Molecular Engineering of Ghfp, the Gonococcal Orthologue of Neisseria meningitidis Factor H Binding Protein.

Knowledge of the sequences and structures of proteins produced by microbial pathogens is continuously increasing. Besides offering the possibility of unraveling the mechanisms of pathogenesis at the molecular level, structural information provides new tools for vaccine development, such as the opportunity to improve viral and bacterial vaccine candidates by rational design. Structure-based rational design of antigens can optimize the epitope repertoire in terms of accessibility, stability, and variability.

The adjuvant MF59 induces ATP release from muscle that potentiates response to vaccination.

Vaccines are the most effective agents to control infections. In addition to the pathogen antigens, vaccines contain adjuvants that are used to enhance protective immune responses. However, the molecular mechanism of action of most adjuvants is ill-known, and a better understanding of adjuvanticity is needed to develop improved adjuvants based on molecular targets that further enhance vaccine efficacy.

Role of p16(INK4a) cytology testing as an adjunct to enhance the diagnostic specificity and accuracy in human papillomavirus-positive women within an organized cervical cancer screening program.

Objective: We evaluated the performance of cytologic p16(INK4a) (p16) immunostaining within a cervical cancer screening program for the categories of atypical squamous cells of undetermined significance (ASC-US) and low-grade squamous intraepithelial lesion (LS after triage with high-risk human papillomavirus (HR-HPV) testing and atypical squamous cells, cannot exclude high-grade intraepithelial squamous lesion (ASC-H) and high-grade squamous intraepithelial lesion (HSIL). We also verified whether the routine introduction of p16 staining might enhance the specificity and positive predictive value (PPV) for cervical intraepithelial neoplasia grade 2 or higher (CIN2+) lesions predicted by a cytological screening test.

Study Design: Performance of the p16 cytology test was estimated in 578 cytological samples, of which 213 were HR-HPV+ ASC-US, 186 were HR-HPV+ LSIL, 74 were ASC-H, 56 were HSIL-CIN2 and 49 were HSIL-CIN3.

Lytic failure in the current pharmacointensive ST-elevated acute myocardial infarction care: insights from a pilot real-world study.

Background: Thrombolysis remains a very acceptable reperfusion option for ST-elevated acute myocardial infarction (STEMI); however, it fails relatively frequently and unpredictably.

Aim And Methods: To investigate correlates of lytic failure (according to the standard ST resolution criterion) in current pharmacointensive STEMI care (dual antiplatelets with antithrombin), we analyzed retrospectively clinical data and echocardiographic left ventricular systolic function before initiation of reperfusion treatment in Killip I-III STEMI patients admitted to our 'spoke' intensive cardiac care unit between 1 January and 31 December 2010.

Results: Of the 53 STEMI patients enrolled, 28% failed thrombolysis.

UbcH10 expression on thyroid fine-needle aspirates.

Background: Thyroid fine-needle aspiration (FNA) samples belonging to the follicular neoplasm/suspicious for malignancy classes are controversial. The authors identified UbcH10 as a marker useful in the diagnosis of several neoplasms, including thyroid cancer. Here, analysis of UbcH10 expression by quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry was applied to FNAs.

Identifying a higher throughput assay for metabolism dependent inhibition (MDI).

A higher throughput method of screening for the metabolism dependent inhibition of 56 marketed drugs was evaluated and compared data from the PHLM assay (using midazolam as probe) with Cypex assay (using diethoxyfluoresin (DEF) as probe) for CYP3A4 by using 96 well plate. Also 27 marketed drugs were selected to evaluate the reproducibility of Cypex assay using 7-benzyloxyquinoline (7-BQ) as second probe substrate for CYP3A4. Furthermore Cypex CYP2D6 was used to evaluate the reproducibility of this system using 4-methylaminomethyl-7-methoxycoumarin (MMC) as probe substrate with 15 marketed drugs.

Novel wall motion score-based method for estimating global left ventricular ejection fraction: validation by real-time 3D echocardiography and global longitudinal strain.

Aims: To evaluate the reliability of a regional wall motion score index (WMSI)-based method for assessment of left ventricular (LV) ejection fraction (EF).

Methods And Results: Two-dimensional (2D) echocardiography was used to assess a LV 16-segment-based regional wall motion. Each segment received a score based on contractility status: 4, normal kinesis; 3, mild; 2.

Cyclin D1 and D3 overexpression predicts malignant behavior in thyroid fine-needle aspirates suspicious for Hurthle cell neoplasms.

Background: Thyroid fine-needle aspiration (FNA) samples that feature a follicular-patterned, monotonous Hurthle (oncocytic) cell population cannot be diagnosed reliably. The authors of this report recently identified cyclin D3 overexpression on histologic sections of Hurthle cell carcinoma. In this study, they assessed the diagnostic value of cyclin D3 immunohistochemistry added to routine cytology.

Changes in components of left ventricular mechanics under selective beta-1 blockade: insight from traditional and new technologies in echocardiography.

Aims: Myocardial inotropism is considered to be reduced under beta-1 adrenoreceptor blockage (beta1-block). However, relationships between components of left ventricular (LV) systolic mechanics under beta1-block accounting for physiological correlates are only partially explored.

Methods And Results: Hypertensive outpatient without previous cardiovascular events and with normal LV ejection fraction (EF) at rest underwent echocardiographic evaluations of LV size and systolic function by standard, tissue-Doppler, and speckle-tracking methods before and after 2 weeks of treatment with bisoprolol to obtain change in LV systolic mechanics at a stable heart rate reduction (-20 +/- 10% from baseline) without significant change in LV mass.

UbcH10 expression in human lymphomas.

Aims: The UbcH10 ubiquitin-conjugating enzyme plays a key role in regulating mitosis completion. We have previously reported that UbcH10 overexpression is associated with aggressive thyroid, ovarian and breast carcinomas. The aim of this study was to investigate UbcH10 expression in human lymphomas.

Impact of resistance to thyroid hormone on the cardiovascular system in adults.

Background: The clinical manifestations of resistance to thyroid hormone (RTH) are highly variable, and the impact of RTH on the cardiovascular system has been poorly investigated.

Aim: The objective of the study was to evaluate the cardiovascular characteristics of 16 untreated and asymptomatic patients with RTH compared with 16 euthyroid healthy controls to define the cardiovascular involvement in RTH syndrome.

Patients And Methods: Sixteen untreated and asymptomatic RTH patients (eight males; aged 33 +/- 12 yr, range 21-45 yr) and 16 controls (nine males; aged 33 +/- 5 yr, range 24-42 yr) were enrolled.

Effects of growth hormone on exercise capacity and cardiopulmonary performance in patients with chronic heart failure.

Background: Because GH exerted beneficial effects in various experimental models of heart failure, we investigated the effects of GH on physical exercise capacity and cardiopulmonary performance in patients with dilated cardiomyopathy and chronic heart failure (CHF).

Methods: Twenty-two patients with CHF (New York Heart Association functional class II-III) underwent spirometry and a symptom-limited, cardiopulmonary exercise testing before and after 3 months of GH (n = 11; seven males; seven idiopathic; 57 +/- 11 yr; 4 IU sc every other day) or placebo (n = 11; eight males; six idiopathic; 54 +/- 10 yr) administration, in a randomized, double-blind trial. Background CHF therapy remained unchanged.

Isolated left ventricular diastolic dysfunction: implications for exercise left ventricular performance in patients without congestive heart failure.

Objective: Clinical relevance of left ventricular (LV) diastolic dysfunction in the absence of congestive heart failure (CHF) and LV systolic dysfunction is not fully established.

Methods: Asymptomatic outpatients, sedentary, with cardiovascular risk factors but no history of cardiovascular events, underwent echocardiographic evaluation of LV structure and function by standard Doppler, color M-mode, and Doppler tissue methods, and exercise testing with simultaneous noninvasive assessment of LV stroke index and cardiac index. LV ejection fraction less than 50% and significant valvular disease or stress test suggestive of coronary disease were additional exclusion criteria.

An exaggerated systolic blood pressure response to exercise is associated with cardiovascular remodeling in subjects with prehypertension.

Background: Although many observers consider the cardiovascular risk associated with isolated prehypertension to be low and not worth pharmacological treating, the cardiovascular disease rate is increased among individuals within this blood pressure stratum.

Methods: We performed Doppler echocardiography and submaximal bicycle ergometry in 20 nonsmoking sedentary prehypertensive subjects and 20 age- and sex-matched nonsmoking sedentary normotensive subjects, and investigated the association between the systolic blood pressure response to exercise (SBPRE) and hypertensive target organ damage. An exaggerated SBPRE (E-SBPRE) and a normal SBPRE (N-SBPRE) were diagnosed using the mean +2 standard deviations of systolic blood pressure at 100 W in normotensives.

Growth hormone- and pressure overload-induced cardiac hypertrophy evoke different responses to ischemia-reperfusion and mechanical stretch.

Objective: To compare the molecular, histological, and functional characteristics of growth hormone (GH)- and pressure overload-induced cardiac hypertrophy, and their responses to ischemia-reperfusion and mechanical stretch.

Design: Four groups of male Wistar rats were studied: aortic banding (n=24, AB) or sham (n=24, controls) for 10 weeks, and GH treatment (n=24; 3.5mg/kg/day, GH) or placebo (n=24, controls) for 4 weeks.

Association between post-ischemic forearm blood flow and blood pressure response to maximal exercise in well trained healthy young men.

Background: The relationship between peripheral circulation and blood pressure (BP) response to maximal exercise is an intriguing and not yet well defined topic.

Aims: Aims of the present study were to investigate in well trained young healthy males the possible relationships between the endothelial or the smooth muscle component of the peripheral circulation and 1) the BP response to physical exercise on treadmill 2) the body mass composition.

Subjects And Methods: Fifteen subjects (18-36 years), regularly performing physical activity 3 times weekly underwent the following examinations: body composition by bioelectrical impedance analysis; measurement of the forearm blood flow (FBF) at rest and during post-ischemic hyperemia by strain-gauge plethysmography at the upper arm; measurement of brachial artery diameter (BAD) at rest and after 4-min ischemia by echography; BP response to maximal exercise on treadmill with the determination of maximal oxygen consumption and the measurement of lactic acid serum concentration.

Tadalafil improves quality of life and exercise tolerance in idiopathic pulmonary arterial hypertension.

Pulmonary arterial hypertension has a poor prognosis quoad vitam et valitudinem. Herein, we report on a middle-aged woman affected by idiopathic pulmonary arterial hypertension whose quality of life and exercise tolerance improved remarkably after a six-month course of treatment with the long-acting phosphodiesterase-5 inhibitor tadalafil.

Subclinical hypothyroidism and cardiovascular risk: a reason to treat?

Subclinical hypothyroidism (SH), defined by elevated serum levels of thyroid stimulating hormone (TSH) with normal levels of free thyroid hormones, is common in adults, especially in women over 60 years of age. Among individuals with this condition, up to two-thirds have serum TSH levels between 5-10 mU/L and thyroid autoantibodies; almost half of them may progress to overt thyroid failure, the annual percent risk increasing with serum TSH level. There is evidence that elevated TSH levels in patients with SH do not reflect pituitary compensation to maintain euthyroidism, but a mild tissue hypothyroidism sensu strictu.

Subclinical hyperthyroidism: clinical features and treatment options.

Subclinical hyperthyroidism appears to be a common disorder. It may be caused by exogenous or endogenous factors: excessive TSH suppressive therapy with L-thyroxine (L-T4) for benign thyroid nodular disease, differentiated thyroid cancer, or hormone over-replacement in patients with hypothyroidism are the most frequent causes. Consistent evidence indicates that 'subclinical' hyperthyroidism reduces the quality of life, affecting both the psycho and somatic components of well-being, and produces relevant signs and symptoms of excessive thyroid hormone action, often mimicking adrenergic overactivity.

Complex regulation of the cyclin-dependent kinase inhibitor p27kip1 in thyroid cancer cells by the PI3K/AKT pathway: regulation of p27kip1 expression and localization.

Functional inactivation of the tumor suppressor p27(kip1) in human cancer occurs either through loss of expression or through phosphorylation-dependent cytoplasmic sequestration. Here we demonstrate that dysregulation of the PI3K/AKT pathway is important in thyroid carcinogenesis and that p27(kip1) is a key target of the growth-regulatory activity exerted by this pathway in thyroid cancer cells. Using specific PI3K inhibitors (LY294002, wortmannin, and PTEN) and a dominant active AKT construct (myrAKT), we demonstrated that the PI3K/AKT pathway controlled thyroid cell proliferation by regulating the expression and subcellular localization of p27.

p27Kip1 is expressed in proliferating cells in its form phosphorylated on threonine 187.

BACKGROUND: G1/S cell cycle progression requires p27Kip1 (p27) proteolysis, which is triggered by its phosphorylation on threonine (Thr) 187. Since its levels are abundant in quiescent and scarce in cycling cells, p27 is an approved marker for quiescent cells, extensively used in histopathology and cancer research. METHODS: However here we showed that by using a specific phosphorylation site (pThr187) antibody, p27 is detectable also in proliferative compartments of normal, dysplastic and neoplastic tissues.

Aerobic exercise performance correlates with post-ischemic flow-mediated dilation of the brachial artery in young healthy men.

In older healthy men, aerobic exercise capacity is related to postischemic flow-mediated dilation of the brachial artery (FMD), but corresponding data in a younger population is not available. In addition, whether submaximal aerobic exercise performance also correlates with this kind of vasomotor reactivity is not known. Therefore, in 15 nonsmoking young healthy men [age 27 (5) years; body mass index: 24 (2) kg/m(2); mean (SD)] with different levels of ordinary physical activity, but not performing upper-extremity training, we measured FMD at 1 min after reactive hyperemia, and pulmonary oxygen uptake (VO(2)) at ventilatory anaerobic threshold (VO(2)AT) and at peak effort (peak VO(2)) during an incremental exercise on a treadmill.

HMGA1 protein overexpression in human breast carcinomas: correlation with ErbB2 expression.

We measured, by immunohistochemistry, HMGA1 protein expression in 212 breast tissue specimens: 6 normal samples, 28 hyperplastic lesions (13 with cellular atypia), 11 fibroadenomas, 10 in situ ductal carcinomas, 144 ductal carcinomas, and 13 lobular carcinomas. HMGA1 was not expressed in normal breast tissue; HMGA1 staining was intense in 40% of hyperplastic lesions with cellular atypia and in 60% of ductal carcinomas and weak in fibroadenomas and in hyperplastic lesions without cellular atypia. Because HMGA1 expression was similar among ductal breast carcinomas with different histologic grading, we evaluated the association between HMGA1 expression and that of other markers of breast carcinoma invasion (estrogen and progesterone receptors, Ki-67 antigen, and ErbB2) in 21 cases of grade 3 breast ductal carcinomas and 7 cases of breast lobular carcinomas.