Cardiovascular risk in hypertensive patients: results of the Pandora project

BACKGROUND: The aim of the Pandora project is to collect epidemiological information, check diagnostic and therapeutic pathways, and assess outcomes in a large hypertensive population. This report presents the results on patients enrolled in the study between 1997-1999. METHODS: Twenty-one general practitioners working in the Ravenna Local Health Service took part in the study. They were supplied with IBM compatible PCs and were trained to enter the patient's data (age, gender, familiarity for cardiovascular diseases, smoking, hospitalisations for cardiovascular disorders, diabetes, blood pressure, total cholesterolemia, creatininemia, antihypertensive therapy) on So.Ge.Pa. software. Cardiovascular risk factors were assessed according to the WHO - ISH joint committee recommendations. RESULTS: 2,608 treated hypertensive patients were enrolled, 65% of whom showed inadequate blood pressure control. The prevalence of inadequate BP control was higher in patients on multiple-drug antihypertensive therapy compared with those on monotherapy (71.9% vs. 47.9%), in older than in younger patients (70.7% vs. 56.1%) and in patients with three cardiovascular risk factors, or diabetes, or affected target organs, compared to those with two or less risk factors (72.4% vs. 63.3%), (p < 0.001 for all). 63.6% of patients were at risk for age, 36.6% for family history of cardiovascular diseases and 31.7% for severe hypercholesterolemia. CONCLUSIONS: BP control was inadequate in a large percentage of patients, but it was particularly unsatisfactory in the elderly and in patients with high cardiovascular risk. A cluster of cardiovascular risk factors was found in both adequately and inadequately controlled hypertensive patients.     

A novel PTPN11 gene mutation bridges Noonan syndrome, multiple lentigines/LEOPARD syndrome and Noonan-like/multiple giant cell lesion syndrome

Noonan (NS) and multiple lentigines/LEOPARD syndromes (LS) have proved to be associated with distinct PTPN11 mutations. Noonan-like/multiple giant cell lesion syndrome (NLS) is a rare disease, characterised by short stature, facial dysmorphisms, congenital heart defect (CHD) and central giant cell lesions. PTPN11 gene mutations have been reported in a single NLS family and two sporadic patients. Here we report a patient with a complex phenotype progressing throughout the years from NS at birth towards LS and NLS. PTPN11 gene analysis disclosed a novel missense mutation (Ala461Thr) in exon 12, affecting the consensus sequence of the SHP2-active site. This observation joins together NS and LS to NLS into a unique genetic defect, broadening the clinical and molecular spectrum of PTPN11-related disorders.     

Use of DDDRP pacing device in prevention and treatment of tachy-brady syndrome after Mustard procedure

A 13-year-old male patient, who underwent Mustard operation for a very complex congenital heart disease (CHD), after palliation presented a decrease of the sinus node function, developing a tachy-brady syndrome and a mild dysfunction of atrioventricular (AV) conduction. He was successfully treated using a DDDRP pacemaker, which ensured a suitable atrial rhythm and was able to interrupt supraventricular tachycardia episodes. Until now, hospitalization related to episodes of heart failure or symptomatic arrhythmia, has not been necessary.     

1-Thioangelicin: crystal structure, computer-aided studies and photobiological activity

1-Thioangelicin is a furocoumarin analog synthesized to investigate the role of the substitution of sulfur for oxygen in the parent compound angelicin. The compound was examined by X-ray diffraction, and its interaction with DNA, both in the dark and by UVA irradiation, studied by means of linear flow dichroism, chromatography and (1)H NMR. Further insight into the steric and electronic features of 1-thioangelicin has been reached through theoretical calculations, including molecular mechanics optimization, docking studies and frontier molecular orbital investigations. The experimental data indicate that thioangelicin is able to intercalate in the DNA helix and subsequent irradiation yields a cis-syn adduct, in agreement with theoretical calculations within the lower/higher singly occupied molecular orbital formalism. Antiproliferative activity has been assessed on Balb/c 3T3 cultured cells.     

Breast irradiation with three conformal photon fields for patients with high lung involvement

Since 2001, 50 breast cancer patients, for whom extensive lung/heart involvement was expected from the use of conventional tangential 2-field technique (2F) owing to complex anatomies, were irradiated using a 3-field conformal technique (3F). Dose plans were designed for both 3F and 2F and a dose volume histogram analysis on ipsilateral lung, heart, and target was conducted. The 3F technique allowed a significant reduction in ipsilateral lung irradiation: mean dose dropped from 16.0±3.8 (2F) to 12.0±2.7 Gy (3F) and V_45Gy from 20.7±6.8 (2F) to 3.2±2.9% (3F). Similarly, in patients irradiated to the left breast, heart mean dose was reduced from 8.1 Gy (2F) to 6.8 Gy (3F) and D_15% from 19.0 Gy to 14.0 Gy. All differences reached a high degree of significance. The target coverage was not clinically compromised since the slight reduction using 3F compared with 2F is limited to V_95% while V_90% difference, even if statistically significant, is small: 98.2±1.8% (3F) and 98.8±1.6 (2F). A preliminary report on clinical follow up is also included; with a mean follow up of 15.8 months, no pulmonary or cardiac complications were observed.     

Diagnostic applications of cardiac multislice CT with sixteen-row scanner: state of the art

Coronary angiography is nowadays the diagnostic standard in the evaluation of coronary artery anatomy, in the identification of stenoses and in the follow-up of revascularization procedures (PTCA-stenting, bypass). The limitations of such technique in terms of invasivity and high cost has targeted research efforts towards the development of non invasive diagnostic tools. Technological evolution in the field of helical CT has provided 2, 4, 8 and 16 detector-row multislice scanners characterized by progressive improvements in terms of spatial and temporal resolution that have made them increasingly suitable for the analysis of moving structures with high quality anatomic detail. The main cardiologic applications of multislice CT include coronary calcium scoring, the evaluation of coronary vascular anatomy and disease, follow-up of revascularization procedures (stenting, bypass), and the evaluation of cardiac walls and chambers. The aim of this paper is to describe the applications of sixteen detector-row multisclice CT in non invasive evaluation of cardiac and coronary diseases.     

Arrhythmogenic right ventricular cardiomyopathy type 1 (ARVD1): confirmation of locus assignment and mutation screening of four candidate genes

Arrhythmogenic right ventricular cardiomyopathy type 1 (ARVD1) is an autosomal dominant disorder characterised by progressive degeneration of right ventricular myocardium, arrhythmias and risk of sudden death. By linkage analysis, we previously mapped the involved gene to chromosome 14q24.3. In the present study we report on linkage analysis of one additional and unrelated family, which enabled to confirm previous locus assignment. Another family is reported, in which genetic and clinical data suggest linkage to the same locus. Direct sequencing of DNA from individuals belonging to established ARVD1 families failed to detect causative mutations in exonic sequences of four genes (POMT2, TGFbeta3, KIAAA1036 and KIAA0759) expressed in the heart and which defects could possibly induce plasma membrane instability or apoptosis, key features of ARVD pathogenesis.     

Medicinal chemistry of A2A adenosine receptor antagonists

Due to the clearly demonstrated receptor-receptor interaction between adenosine A(2A) and dopamine D(2) receptors in the basal ganglia, the discovery and development of potent and selective A(2A)adenosine receptor antagonists became, in the last ten years, an attractive field of research to discovery new drugs for the treatment of neurodegenerative disorders, such as Parkinsons disease. Different compounds have been deeply investigated as A(2A) adenosine receptor antagonists, which could be classified in two great families: xanthine derivatives and nitrogen poliheterocyclic systems. These studies led to the discovery of some highly potent and selective A(2A) adenosine receptor antagonists such as ZM241385, SCH58261 and some xanthine derivatives (KW6002), which have been used as pharmacological tools for studying this receptor subtype. However, those compounds showed some problems that do not permit their use in clinical studies, such as poor water solubility (SCH58261, and xanthine derivatives) or good affinity for A(2B) adenosine receptor subtype (ZM241385). In the last few years great efforts have been made to overcome these problems, trying to optimize not only the pharmacological profile but also the pharmacokinetic character of this class of compounds. The aim of this report is to briefly summarize the recent progress made in this attractive field of research.     

Pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine derivatives as adenosine receptor antagonists. Influence of the N5 substituent on the affinity at the human A 3 and A 2B adenosine receptor subtypes: a molecular modeling investigation

A new series of pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines bearing various substituents at both the N5-pyrimidinyl and N8-pyrazolyl positions have been synthesized, and their binding affinities at the four human adenosine receptor subtypes (hA(1), hA(2A), hA(2B), and hA(3)) have been evaluated. All the described compounds contain arylacetyl moieties at the N5 position and arylalkyl substituents at the N8 position. Surprisingly, all the compounds present their most potent affinities at the hA(2B) adenosine receptor with a range of selectivities against the other subtypes. When bulky groups are present simultaneously at the N5 and N8 positions (e.g., compound 9), the best selectivity for the hA(2B) receptor was observed (K(i)(hA(1)) = 1100 nM; K(i)(hA(2A)) = 800 nM; K(i)(hA(2B)) = 20 nM; K(i)(hA(3)) = 300 nM, K(i)(hA(1)/A(2B)) = 55, K(i)(hA(2A)/A(2B)) = 40, K(i)(hA(3)/hA(2B)) = 15). To understand the molecular significance of these results, we compared the putative TM (transmembrane) binding motif of compound 9 on both hA(2B) and hA(3) receptors. From our docking studies, compound 9 fits neatly inside the TM region of the hA(2B) receptor but not in the corresponding hA(3) region, illustrating significant differences between the two subtypes. The study herein presented permits an understanding of why the bioisosteric replacement of an -NH, present in previously reported hA(3) receptor antagonists, with a -CH(2) group at the N5 position induces such large differences in hA(2B)/hA(3) affinity. In the molecular structure of the hA(3) receptor, two residues, Ser243 (TM6) and Ser271 (TM7), create a hydrophilic region, which seems to permit a better accommodation of the phenylurea series into this putative hA(3) binding site than the phenylacetyl series.     

Injectable Versus Oral First-Line Disease-Modifying Therapies: Results from the Italian MS Register

The current study aims to compare injectable and oral first-line disease-modifying therapies (DMTs) for time to first relapse, time to confirmed disability progression (CDP), and time to discontinuation using a cohort of relapsing remitting multiple sclerosis (RRMS) patients, with data extracted from the Italian MS Register. This multicenter, observational, retrospectively acquired, and propensity-adjusted cohort study utilized RRMS-naïve patients from the Italian MS Register who started either injectable or oral first-line DMTs between January 1, 2010, and December 31, 2017, to evaluate the impact on disability outcomes in patients. Enrolled patients were divided into two groups, namely the injectable group (IG) and the oral group (OG). Of a cohort of 11,416 patients, 4602 were enrolled (3919 in the IG and 683 in the OG). The IG had a higher rate of women (67.3% vs 63.4%, p < 0.05) and a lower mean age (36.1 ± 10.9 vs 38.9 ± 11.8, p < 0.001). The event time to first relapse demonstrated a lower risk in the OG (HR = 0.58; CI 95% 0.48–0.72, p < 0.001). However, no differences were found between the two groups with respect to the risk of CDP (HR = 0.94; CI 95% 0.76–1.29, p = 0.941), while a lower risk of DMT was found in the OG (HR = 0.72; CI 95% 0.58–0.88, p = 0.002) for the event time to discontinuation. Real-world data from the Italian MS Register suggests that first-line oral DMTs are associated with a lower risk of experiencing a new relapse and of therapy discontinuation compared to injectable DMTs.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-020-01001-6.Key Words: Multiple sclerosis, injectable DMTs, oral DMTs, real-world setting, EDSS score