Sociodemographic, behavioral and genetic determinants of allostatic load in a Swiss population-based study.

Allostatic load (AL) is a marker of physiological dysregulation which reflects exposure to chronic stress. High AL has been related to poorer health outcomes including mortality. We examine here the association of socioeconomic and lifestyle factors with AL. Additionally, we investigate the extent to which AL is genetically determined. We included 803 participants (52% women, mean age 48±16years) from a population and family-based Swiss study. We computed an AL index aggregating 14 markers from cardiovascular, metabolic, lipidic, oxidative, hypothalamus-pituitary-adrenal and inflammatory homeostatic axes. Education and occupational position were used as indicators of socioeconomic status. Marital status, stress, alcohol intake, smoking, dietary patterns and physical activity were considered as lifestyle factors. Heritability of AL was estimated by maximum likelihood. Women with a low occupational position had higher AL (low vs. high OR=3.99, 95%CI [1.22;13.05]), while the opposite was observed for men (middle vs. high OR=0.48, 95%CI [0.23;0.99]). Education tended to be inversely associated with AL in both sexes(low vs. high OR=3.54, 95%CI [1.69;7.4]/OR=1.59, 95%CI [0.88;2.90] in women/men). Heavy drinking men as well as women abstaining from alcohol had higher AL than moderate drinkers. Physical activity was protective against AL while high salt intake was related to increased AL risk. The heritability of AL was estimated to be 29.5% ±7.9%. Our results suggest that generalized physiological dysregulation, as measured by AL, is determined by both environmental and genetic factors. The genetic contribution to AL remains modest when compared to the environmental component, which explains approximately 70% of the phenotypic variance.

A new method for intraoperative localization of epilepsy focus by means of a gamma probe

Objective To evaluate the utility of a new multimodal image-guided intervention technique to detect epileptogenic areas with a gamma probe as compared with intraoperative electrocorticography. Materials and Methods Two symptomatic patients with refractory epilepsy underwent magnetic resonance imaging, videoelectroencephalography, brain SPECT scan, neuropsychological evaluation and were submitted to gamma probe-assisted surgery. Results In patient 1, maximum radioactive count was initially observed on the temporal gyrus at about 3.5 cm posteriorly to the tip of the left temporal lobe. After corticotomy, the gamma probe indicated maximum count at the head of the hippocampus, in agreement with the findings of intraoperative electrocorticography. In patient 2, maximum count was observed in the occipital region at the transition between the temporal and parietal lobes (right hemisphere). During the surgery, the area of epileptogenic activity mapped at electrocorticography was also delimited, demarcated, and compared with the gamma probe findings. After lesionectomy, new radioactive counts were performed both in the patients and on the surgical specimens (ex-vivo). Conclusion The comparison between intraoperative electrocorticography and gamma probe-assisted surgery showed similarity of both methods. The advantages of gamma probe include: noninvasiveness, low cost and capacity to demonstrate decrease in the radioactive activity at the site of excision after lesionectomy.

Aetiologies of pulseless electrical activity in out-of-hospital cardiac arrests:A retrospective study and analysis of specific causes

Background: Pulseless electrical activity (PEA) cardiac arrest is defined as a cardiac arrest (CA) presenting with a residual organized electrical activity on the electrocardiogram. In the last decades, the incidence of PEA has regularly increased, compared to other types of CA like ventricular fibrillation or pulseless ventricular tachycardia. PEA is frequently induced by reversible conditions. The "4 (or 5) H" & "4 (or 5) T" are proposed as a mnemonic to asses for Hypoxia, Hypovolemia, Hypo- /Hyperkalaemia, Hypothermia, Thrombosis (cardiac or pulmonary), cardiac Tamponade, Toxins, and Tension pneumothorax. Other pathologies (intracranial haemorrhage, severe sepsis, myocardial contraction dysfunction) have been identified as potential causes for PEA, but their respective probability and frequencies are unclear and they are not yet included into the resuscitation guidelines. The aim of this study was to analyse the aetiologies of PEA out-of-hospital CA, in order to evaluate the relative frequencies of each cause and therefore to improve the management of patients suffering a PEA cardiac arrest. Method: This retrospective study was based on data routinely and prospectively collected for each PEMS intervention. All adult patients treated from January 1st 2002 to December 2012 31st by the PEMS for out-of-hospital cardiac arrest, with PEA as the first recorded rhythm, and admitted to the emergency department (ED) of the Lausanne University Hospital were included. The aetiologies of PEA cardiac arrest were classified into subgroups, based on the classical H&T's classification, supplemented by four other subgroups analysis: trauma, intra-cranial haemorrhage (ICH), non-ischemic cardiomyopathy (NIC) and undetermined cause. Results: 1866 OHCA were treated by the PEMS. PEA was the first recorded rhythm in 240 adult patients (13.8 %). After exclusion of 96 patients, 144 patients with a PEA cardiac arrest admitted to the ED were included in the analysis. The mean age was 63.8 ± 20.0 years, 58.3% were men and the survival rate at 48 hours was 29%. 32 different causes of OHCA PEA were established for 119 patients. For 25 patients (17.4 %), we were unable to attribute a specific cause for the PEA cardiac arrest. Hypoxia (23.6 %), acute coronary syndrome (12.5%) and trauma (12.5 %) were the three most frequent causes. Pulmonary embolism, Hypovolemia, Intoxication and Hyperkaliemia occurs in less than 10% of the cases (7.6 %, 5.6 %, 3.5%, respectively 2.1 %). Non ischemic cardiomyopathy and intra-cranial haemorrhage occur in 8.3 % and 6.9 %, respectively. Conclusions: According to our results, intra-cranial haemorrhage and non-ischemic cardiomyopathy represent noticeable causes of PEA in OHCA, with a prevalence equalling or exceeding the frequency of classical 4 H's and 4 T's aetiologies. These two pathologies are potentially accessible to simple diagnostic procedures (native CT-scan or echocardiography) and should be included into the 4 H's and 4 T's mnemonic.

Balloon-based adjuvant radiotherapy in breast cancer: comparison between 99mTc and HDR 192Ir

Abstract Objective: To perform a comparative dosimetric analysis, based on computer simulations, of temporary balloon implants with 99mTc and balloon brachytherapy with high-dose-rate (HDR) 192Ir, as boosts to radiotherapy. We hypothesized that the two techniques would produce equivalent doses under pre-established conditions of activity and exposure time. Materials and Methods: Simulations of implants with 99mTc-filled and HDR 192Ir-filled balloons were performed with the Siscodes/MCNP5, modeling in voxels a magnetic resonance imaging set related to a young female. Spatial dose rate distributions were determined. In the dosimetric analysis of the protocols, the exposure time and the level of activity required were specified. Results: The 99mTc balloon presented a weighted dose rate in the tumor bed of 0.428 cGy.h-1.mCi-1 and 0.190 cGyh-1.mCi-1 at the balloon surface and at 8-10 mm from the surface, respectively, compared with 0.499 and 0.150 cGyh-1.mCi-1, respectively, for the HDR 192Ir balloon. An exposure time of 24 hours was required for the 99mTc balloon to produce a boost of 10.14 Gy with 1.0 Ci, whereas only 24 minutes with 10.0 Ci segments were required for the HDR 192Ir balloon to produce a boost of 5.14 Gy at the same reference point, or 10.28 Gy in two 24-minutes fractions. Conclusion: Temporary 99mTc balloon implantation is an attractive option for adjuvant radiotherapy in breast cancer, because of its availability, economic viability, and similar dosimetry in comparison with the use of HDR 192Ir balloon implantation, which is the current standard in clinical practice.

The lipopolysaccharide of Aeromonas spp: structure-activity relationships.

Marine microorganisms, including Aeromonas, are a source of compounds for drug development that have generated great expectations in the last decades. Aeromonas infections produce septicaemia, and ulcerative and haemorrhagic diseases in fish. Among the pathogenic factors associated with Aeromonas, the lipopolysaccharides (LPS), a surface glyconconjugate unique to Gram-negative bacteria consisting of lipid A (lipid anchor of the molecule), core oligosaccharide and O-specific polysaccharide (O antigen), are key elicitors of innate immune responses. The chemical structure of these three parts has been characterized in Aeromonas. Based on the high variability of repeated units of O-polysaccharides, a total of 97 O-serogroups have been described in Aeromonas species, of which four of them (O:11; O:16; O:18 and O:34) account for more than 60% of the septicemia cases. The core of LPS is subdivided into two regions, the inner (highly conserved) and the outer core. The inner core of Aeromonas LPS is characterized by the presence of 3-deoxy-D-manno-oct-2-ulosonic (ketodeoxyoctonic) acid (Kdo) and L-glycero-D-manno-Heptoses (L,D-Hep), which are linked to the outer core, characterized by the presence of Glc, GlcN, Gal, and GalNAc (in Aeromonas salmonicida), D,D-Hep (in Aeromonas salmonicida), and L,D-Hep (in Aeromonas hydrophila). The biological relevance of these differences in the distal part of the outer core among these species has not been fully assessed to date. The inner core is attached to the lipid A, a highly conserved structure that confers endotoxic properties to the LPS when the molecule is released in blood from lysed bacteria, thus inducing a major systemic inflammatory response known as septic or endotoxic shock. In Aeromonas salmonicida subsp. salmonicida the Lipid A components contain three major lipid A molecules, differing in acylation patterns corresponding to tetra-, penta- and hexaacylated lipid A species and comprising of 4′-monophosphorylated β-2-amino-2-deoxy-D-glucopyranose-(1→6)-2-amino-2-deoxy-D-glucopyranose disaccharide. In the present review, we discuss the structure-activity relationships of Aeromonas LPS, focusing on its role in bacterial pathogenesis and its possible applications.

Role of Membrane Transporters, P-Glycoprotein and Mrp1, in The Placental Transfer of Drugs With Special Reference to Saquinavir and Quetiapine

Drug transporting membrane proteins are expressed in various human tissues and blood-tissue barriers, regulating the transfer of drugs, toxins and endogenous compounds into or out of the cells. Various in vitro and animal experiments suggest that P-glycoprotein (P-gp) forms a functional barrier between maternal and fetal blood circulation in the placenta thereby protecting the fetus from exposure to xenobiotics during pregnancy. The multidrug resistance-associated protein 1 (MRP1) is a relatively less studied transporter protein in the human placenta. The aim of this study series was to study the role of placental transporters, apical P-gp and basal MRP1, using saquinavir as a probe drug, and to study transfer of quetiapine and the role of P-gp in its transfer in the dually perfused human placenta/cotyledon. Furthermore, two ABCB1 (encoding P-gp) polymorphisms (c.3435C>T, p.Ile1145Ile and c.2677G>T/A, p.Ala893Ser/Thr) were studied to determine their impact on P-gp protein expression level and on the transfer of the study drugs. Also, the influence of the P-gp protein expression level on the transfer of the study drugs was addressed. Because P-gp and MRP1 are ATP-dependent drug-efflux pumps, it was studied whether exogenous ATP is needed for the function of ATP-dependent transporter in the present experimental model. The present results indicated that the addition of exogenous ATP was not necessary for transporter function in the perfused human placental cotyledon. Saquinavir and quetiapine were both found to cross the human placenta; transplacental transfer (TPTAUC %) for saquinavir was <0.5% and for quetiapine 3.7%. Pharmacologic blocking of P-gp led to disruption of the blood-placental barrier (BPB) and increased the placental transfer of P-gp substrate, saquinavir, into the fetal circulation by 6- to 8-fold. In reversed perfusions P-gp, MRP1 and possibly OATP2B1 had a negligible role in the fetal-to-maternal transfer of saquinavir. The TPTAUC % of saquinavir was about 100-fold greater from the fetal side to the maternal side compared with the maternal-to-fetal transfer. P-gp activity is not likely to modify the placental transfer of quetiapine. Higher P-gp protein expression levels were associated with the variant allele 3435T, but no correlation was found between the TPTAUC % of saquinavir and placental P-gp protein expression. The present results indicate that P-gp activity drastically affects the fetal exposure to saquinavir, and suggest that pharmacological blockade of the P-gp activity during pregnancy may pose an increased risk for adverse fetal outcome. The blockade of P-gp activity could be used in purpose to obtain higher drug concentration to the fetal side, for example, in prevention (to decrease virus transfer to fetal side) or in treating sick fetus.

Consideraciones sobre la fundamentación psicopedagógica del ABP : aspectos esenciales

La metodología ABP respeta la tendencia innata al crecimiento y la autorrealización defendida desde la psicología humanista, y permite crear el contexto de desarrollo idóneo para satisfacer las necesidades psicológicas básicas propuestas desde la teoría de la autodeterminación. Por su contribución al desarrollo de las competencias personales y sociales, está indicada tanto para universitarios como para alumnado de niveles preuniversitarios

The lipopolysaccharide of Aeromonas spp: structure-activity relationships

Marine microorganisms, including Aeromonas, are a source of compds. for drug development that have generated great expectations in the last decades. Aeromonas infections produce septicemia, and ulcerative and haemorrhagic diseases in fish. Among the pathogenic factors assocd. with Aeromonas, the lipopolysaccharides (LPS)​, a surface glyconconjugate unique to Gram-​neg. bacteria consisting of lipid A (lipid anchor of the mol.)​, core oligosaccharide and O-​specific polysaccharide (O antigen)​, are key elicitors of innate immune responses. The chem. structure of these three parts has been characterized in Aeromonas. Based on the high variability of repeated units of O-​polysaccharides, a total of 97 O-​serogroups have been described in Aeromonas species, of which four of them (O:11; O:16; O:18 and O:34) account for more than 60​% of the septicemia cases. The core of LPS is subdivided into two regions, the inner (highly conserved) and the outer core. The inner core of Aeromonas LPS is characterized by the presence of 3-​deoxy-​d-​manno-​oct-​2-​ulosonic (ketodeoxyoctonic) acid (Kdo) and l-​glycero-​d-​manno-​Heptoses (l,​d-​Hep)​, which are linked to the outer core, characterized by the presence of Glc, GlcN, Gal, and GalNAc (in Aeromonas salmonicida)​, d,​d-​Hep (in Aeromonas salmonicida)​, and l,​d-​Hep (in Aeromonas hydrophila)​. The biol. relevance of these differences in the distal part of the outer core among these species has not been fully assessed to date. The inner core is attached to the lipid A, a highly conserved structure that confers endotoxic properties to the LPS when the mol. is released in blood from lysed bacteria, thus inducing a major systemic inflammatory response known as septic or endotoxic shock. In Aeromonas salmonicida subsp. salmonicida the Lipid A components contain three major lipid A mols., differing in acylation patterns corresponding to tetra-​, penta- and hexa-​acylated lipid A species and comprising of 4'-​monophosphorylated β-​2-​amino-​2-​deoxy-​d-​glucopyranose-​(1→6)​-​2-​amino-​2-​deoxy-​d-​glucopyranose disaccharide. In the present review, we discuss the structure-​activity relationships of Aeromonas LPS, focusing on its role in bacterial pathogenesis and its possible applications.

The lipopolysaccharide of Aeromonas spp: structure-activity relationships

Marine microorganisms, including Aeromonas, are a source of compds. for drug development that have generated great expectations in the last decades. Aeromonas infections produce septicemia, and ulcerative and haemorrhagic diseases in fish. Among the pathogenic factors assocd. with Aeromonas, the lipopolysaccharides (LPS)​, a surface glyconconjugate unique to Gram-​neg. bacteria consisting of lipid A (lipid anchor of the mol.)​, core oligosaccharide and O-​specific polysaccharide (O antigen)​, are key elicitors of innate immune responses. The chem. structure of these three parts has been characterized in Aeromonas. Based on the high variability of repeated units of O-​polysaccharides, a total of 97 O-​serogroups have been described in Aeromonas species, of which four of them (O:11; O:16; O:18 and O:34) account for more than 60​% of the septicemia cases. The core of LPS is subdivided into two regions, the inner (highly conserved) and the outer core. The inner core of Aeromonas LPS is characterized by the presence of 3-​deoxy-​d-​manno-​oct-​2-​ulosonic (ketodeoxyoctonic) acid (Kdo) and l-​glycero-​d-​manno-​Heptoses (l,​d-​Hep)​, which are linked to the outer core, characterized by the presence of Glc, GlcN, Gal, and GalNAc (in Aeromonas salmonicida)​, d,​d-​Hep (in Aeromonas salmonicida)​, and l,​d-​Hep (in Aeromonas hydrophila)​. The biol. relevance of these differences in the distal part of the outer core among these species has not been fully assessed to date. The inner core is attached to the lipid A, a highly conserved structure that confers endotoxic properties to the LPS when the mol. is released in blood from lysed bacteria, thus inducing a major systemic inflammatory response known as septic or endotoxic shock. In Aeromonas salmonicida subsp. salmonicida the Lipid A components contain three major lipid A mols., differing in acylation patterns corresponding to tetra-​, penta- and hexa-​acylated lipid A species and comprising of 4'-​monophosphorylated β-​2-​amino-​2-​deoxy-​d-​glucopyranose-​(1→6)​-​2-​amino-​2-​deoxy-​d-​glucopyranose disaccharide. In the present review, we discuss the structure-​activity relationships of Aeromonas LPS, focusing on its role in bacterial pathogenesis and its possible applications.

Membrane interaction of a new synthetic antimicrobial lipopetide sp-85 with broad spectrum activity

Antimicrobial peptides offer a new class of therapeutic agents to which bacteria may not be able todevelop genetic resistance, since their main activity is in the lipid component of the bacterial cell mem-brane. We have developed a series of synthetic cationic cyclic lipopeptides based on natural polymyxin,and in this work we explore the interaction of sp-85, an analog that contains a C12 fatty acid at theN-terminus and two residues of arginine. This analog has been selected from its broad spectrum antibac-terial activity in the micromolar range, and it has a disruptive action on the cytoplasmic membrane ofbacteria, as demonstrated by TEM. In order to obtain information on the interaction of this analog withmembrane lipids, we have obtained thermodynamic parameters from mixed monolayers prepared withPOPG and POPE/POPG (molar ratio 6:4), as models of Gram positive and Gram negative bacteria, respec-tively. LangmuirBlodgett films have been extracted on glass plates and observed by confocal microscopy,and images are consistent with a strong destabilizing effect on the membrane organization induced bysp-85. The effect of sp-85 on the membrane is confirmed with unilamelar lipid vesicles of the same com-position, where biophysical experiments based on fluorescence are indicative of membrane fusion andpermeabilization starting at very low concentrations of peptide and only if anionic lipids are present.Overall, results described here provide strong evidence that the mode of action of sp-85 is the alterationof the bacterial membrane permeability barrier.

Cu and Co exchanged ZSM-5 zeolites: activity towards no reduction and hydrocarbon oxidation

|Cu x|[Si yAl]-MFI and |Co x|[Si yAl]-MFI catalysts were prepared by ion exchange from |Na|[Si yAl]-MFI zeolites (y = 12, 25 and 45). The activity of the catalysts was evaluated in the reduction of NO to N2 in an oxidative atmosphere using propane or methane as reducing agents. The Cu catalysts were only active with propane and they presented higher activity than the Co-based catalysts, the latter being active with both hydrocarbons. H2-TPR and DRS-UV/Vis data allowed correlation between the activity towards NO reduction and the presence of cationic charge-compensating species in the zeolite. It was also verified that the hydrocarbons are preferentially oxidised by O2, a reaction that occurs simultaneously with their oxidation with NO.

Computer-aided discovery of biological activity spectra for anti-aging and anti-cancer olive oil oleuropeins

Aging is associated with common conditions, including cancer, diabetes, cardiovascular disease, and Alzheimer"s disease. The type of multi‐targeted pharmacological approach necessary to address a complex multifaceted disease such as aging might take advantage of pleiotropic natural polyphenols affecting a wide variety of biological processes. We have recently postulated that the secoiridoids oleuropein aglycone (OA) and decarboxymethyl oleuropein aglycone (DOA), two complex polyphenols present in health‐promoting extra virgin olive oil (EVOO), might constitute a new family of plant‐produced gerosuppressant agents. This paper describes an analysis of the biological activity spectra (BAS) of OA and DOA using PASS (Prediction of Activity Spectra for Substances) software. PASS can predict thousands of biological activities, as the BAS of a compound is an intrinsic property that is largely dependent on the compound"s structure and reflects pharmacological effects, physiological and biochemical mechanisms of action, and specific toxicities. Using Pharmaexpert, a tool that analyzes the PASS‐predicted BAS of substances based on thousands of"mechanism‐ effect" and"effect‐mechanism" relationships, we illuminate hypothesis‐generating pharmacological effects, mechanisms of action, and targets that might underlie the anti‐aging/anti‐cancer activities of the gerosuppressant EVOO oleuropeins.

Physical activity in adolescence - with special reference to cardiovascular health

Liikunta ja sydän- ja verisuoniterveys nuorilla Aikuisiällä ilmenevien sydän- ja verisuonisairauksien kehitys alkaa lapsuudessa. Vähäinen liikunta lisää vaaraa sairastua sydän- ja verisuonisairauksiin sekä vaikuttaa haitallisesti näiden sairauksien riskitekijöihin läpi elämän. Tämän tutkimuksen tavoitteena oli tutkia nuorten liikuntaa ja sen yhteyttä sydän- ja verisuoniterveyteen. Sydän- ja verisuoniterveyttä tutkittiin riskitekijöiden sekä valtimon laajentumiskyvyn avulla. Tutkittavat koostuivat nuorista, jotka osallistuivat pitkäaikaisen sepelvaltimotaudin ehkäisytutkimuksen (STRIP) 13-vuotistutkimuskäynnille ja jotka raportoivat vapaa-ajan liikuntatottumuksensa (n=560). Liikunnan lisäksi nuorten pituus, paino, verenpaine ja olkavaltimon laajentumiskyky mitattiin sekä analysoitiin laboratorionäytteitä (otettiin verinäyte) ja selvitettiin ruoankäyttöä. Vähäinen vapaa-ajan liikunta oli yleistä etenkin tytöillä. Vapaa-ajallaan vähän liikkuvat pojat viettivät enemmän aikaa televisio- ja tietokoneruudun ääressä kuin vapaa-ajallaan paljon liikkuvat pojat. Äidin, toisin kuin isän, vapaa-ajan liikunta ja paino olivat yhteydessä lapsen vapaa-ajan liikuntaan. Vähän liikkuvat tytöt olivat olleet jo kahden vuoden iästä saakka useammin ylipainoisia kuin runsaammin liikkuvat ikätoverinsa. Sydän- ja verisuonisairauksien riskitekijöiden kasautuminen oli tavallisempaa vähän kuin paljon liikkuvilla nuorilla. Vähän liikkuvilla pojilla oli lisäksi huonompi olkavaltimon laajentumiskyky kuin paljon liikkuvilla pojilla. Tämä on tärkeä löydös, koska valtimon laajentumiskyky kuvannee sydän- ja verisuoniterveyttä jo ennen rakenteellisten muutosten ilmaantumista. Useat nuoret, etenkin tytöt, liikkuivat vähän vapaa-ajallaan. Vähäisellä vapaa-ajan liikunnalla oli haitallinen yhteys sydän- ja verisuonisairauksien riskitekijöihin sekä valtimon laajentumiskykyyn. Nuorten kannustaminen liikunnalliseen elämäntapaan on erittäin tärkeää sydän- ja verisuoniterveyden edistämiseksi sekä nuoren että kansanterveyden kannalta.

La promoción del pensamiento crítico en el Aprendizaje Basado en Problemas (ABP). Un análisis a partir de los instrumentos de medición

[spa] La literatura científica sobre el Aprendizaje Basado en Problemas (ABP) ha dedicado una atención creciente a la cuestión del pensamiento crítico a lo largo de las dos últimas décadas. Los trabajos de investigación que se han llevado a cabo en los distintos contextos disciplinares de la educación superior presentan definiciones e instrumentos de medición del pensamiento crítico dispares. El presente artículo parte de dicha apreciación y trata de revisar sistemáticamente los mencionados trabajos con un doble objetivo: por un lado, esbozar una clasificación de los instrumentos de medición del pensamiento crítico de estudiantes de ABP y, por el otro, mostrar una panorámica de las evidencias hasta ahora obtenidas; todo ello con la finalidad de animar a profesores, estudiosos y autoridades académicas a seguir avanzando en esta línea de investigación. [eng] Critical thinking has received growing attention from scientific literature on Problem-Based Learning (PBL)during the last two decades. The research carried out in different disciplinary contexts of higher education presents disparate definitions and measuring instruments of critical thinking. This article aims to review systematically the mentioned literature with a dual purpose: on the one hand, to outline a classification of instruments measuring PBL students' critical thinking, on the other, to show an overview of the evidence so far obtained; all of this with the ultimate purpose of encouraging teachers, scholars and academical authorities to proceed further in this line of research.

A bioinspired peptide scaffold with high antibiotic activity and low in vivo toxicity

Bacterial resistance to almost all available antibiotics is an important public health issue. A major goal in antimicrobial drug discovery is the generation of new chemicals capable of killing pathogens with high selectivity, particularly multi-drug-resistant ones. Here we report the design, preparation and activity of new compounds based on a tunable, chemically accessible and upscalable lipopeptide scaffold amenable to suitable hit-to-lead development. Such compounds could become therapeutic candidates and future antibiotics available on the market. The compounds are cyclic, contain two D-amino acids for in vivo stability and their structures are reminiscent of other cyclic disulfide-containing peptides available on the market. The optimized compounds prove to be highly active against clinically relevant Gram-negative and Gram-positive bacteria. In vitro and in vivo tests show the low toxicity of the compounds. Their antimicrobial activity against resistant and multidrug-resistant bacteria is at the membrane level, although other targets may also be involved depending on the bacterial strain.