Effect of empagliflozin on ectopic fat stores and myocardial energetics in type 2 diabetes: the EMPACEF study.

BACKGROUND: Empagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor that has demonstrated cardiovascular and renal protection in patients with type 2 diabetes (T2D). We hypothesized that empaglifozin (EMPA) could modulate ectopic fat stores and myocardial energetics in high-fat-high-sucrose (HFHS) diet mice and in type 2 diabetics (T2D). METHODS: C57BL/6 HFHS mice (n = 24) and T2D subjects (n = 56) were randomly assigned to 12 weeks of treatment with EMPA (30 mg/kg in mice, 10 mg/day in humans) or with placebo. A 4.7 T or 3 T MRI with 1H-MRS evaluation-myocardial fat (primary endpoint) and liver fat content (LFC)-were performed at baseline and at 12 weeks. In humans, standard cardiac MRI was coupled with myocardial energetics (PCr/ATP) measured with 31P-MRS. Subcutaneous (SAT) abdominal, visceral (VAT), epicardial and pancreatic fat were also evaluated. The primary efficacy endpoint was the change in epicardial fat volume between EMPA and placebo from baseline to 12 weeks. Secondary endpoints were the differences in PCr/ATP ratio, myocardial, liver and pancreatic fat content, SAT and VAT between groups at 12 weeks. RESULTS: In mice fed HFHS, EMPA significantly improved glucose tolerance and increased blood ketone bodies (KB) and ß-hydroxybutyrate levels (p < 0.05) compared to placebo. Mice fed HFHS had increased myocardial and liver fat content compared to standard diet mice. EMPA significantly attenuated liver fat content by 55%, (p < 0.001) but had no effect on myocardial fat. In the human study, all the 56 patients had normal LV function with mean LVEF = 63.4 ± 7.9%. Compared to placebo, T2D patients treated with EMPA significantly lost weight (- 2.6 kg [- 1.2; - 3.7]) and improved their HbA1c by 0.88 ± 0.74%. Hematocrit and EPO levels were significantly increased in the EMPA group compared to placebo (p < 0.0001, p = 0.041). EMPA significantly increased glycosuria and plasma KB levels compared to placebo (p < 0.0001, p = 0.012, respectively), and significantly reduced liver fat content (- 27 ± 23 vs. - 2 ± 24%, p = 0.0005) and visceral fat (- 7.8% [- 15.3; - 5.6] vs. - 0.1% [- 1.1;6.5], p = 0.043), but had no effect on myocardial or epicardial fat. At 12 weeks, no significant change was observed in the myocardial PCr/ATP (p = 0.57 between groups). CONCLUSIONS: EMPA effectively reduced liver fat in mice and humans without changing epicardial, myocardial fat or myocardial energetics, rebutting the thrifty substrate hypothesis for cardiovascular protection of SGLT2 inhibitors. Trial registration NCT, NCT03118336. Registered 18 April 2017, https://clinicaltrials.gov/ct2/show/NCT03118336.

Caplacizumab to treat immune-mediated thrombotic thrombocytopenic purpura.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare and life-threatening disease characterized by microangiopathic hemolytic anemia, thrombocytopenia and multiorgan failure, resulting from autoantibody-mediated severe A disintegrin and metalloproteinase with thrombospondin motifs 13 (ADAMTS13) deficiency. In spite of treatment with plasma exchange and immunosuppression, patients remain at risk of exacerbations, refractoriness and death. Caplacizumab (Cablivi; Ablynx, a Sanofi company), a nanobody targeting von Willebrand factor (vWF), has been recently approved in the E.U. and the U.S. as the first therapeutic specifically indicated for the treatment of adults experiencing an episode of iTTP. Caplacizumab blocks the interaction of all multimers with platelets and, therefore, has an immediate effect on platelet aggregation and the ensuing formation and accumulation of platelet-rich microthrombi. This immediate effect of caplacizumab has the potential to protect the patient from tissue ischemia and organ dysfunction while the underlying disease process resolves. We detail here the preclinical and clinical data on caplacizumab for iTTP, including the recent studies that led to approval by the U.S. Food and Drug Administration (FDA) in 2019.

Stability Studies of Antipyocyanic Beta-Lactam Antibiotics Used in Continuous Infusion.

In intensive care, beta-lactams can be reconstituted in 50 mL polypropylene syringes with NaCl 0.9 % and administered for 8 to 12 h at various concentrations with motor-operated syringe pumps. The feasibility and/or the stability of these antibiotic therapies are often poorly known by clinicians. The purpose of this study was to determine the stability of seven antipyocyanic beta-lactam antibiotics and cilastatin under real-life conditions. Stability indicating HPLC methods allowing quantification in pharmaceutical preparations and subsequent stability studies were performed. The stability studies showed that continuous infusion of piperacillin/tazobactam 80/10 mg/mL, of cefepime 20 and 40 mg/mL and of aztreonam 40 and 120 mg/mL can be used over 12 h. Moreover, continuous infusion of cefepime 120 mg/mL can be used over 10 h, whereas meropenem 10 and 20 mg/mL and ceftazidime 40 mg/mL remained stable only over 8 h, and meropenem 40 mg/mL was significantly degraded after 6 h. Finally, imipenem/cilastatin 5/5 mg/mL and piperacillin/tazobactam 320/40 mg/mL should not be used as continuous infusion. These data allow the establishment of protocols of administration of antipyocyanic beta-lactams by continuous infusion. Some of them are not appropriate to this mode of administration (imipenem/cilastatin, piperacillin/ tazobactam 320/40 mg/mL) or must be avoided if possible (ceftazidime 40 mg/mL).

Methods to control anticancer chemotherapy preparations ranked by risk analysis.

The observed increase in cancer led to a continuous rise in anticancer drug preparations in Hospital Centres. The quality and security of these preparations are essential to ensure the efficacy and to limit the risk of iatrogenic toxicity. Several methods have been described to secure the process of preparation (i.e. non-analytical methods for the control during the fabrication; analytical methods for the final product evaluation). These different methods have been presented in many studies, in particular in descriptive studies, but in practice, selecting a method is difficult and related to needs and hospital priorities. Therefore, we decided to conduct this present review focused on various existing methods allowing enhancement in security of anti-cancer drugs preparation process. A proactive hazard analysis method was applied, considering preparation and control steps, to discuss the choice of a method in terms of quality and security and to identify potential risks of failure. The results show that none method is perfect. Methods with the lowest criticality score are the robotization closely followed by Drugcam® in the case of re-labelling of all containers. According to these elements a University Hospital Centre could consider these risk indexesimplementing control methods.

Meningococcal vaccines: Current state and future outlook.

Neisseria meningitidis infections are a major public health problem worldwide. Although conventional approaches have not led to development of a serogroup B meningococcal vaccine, a new technique based on genome sequencing has created new perspectives. Recently, a universal serogroup B meningococcal vaccine, Bexsero(®), was licensed in Europe, Australia and United States, following several clinical studies demonstrating its immunogenicity and safety. Availability of this vaccine could contribute positively to human health, by significantly reducing the incidence of meningococcal infections. However, unfavorable cost-effectiveness analysis means that routine vaccination is not currently recommended. Another serogroup meningococcal vaccine, Trumemba(®), was also recently licensed in United States. Like any drug, Bexsero(®) and Trumemba(®) will require close observation to assess their impact on meningococcal epidemiology.

Pathophysiology and treatment of typical and atypical hemolytic uremic syndrome.

Hemolytic uremic syndrome is a rare disease, frequently responsible for renal insufficiency in children. Recent findings have led to renewed interest in this pathology. The discovery of new gene mutations in the atypical form of HUS and the experimental data suggesting the involvement of the complement pathway in the typical form, open new perspectives for treatment. This review summarizes the current state of knowledge on both typical and atypical hemolytic uremic syndrome pathophysiology and examines new perspectives for treatment.

[Severe hypoglycemia induced by tramadol: two new cases of an unlisted side effect]. / Hypoglycémies sévères au tramadol : deux nouvelles observations d'un effet indésirable non référencé

INTRODUCTION: Tramadol is a weak opioid analgesic used as a step two analgesic, approved in France for the treatment of moderate to severe pain in adult patients. The most common side effects are gastrointestinal and neurologic. Hypoglycaemia is an almost unknown side effect. CASE REPORTS: We report two patients who presented with severe hypoglycaemia related to oral administration of tramadol in non diabetic patients. The underlying mechanisms of hypoglycaemia induced by tramadol are unclear. The only weak opioid analgesic drug reported to cause hypoglycaemia is propoxyphene, which has been widely used in France. The recent withdrawal of dextropropoxyphene in France might increase the prescriptions of tramadol and healthcare professionals should be aware of the risk of hypoglycaemia. CONCLUSION: The risk of hypoglycaemia should be added to the summary of product characteristics of tramadol.

Implantable contact lens for moderate to high myopia: short-term follow-up of 2 models.

PURPOSE: To confirm the safety, efficacy, and predictability of the surgical correction of moderate to high myopia by the ICM V3 and ICM V4 implantable contact lenses (ICLs), with emphasis on vaulting, intraocular pressure (IOP), and pigment dispersion. SETTING: University Eye Hospital, Lausanne, Switzerland. METHODS: Thirty-two eyes had implantation of an ICL. In 22 eyes with a mean spherical equivalent (SE) of -11.5 diopters (D), the target was emmetropia; in 10 eyes with a mean SE of -22.3 D, the goal was a reduction in the myopia. Nineteen eyes received the ICM V3 ICL and 13, the ICM V4 ICL. The mean follow-up was 7.4 months. RESULTS: The mean postoperative SE in the 32 eyes was -2.16 D. Best spectacle-corrected visual acuity was maintained or improved in all eyes. In the 22 eyes targeted to achieve emmetropia, 10 (45%) were within +/-1.00 D; 15 (68%) had an uncorrected visual acuity of 20/40 or better and 4 (18%), of 20/20 or better. Vaulting of the ICL over the crystalline lens was more pronounced with the V4 than with the V3, and the difference was statistically significant. Subtle, localized anterior subcapsular opacification was encountered in 4 eyes. In 3 of them, the ICL (model V3) vaulting was minimal and 1 ICL (model V4) did not show any vaulting. Eighteen eyes had an IOP higher than the preoperative level, and the difference was statistically significant. No correlation was seen between final IOP and vaulting. Pigment dispersion on the ICL did not appear to be related to vaulting or ICL thickness. CONCLUSION: Implantation of an ICL was effective in correcting moderate to high myopia of up to -17.50 D. Although the procedure appears to be safe, the predictability of the refractive outcome must be improved. The new generation of ICLs for myopia (ICM V4) offers a better vault over the crystalline lens than the older models (ICM V3), which should decrease the risk of cataract. No explanation was found for the IOP increase in several eyes 3 months or more after surgery.

[Study of panophthalmitis after cataract surgery from 1997 to 1999]. / Etude sur les panophtalmies après chirurgie de la cataracte de 1997 à 1999.

PURPOSE: To define the clinical outcome and microbiological pattern of bacterial endophthalmitis that were referred at the Jules Gonin Eye Hospital from January 1997 to September 1999. METHODS: Patients were recorded in a computerised databank and were managed according to a standard protocol. An anterior chamber tap combined with a vitreous biopsy by the pars plana was performed in all patients. The treatment included an intravitreal injection of 1 mg Vancomycin and 400 micrograms Amikacin diluted in 0.2 ml NaCl 0.9%. Postoperatively hourly therapy Cefazolin 50 mg/ml and Garamycin 9 mg/ml was applied. To determine possible risks factors a standard form was sent to all referring surgeons. The following data were analysed: delay of onset, risk factors, initial and final visual acuity. RESULTS: From January 1997 to September 1999, 31 patients were referred. 18/31 (58%) of the cases were admitted between April and June of each years. The mean age was of 75 +/- 10 years. Initial visual acuity ranged from light perception to 20/40. 17/31 of the patient's cultures were positive. The major pathogen were Staphylococcus epidermidis in 9/31 patients and Staphylococcus aureus in 4/31 patients. No correlation between the endophthalmitis and the surgical technique or perioperative management of the patient, could be determined. Visual outcome was significantly improved in 56.7% of the patients. CONCLUSIONS: The severity of outcome could be correlated to the type of bacteria isolated. The high prevalence of panophthalmitis from March to June suggests that a climatic factors may be involved in its pathogenesis.

Imipenem resistance of enterobacter aerogenes mediated by outer membrane permeability.

Multidrug-resistant Enterobacter aerogenes strains are increasingly isolated in Europe and especially in France. Treatment leads to imipenem resistance, because of a lack of porin. We studied the evolution of resistance in 29 strains isolated from four patients during their clinical course. These strains belonged to the prevalent epidemiological type observed in France in previous studies (C. Bosi, et al., J. Clin. Microbiol. 37:2165-2169, 1999; A. Davin-Regli et al., J. Clin. Microbiol. 34:1474-1480, 1996). They also harbored a TEM-24 extended-spectrum beta-lactamase-coding gene. Thirteen strains were susceptible to gentamicin and resistant to imipenem and cefepime. All of the patients showed E. aerogenes strains with this resistance after an imipenem treatment. One patient showed resistance to imipenem after a treatment with cefpirome. Twelve of these 13 strains showed a lack of porin. Cessation of treatment with imipenem for three patients was followed by reversion of susceptibility to this antibiotic and the reappearance of porins, except in one case. For one patient, we observed three times in the same day the coexistence of resistant strains lacking porin and susceptible strains possessing porin. The emergence of multidrug-resistant E. aerogenes strains is very disquieting. In our study, infection by E. aerogenes increased the severity of the patients' illnesses, causing a 100% fatality rate.

The analysis of peculiar urinary (and other) calculi: an endless source of challenge.

The exact composition of calculi is clinically important, but many specimens are not examined, with resultant loss of important information. We describe the incidence and nature of false stones, peculiar calculi and crystals growing on surprising materials. We studied 3100 calculi (97% urinary, 2% digestive and 1% others). Fourier transform infrared spectroscopy was used to identify calculi by detailed comparison with libraries of reference spectra. We also used UV-visible spectroscopy, nuclear magnetic resonance and gas chromatography-mass spectrometry for specific situations. Among 3100 calculi, 154 (5%) had an unusual composition; 101 specimens (3.3%) were false calculi or artifacts, 31 (1%) contained drugs or metabolites and 22 (0.7%) corresponded to crystallizations around other materials. The findings contribute to immediate patient management and to advances in scientific and medical knowledge. We conclude that the analysis of all calculi must be carried out, to determine their composition, and an efficient strategy must be used.

Most Enterobacter aerogenes strains in France belong to a prevalent clone.

The aim of this study was to determine the distribution in France of the Enterobacter aerogenes prevalent clone isolated in the hospitals of the Marseille area (A. Davin-Regli, D. Monnet, P. Saux, C. Bosi, R. Charrel, A. Barthelemy, and C. Bollet, J. Clin. Microbiol. 34:1474-1480, 1996). A total of 123 E. aerogenes isolates were collected from 23 hospital laboratories and analyzed by random amplification of polymorphic DNA and enterobacterial repetitive intergenic consensus-PCR to determine their epidemiological relatedness. Molecular typing revealed that 21 of the 23 laboratories had isolated this prevalent clone harboring the plasmid encoding for extended-spectrum beta-lactamase of the TEM-24 type. Most isolates were susceptible only to imipenem and gentamicin. Their dissemination seems to be clonal and was probably the result of the general use of broad-spectrum cephalosporins and quinolones. Four isolates showed an alteration of their outer membrane proteins, causing decrease of susceptibility to third-generation cephalosporins and imipenem and leading to the critical situation of having no alternative therapeutic. The large dissemination of the E. aerogenes prevalent clone probably results from its good adaptation to the antibiotics administered in France and the hospital environment, particularly in intensive care units.

Estomatitis eritemato-aftoide de erupción: ¿primoinfección herpética? (trad) / Eruptive erythemato-aphthous stomatitis: herpetic primoinfection?

La estomatitis eritemato-aftoide parece bien debida a una localización del virus herpético a la mucosa bucal, en la ocasión de la erupción dentaria. Se trata de una estomatitis herpética de primoinfección en el niño joven pero puede tratarse de localización mucosa de este virus "de entrada" en el niño mayor (AU)

Estomatitis eritemato-aftoide de erupción: ¿primoinfección herpética? (trad) / Eruptive erythemato-aphthous stomatitis: herpetic primoinfection?

La estomatitis eritemato-aftoide parece bien debida a una localización del virus herpético a la mucosa bucal, en la ocasión de la erupción dentaria. Se trata de una estomatitis herpética de primoinfección en el niño joven pero puede tratarse de localización mucosa de este virus "de entrada" en el niño mayor