Prothrombotic mutations, family history and the risk of thrombosis in postmenopausal women: implications for hormone replacement therapy

Objective Hormone replacement therapy (HRT) is acknowledged as the gold standard for the alleviation of climacteric vasomotor symptoms. Prothrombotic genetic variants have been suggested to increase thrombotic risk among HRT users. The aim of the study was to determine whether a positive family history may identify a genetic predisposition for thrombosis in women before prescribing HRT. Methods From January 2005 to May 2009, we consecutively enrolled 145 asymptomatic women (mean age 51.2+5.4 years) without previous episodes of venous and/or arterial thrombosis referred to our Genetics Research Unit before starting HRT. A detailed family history was reconstructed and we identified 48 women (33.1%) with a positive family history, defined as venous thromboembolism and/or stroke or heart attack, in first-degree relatives before 60 years for men and 65 years for women. A group of 121 women (mean age 54.0+9.1 years) with an episode of venous and/or arterial thrombosis was also included. Genetic screening for factor V Leiden, prothrombin G20210A and methylenetetrahydrofolate reductase C677T polymorphisms was performed. Results The frequency of factor V Leiden or prothrombin G20210A mutations was significantly higher both in asymptomatic women with a positive family history (16.7% vs. 2.1%, p?0.001) and in patients with thrombosis (12.4% vs. 2.1%; p?0.005) compared with asymptomatic women without a family history. Multivariate regression analysis showed a synergic effect between the presence of one prothrombotic mutation and family history on the risk of thrombosis (odds ratio 3.7, 95% confidence interval 1.9-7.2). Conclusions A positive family history of thrombosis is a sensitive indicator for selected genetic testing in high-risk women before starting HRT

Expression level of CCR5 chemokine receptor on blood CD4+ and CD8+ T-cells plays an important role in the Ascending Aortic Aneurysm pathophysiology.

Background and aim: The CC chemokine receptor 5 (CCR5) is involved in the migration of circulating NK and Th1 cells towards inflammatory sites. CCR5 expression has also been demonstrated on endothelial cells, aortic smooth muscle cells and implicated in the development of abdominal aortic aneurysm. Thoracic aortic aneurysm (TAA) is a lethal disease burdened by complications such as aortic dissection/rupture. The risk of these acute events has been related to the severity of aortic enlargement. The aim of our study is to investigate a possible role of CCR5 expression on peripheral blood CD4+ and CD8+ T-lymphocytes in the pathogenesis of TAA. Methods: We have studied 14 patients (8 female, 6 male) with mean age of 67.35?7.70, undergoing isolated aortic valve replacement (AVR) and/or TAA surgery. Preoperatively, venous blood samples were obtained. A three colors flow cytometric analysis was performed by appropriate combinations of monoclonal antibodies directed against the following surface molecules: CD3, CD4, CD8, CCR5. Data are expressed in terms of percentage of positivity. Maximal aortic diameter (MAD) was determined by transesophageal echocardiography. For each patient we calculated the aortic size index (ASI), defined as MAD/BSA (mm/m2). Results: Aortic index was 21.52?3.14 mm/m2. Nine patients underwent isolated AVR (group 1) and five patients underwent TAA surgery (group 2). The percentage of CCR5+ on CD4+ was significantly higher in group 2 (17.03?3.08 vs 13.03?2.72, p=0.0269). A trend towards a higher percentage of CCR5+ on CD8+ was observed in group 2 (22.74?8,39 vs 16.26?3.75, p=0.0653). A significant correlation between aortic index and the percentage of CD4+ and CD8+ T-cells expressing CCR5 was observed (p=0.048, R2=0.287 and p=0.0067, R2=0.471 respectively). Conclusions: The correlation between the percentage of CD4+ and CD8+ T-cells expressing CCR5 and aortic index suggests the role of a T-cell immune-mediated cytotoxic mechanism in the progression of TAA disease

Bone Marrow Clonogenic Capability, Cytokine Production, and Thymic Output in Patients with Common Variable Immunodeficiency

AbstractIn patients with primary Ab deficiencies, hematological and immunological abnormalities are frequently observed. A regenerative failure of hemopoietic stem/progenitor cells has been hypothesized. We evaluated in the bone marrow (BM) of 11 patients with common variable immunodeficiency, the phenotype of BM progenitors and their in vitro growth by colony-forming cell (CFC) and long-term culture (LTC) assays. A significant decrease in erythroid and mixed CFC and, to a greater extent, in primitive LTC-CFC progenitors was observed in patients compared with healthy controls. The frequency of BM pre-B and pro-B cells correlated directly with the absolute number of CD19+ lymphocytes. BM cells cultured in vitro produced spontaneously lower amounts of IL-2 and elevated levels of TNF-α compared with controls, indicating a skewing toward a proapoptotic cytokine pattern. In addition, stromal cells generated after BM LTC secreted less IL-7 and displayed by immunohistochemistry an altered phenotype. These findings were associated with a significant decrease in naive Th cells coexpressing CD31 in the peripheral blood. These results indicate an impaired growth and differentiation capacity of progenitor cells in patients with common variable immunodeficiency

Ascending aortic aneurysm in a patient with bicuspid aortic valve, positive history of systemic autoimmune diseases and common genetic factors: a case report

The bicuspid aortic valve (BAV) and specific systemic autoimmune diseases are associated with cardiovascular manifestation, including aortic aneurysm. We reported a case of 64 year-old patient with BAV and a history of ankylosing spondylitis (AS) and systemic lupus erythematosus (SLE), and who developed ascending thoracic aortic aneurysm. The patient presented also the homozygosity for genetic variants of MMP9, ACE, MTHFR and PAI-1 genes. Gene-environmental interactions may represent an additional pathogenetic dimension in the still challenging management of the abnormalities of the aortic wall, including dilatation, aneurysm and dissection

Potency of Netilmicin against Staphylococci Compared to Other Ophthalmic Antibiotics

Netilmicin is a potent and safe antibiotic with a very low incidence of resistance used as a topical ophthalmic medication in bacterial ocular infections. The aim of this study was to compare netilmicin’s Quotient of Inhibitions (QIs) and killing kinetics vs Staphylococci with other ophthalmic antimicrobials. Conjunctival and corneal QIs of netilmicin formulations, in single and multiple doses of administration, were compared with those of tobramycin, ofloxacin, levofloxacin and azithromycin preparations. The same analysis was performed in human tears, comparing netilmicin eye drops solution with tobramycin ofloxacin and levofloxacin. Furthermore, killing kinetics against Staphylococci (ATCC strains and ocular isolates) of the above-cited antibiotics, as well as chloramphenicol, were compared at different time points. QI results showed that in the conjunctiva, netilmicin, in both single and multiple doses of administration, is highly effective against all staphylococcal strains tested, while in the cornea it was particularly active against methicillin-resistant Staphylococci strains. Moreover, in human tears, netilmicin eye drops solution showed a more favourable QI against Staphylococci than tobramycin, ofloxacin and levofloxacin all in single-dose administration regimen. Killing kinetic results showed that netilmicin has a great bactericidal activity vs all the microbe strains tested as netilmicin showed to be almost the most active antibiotic. Results suggest that netilmicin has one of the most favourable killing kinetic and tissue inhibitory effects against Staphylococci than the principal ophthalmic antibiotics on the market

Health-related quality of life and functional changes in DMD: A 12-month longitudinal cohort study

In Duchenne muscular dystrophy (DMD) little has been reported on the association between clinical outcome measures and patient health-related quality of life (HRQOL) tools. Our study evaluated the relationship between 12 month changes on the Generic Core Scales (GCS), the Multidimensional Fatigue Scale and the Neuromuscular Module of the PedsQL\u2122 with several outcome measures (6 minute walk test, North Star Ambulatory Assessment and timed items) in ambulatory DMD. Ninety-eight ambulatory DMD in a multicentric setting were included in the study. At baseline, the PedsQL\u2122 inventories correlated with almost all the functional measures On the Child Self-Report there was a significant decrease between baseline and 12 months on the PedsQL\u2122 GCS and its first domain, in parallel with the decrement in the functional outcome measures. Correlation between the 12 month changes on the PedsQL\u2122 inventories and functional measures were almost all negligible. Similar results were obtained on the Parent Proxy-Report.In conclusion, PedsQL\u2122 correlates with the level of impairment at baseline, but this does not hold true when 12 month changes are considered. Further studies comparing different tools are needed to better elucidate the complexity of the relationship between HRQOL and functional performances

Timed rise from floor as a predictor of disease progression in Duchenne muscular dystrophy: An observational study

The role of timed items, and more specifically, of the time to rise from the floor, has been reported as an early prognostic factor for disease progression and loss of ambulation. The aim of our study was to investigate the possible effect of the time to rise from the floor test on the changes observed on the 6MWT over 12 months in a cohort of ambulant Duchenne boys.A total of 487 12-month data points were collected from 215 ambulant Duchenne boys. The age ranged between 5.0 and 20.0 years (mean 8.48 ±2.48 DS).The results of the time to rise from the floor at baseline ranged from 1.2 to 29.4 seconds in the boys who could perform the test. 49 patients were unable to perform the test at baseline and 87 at 12 month The 6MWT values ranged from 82 to 567 meters at baseline. 3 patients lost the ability to perform the 6mwt at 12 months. The correlation between time to rise from the floor and 6MWT at baseline was high (r = 0.6, p<0.01).Both time to rise from the floor and baseline 6MWT were relevant for predicting 6MWT changes in the group above the age of 7 years, with no interaction between the two measures, as the impact of time to rise from the floor on 6MWT change was similar in the patients below and above 350 m. Our results suggest that, time to rise from the floor can be considered an additional important prognostic factor of 12 month changes on the 6MWT and, more generally, of disease progression

Benefits of glucocorticoids in non-ambulant boys/men with Duchenne muscular dystrophy: A multicentric longitudinal study using the Performance of Upper Limb test

The aim of this study was to establish the possible effect of glucocorticoid treatment on upper limb function in a cohort of 91 non-ambulant DMD boys and adults of age between 11 and 26 years. All 91 were assessed using the Performance of Upper Limb test. Forty-eight were still on glucocorticoid after loss of ambulation, 25 stopped steroids at the time they lost ambulation and 18 were GC naive or had steroids while ambulant for less than a year. At baseline the total scores ranged between 0 and 74 (mean 41.20). The mean total scores were 47.92 in the glucocorticoid group, 36 in those who stopped at loss of ambulation and 30.5 in the naive group (p <0.001). The 12-month changes ranged between -20 and 4 (mean -4.4). The mean changes were -3.79 in the glucocorticoid group, -5.52 in those who stopped at loss of ambulation and -4.44 in the naive group. This was more obvious in the patients between 12 and 18 years and at shoulder and elbow levels. Our findings suggest that continuing glucocorticoids throughout teenage years and adulthood after loss of ambulation appears to have a beneficial effect on upper limb function. (C) 2015 The Authors. Published by Elsevier B.V

Upper limb function in Duchenne muscular dystrophy: 24 month longitudinal data

The aim of the study was to establish 24 month changes in upper limb function using a revised version of the performance of upper limb test (PUL 2.0) in a large cohort of ambulant and non-ambulant boys with Duchenne muscular dystrophy and to identify possible trajectories of progression. Of the 187 patients studied, 87 were ambulant (age range: 7\u201315.8 years), and 90 non-ambulant (age range: 9.08\u201324.78). The total scores changed significantly over time (p&lt;0.001). Non-ambulant patients had lower total scores at baseline (mean 19.7) when compared to the ambulant ones (mean 38.4). They also had also a bigger decrease in total scores over 24 months compared to the ambulant boys (4.36 vs 2.07 points). Multivariate model analysis showed that the Performance of Upper Limb changes reflected the entry level and ambulation status, that were independently associated to the slope of Performance of Upper Limb changes. This information will be of help both in clinical practice and at the time of designing clinical trials

Reliability of the Performance of Upper Limb assessment in Duchenne muscular dystrophy

Abstract The Performance of Upper Limb was specifically designed to assess upper limb function in Duchenne muscular dystrophy. The aim of this study was to assess (1) a cohort of typically developing children from the age of 3 years onwards in order to identify the age when the activities assessed in the individual items are consistently achieved, and (2) a cohort of 322 Duchenne children and young adults to establish the range of findings at different ages. We collected normative data for the scale validation on 277 typically developing subjects from 3 to 25 years old. A full score was consistently achieved by the age of 5 years. In the Duchenne cohort there was early involvement of the proximal muscles and a proximal to distal progressive involvement. The scale was capable of measuring small distal movements, related to activities of daily living, even in the oldest and weakest patients. Our data suggest that the assessment can be reliably used in both ambulant and non ambulant Duchenne patients in a multicentric setting and could therefore be considered as an outcome measure for future trials