debate. We devised a laboratory approach to detect patients with antiplatelet resistance at risk to develop thrombotic events. METHODS: One hundred and eighty patients, under aspirin and clopidogrel after angioplasty and stent implantation, were studied by PFA100(®) with collagen/epinephrine (CoEPI, cutoff 165s) cartridge and by Multiplate(®) using arachidonic acid (ASPItest, pos < 862AUC), ADP (ADPtest, pos < 417AUC), and collagen (COLtest, pos < 607AUC). RESULTS: Only 67 of 173 patients with ASPI < 862 displayed a prolonged CoEPI and up to 65 patients had normal CoEPI despite ASPI < 300. Patients with ASPI < 300 had significantly lower COL than patients with ASPI > 300. One hundred and thirty-eight patients displaying ADP < 417 had significantly lower COL than those with ADP > 417. Association between COL and ADP remained after ASPI stratification: in patients with suboptimal (ASPI 300-892) or maximal (ASPI < 300) response to aspirin, having ADP < 417 (clopidogrel responsive) increased COL positivity, respectively, from 9.5 to 58.8% and from 47.6 to 82.7%. CONCLUSION: A combination of specific tests may be useful in identifying higher-risk patients with poor compliance or drug resistance who potentially may benefit from therapy change.

Association of haplotype combination of serotonin transporter gene polymorphisms with monthly headache days in MOH patients.

OBJECTIVES: To evaluate the role of 5-HTTLPR, STin2 VNTR, and rs1042173T>G polymorphisms of the serotonin transporter gene (SLC6A4) as susceptibility factors for medication overuse headache (MOH) and to assess their value as predictors of the number of headache days per month, a potential marker of disease severity. METHODS: Genotyping was performed by PCR and PCR-RFLP on genomic DNA extracted from peripheral blood of 227 MOH patients and 312 control subjects. Logistic regression analysis was used to evaluate the association between the SL6A4 gene polymorphisms and MOH risk. The association between polymorphic variants and monthly headache days was evaluated by linear regression analysis. RESULTS: Logistic regression analysis, adjusted for age and gender, revealed a nominal association between rs1042173T>G and MOH risk (TT vs. TG + GG, OR: 1.58 95% CI: 1.05-2.37, P = 0.028). In the linear regression analysis adjusted for age, gender, primary headache diagnosis, acute drug overused and monthly drug number, STin2 VNTR was found nominally associated with monthly headache days (12/12 vs. others, difference: 1.55 days, 95% CI: 0.01-3.08, P = 0.050). When STin2 VNTR and rs1042173T>G were analyzed in haplotypic combination, a global haplotype association emerged with monthly headache days which remained significant after Bonferroni correction for multiple comparisons (global haplotype association P = 0.0056). CONCLUSION: Although a minor contribution of SLC6A4 variants in the genetic liability of MOH cannot be excluded, haplotype-based analysis of STin2 VNTR and rs1042173T>G polymorphisms allowed to identify a subgroup of MOH patients with a higher number of monthly headache and, possibly, with a more severe disease.

Uric acid does not affect the prevalence and extent of coronary artery disease. Results from a prospective study.

BACKGROUND: Hyperuricemia may be involved in the atherosclerotic process due to endothelial dysfunction and facilitation of smooth muscle cell proliferation. However, debates still exist on the independent role of hyperuricemia, due to its association with several cardiovascular risk factors, such as hypertension, hyperlipidemia, obesity and insulin resistance. Thus, the aim of the current study was to investigate in a consecutive cohort of patients undergoing coronary angiography whether hyperuricemia is associated with the extent of coronary artery disease. METHODS AND RESULTS: Our population is represented by a total of 1901 consecutive patients undergoing coronary angiography between May 2007 and January 2010 at the Azienda Ospedaliera "Maggiore della Carità", Novara, Italy. We additionally evaluated platelet aggregation by PFA-100 (Collagen/Epinefrine) and Multiplate. Quantitative coronary angiography and analysis of IMT were performed by experienced cardiologists who had no knowledge of the patients' clinical information. Higher uric acid was associated with advanced age, larger prevalence of male gender, diabetes, renal insufficiency, hypertension, previous CABG and MI, but with a lower prevalence of family history of CAD. Patients with high uric acid were more often on calcium antagonists, ace-inhibitors, angiotensin receptor antagonists, and, as expected, on diuretics. A significant relationship was observed between uric acid and the prevalence (OR [95% CI] = 1.18 [1.04-1.32], p = 0.01) and severity of CAD (OR [95% CI] = 1.17 [1.03-1.33], p = 0.014). However, the relationship disappeared after correction for baseline confounding factors for both prevalence (OR [95% CI] = 1.06 [0.93-1.21], p = 0.35) and extent of CAD (OR [95% CI] = 1.0 [0.87-1.15], p = 0.96). No relationship was observed between acid uric and IMT (p = 0.73) analyzed in 359 consecutive patients. Finally, there was no relationship between uric acid and platelet aggregation in patients with or without aspirin therapy, as measured by PFA-100 and Multiplate. CONCLUSIONS: Our study showed that uric acid is not associated with platelet aggregation, the extent of coronary artery disease and IMT. Thus, waiting for the results of additional large studies, uric acid may not be considered as a risk factor for coronary artery disease, and its reduction by specific therapies may not be recommended to prevent coronary artery disease and atherosclerosis.

Side effects associated with ultrarapid cytochrome P450 2D6 genotype among women with early stage breast cancer treated with tamoxifen.

BACKGROUND: The side effects of tamoxifen, a drug widely used for the treatment and the prevention of recurrence in patients with estrogen receptor positive breast cancers (ER+), have been reported in clinical trials, but to date no information is available on their possible association with an increased enzymatic activity of CYP2D6 (ultra-metabolizers, UMs). The aim of this study was therefore to evaluate the association between the presence of multiple functional CYP2D6 alleles and the occurrence of side effects. METHODS: 61 women with ER+ breast cancer receiving tamoxifen monotherapy were investigated in order to assess the relationships between CYP2D6 UM phenotype and side effects. Genotyping of 16 CYP2D6 polymorphisms was performed using a new DNA microarray technology. RESULTS: A highly significant difference was detected (41.2% of difference, 95% CI 6 - 61%, Fisher's exact test, p = 0.030) between the numbers of Ultrarapid Metabolizer patients (UM; high activity) with two or more adverse drug reactions to tamoxifen (7/9; 77.8%), compared to the number of Extensive Metabolizers (EM; normal activity), Intermediate Metabolizers (IM; reduced activity), and Poor Metabolizers (PM; no activity) with at least two side effects (19/52, 36.5%). A similar difference was also observed comparing the two groups (UM vs EM-IM-PM) for the number of side effects (median and inter quartile range, IQR: AM/EM/IM 1, IQR 0-2 vs. ULTRA 2, IQR 2-4; Mann-Whitney p = 0.005). CONCLUSIONS: Our results suggest a new association between CYP2D6 gene duplication and side effects to tamoxifen, indicating a possible role of CYP2D6 in their occurrence.

Soluble CD138 serum levels are not associated with other poor prognostic markers in patients with B-chronic lymphocytic leukaemia.

The clinical course of CLL is highly variable, and survival from the time of diagnosis of CLL can range from months to decades. Novel biological markers such as IgVH mutation, CD38, and ZAP-70 expression have shown to offer important prognostic informations. Few reports deal with the sCD138 levels and bad prognostic factors in patients with CLL, and contrasting data are reported in literature. In our study, we evaluated the serum level of sCD138 in patients with B-CLL and its relationship with other prognostic markers. There was a significant association between advanced Rai stage and serum sCD138 levels in CLL subjects. Patients with Rai stage III-IV had significantly higher levels of sCD138 with respect to controls (48.85±34 ng/ml vs. 31.1±19.34 ng/ml; P<0.05). We were unable to demonstrate a significant association between sCD138 serum levels and IgVH gene status, ZAP-70 expression, CD38 expression, beta-2 microglobulin, absolute peripheral blood lymphocytosis, haemoglobin or LDH levels. Our finding that high sCD138 serum levels correlates with advanced stages in patients with B-CLL is consistent with the possibility molecule can identify patients with high tumour burden, but the lack of correlation between sCD138 serum levels and markers such the mutation status of IgVH, ZAP-70, and CD38 suggests that sCD138 levels only reflect the clinical stage of disease than the clinical course or progression.