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It is important to evaluate whether a new treatment for heart failure with reduced ejection fraction (HFrEF) provides additive benefit to background foundational treatments. As such, we aimed to evaluate the efficacy and safety of empagliflozin in patients with HFrEF in addition to baseline treatment with specific doses and combinations of disease-modifying therapies.

AbstractBackgroundWe conducted a nationwide survey to describe the in-and out-of-hospital flow (diagnosis, treatment and follow-up) of patients with heart failure with reduced ejection fraction (HFrEF).MethodA survey was developed with five dedicated HF cardiologists. The data are all self-reported by cardiologists.ResultsThe response rate was 84%. Presence of a dedicated HF cardiologist or HF nurse was indicated by 49% and 46% of the hospitals respectively. Devices (p < .05), angiotensin receptor neprilysin inhibitors, and rehabilitation are considered more standard of care therapy by dedicated compared to non-dedicated HF cardiologists. Most cardiologists indicated that target dosages of HF drugs can be reached in 25‒75% of patients. Achieving >75% of the target dose seems easier for angiotensin converting enzyme inhibitor/angiotensin receptor blockers (ACEI/ARB) (22%) and mineralocorticoid receptor antagonists (25%), compared to β-blockers (10%) and angiotensin receptor neprilysin inhibitors (7%). 62%, 49% and 4% of the cardiologists indicated to use subtypes of angiotensin converting enzyme inhibitors, angiotensin receptor blockers and β-blockers respectively not validated in the HF population. In the acute setting, dedicated HF cardiologists (23%) are less influenced by blood parameters for decongestion compared to non-dedicated HF cardiologists (39%). They tend to change patients more to guideline-recommended drugs (60% vs 47%). Six minutes walk test and ergospirometry are significantly more used by dedicated compared to non-dedicated HF cardiologists for HF drug change (17% and 29% vs 2% and 4%).ConclusionThis survey showed that a minority of hospitals have HF care. Those that do, report a higher implementation of guideline-recommended diagnosis, treatment and follow-up of HF patients. Competent authorities could use this survey as a tool to improve HF care.

Cardiovascular disorders have been extensively reported during COVID-19 illness, including arrhythmias such as atrioventricular conduction disturbances. To date, one case of transient heart block has been reported after COVID-19 vaccine.

The type III secretion (T3S) pathway allows bacteria to inject effector proteins into the cytosol of target animal or plant cells. T3S systems evolved into seven families that were distributed among Gram-negative bacteria by horizontal gene transfer. There are probably a few hundred effectors interfering with control and signaling in eukaryotic cells and offering a wealth of new tools to cell biologists.

All pathogenic Yersinia enterocolitica strains carry the pYV plasmid encoding the Ysc-Yop type III secretion (TTS) system, which operates at 37 degrees C. In addition, biovar 1B Y. enterocolitica strains possess a second, chromosomally encoded, TTS system called Ysa, which operates, at least in vitro, under low-temperature and high-salt (LTHS) conditions. Six open reading frames, sycB, yspB, yspC, yspD, yspA, and acpY, neighbor the ysa genes encoding the Ysa TTS apparatus. Here we show that YspA, YspB, YspC, and YspD are secreted by the Ysa TTS system under LTHS conditions. SycB is a chaperone for YspB and YspC and stabilizes YspB. YspB, YspC, and SycB share some similarity with TTS substrates and the chaperone encoded by the Mxi-Spa locus of Shigella flexneri and SPI-1 of Salmonella enterica. In addition, Ysa also secretes the pYV-encoded YopE under LTHS conditions, indicating that YopE is a potential effector of both Y. enterocolitica TTS systems. YspC could also be secreted by S. flexneri, but no functional complementation of ipaC was observed, which indicates that despite their similarity the Ysa and the Mxi-Spa systems are not interchangeable. When expressed from the yopE promoter, YspB and YspC could also be secreted via the Ysc injectisome. However, they could not form detectable pores in eukaryotic target cells and could not substitute for YopB and YopD for translocation of Yop effectors.

ABSTRACTAll pathogenic Yersinia enterocoliticastrains carry the pYV plasmid encoding the Ysc-Yop type III secretion (TTS) system, which operates at 37°C. In addition, biovar 1B Y. enterocoliticastrains possess a second, chromosomally encoded, TTS system called Ysa, which operates, at least in vitro, under low-temperature and high-salt (LTHS) conditions. Six open reading frames, sycB, yspB, yspC, yspD, yspA, and acpY, neighbor the ysagenes encoding the Ysa TTS apparatus. Here we show that YspA, YspB, YspC, and YspD are secreted by the Ysa TTS system under LTHS conditions. SycB is a chaperone for YspB and YspC and stabilizes YspB. YspB, YspC, and SycB share some similarity with TTS substrates and the chaperone encoded by the Mxi-Spa locus of Shigella flexneriand SPI-1 of Salmonella enterica. In addition, Ysa also secretes the pYV-encoded YopE under LTHS conditions, indicating that YopE is a potential effector of both Y. enterocoliticaTTS systems. YspC could also be secreted by S. flexneri, but no functional complementation of ipaCwas observed, which indicates that despite their similarity the Ysa and the Mxi-Spa systems are not interchangeable. When expressed from the yopEpromoter, YspB and YspC could also be secreted via the Ysc injectisome. However, they could not form detectable pores in eukaryotic target cells and could not substitute for YopB and YopD for translocation of Yop effectors.

Pathogenic strains of Yersinia spp. inject a set of Yop effector proteins into eukaryotic cells by using a plasmid-encoded type III secretion system. In this study, we analyzed the inflammatory response of human umbilical vein endothelial cells (HUVECs) after infection with different Yersinia enterocolitica strains. We found that both expression of intercellular adhesion molecule 1 and release of the cytokines interleukin-6 (IL-6) and IL-8 by HUVECs are downregulated in a YopP-dependent way, demonstrating that YopP plays a major role in the inflammatory response of these cells. Infection of HUVECs with several low-virulence (biotype 2, 3, and 4) and high-virulence (biotype 1B) Y. enterocolitica strains showed that biotype 1B isolates are more efficient in inhibiting the inflammatory response than low-virulence Y. enterocolitica strains and that this effect depends on the time of contact. We extended the results of Ruckdeschel et al. and found that on the basis of the presence or absence of arginine-143 of YopP (K. Ruckdeschel, K. Richter, O. Mannel, and J. Heesemann, Infect. Immun. 69:7652-7662, 2001) all the Y. enterocolitica strains used fell into two groups, which correlate with the low- and high-virulence phenotypes. In addition, we found that high-virulence strains inject more YopP into the cytosol of eukaryotic target cells than do low-virulence strains.

ABSTRACTPathogenic strains of Yersiniaspp. inject a set of Yop effector proteins into eukaryotic cells by using a plasmid-encoded type III secretion system. In this study, we analyzed the inflammatory response of human umbilical vein endothelial cells (HUVECs) after infection with different Yersinia enterocoliticastrains. We found that both expression of intercellular adhesion molecule 1 and release of the cytokines interleukin-6 (IL-6) and IL-8 by HUVECs are downregulated in a YopP-dependent way, demonstrating that YopP plays a major role in the inflammatory response of these cells. Infection of HUVECs with several low-virulence (biotype 2, 3, and 4) and high-virulence (biotype 1B) Y. enterocoliticastrains showed that biotype 1B isolates are more efficient in inhibiting the inflammatory response than low-virulence Y. enterocoliticastrains and that this effect depends on the time of contact. We extended the results of Ruckdeschel et al. and found that on the basis of the presence or absence of arginine-143 of YopP (K. Ruckdeschel, K. Richter, O. Mannel, and J. Heesemann, Infect. Immun. 69:7652-7662, 2001) all the Y. enterocoliticastrains used fell into two groups, which correlate with the low- and high-virulence phenotypes. In addition, we found that high-virulence strains inject more YopP into the cytosol of eukaryotic target cells than do low-virulence strains.

Nefazodone, a phenylpiperazine antidepressant, exhibits novel dual activity on serotonin (5-HT) neurons; it binds to 5-HT2 receptors and inhibits 5-HT reuptake. Flexible doses of nefazodone (100–400 mg/day) and amitriptyline (50–200 mg/day) were compared in 106 major depressive inpatients in a 6-week double-blind study. Results showed significant superiority of amitriptyline over nefazodone on all rating instruments: Montgomery and Asberg depression rating scale (P<0.0001), Hamilton depression scale (P<0.0006), Clinical Global Impressions (P<0.0001) and Patient Global Assessment (P<0.01). A total of 65% of patients under amitriptyline and 56% of patients under nefazodone reported adverse events during the study, with significantly more dry mouth in the amitriptyline group (39% versus 11%,P=0.001). Modal daily doses within the last treatment week reached 242 mg with nefazodone and 124 mg with amitriptyline. The lower efficacy of nefazodone, which contradicts comparative trials with imipramine in US patients, is discussed with regard to the dose of nefazodone, probably below the optimal therapeutic range for melancholic patients, and to the clinical differences between the patient samples.

The efficacy and the tolerance of milnacipran (100 mg/day), a second generation antidepressant which equipotently inhibits both noradrenaline and serotonin reuptake, was compared to fluoxetine (20 mg/day), a selective serotonin reuptake inhibitor, in two parallel groups of, respectively, 97 and 93 major depressive outpatients. The duration of the study was 6 weeks, with assessments every 2 weeks by means of the Montgomery and Asberg depression scale (MADRS), the Hamilton depression scale, the clinical global impressions (CGI), and a checklist of symptoms and side-effects. Results showed significant superiority of fluoxetine over milnacipran on most rating instruments: MADRS (P=0.01) including five individual items, Hamilton depression scale (P=0.002) including ten individual items, CGI of severity (P=0.01) and therapeutical index (P=0.002). On visual analogue scales assessing the clinical profile of the compounds, fluoxetine was rated as exhibiting more psychostimulating activity than milnacipran (P=0.0008). The tolerance of the two antidepressants was very similar, with the exception of symptoms of dizziness which were more frequently reported with milnacipran (P=0.01). These differences in efficacy favoring fluoxetine could result from the selection of a dose of milnacipran below the optimal therapeutic dose for this type of psychiatric patients or to the administration of the compounds in single daily intakes, whereas milnacipran possesses a plasma elimination half-life of only 7 h.

Summary Unlike conventional antidepressants, rolipram (a new approach in the treatment of depression) stimulates both the presynaptic and the postsynaptic component of monoaminergic transmission. Several double blind trials are under way to assess the clinical efficacy and safety of this compound. The present study was a randomized, 4-week interindividual double blind double-dummy comparison with desipramine in inpatients with major (DSM-III) and/or endogenous (ICD-9) depressions. After a minimum washout period of three days the patients received either 0.50 mg rolipram or 25 mg desipramine orally t.i.d. for the first three days, then 0.75 mg rolipram or 50 mg desipramine t.i.d. until day 28. Rating tests were based principally on the AMDP-system and the HAMD scale. The study showed no differences between the two drugs as regards the efficacy, but a definite trend in favour of rolipram as regards the side effects and, in particular, anticholinergic effects.