Biotransformations of lipoglycopeptides to obtain novel antibiotics

The emergence of resistance among Gram-positive pathogens towards glycopeptide antibiotics has stimulated the research of second-generation molecules with improved activity and expanded antimicrobial spectrum. In this paper we investigate biotransformations as a way to generate novel teicoplanin- and A40926-like molecules. A range of commercial enzymes, fungi and actinomycetes were tested on A40926 and on its semi-synthetic derivatives (MDL 63,246 and dalbavancin). Oxidation of dalbavancin to MDL 63,246 was achieved by Nonomuraea sp. ATCC 39727 and Actinomadura parvosata ATCC 53463, while Actinoplanes sp. NRRL 3884, Actinoplanes missouriensis ATCC 23342 and Actinoplanes teichomyceticus ATCC 31121 deacylated MDL 63,246, dalbavancin and A40926. It is worth noting that the actinomycetes able to catalyze the deacylation of lipoglycopeptides are themselves producers of microbiologically active glycopeptides. Structurally related antibiotics (mideplanin and teicoplanin) were not transformed. Biotransformation conditions were optimised and scaled-up for the use of Actinoplanes sp. NRRL 3884 in the production of novel deacylated derivatives.     

Hypertension prevalence, awareness, control and association with metabolic abnormalities in the San Marino population: the SMOOTH study

BACKGROUND: The aim of the SMOOTH (San Marino Observational Outlooking Trial on Hypertension) study was to explore hypertension awareness, treatment and control and the associated metabolic abnormalities and risk factors in the population of San Marino, a small state in the Mediterranean area, for which limited evidence is available. METHODS: Nine general practitioners enrolled 4590 consecutive subjects (44% of the San Marino population age 40-75 years), seen in their office by collecting history, physical and laboratory data and office blood pressure (BP) measurements. RESULTS: Of these subjects, 2446 were normotensive and 2144 hypertensive; 62.3% of hypertensive patients were aware of their condition, 58.6% were treated (monotherapy 31.5%, combination therapy 27.1%), and 21.7% were controlled. Hypertension awareness and treatment were more frequent above age 50 and in females; BP control was similarly low in both genders. As compared to normotensives, hypertensive subjects were less frequently smokers (20.1 versus 27.8%), had greater body mass index (28.1 +/- 4.5 versus 25.8 +/- 3.7 g/m), and a higher prevalence of diabetes mellitus (15.8 versus 6.3%), lower high-density lipoprotein (HDL) cholesterol and higher prevalence of increased blood total cholesterol (66.1 versus 51.3%), triglycerides and serum uric acid. Values of subjects with 'high-normal' blood pressure were closer to those of hypertensive subjects. The prevalence of metabolic syndrome was higher in hypertensive than in normotensive subjects, and in treated than in untreated hypertensives. CONCLUSIONS: Even in a small Mediterranean country with high health-care standards, hypertension awareness, treatment and control are inadequate and hypertension clusters with metabolic abnormalities and risk factors as in non-Mediterranean areas.     

Long-Term Outcome of Neoadjuvant Endocrine Therapy with Aromatase Inhibitors in Elderly Women with Hormone Receptor-Positive Breast Cancer

Background

Aromatase inhibitors (AIs) are more effective than tamoxifen as neoadjuvant endocrine therapy (NET) for hormone receptor (HR)-positive breast cancer. Here we report the surgical and long-term outcome of elderly postmenopausal patients with locally advanced, HR-positive breast cancer treated with preoperative AIs.

Methods

Between January 2003 and December 2012, 144 postmenopausal patients inoperable with breast conservative surgery (BCS) received letrozole, anastrozole, or exemestane as NET. Patients underwent breast surgery and received adjuvant AIs. Adjuvant systemic therapy, chemotherapy and/or trastuzumab, and adjuvant radiotherapy were administered as appropriate, but limited to high-risk patients with few or no comorbidities.

Results

After a median follow-up of 49 months, 4 (3.0 %) patients had local relapse, 18 (12.5 %) had distant metastases, and 24 (17.0 %) died. BCS was performed in 121 (84.0 %) patients. A tumor size <3 cm and human epidermal growth factor receptor 2 (HER2) negativity were predictors of BCS. The achievement of BCS and grade G1 were significantly associated with longer disease-free survival (DFS) (p = 0.009 and p = 0.01, respectively) and overall survival (p = 0.002 and p = 0.005, respectively). Residual tumor ≤2 cm (yT0–yT1) in the longest diameter after NET was also statistically associated with longer DFS (p = 0.005).

Conclusions

The results of this retrospective study indicate that elderly breast cancer patients with a tumor size <3 cm at diagnosis and HER2 negativity have a higher probability of achieving BCS after NET. Moreover, patients treated with BCS and with grade G1 tumor have a reduced risk of recurrence and death in the long-term follow-up.     

Protracted COVID-19 pneumonitis early post-ABO incompatible kidney transplantation: Management considerations and the role of whole genome sequencing

We present the case of a recent ABO incompatible kidney transplant recipient with persistent SARS-CoV-2 infection and pneumonitis. Serial whole genome sequencing confirmed intra-host viral evolution, which was used as a surrogate to confirm active viral replication and support re-treatment with antivirals, late in the course of infection. A prolonged course of remdesivir combined with immunosuppression modulation resulted in successful clearance of virus and clinical improvement. The diagnostic process undertaken in this case provides a useful guide for other clinicians when approaching similar patients.     

Effects of Water/Alcohol Soluble Cationic Polythiophenes as Cathode Interlayers for Eco-Friendly Solar Cells

Three new ionic polythiophene derivatives, soluble in polar solvents, are synthesized with good yields using simple, low-cost, and straightforward procedures. They are investigated as interfacial cationic conjugated polyelectrolyte (CPE) layers for halogen-free bulk heterojunction polymeric solar cells, based on a water-soluble electron-donor polymer (poly[3-(6-diethanolaminohexyl)thiophene]) and a water-soluble electron-acceptor fullerene derivative (malonodiserinolamide fullerene). The simple insertion of the CPE interlayer between the active layer and the aluminum cathode dramatically increases the power conversion efficiency of the final device up to nearly 5%, resulting from a decrease of the electrode work function, improved electron extraction, and optimization of the morphology of the layers. The obtained results demonstrate that the incorporation of CPE layer is a powerful and convenient methodology for the development of highly efficient and eco-friendly processable polymeric solar cells.     

Endocannabinoid signaling in microglia

Microglia, the innate immune cells of the central nervous system (CNS), execute their sentinel, housekeeping and defense functions through a panoply of genes, receptors and released cytokines, chemokines and neurotrophic factors. Moreover, microglia functions are closely linked to the constant communication with other cell types, among them neurons. Depending on the signaling pathway and type of stimuli involved, the outcome of microglia operation can be neuroprotective or neurodegenerative. Accordingly, microglia are increasingly becoming considered cellular targets for therapeutic intervention. Among signals controlling microglia activity, the endocannabinoid (EC) system has been shown to exert a neuroprotective role in many neurological diseases. Like neurons, microglia express functional EC receptors and can produce and degrade ECs. Interestingly, boosting EC signaling leads to an anti-inflammatory and neuroprotective microglia phenotype. Nonetheless, little evidence is available on the microglia-mediated therapeutic effects of EC compounds. This review focuses on the EC signals acting on the CNS microglia in physiological and pathological conditions, namely on the CB1R, CB2R and TRPV1-mediated regulation of microglia properties. It also provides new evidence, which strengthens the understanding of mechanisms underlying the control of microglia functions by ECs. Given the broad expression of the EC system in glial and neuronal cells, the resulting picture is the need for in vivo studies in transgenic mouse models to dissect the contribution of EC microglia signaling in the neuroprotective effects of EC-derived compounds.     

Antibody response elicited by the SARS-CoV-2 vaccine booster in patients with multiple sclerosis: Who gains from it?

Background and purpose

Although two doses of COVID-19 vaccine elicited a protective humoral response in most persons with multiple sclerosis (pwMS), a significant group of them treated with immunosuppressive disease-modifying therapies (DMTs) showed less efficient responses.

Methods

This prospective multicenter observational study evaluates differences in immune response after a third vaccine dose in pwMS.

Results

Four hundred seventy-three pwMS were analyzed. Compared to untreated patients, there was a 50-fold decrease (95% confidence interval [CI] = 14.3–100.0, p < 0.001) in serum SARS-CoV-2 antibody levels in those on rituximab, a 20-fold decrease (95% CI = 8.3–50.0, p < 0.001) in those on ocrelizumab, and a 2.3-fold decrease (95% CI = 1.2–4.6, p = 0.015) in those on fingolimod. As compared to the antibody levels after the second vaccine dose, patients on the anti-CD20 drugs rituximab and ocrelizumab showed a 2.3-fold lower gain (95% CI = 1.4–3.8, p = 0.001), whereas those on fingolimod showed a 1.7-fold higher gain (95% CI = 1.1–2.7, p = 0.012), compared to patients treated with other DMTs.

Conclusions

All pwMS increased their serum SARS-CoV-2 antibody levels after the third vaccine dose. The mean antibody values of patients treated with ocrelizumab/rituximab remained well below the empirical "protective threshold" for risk of infection identified in the CovaXiMS study (>659 binding antibody units/mL), whereas for patients treated with fingolimod this value was significantly closer to the cutoff.