Mycobacterium leprae in skin and nasal scrapings during sulfone treatment

The results of skin and nasal scrapings are recorded in 146 cases of leprosy during periods of sulfone thaerapy ranging from six to ten years: 1- The nasal mucosa is apparently freed of M. leprae in more than 50 per cent of cases within one year of sulfone treatment. 2- The skin is apparently freed of M. leprae, as shown by routine skin scrapings, in less than 10 per cent of cases in from one to ten years of sulfone treatment.

A clinico-serologic study of leprosy. I- Results of serologic tests for syphilis, including the treponema pallidum immobilization test

The results obtained in a clinico-serologic study of leprosy patients in the U. S. Public Health Service leprosarium at

Hemoglobin types in leprosy

Paper electrophoresis studies were made to ascertain the frequency of abnormal hemoglobin types among 205 patients (187 lepromatous and 18 tuberculoid) hospitalized at the Public Health Service Hospital, Carville, LOuisiana. As controls, blood was obtained from 21 nonpatients with normal hemoglobin patterns and 3 nonpatients having abnormal patterns. Hemoglobin A, the normal pattern, was found in 163 (79,5%) of the patients. Atypical patterns were observed in 28 of the patients by the method we used. Hemolysates from 12 of the 28 patients were submitted to Chernoff who, using a different method than we had used, identifies 5 of the 12 patterns as follows: hemoglobin C trait, 2; sickle-cell trait, 1; sickle-cell trait with a fast-moving component (unidentified), 1; hemoglobin A plus a fast-moving component (unidentified), 1. Hemoglobin C patterns were noted in 13 instances and hemoglobin C trait pattern in 1 instance. Sickling of the erythrocytes or target cells could not be demonstrated in the group showing atypical patterns, or in those patients exhibiting a hemoglobin C pattern. Fetal hemoglobin F as measured by an alkaline denaturation method showed values within the normal range of less than 1 per cent.

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.

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.

Does asymmetric dimethylarginine (ADMA) plasma concentration predict esophageal varices in patients with cirrhosis?

BACKGROUND: In previous studies elevated Asymmetric NG, NG - dimethylarginine (ADMA) plasma levels, an endogenous nitric oxide synthase inhibitor, correlated with the severity of hepatic venous pressure gradient measurement, both in peripheral and in hepatic veins. The aim of this study was to explore whether elevated ADMA plasma levels were able to predict the presence of esophageal varices (EV) and/or large EV in patients with cirrhosis. METHODS: 74 cirrhotic patients who had undergone elective upper gastrointestinal endoscopy in order to assess the presence of portal hypertension and predictors of EV and/or large EV. ADMA levels were assayed by an ELISA test (Immundiagnostik AG, Germany). RESULTS: 53 patients had EV (26/53 had large EV). Univariate analysis of low hemoglobin (p = 0.045), PT-INR (p = 0.003), albumin (p = 0.024), bilirubin (p = 0.036), Child-Pugh score (p = 0.026), and ascites (p = 0.036) predicted the presence of EV. Multivariate analysis predicted EV for only PT-INR. The presence of large EV was predicted with univariate analysis of ADMA plasma levels (p = 0.013), low hemoglobin (p < 0.001), PT-INR (p = 0.001), albumin (p = 0.001), bilirubin (p = 0.026), Child-Pugh score (p < 0.001), ascites (p = 0.004). Sensitivity, specificity, predictive positive and negative values of ADMA plasma level > 0.5 micromol/L(-1) in predicting large EV were 0.69 (95% CI 0.53 - 0.82), 0.51 (95% CI 0.40 - 0.62), 0.43 (95% CI 0.31 - 0.56), 0.76 (95% CI 0.62 - 0.86), while the area under the ROC curve was 0.65 (95% CI 0.51 - 0.79). CONCLUSIONS: ADMA plasma levels were increased in cirrhotics with more advanced liver failure but did not prove to be a useful clinical tool for predicting the presence of esophageal varices or large esophageal varices.

An observational study of Venlafaxine and CYP2D6 in clinical practice.

BACKGROUND: Venlafaxine (V) is a serotonin-norepinephrine selective reuptake inhibitor, mainly metabolized by cytochrome P4502D6 (CYP2D6). CYP2D6 polymorphisms result in a variety of phenotypes: poor (PMs), intermediate (IMs), extensive (EMs), and ultrarapid metabolizers (UMs). PMs usually show poor tolerance to drugs metabolized by CYP2D6, while UMs need greater doses. The aim of this study was to evaluate the impact of CYP2D6 genotype on V dosage, therapeutic response, and side effects in a clinical outpatient setting. METHODS: 47 patients with Major Depressive Disorder, treated with V 75 - 300 mg/day, underwent CYP2D6 genotyping using the INFINITI-CYP2D6 assay. Duration of treatment and clinical outcome (Clinical Global Impression [CGI] effectiveness index) were assessed. RESULTS: CGI assessment was performed after 6 weeks, 6 months, and 1 year of treatment with a V median dose of 150 mg/day. CYP2D6 genotyping resulted in 1 PM, 3 IMs, 42 EMs, and 1 UM. The UM took the greatest V dose (375 mg) without side effects; IMs/PMs took moderate/high doses of V (150 - 300 mg) without adverse effects; EMs displayed high response variability. CONCLUSIONS: PM/IM patients responded to V differently than expected according to genotype. However, the UM patient responded to a dosage higher than the usual therapeutic range and without developing side effects, suggesting an association between CYP2D6 gene duplication and the therapeutic efficacy of venlafaxine. The CYP2D6 genotyping may thus provide clinicians with a potential explanation for those patients requiring greater doses of CYP2D6 substrates in order to obtain the same therapeutic efficacy.

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.

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.