Pulse pressure amplification, pressure waveform calibration and clinical applications

Obtaining pulse pressure non-invasively from applanation tonometry requires the calibration of pressure waveform with brachial systolic and diastolic blood pressure. In the literature, several calibration methodologies are applied, and clinical studies disagree about the predictive value of central hemodynamic parameters. Our aim was to compare 4 calibration methodologies and assess the usefulness of pulse pressure amplification as an index independent of calibration. We investigated 108 subjects with tonometry in carotid, femoral, brachial, radial and dorsalis-pedis arteries; pulse pressure amplification between arterial waveforms was calculated. Four methods to calibrate the waveforms were compared: the 1/3 rule, the 40% rule, the integral of radial and brachial waveforms. Pulse pressure amplification in 5 arterial territories (carotid-femoral, carotid-brachial, carotid-radial and carotid-pedis amplifications; femoral-pedis amplification) was studied. Pulse pressure was successfully measured non-invasively at the 5 arterial sites. Pulse pressure was markedly dependent on calibration, with differences up to 18 mmHg between methods. Calculation of pulse pressure amplification eliminated effects of calibration method. Furthermore, pulse pressure amplifications in the 5 arterial sites presented a distinct pattern of clinical/biological determinants: heart rate and body height were common determinants of carotid to brachial, radial and femoral amplifications; diabetes was related to carotid to brachial amplification and pulse wave velocity to femoral to pedis amplification. In conclusion, the calibration of pulse pressure will influence results of clinical trials, but calculation of pulse pressure amplification can avoid this. We also suggest that the alteration of amplification in each arterial territory might be considered as a signal of clinical/subclinical damage.     

High-fibre diet and Lactobacillus paracasei B21060 in symptomatic uncomplicated diverticular disease

AIM:To investigate in symptomatic uncomplicated diverticular disease the efficacy of symbiotics associated with a high-fibre diet on abdominal symptoms.METHODS:This study was a multicentre,6-mo randomized,controlled,parallel-group intervention with a preceding 4-wk washout period.Consecutive outpatients with symptomatic uncomplicated diverticular disease,aged 40-80 years,evaluated in 4 Gastroenter-ology Units,were enrolled.Symptomatic uncomplicated diverticular disease patients were randomized to two treatment arms A or B.Treatment A(n = 24 patients) received 1 symbiotic sachet Flortec(Lactobacillus paracasei B21060) once daily plus high-fibre diet for 6 mo.Treatment B(n = 21 patients) received high-fibre diet alone for 6 mo.The primary endpoint was regression of abdominal symptoms and change of symptom severity after 3 and 6 mo of treatment.RESULTS:In group A,the proportion of patients with abdominal pain 24 h decreased from 100% at baseline to 35% and 25% after 3 and 6 mo,respectively(P 0.001).In group B the proportion of patients with this symptom decreased from 90.5% at baseline to 61.9% and 38.1% after 3 and 6 mo,respectively(P = 0.001).Symptom improvement became statistically significant at 3 and 6 mo in group A and B,respectively.The proportion of patients with abdominal pain 24 h decreased from 60% to 20% then 5% after 3 and 6 mo,respectively in group A(P 0.001) and from 33.3% to 9.5% at both 3 and 6 mo in group B(P = 0.03).In group A the proportion of patients with abdominal bloating significantly decreased from 95% to 60% after 3 mo,and remained stable(65%) at 6-mo follow-up(P = 0.005) while in group B,no significant changes in abdominal bloating was observed(P = 0.11).After 6 mo of treatment,the mean visual analogic scale(VAS) values of both short-lasting abdominal pain(VAS,mean ± SD,group A:4.6 ± 2.1 vs 2.2 ± 0.8,P = 0.02;group B:4.6 ± 2.9 vs 2.0 ± 1.9,P = 0.03) and abdominal bloating(VAS,mean ± SD,group A:5.3 ± 2.2 vs 3.0 ± 1.7,P = 0.005;group B:5.3 ± 3.2 vs 2.3 ± 1.9,P = 0.006) decreased in both groups,whilst the VAS values of prolonged abdominal pain decreased in the Flortec group,but remained unchanged in the high-fibre diet group(VAS,mean ± SD,group A:6.5 ± 1.5 vs 4.5 ± 2.1,P = 0.052;group B:4.5 ± 3.8 vs 5.5 ± 3.5).CONCLUSION:A high-fibre diet is effective in relievingabdominal symptoms in symptomatic uncomplicated diverticular disease.This treatment may be implemented by combining the high-fibre diet with Flortec.     

High-frequency and adaptive-like dynamics of human CD1 self-reactive T cells

CD1 molecules present lipid antigens to T cells. An intriguing subset of human T cells recognize CD1‐expressing cells without deliberately added lipids. Frequency, subset distribution, clonal composition, naïve‐to‐memory dynamic transition of these CD1 self‐reactive T cells remain largely unknown. By screening libraries of T‐cell clones, generated from CD4⁺ or CD4^?CD8^? double negative (DN) T cells sorted from the same donors, and by limiting dilution analysis, we find that the frequency of CD1 self‐reactive T cells is unexpectedly high in both T‐cell subsets, in the range of 1/10–1/300 circulating T cells. These T cells predominantly recognize CD1a and CD1c and express diverse TCRs. Frequency comparisons of T‐cell clones from sorted naïve and memory compartments of umbilical cord and adult blood show that CD1 self‐reactive T cells are naïve at birth and undergo an age‐dependent increase in the memory compartment, suggesting a naïve/memory adaptive‐like population dynamics. CD1 self‐reactive clones exhibit mostly Th1 and Th0 functional activities, depending on the subset and on the CD1 isotype restriction. These findings unveil the unanticipated relevance of self‐lipid T‐cell response in humans and clarify the basic parameters of the lipid‐specific T‐cell physiology.     

Salmeterol & fluticasone 50 microg/250 microg bid in combination provides a better long-term control than salmeterol 50 microg bid alone and placebo in COPD patients already treated with theophylline

Bronchodilator agents are central to the symptomatic management of Chronic Obstructive Pulmonary Disease (COPD), and long-acting inhaled bronchodilators are regarded as more convenient. The role of inhaled corticosteroids still remains controversial, but there is increasing evidence that they may improve FEV(1) and symptoms in the long-term. AIM: of the present small pilot study was to compare Salmeterol & Fluticasone (SM&FP) 50/250 microg bid via a single Diskus inhaler with SM 50 microg bid alone, and with placebo (P) in the treatment of moderate COPD. METHODS: Eighteen moderate COPD patients (53-77 yr, mean basal FEV(1)=49.1% pred.+/-5.0 s.d.; mean FEV(1) reversibility=3.6% bsln+/-3.8 s.d.) treated with theophylline 400 mg/day and beta(2) short acting prn, were divided into three matched groups of six subjects according to a double-blind design, and treated with SM&FP 50/250 microcg, or SM 50 microcg alone, or P via Diskus inhaler bid for 52 weeks. In bsln, after 4, 12, 24, 36 and 52 weeks, FEV(1) (% pred), morning PEF (l/s), the daily symptom score, and the number of exacerbations (compared with the previous year) were considered. Statistics. t-test, anova in each treatment group, and anova among basal values and among the 52 week values were used, being p<0.05 accepted. Also changes (DeltaFEV(1)) from baseline were compared at different control times. RESULTS: The mean number of exacerbations/yr decreased from 3.5+/-0.8 to 1.16+/-0.75 s.d. exacerbation/yr in the SM&FP group (t-test p<0.001); from 3.0+/-0.89 to 2.3+/-0.81 s.d. in the SM group (t-test p=ns); and from 3.16+/-1.16 to 4.16+/-0.75 s.d. in the P group (t-test p=ns).Patients receiving SM&FP showed the highest mean improvement in FEV(1) (+7.3%+/-3.3 s.d.) over the baseline pre-treatment value after 36 weeks of treatment (anova p<0.001), being FEV(1) unchanged after 52 weeks of treatment in SM group (+0.33%+/-2.4 s.d.) and with a substantial decrease following P (-2.6%+/-1.2 s.d.) (anova p<0.001).Morning PEF (l/min) increased in subjects treated with SM&FP (anova p<0.001), while it remained unchanged in SM and P group (in both, anova p=ns).After 52 weeks of treatment, only subjects treated with SM&FP showed a reduction of the daily symptoms score from 3.6+/-0.7 to 2.0+/-0.2 s.d. (anova p=0.008). Daily beta(2) short acting prn consumption was reduced only in SM&FP group from 4.2+/-0.81 to 2.2+/-1.2 s.d. after 52 weeks (anova p<0.001). CONCLUSIONS: SM&FP 50/250 microcg regularly assumed in combination via a single Diskus inhaler for a 52 week period improves respiratory function (such as FEV(1), morning PEF), and and symptom score significantly in moderate COPD previously treated with theophylline, and at an higher extent than SM alone or P. The use of beta(2) short acting prn is also reduced, together with the number of exacerbations.     

Novel epigenetic-based therapies useful in cardiovascular medicine

Epigenetic modifications include DNA methylation, his-tone modifications, and micro RNA. Gene alterations have been found to be associated with cardiovascular diseases, and epigenetic mechanisms are continuously being studied to find new useful strategies for the clinical management of afflicted patients. Numerous cardiovascular disorders are characterized by the abnormal methylation of Cp G islands and so specific drugs that could inhibit DNA methyltransferase directly or by reducing its gene expression(e.g., hydralazine and procainamide) are currently under investigation. The anti-proliferative and anti-inflammatory properties of histone deacetylase inhibitors and their cardio-protective effects have been confirmed in preclinical studies. Furthermore, the regulation of the expression of micro RNA targets through pharmacological tools is still under development. Indeed, large controlled trials are required to establish whether current possible candidate antisense micro RNAs could offer better therapeutic benefits in clinical practice. Here, we updated therapeutic properties, side effects, and feasibility of eme-rging epigenetic-based strategies in cardiovascular diseases by highlighting specific problematic issues that still affect the development of large scale novel therapeutic protocols.     

Application of inter-simple sequence repeat PCR to mouse models: assessment of genetic alterations in carcinogenesis

Genomic instability is believed to play a significant role in cancer development by facilitating tumor progression and tumor heterogeneity. Inter-simple sequence repeat (inter-SSR) PCR has been proved to be a fast and reproducible technique for quantitation of genomic instability (amplifications, deletions, translocations, and insertions) in human sporadic tumors. However, the use of inter-SSR PCR in animal models of cancer has never been described. This new technique has been adapted in our laboratory for the analysis of spontaneous and induced mouse tumors. We established the best PCR conditions for each microsatellite-anchored primer and critically evaluated the reproducibility of the band patterns. We also studied the variation of the fingerprints between and within various inbred mouse strains, including wild-derived lines. Tumor-specific alterations were detected as gains, losses, or intensity changes in bands when compared with matched normal DNA. We quantitated the extent of alterations by dividing the number of altered bands in the tumor by the total number of bands in normal DNA (instability index). By means of inter-SSR PCR, we successfully analyzed genomic alterations in various mouse tumors, including spontaneous thymic lymphomas developed in Msh2 knockout mice as well as chemically induced squamous cell carcinomas and thymic lymphomas. Instability index values ranged between 0 and 9%, the highest levels observed in N-methyl-N-nitrosourea-induced thymic lymphomas generated in Trp53 (p53) nullizygote (-/-) mice. We report here, for the first time, the use of inter-SSR PCR to detect somatic mutations in mouse tumoral DNA, including laser-capture microdissected, methanol-fixed tissues. These PCR-based fingerprints provide a novel approach to assessing the number and onset of mutational events in mouse tumors and will help to understand better the mechanisms of carcinogenesis in mouse models.     

Gut microbiota,inflammatory bowel disease and colorectal cancer

The gut microbiota is a complex community of microorganisms that inhabit the digestive tracts of humans, living in symbiosis with the host. Dysbiosis, characterized by an imbalance between the beneficial and opportunistic gut microbiota, is associated with several gastrointestinal disorders, such as irritable bowel syndrome (IBS); inflammatory bowel disease (IBD), represented by ulcerative colitis and Crohn’s disease; and colorectal cancer (CRC). Dysbiosis can disrupt the mucosal barrier, resulting in perpetuation of inflammation and carcinogenesis. The increase in some specific groups of harmful bacteria, such as Escherichia coli (E. coli) and enterotoxigenic Bacteroides fragilis (ETBF), has been associated with chronic tissue inflammation and the release of pro-inflammatory and carcinogenic mediators, increasing the chance of developing CRC, following the inflammation-dysplasia-cancer sequence in IBD patients. Therefore, the aim of the present review was to analyze the correlation between changes in the gut microbiota and the development and maintenance of IBD, CRC, and IBD-associated CRC. Patients with IBD and CRC have shown reduced bacterial diversity and abundance compared to healthy individuals, with enrichment of Firmicute sand Bacteroidetes. Specific bacteria are also associated with the onset and progression of CRC, such as Fusobacterium nucleatum, E. coli, Enterococcus faecalis, Streptococcus gallolyticus, and ETBF. Future research can evaluate the advantages of modulating the gut microbiota as preventive measures in CRC high-risk patients, directly affecting the prognosis of the disease and the quality of life of patients.     

An area-based study on intrapartum antibiotic prophylaxis for preventing group B streptococcus early-onset disease: advances and limitations

Introduction: The prevalence of maternal group-B-streptococcus (GBS) colonization and risk factors (RFs) for neonatal early-onset disease (EOD) in Europe are poorly defined. Large-scale information concerning adherence to recommendations for preventing GBS-EOD are lacking.

Materials and methods: This was a 3-month retrospective area-based study including all regional deliveries ≥35 weeks' gestation (in 2012). The sensitivity, specificity, positive and negative predictive values, odds ratio and receiver operating characteristic (ROC) curve for intrapartum antibiotic prophylaxis (IAP) among full-term and preterm deliveries and prolonged membrane rupture (PROM) were calculated.

Results: Among 7133 women, 259 (3.6%) were preterm (35–36 weeks' gestation). Full-term women were 6874, and 876 (12.7%) had at least 1?RF. Most women (6495) had prenatal screening and 21.4% (1390) were GBS positive.

IAP was given to 2369 (33.2%) women (preterm, n?=?166; full term, n?=?2203). Compared to full-term, preterm women were less likely to receive IAP when indicated (73.2% versus 90.3%, p?Conclusions: Large-scale prenatal screening and IAP are feasible. Women delivering preterm are less likely to receive IAP when indicated. Most unnecessary antibiotics are given in cases of PROM.     

Delafloxacin for the treatment of respiratory and skin infections

Introduction: There has been a striking increase in the emergence of multidrug-resistant pathogens in recent times. Delafloxacin is a novel, broad-spectrum fluoroquinolone with antimicrobial activity against resistant Gram-positive, Gram-negative and anaerobic organisms. It has the potential to treat a variety of infections including complicated skin and skin structure infections and respiratory tract infections.

Areas covered: In this review, the authors report the microbiological spectrum of activity of delafloxacin as well as its pharmacokinetic characteristics. They also report the results of recent studies investigating its safety and efficacy.

Expert opinion: The profile of delafloxacin offers several advantages. Delafloxacin presents a broad spectrum of activity against pathogens involved in respiratory infections and complicated skin and skin structure infections (SSSIs), including methicillin-resistant Staphylococcus aureus. It has also shown activity against Gram-negative pathogens, such as quinolone-susceptible and -resistant strains of Escherichia coli and Klebsiella pneumoniae and quinolone-susceptible Pseudomonas aeruginosa. The availability of an oral formulation supports its use in sequential therapy. The efficacy and tolerability of delafloxacin have been demonstrated in Phase II clinical trials in comparison with moxifloxacin for respiratory infections and linezolid and vancomycin in SSSIs. Compared with other quinolones such as moxifloxacin, delafloxacin showed comparable efficacy and a lower rate of adverse effects. The results of new Phase III studies are awaited to confirm delafloxacin’s future applications in the treatment of SSSIs.