Novel peptidomimetics related to Gonadotropin releasing hormone (GnRH)

Novel GnRH I and II analogues were designed and synthesized by Solid Phase Peptides Synthesis (SPPS), since GnRH has antiproliferative property, but poor metabolic stability. To rationalize synthetic difficulties, molecular dynamics simulations were performed, showing the conformational behavior of three derivatives. Among the two peptidomimetics series (Ie,f and IIe,f , GnRH I and GnRH II analogues respectively) several compounds (Id-f and IIc-e) showed a significant binding affinity. In particular, derivative Ie has an increased metabolic stability with respect to the physiological ligand (Ie t1/2= 3.96 h versus GnRH I t1/2 = 2.63 h)

The e-Business Readiness Composite Indicator for 2003. A Pilot Study

Abstract not availableJRC.G-Institute for the Protection and the Security of the Citizen (Ispra

Identification of cancer predisposition variants in apparently healthy individuals using a next-generation sequencing-based family genomics approach

Cancer, like many common disorders, has a complex etiology, often with a strong genetic component and with multiple environmental factors contributing to susceptibility. A considerable number of genomic variants have been previously reported to be causative of, or associated with, an increased risk for various types of cancer. Here, we adopted a next-generation sequencing approach in 11 members of two families of Greek descent to identify all genomic variants with the potential to predispose family members to cancer. Cross-comparison with data from the Human Gene Mutation Database identified a total of 571 variants, from which 47 % were disease-associated polymorphisms, 26 % disease-associated polymorphisms with additional supporting functional evidence, 19 % functional polymorphisms with in vitro/laboratory or in vivo supporting evidence but no known disease association, 4 % putative disease-causing mutations but with some residual doubt as to their pathological significance, and 3 % disease-causing mutations. Subsequent analysis, focused on the latter variant class most likely to be involved in cancer predisposition, revealed two variants of prime interest, namely MSH2 c.2732T>A (p.L911R) and BRCA1 c.2955delC, the first of which is novel. KMT2D c.13895delC and c.1940C>A variants are additionally reported as incidental findings. The next-generation sequencing-based family genomics approach described herein has the potential to be applied to other types of complex genetic disorder in order to identify variants of potential pathological significance

Effect of intravenous clarithromycin in patients with sepsis, respiratory and multiple organ dysfunction syndrome: a randomized clinical trial.

Clarithromycin may act as immune-regulating treatment in sepsis and acute respiratory dysfunction syndrome. However, clinical evidence remains inconclusive. We aimed to evaluate whether clarithromycin improves 28-day mortality among patients with sepsis, respiratory and multiple organ dysfunction syndrome. We conducted a multicenter, randomized, clinical trial in patients with sepsis. Participants with ratio of partial oxygen pressure to fraction of inspired oxygen less than 200 and more than 3 SOFA points from systems other than the respiratory function were enrolled between December 2017 and September 2019. Patients were randomized to receive 1 gr of clarithromycin or placebo intravenously once daily for 4 consecutive days. The primary endpoint was 28-day all-cause mortality. Secondary outcomes were 90-day mortality; sepsis response (defined as at least 25% decrease in SOFA score by day 7); sepsis recurrence; and differences in peripheral blood cell populations and leukocyte transcriptomics. Fifty-five patients were allocated to each arm. By day 28, 27 (49.1%) patients in the clarithromycin and 25 (45.5%) in the placebo group died (risk difference 3.6% [95% confidence interval (CI) - 15.7 to 22.7]; P = 0.703, adjusted OR 1.03 [95%CI 0.35-3.06]; P = 0.959). There were no statistical differences in 90-day mortality and sepsis response. Clarithromycin was associated with lower incidence of sepsis recurrence (OR 0.21 [95%CI 0.06-0.68]; P = 0.012); significant increase in monocyte HLA-DR expression; expansion of non-classical monocytes; and upregulation of genes involved in cholesterol homeostasis. Serious and non-serious adverse events were equally distributed. Clarithromycin did not reduce mortality among patients with sepsis with respiratory and multiple organ dysfunction. Clarithromycin was associated with lower sepsis recurrence, possibly through a mechanism of immune restoration. Clinical trial registration clinicaltrials.gov identifier NCT03345992 registered 17 November 2017; EudraCT 2017-001056-55

Clinical epidemiology, treatment and prognostic factors of extensively drug-resistant Acinetobacter baumannii ventilator-associated pneumonia in critically ill patients

Limited data exist regarding prognostic factors and optimal antimicrobial treatment of infections caused by extensively drug-resistant Acinetobacter baumannii (XDR-AB). This retrospective cohort study included 93 adult patients who developed ventilator-associated pneumonia (VAP) due to XDR-AB in the ICU of the University Hospital of Heraklion, Greece, from October 2012 to April 2015. XDR-AB isolates were mainly susceptible to colistin (93.5%) and tigecycline (25.8%), whereas 6 (6.5%) were pandrug-resistant. Prior to infection, patients had long durations of mechanical ventilation and hospital stay and multiple exposures to antibiotics. Median Charlson co-morbidity and APACHE II scores were 2 and 17, respectively. Mortality at 28 days of infection onset was high (34.4%) despite high rates of in-vitro-active empirical (81.7%) and definitive (90.3%) treatment. Active colistin-based combination therapy (n = 55) and monotherapy (n = 29) groups had similar 28-day mortality (27.6% vs. 30.9%, respectively) and Kaplan–Meier survival estimates over time. In multivariable Cox regression, advanced age (aHR = 1.05 per year increase, 95% CI 1.02–1.09), rapidly fatal underlying disease (aHR = 2.64, 95% CI 0.98–9.17) and APACHE II score (aHR = 1.06 per unit increase, 95% CI 0.99–1.14) were identified as independent predictors of 28-day mortality, but no difference in mortality hazards between the active colistin-based combination therapy and monotherapy groups was produced (aHR = 0.88, 95% CI 0.35–2.38). These results support the use of colistin as a first-line agent against VAP in settings where XDR-AB is endemic, but oppose the introduction of colistin-based combination therapy as standard treatment

Mucopolysaccharidosis VI

Mucopolysaccharidosis VI (MPS VI) is a lysosomal storage disease with progressive multisystem involvement, associated with a deficiency of arylsulfatase B leading to the accumulation of dermatan sulfate. Birth prevalence is between 1 in 43,261 and 1 in 1,505,160 live births. The disorder shows a wide spectrum of symptoms from slowly to rapidly progressing forms. The characteristic skeletal dysplasia includes short stature, dysostosis multiplex and degenerative joint disease. Rapidly progressing forms may have onset from birth, elevated urinary glycosaminoglycans (generally >100 μg/mg creatinine), severe dysostosis multiplex, short stature, and death before the 2nd or 3rd decades. A more slowly progressing form has been described as having later onset, mildly elevated glycosaminoglycans (generally <100 μg/mg creatinine), mild dysostosis multiplex, with death in the 4th or 5th decades. Other clinical findings may include cardiac valve disease, reduced pulmonary function, hepatosplenomegaly, sinusitis, otitis media, hearing loss, sleep apnea, corneal clouding, carpal tunnel disease, and inguinal or umbilical hernia. Although intellectual deficit is generally absent in MPS VI, central nervous system findings may include cervical cord compression caused by cervical spinal instability, meningeal thickening and/or bony stenosis, communicating hydrocephalus, optic nerve atrophy and blindness. The disorder is transmitted in an autosomal recessive manner and is caused by mutations in the ARSB gene, located in chromosome 5 (5q13-5q14). Over 130 ARSB mutations have been reported, causing absent or reduced arylsulfatase B (N-acetylgalactosamine 4-sulfatase) activity and interrupted dermatan sulfate and chondroitin sulfate degradation. Diagnosis generally requires evidence of clinical phenotype, arylsulfatase B enzyme activity <10% of the lower limit of normal in cultured fibroblasts or isolated leukocytes, and demonstration of a normal activity of a different sulfatase enzyme (to exclude multiple sulfatase deficiency). The finding of elevated urinary dermatan sulfate with the absence of heparan sulfate is supportive. In addition to multiple sulfatase deficiency, the differential diagnosis should also include other forms of MPS (MPS I, II IVA, VII), sialidosis and mucolipidosis. Before enzyme replacement therapy (ERT) with galsulfase (Naglazyme®), clinical management was limited to supportive care and hematopoietic stem cell transplantation. Galsulfase is now widely available and is a specific therapy providing improved endurance with an acceptable safety profile. Prognosis is variable depending on the age of onset, rate of disease progression, age at initiation of ERT and on the quality of the medical care provided