Real world experience of therapeutic monitoring of medically treated prosthetic valve infective endocarditis by 18F-FDG-PET/CT.

INTRODUCTION: 18F-FDG-PET/CT is recommended to improve the diagnosis of prosthetic valve infective endocarditis (PVIE) and is a major criterion in the ESC-2015 classification. However, there is little evidence for its usefulness in the follow-up of medically treated PVIE patients. METHODS: A monocentric retrospective analysis of patients hospitalized for PVIE between January 2013 and December 2019 who were not treated with surgery and who had at least two 18F-FDG-PET/CT examinations during their medical management. RESULTS: Among 170 patients with PVIE, 117 were treated with antibiotic therapy but no surgery. Of these, 36 (31%) had at least two 18F-FDG-PET/CT examinations. At initial imaging, 28 patients had heterogeneous FDG uptake on their prosthetic valve and eight on their associated aortic graft. Hypermetabolism of spleen and bone marrow (HSBM) was observed in 18 and 19 patients, respectively. At the first follow-up 18F-FDG-PET/CT, 21 (58%) patients still had heterogeneous uptake, indicating persistent active endocarditis. HSBM was still present at the last follow-up imaging in four of the six patients with recurrent PVIE. CONCLUSION: 18F-FDG-PET/CT monitoring of medically treated patients with PVIE provides valuable additional information and prospective multicentric study should be conducted to assess its usefulness.

Over-blending effect of lubricants on capsules manufacturing: a simple and fast wettability technique to predict batch dissolution performance.

Mixing/blending is a crucial operation in the manufacturing of solid drug products in the pharmaceutical industry. Although usually described and controlled in specific steps, blending is also inherent to other operations such as the transference of materials and equipment feeding systems. This study aimed to investigate a simple and fast wettability testing procedure capable to foresee the potential over-blending effects of lubricants occurring during the manufacturing of solid dosage forms. An industrial batch blend was submitted to two mixing mechanisms studies (diffusion and shear) during increasing time periods, and the developed wettability testing procedure was applied to assess their impact on blend water uptake. Capsules filled with these blends were tested for dissolution and disintegration. The method was applied to capsules with known dissolution results manufactured at an industrial scale. Results demonstrated that processes inducing shear stress led to less permeable blends with consequent retardation on capsules dissolution of at least 35% in the tested timepoints and obtained study metrics above 500 s. Moreover, disintegration testing was not able to detect non-compliant dissolutions, while the proposed wettability testing procedure proved to be able to identify performance failures. Wettability results correlate the effect of mixing mechanisms to capsules dissolution performance, evidencing that this technique can be applied in the pharmaceutical industry to evaluate possible over-blending effects.

[Chyle leak after cervical surgery: Meta analysis--Management strategy]. / Lymphorrhée après chirurgie cervicale: méta-analyse--stratégie thérapeutique.

OBJECTIVE: Chyle fistula is a known complication in cervical surgery. It can lead to a postoperative lymphorrhea. There is no consensus on its management. The aim of this work is to propose a management strategy for postoperative chyle leak. MATERIALS AND METHODS: A literature review was conducted using PubMed database. RESULTS: Six prospectives articles were included. The enteral diet allowed a success in 57% of cases, and in these cases a lymph flow less than 580 mL/day. Parenteral nutrition was effective when the flow was less than 1050 mL/day. Reoperation was performed in case of failure of the nutritional treatments. CONCLUSION: Several therapeutics are available. From this meta-analysis, we developed a management strategy. We initiate an enteral diet when lymph flow is less than 500 mL/ day. Parenteral nutrition is used if the flow rate is between 500 and 1000 mL/day or in case of inefficiency of enteral diet during 10 days. Finally, revision surgery is necessary when the flow is greater than 1000 mL/day or when parenteral nutrition was ineffective in 10 days.

Lack of involvement of type 7 phosphodiesterase in an experimental model of asthma.

Type 7 phosphodiesterases (PDE7) are responsible for the decrease of intracellular cyclic AMP (cAMP) in many cells involved in allergic asthma by suppressing their potential to respond to many activating stimuli. The elevation of intracellular cAMP has been associated with immunosuppressive and anti-inflammatory activities and represents a potential treatment of asthma. Our aim was to evaluate the impact of the deletion of the murine phosphodiesterase (PDE)7B gene and then to evaluate the efficacy of a newly described selective PDE7A and -B inhibitor on an ovalbumin (OVA)-induced airway inflammation and airway hyperreactivity (AHR) model in mice. Inflammation was determined 72 h after single OVA challenge or 24 h after multiple challenges by the relative cell influx and cytokine content in bronchoalveolar lavage fluid. AHR and immunoglobulin E levels in serum were determined after multiple challenges. For the first time, we have demonstrated that the deletion of the PDE7B gene or the pharmacological inhibition of PDE7A and -B had no effect on all the parameters looked at in this model. These results highlight the absence of any implication of the PDE7 enzyme in our model.

The ScRALF3 secreted peptide is involved in sporophyte to gametophyte signalling and affects pollen mitosis I.

Signalling events through small peptides are essential in multiple aspects of plant reproduction. The ScRALF3 Solanum chacoense Rapid Alkalinization Factor (RALF) peptide was previously shown to regulate multiple aspects of cell-cell communication between the surrounding sporophytic tissue and the female gametophyte during ovule development. We analysed the global expression pattern of ScRALF3 with GUS reporter gene under control of the ScRALF3 promoter and validated it with in situ hybridisation. To better understand the role of ScRALF3 we used three different RNA interference (RNAi) lines that reduced the expression of ScRALF3 during pollen development. Both expression methods showed the presence of ScRALF3 in different tissues, including stigma, style, vascular tissues and during stamen development. Down-regulation of ScRALF3 expression through RNAi showed drastic defects in early stages of pollen development, mainly on the first mitosis. These results suggest that the ScRALF3 secreted peptide regulates the transition from sporogenesis to gametogenesis in both male and female gametophytes.

Single dose escalation studies with inhaled POL6014, a potent novel selective reversible inhibitor of human neutrophil elastase, in healthy volunteers and subjects with cystic fibrosis.

BACKGROUND: POL6014 is a novel, orally inhaled neutrophil elastase (NE) inhibitor in development for cystic fibrosis (CF). METHODS: Two studies, one in healthy volunteers (HVs, doses 20 to 960 mg) and one in subjects with CF (doses 80 to 320 mg) were conducted to evaluate the safety, tolerability and pharmacokinetics (PK) of single ascending doses of inhaled POL6014 with a Pari eFlow® nebuliser. PK was evaluated over a period of 24 h. In addition, NE activity in CF sputum was measured. RESULTS: After single doses, POL6014 was safe and well tolerated up to 480 mg in HVs and at all doses in subjects with CF. POL6014 showed a dose-linear PK profile in both populations with Cmax between 0.2 and 2.5 µM in HVs and between 0.2 and 0.5 µM in subjects with CF. Tmax was reached at approximately 2-3 h. Mean POL6014 levels in CF sputum rapidly reached 1000 µM and were still above 10 µM at 24 h. >1-log reduction of active NE was observed at 3 h after dosing. CONCLUSION: Inhalation of POL6014 can safely lead to high concentrations within the lung and simultaneously low plasma concentrations, allowing for a clear inhibition of NE in the sputum of subjects with CF after single dosing. TRIAL REGISTRATION: European Medicines Agency EudraCT-Nr. 2015-001618-83 and 2016-000493-38.

Comparison of low-shear and high-shear granulation processes: effect on implantable calcium phosphate granule properties.

BACKGROUND: Calcium phosphate porous ceramics present a great interest not only as complex bone defect fillers but also as drug delivery systems. Most of the methods described in the literature to fabricate pellets are based on compaction, casting into spherical molds, or on processes such as liquid immiscibility or foaming. Despite wet granulation is used in a wide range of applications in pharmaceuticals, food, detergents, fertilizers, and minerals, it is not applied in the biomaterial field to produce granules. METHODS: In this study physicochemical and in vitro drug delivery properties of implantable calcium phosphate granules, produced by two wet agglomeration processes, were compared. Pellets obtained by high shear granulation (granulation in a Mi-Pro apparatus) were shown to be more spherical and less friable than granules elaborated by low shear process (granulation in a Kenwood apparatus). Although Mi-Pro pellets had a slightly lower porosity compared to Kenwood granules, ibuprofen loading efficiency and dissolution profiles were not statistically different and the release mechanism was mainly controlled by diffusion, in both cases. CONCLUSION: Mi-Pro pellets appeared to be better candidates as bone defect fillers and local drug delivery systems as far as they were more spherical and less friable than Kenwood agglomerates.

[Assessing quality in the process of using hazardous drugs-prescription and preparation]. / Evaluación de la calidad en el proceso de utilización de fármacos peligrosos: prescripción y preparación.

OBJECTIVE: To evaluate the quality of cytotoxic drug prescription based on the results of an interventional pharmaceutical program and the quality of the final product based on quality-control prior to preparation. STUDY PERIOD: July 2002-March 2003. Hazardous drug prescription was evaluated through an analysis of pharmaceutical interventions during therapeutical monitoring. Depending on repercussion in patients, they were classified in three categories (treatment optimization, resource optimization or criteria unification). Data obtained from manual quality control programs prior to hazardous drug preparation were evaluated. RESULTS: Sixty-four interventions were made (9 interventions per 100 prescriptions): 55% were classified as treatment optimization, 28% as resource optimization and 17% as criteria unification. A total of 66% of the interventions focused on treatment optimization were caused by prescription errors. Ninety-seven per cent were accepted. Out of 2,074 preparations, 1,951 were evaluated (94.9%). A 5.1% of non-evaluated preparations were due to a lack of registration and 0.8% to violations in the established protocol. CONCLUSIONS: Results of the interventional Pharmaceutical program show that an assisted prescription system is necessary, not only to detect prescription errors but also to prevent them. Manual controls in different stages of the process are useful and they should be complementary to other more reliable dosification controls.

Involvement of prostaglandins and CGRP-dependent sensory afferents in peritoneal irritation-induced visceral pain.

This study investigates the contribution of prostaglandins (PG) and calcitonin gene-related peptide (CGRP) pathways in visceral pain induced by peritoneal irritation in rats. Peritoneal irritation was produced by i.p. administration of acetic acid (AA: 0.06-1.0%, 10 ml/kg). Visceral pain was scored by counting abdominal contractions. The effect of CGRP (3-100 microg/kg, i.p.) was also evaluated. Like AA, CGRP induced abdominal pain. Neonatal pretreatment with capsaicin reduced abdominal contractions produced by AA (0.6%) and CGRP (20 microg/kg) with 64.6% and 45.6%, respectively. Abdominal contractions induced by AA and CGRP were blocked by two antinociceptive drugs, mu-and kappa-opioid agonists, morphine and (+/-)-U-50,488H, respectively. Indomethacin (3 mg/kg, s.c.) reduced the number of abdominal contractions produced by AA by 78.1%+/-6.4% but did not inhibit abdominal contractions produced by CGRP. The CGRP, receptor antagonist, hCGRP(8-37) (300 microg/kg, i.v.) inhibited AA- and CGRP-induced abdominal contractions with 57.5%+/-12.4% and 51.6%+/-11.3%, respectively. Concomitant i.p. administration of PGE1 and PGE2 (0.3 mg/kg of each) produced abdominal contractions which were inhibited 45.6%+/-9.3% by hCGRP(8-37) (300 microg/kg i.v.). Taken together, these results suggest that peritoneal irritation is likely to trigger the release of prostaglandins, which in turn produces a release of CGRP from primary sensory afferents.

Reversal by kappa-agonists of peritoneal irritation-induced ileus and visceral pain in rats.

Peritoneal irritation in rats induced by i.p. administration of acetic acid produces abdominal contractions reflecting visceral pain, and gastrointestinal ileus characterized by inhibition of gastric emptying and small intestine transit. In this study, gastric emptying (GE) and intestinal transit, calculated by the geometric center (GC) method, were estimated using a test meal labeled with 51Cr-EDTA. Visceral pain was assessed by counting abdominal contractions. Acetic acid produced abdominal contractions (80.8 +/- 3.3) and inhibition of GE (-54%) and GC (-63%) during the test-period. The kappa-opioid receptor agonists, CI-977 (+/-)-U-50,488H, (+/-)-bremazocine, PD-117,302, (-)-cyclazocine, and U-69,583, reversed abdominal contractions and inhibitions of gastrointestinal transit in a dose-related manner. The mu-opioid receptor agonists and potent analgesics, morphine and fentanyl did not restore normal gastric emptying and intestinal transit. These data suggest that selective kappa-opioid receptor agonists might be used to treat abdominal pain associated with motility and transit impairment during postoperative ileus.

[Infections by Candida sp. in intensive care. Survey of French practices]. / Infections à Candida sp en réanimation. Enquête sur les pratiques françaises.

OBJECTIVE: The isolation of Candida sp in nosocomial infections is on the increase and over the past 10 years many guidelines for "good" practices and recommendations have been published on the modalities for the management of systemic candidiasis. The aim of this paper was to assess the habits in the intensive care units in this domain in France. METHOD: A transversal survey on the habits was conducted from March to May 2001, using a questionnaire mailed to 200 intensive care units. RESULTS: One hundred eighty questionnaires (surgical reanimation: 12%, medical: 18%, medico-surgical: 70%) out of 200 (92.5%) were returned. The indirect diagnostic examinations: serology, search for antigenemia and PCR (Polymerase Chain Reaction) were never used in 21, 35 and 65% of cases. The systematic search for colonisation (a mean of 4 areas sampled) was conducted in all the patients by 19% of the investigators, in some patients by 53%, and never by 28%. An antifungal treatment was prescribed: in the presence of a positive haemoculture alone, once out of twice if the sample had been taken from a central catheter and in 2 cases out of 3 when the sample was peripheral. It was prescribed 6 times out of 10 after isolation of Candida sp following surgery or on needle aspiration of an intra-abdominal abscess, varyingly in the case of cadiduria, isolation of a Candida sp in a broncho-pulmonary sample or in abdominal draining and positive culture of a catheter, depending on the intensity of the colonisation, the severity of the clinical picture and the presence of factors of risk for Candida infection. It is still prescribed empirically depending on the same elements and the absence of explanation for worsening. When faced with candidemia in a non-neutropenic patient, a central catheter is not changed in 18% of cases. Depending on the microbiology, fluconazole is prescribed in: the identification of yeast without further precision (78% of cases), Candida sp without further precision (86% of cases), Candida non albicans without further precision (57% of cases), C. albicans (93% of cases), Candida non albicans other than C. krusei and C. glabrata (62% of cases), C. glabrata (36% of cases) with an increase in dose in 1 out of 2 cases. In the presence of C. glabrata or C. krusei, amphotericin B is the choice in respectively 51 and 75% of cases. To adapt the treatment.

[Aspergillosis of the sphenoid sinus. Apropos of 4 cases]. / Aspergillose du sinus sphénoïdal. A propos de 4 cas.

Aspergillosis of the sphenoid sinus is a rare entity. The authors report four cases of non invasive aspergillosis sinusitis, three isolated cases and one with nasal polyps. All cases were treated by functional endoscopic surgery. Good results were noted with a mean follow-up of 18 months. Frequency, clinical features, treatment, and etiopathogenesis of sphenoidal aspergillosis are discussed.

[Atypical involvement of undifferentiated carcinomas of the nasopharyngeal type. Apropos of 3 cases]. / Localisations atypiques des carcinomes indifférenciés de type nasopharyngé. A propos de 3 cas.

We report 3 cases of undifferentiated carcinomas of nasopharyngeal type (UCNT) found in unusual sites and compare them with histologically identical tumors found in the nasopharynx. Using viral serology and viral marquers found in the tumor cells, we looked for a link with the Epstein Barr Virus (EBV) which exists in the nasopharyngeal site. It appears that UCNT found in unusual sites have a poorer prognostic than the same nasopharyngeal tumors; no link was found with EBV. The number of published cases is too small to form a conclusion, therefore, we propose a systematic search for EBV, presenting our protocol, each time is discovered UCNT in an unusual site.

[Osteoma of the naso-sinusal cavities. Surgical indications and role of endonasal endoscopic surgery]. / Ostéomes des cavités naso-sinusiennes. Indications opératoires et place de la chirurgie endonasale endoscopique.

Osteoma of the para-nasal sinuses is a rare and benign tumor that develops slowly. When therapy becomes mandatory, it is necessarily surgical and requires a standard external approach. This report analyses seven cases of operated osteomas, using different surgical techniques, adapted to different indications. Three patients underwent exclusive endonasal endoscopic surgery, and four patients had external surgery coupled with endonasal surgery. Results have proven successful with a four-year median follow-up. Epidemiological, clinical, histological and therapeutic considerations as well as the value of the endoscopic endonasal surgical approach are discussed. Endonasal endoscopic surgery can be used alone in naso-ethmoidal osteomas. It must, though, be associated with external standard procedure when the osteoma involves important extension to the frontal sinuses. In isolated frontal osteomas, external standard approach is mandatory for resection, endonasal technique being in this case contributive to the repermeabilisation of the infundibulum.

[Use of endoscopy in pituitary surgery]. / Utilisation de l'endoscopie dans la chirurgie pituitaire.

Endoscopy has changed many of surgical procedures concerning nasal and paranasal cavities. It has been proposed for transnasal removal of pituitary adenomas. The authors report their experience concerning four pituitary macroadenomas operated with the neurosurgical team of Sainte-Anne hospital. The endonasal trans-septal route seemed to be more anatomical and less traumatic than the rhinoseptal sublabial route. The 30 degrees rigid Hopkins endoscope was a good help for controlling the absence of any tumor remnant in the supra and parasellar regions after complete removal of the tumor performed through the endoscope or with the operating microscope. The authors discuss the advantages and limitations of such endoscopic procedures in the light of recent literature.

[Apropos of 2 cases of mucocele with major ophthalmologic complications treated by endoscopic endonasal surgery]. / A propos de deux cas de mucocèle avec complications ophtalmologiques majeures traitées par chirurgie endo-nasale endoscopique.

We report two cases of frontal and ethmoidal mucocele revealed by severe ophtalmologic complications and present the clinical data and computed tomography and magnetic resonance imaging results together with the treatment. The surgical approach and technique are discussed. Recovery of ophtalmologic deficiency was excellent.

[Atelectasis of the maxillary sinus. Analysis of progression stages. Apropos of 4 cases]. / Processus atélectasique du sinus maxillaire. Analyse des stades évolutifs. A propos de 4 cas.

We analyzed atelectasic processes occurring in the maxillary sinus. Several publications in the literature have tempted to analyze the pathogenesis. Clinically the processes are often silent and only revealed when the major opthalmological complication, enophthalmia, becomes patent. In other cases there is a long history of chronic sinusitis. There is a spectacular retraction of the maxillary sinus walls leading to collapse of the orbital floor and enophthalmia. We report four cases of maxillary sinusitis with atelectasia of the sinus walls at different stages of progression. These observations and data in the literature emphasize the importance, whatever the state of development, of endoscopic osteal decompression to avoid ophthalmological complications.

The novel CXCR4 antagonist POL5551 mobilizes hematopoietic stem and progenitor cells with greater efficiency than Plerixafor.

Mobilized blood has supplanted bone marrow (BM) as the primary source of hematopoietic stem cells for autologous and allogeneic stem cell transplantation. Pharmacologically enforced egress of hematopoietic stem cells from BM, or mobilization, has been achieved by directly or indirectly targeting the CXCL12/CXCR4 axis. Shortcomings of the standard mobilizing agent, granulocyte colony-stimulating factor (G-CSF), administered alone or in combination with the only approved CXCR4 antagonist, Plerixafor, continue to fuel the quest for new mobilizing agents. Using Protein Epitope Mimetics technology, a novel peptidic CXCR4 antagonist, POL5551, was developed. In vitro data presented herein indicate high affinity to and specificity for CXCR4. POL5551 exhibited rapid mobilization kinetics and unprecedented efficiency in C57BL/6 mice, exceeding that of Plerixafor and at higher doses also of G-CSF. POL5551-mobilized stem cells demonstrated adequate transplantation properties. In contrast to G-CSF, POL5551 did not induce major morphological changes in the BM of mice. Moreover, we provide evidence of direct POL5551 binding to hematopoietic stem and progenitor cells (HSPCs) in vivo, strengthening the hypothesis that CXCR4 antagonists mediate mobilization by direct targeting of HSPCs. In summary, POL5551 is a potent mobilizing agent for HSPCs in mice with promising therapeutic potential if these data can be corroborated in humans.

Ibuprofen-loaded calcium phosphate granules: combination of innovative characterization methods to relate mechanical strength to drug location.

This paper studies the impact of the location of a drug substance on the physicochemical and mechanical properties of two types of calcium phosphate granules loaded with seven different contents of ibuprofen, ranging from 1.75% to 46%. These implantable agglomerates were produced by either low or high shear granulation. Unloaded Mi-Pro pellets presented higher sphericity and mechanical properties, but were slightly less porous than Kenwood granules (57.7% vs 61.2%). Nevertheless, the whole expected quantity of ibuprofen could be integrated into both types of granules. A combination of surface analysis, using near-infrared (NIR) spectroscopy coupling chemical imaging, and pellet porosity, by mercury intrusion measurements, allowed ibuprofen to be located. It was shown that, from 0% to 22% drug content, ibuprofen deposited simultaneously on the granule surface, as evidenced by the increase in surface NIR signal, and inside the pores, as highlighted by the decrease in pore volume. From 22%, porosity was almost filled, and additional drug substance coated the granule surfaces, leading to a large increase in the surface NIR signal. This coating was more regular for Mi-Pro pellets owing to their higher sphericity and greater surface deposition of drug substance. Unit crush tests using a microindenter revealed that ibuprofen loading enhanced the mechanical strength of granules, especially above 22% drug content, which was favorable to further application of the granules as a bone defect filler.