Targeted modifications of neomycin and paromomycin: Towards resistance-free antibiotics?

Despite their clinical importance, saving numerous human lifes, over- and mis-uses of antibiotics have created a strong selective pressure on bacteria, which induces the emergence of (multi)resistant strains. Antibioresistance is becoming so pregnant that since 2017, WHO lists bacteria threatening most human health (AWaRe, ESKAPE lists), and those for which new antibiotics are urgently needed. Since the century turn, this context is leading to a burst in the chemical synthesis of new antibiotics, mostly derived from natural antibiotics. Among them, aminoglycosides, and especially the neomycin family, exhibit broad spectrum of activity and remain clinically useful drugs. Therefore, numerous endeavours have been undertaken to modify aminoglycosides with the aim of overcoming bacterial resistances. After having replaced antibiotic discovery into an historical perspective, briefly surveyed the aminoglycoside mode of action and the associated resistance mechanisms, this review emphasized the chemical syntheses performed on the neomycin family and the corresponding structure activity relationships in order to reveal the really efficient modifications able to convert neomycin and its analogues into future drugs. This review would help researchers to strategically design novel aminoglycoside derivatives for the development of clinically viable drug candidates.

Prevention of potentially inappropriate medication in internal medicine patients: A prospective study using the electronic application PIM-Check.

WHAT IS KNOWN: Potentially inappropriate medication (PIM) is a risk factor for drug-related problems (DRPs) and an important inpatient safety issue. PIM-Check is a screening tool designed to detect PIM in internal medicine patients. OBJECTIVE: This study aimed to determine whether PIM-Check could help to identify and reduce DRPs. METHOD: Prospective interventional study conducted on patients admitted to internal medicine wards in a university hospital between 1 September 2015 and 30 October 2015. Adult patients were included if they were hospitalized for more than 48 hours. Patients received either usual care (period 1 = control) or usual care plus medication screening by the wards' chief residents using PIM-Check (period 2 = intervention). An expert panel, composed of a clinical pharmacist, a clinical pharmacologist and two attending physicians in internal medicine, blinded to patient groups, identified DRPs. RESULTS: A total of 297 patients were included (intervention: 109). The groups' demographic parameters were similar. The expert panel identified 909 DRPs (598: control; 311: intervention). The mean number of DRPs per patient was similar in the control (3.2; 95% CI: 2.9-3.5) and intervention groups (2.9; 95% CI: 2.4-3.3) (P = .12). PIM-Check displayed 33.4% of the 311 DRPs identified in the intervention group. WHAT IS NEW AND CONCLUSION: In this study, PIM-Check had limited value, as the average number of DRPs per person was similar in both groups. Although one-third of DRPs counted in intervention group had been identified by PIM-Check, this did not lead to a reduction in DRPs. This lack of impact of PIM-Check on drug prescription may be explained by the number of alerts displayed by the application and hospital physicians' reluctance to modify the treatments for chronic conditions previously prescribed by general practitioners.

A comparison of two tools to screen potentially inappropriate medication in internal medicine patients.

WHAT IS KNOWN: Potentially inappropriate medication (PIM) is an important issue for inpatient management; it has been associated with safety problems, such as increases in adverse drugs events, and with longer hospital stays and higher healthcare costs. OBJECTIVE: To compare two PIM-screening tools-STOPP/START and PIM-Check-applied to internal medicine patients. A second objective was to compare the use of PIMs in readmitted and non-readmitted patients. METHOD: A retrospective observational study, in the general internal medicine ward of a Swiss non-university hospital. We analysed a random sample of 50 patients, hospitalized in 2013, whose readmission within 30 days of discharge had been potentially preventable, and compared them to a sample of 50 sex- and age-matched patients who were not readmitted. PIMs were screened using the STOPP/START tool, developed for geriatric patients, and the PIM-Check tool, developed for internal medicine patients. The time needed to perform each patient's analysis was measured. A clinical pharmacist counted and evaluated each PIM detected, based on its clinical relevance to the individual patient's case. The rates of screened and validated PIMs involving readmitted and non-readmitted patients were compared. RESULTS: Across the whole population, PIM-Check and STOPP/START detected 1348 and 537 PIMs, respectively, representing 13.5 and 5.4 PIMs/patient. Screening time was substantially shorter with PIM-Check than with STOPP/START (4 vs 10 minutes, respectively). The clinical pharmacist judged that 45% and 42% of the PIMs detected using PIM-Check and STOPP/START, respectively, were clinically relevant to individual patients' cases. No significant differences in the rates of detected and clinically relevant PIM were found between readmitted and non-readmitted patients. WHAT IS NEW AND CONCLUSION: Internal medicine patients are frequently prescribed PIMs. PIM-Check's PIM detection rate was three times higher than STOPP/START's, and its screening time was shorter thanks to its electronic interface. Nearly half of the PIMs detected were judged to be non-clinically relevant, however, potentially overalerting the prescriber. These tools can, nevertheless, be considered useful in daily practice. Furthermore, the relevance of any PIM detected by these tools should always be carefully evaluated within the clinical context surrounding the individual patient.

Increased incidence of chronic GvHD and CMV disease in patients with vitamin D deficiency before allogeneic stem cell transplantation.

Vitamin D has emerged as a central player in the immune system, with its deficiency being implicated in the pathogenesis of several autoimmune diseases, including chronic GvHD. This is a retrospective cohort analysis of 166 patients, who underwent allogeneic hematopoietic stem cell transplantation (HSCT) at the Karolinska University Hospital, evaluating GvHD, graft failure, infectious complications and survival after HSCT in relation to pre-transplantation vitamin D levels. Most of the patients were deficient in vitamin D before HSCT (median 42 nmol/L). In multivariate analysis, vitamin D level before HSCT was identified as a significant independent risk factor for development of cGvHD. The increased incidence of cGvHD was not coupled to better disease-free survival; instead there was a trend towards lower overall survival in the vitamin D-deficient patients. In addition, we found a significant correlation between vitamin D deficiency and incidence of CMV disease, with no case of CMV disease occurring in patients with sufficient levels of vitamin D before HSCT. Our results support a role of vitamin D in immune tolerance following HSCT. These findings could be highly relevant for the care of HSCT patients, and prospective, randomized studies on the effect of vitamin D supplementation are therefore needed.

[Practical guide to the examination and interpretation of genital lesions of minor female victims of sexual assault]. / Victimes féminines mineures d'agressions sexuelles : guide pratique pour l'examen et l'interprétation des lésions génitales.

Through a comprehensive review of the literature on sexual assault, the authors propose to clarify the different stages of the exam and help the practitioner to the forensic interpretation of lesions. The authors describe the basic principles that make consensus in how to interview victims in order to increase the reliability of the information collected. The various medical data that must be collected allowing to guide diagnosis (urogenital symptoms, sexual behaviour disorder) or facilitate the interpretation of lesions (age of puberty, use of tampons…) are specified as well as the different positions of examination and their association to other complementary techniques (Foley catheter, colposcopy, toluidine blue). The authors present a simple decision tree that can help the practitioner to interpret the laceration of the hymen. They detail the description and forensic interpretation of all genital lesions that may be encountered as a result of sexual assault, and the pitfalls to avoid. Finally, two main problems in the interpretation of lesions are described, the absence of injury after penetration and the accidental genital lesions.

The usefulness of post-mortem CT angiography in injuries caused by falling from considerable heights: three fatal cases.

OBJECTIVE: Post-mortem computed tomography is a diagnostic tool forming part of the arsenal available to forensic pathologists today. In addition to its usefulness in detecting bone lesions, which has long been recognized, this technique has nowadays been enhanced by the development of CT angiography. The role of multiphase post-mortem computed tomography angiography (multiphase PMCTA) is primordial, improving detection of solid organ lesions and permitting vascular lesions to be visualized directly. MATERIAL AND METHODS: Our paper presents a series of three deaths by falling from a considerable height recorded since the beginning of 2012. We report the usefulness of PMCTA and the various mechanisms involved in the trauma. RESULTS: Most of the lesions were diagnosed by both PMCTA and autopsy, including the rare lesions, but the peripheral bone lesions and the hemopneumatocele were diagnosed only by PMCTA, while dislocation of vertebrae and the testicular fractures were detected solely by autopsy. CONCLUSION: PMCTA is a new, minimally-invasive technique which, combined with autopsy, provides better visualization and detection of certain lesions, particularly in the case of death by falling from a great height.

The serine-threonine kinase p90RSK is a new target of enzastaurin in follicular lymphoma cells.

BACKGROUND AND PURPOSE: Follicular lymphoma is the second most common non-Hodgkin's lymphoma and, despite the introduction of rituximab for its treatment, this disease is still considered incurable. Besides genetic alterations involving Bcl-2, Bcl-6 or c-Myc, follicular lymphoma cells often display altered B-cell receptor signalling pathways including overactive PKC and PI3K/Akt systems. EXPERIMENTAL APPROACH: The effect of enzastaurin, an inhibitor of PKC, was evaluated both in vitro on follicular lymphoma cell lines and in vivo on a xenograft murine model. Using pharmacological inhibitors and siRNA transfection, we determined the different signalling pathways after enzastaurin treatment. KEY RESULTS: Enzastaurin inhibited the serine-threonine kinase p90RSK which has downstream effects on GSK3ß. Bad and p70S6K. These signalling proteins control follicular lymphoma cell survival and apoptosis; which accounted for the inhibition by enzastaurin of cell survival and its induction of apoptosis of follicular lymphoma cell lines in vitro. Importantly, these results were replicated in vivo where enzastaurin inhibited the growth of follicular lymphoma xenografts in mice. CONCLUSIONS AND IMPLICATIONS: The targeting of p90RSK by enzastaurin represents a new therapeutic option for the treatment of follicular lymphoma.

Migration of antimony from PET trays into food simulant and food: determination of Arrhenius parameters and comparison of predicted and measured migration data.

Migration experiments with small sheets cut out from ovenable PET trays were performed in two-sided contact with 3% acetic acid as food simulant at various temperatures. The fraction of diffusible antimony (Sb) was estimated to be 62% in the PET sample under study. Apparent diffusion coefficients of Sb in PET trays were determined experimentally. Measurement of migration between 20 and 150°C yielded a linear Arrhenius plot over a wide temperature range from which the activation energy (E(a)) of 188 ± 36 kJ mol(-1) and the pre-exponential factor (D(0)) of 3.6 × 10(14) cm(2) s(-1) were determined for diffusing Sb species. E (a) was similar to previously reported values for PET bottles obtained with a different experimental approach. E (a) and D (0) were applied as model parameters in migration modelling software for predicting the Sb transfer in real food. Ready meals intended for preparation in a baking oven were heated in the PET trays under study and the actual Sb migration into the food phase was measured by isotope dilution ICP-MS. It was shown that the predictive modelling reproduces correctly experimental data.

Occurrence of uranium in Swiss drinking water.

The results of a nationwide survey of uranium in Swiss drinking water are reported. Elevated concentrations of uranium in groundwater are found mainly in the alpine regions and can be traced back to the geology of the bedrock. Water sources were systematically surveyed and analysed for the presence of Li, B, Si, Sc, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Se, Sr, Cd, Sn, Sb, Ba, Tl, Pb and U and the results were analysed to determine if any correlation with uranium concentration was apparent. No correlation was found. The results are interpreted in relation to the current WHO guideline and those of other countries with a view to determining which areas would be affected if a maximum value were to be adopted and which areas require further investigation. Uranium content varied considerably, from below the limit of detection to almost 100 µg L(-1). Of the 5548 data samples, 98% are below the 2004 WHO provisional guideline value of 15 µg L(-1) and 99.7% below the revised (2011) value of 30 µg L(-1).

[Interstitial lung disease due to domestic moulds]. / Pneumopathie interstitielle diffuse secondaire aux moisissures domestiques.

Identifying the role of fungi present in the domestic environment in the development of interstitial pneumonia can be a difficult clinical problem. We report a case of interstitial lung disease case occurring in a 53-year-old patient. He presented with profound hypoxemia (PaO(2) 54mmHg). Chest CT showed diffuse ground glass opacities. Initial blood tests for allergy and autoimmune disease were negative. Faced with a worsening of his clinical status after returning home he was hospitalized several times. At fibreoptic bronchoscopy, multiple white deposits were observed. Bronchoalveolar lavage with differential cell count was performed, revealing a 23% lymphocytosis. Serology for specific household molds showed moderate reaction to various molds found in homes, especially Stachybotrys chartarum. Pulmonary function tests revealed a moderate restrictive pattern with impaired diffusion of carbon monoxide and a bronchiolocentric interstitial pneumonia was found at lung biopsy. After a permanent move to a new residence, clinical parameters, radiological, biological and functional normalized. The final diagnosis was interstitial lung disease related to mycotoxins of S. Chartarum. The diagnosis of hypersensitivity pneumonitis to domestic mold or interstitial lung disease secondary to mycotoxins should be considered in patients presenting with interstitial pneumonia and requires specific investigations to ensure that an environmental cause with an allergic or toxic role is not missed.

Regression of new-onset diabetes mellitus after conversion from tacrolimus to cyclosporine in liver transplant patients: results of a pilot study.

INTRODUCTION: New-onset diabetes mellitus (NODM) has important implications for long-term outcome following liver transplantation. AIM: To evaluate the impact of conversion from tacrolimus to cyclosporine in liver transplant patients presenting NODM. METHOD: In a 12-month pilot study, 39 liver transplant patients with NODM were converted from tacrolimus to cyclosporine. Most patients (59%) were receiving antidiabetic therapy (18% insulin, 41% oral) and all patients had received dietary advice prior to the study. RESULTS: At month 12, NODM had significantly resolved (FBG<7 mmol/L without treatment) in 36% of patients (95% CI 20.8-51.0%). In the 16 patients not receiving antidiabetic drugs at baseline, mean FBG decreased from 8.1 mmol/L to 6.6 mmol/L (P=0.008) and mean HbA(1c) decreased from 6.4 to 6.0% (P=0.05). Steroids were stopped rapidly in the nine patients receiving steroids at inclusion but NODM resolution was observed in only one of these nine patients. No significant factors were identified that could have affected NODM resolution. There were three episodes of biopsy-proven acute rejection (7.7%), no graft losses and one death. Overall, cyclosporine tolerance was good with no significant change in creatinine clearance at month 12. Total cholesterol increased from 4.6 mmol/L to 5.1 mmol/L (P<0.001). CONCLUSIONS: These results suggest that liver transplant patients with NODM may benefit from conversion to cyclosporine from tacrolimus through improved glucose metabolism. Confirmation in a prospective, randomized comparative study is required.

[Pulmonary embolism diagnosed during an endobronchial ultrasound procedure]. / Embolie pulmonaire diagnostiquée au cours d'une échoendoscopie bronchique.

INTRODUCTION: Pulmonary embolism occurs frequently in lung cancer. The clinical features are non-specific and the diagnosis is often missed. CASE REPORT: A 60-year old man presented with a right upper lobe mass associated with right hilar adenopathy. Both had activity on positron emission tomography. As bronchoscopy was normal, an endobronchial, ultrasound guided, transbronchial needle aspiration (EBUS-TBNA) was performed to obtain a diagnosis. During the procedure, a hypoechogenic image was seen in the right pulmonary artery. A CT pulmonary angiogram confirmed the diagnosis of right pulmonary embolism. The transbronchial needle aspiration confirmed the neoplastic nature of the adenopathy. To our knowledge, this is the first description of a pulmonary embolism diagnosed by EBUS. This observation confirms the results of a recently published study showing that known pulmonary embolism can be detected by EBUS. CONCLUSION: Although EBUS is not the classic tool for the diagnosis of pulmonary embolism, it seems advisable to undertake a careful examination of the proximal pulmonary artery during an EBUS procedure.

Immune recovery after fludarabine-cyclophosphamide-rituximab treatment in B-chronic lymphocytic leukemia: implication for maintenance immunotherapy.

Thirty B-cell chronic lymphocytic leukemia patients were treated with fludarabine-cyclophosphamide-rituximab (FCR) and immune cell counts (natural killer (NK) cells, CD4, CD8, Tgammadelta and monocytes) were monitored from the end of treatment (EOT) up to 36 months (M36). Moreover, nonleukemic peripheral blood lymphocyte cytotoxicity (PBL/CTC) as well as rituximab (RTX)-dependent PBL/CTC was also measured at the initiation of therapy, EOT and M12. These parameters were correlated with post-FCR monitoring of the minimal residual disease (MRD) level in blood using a four-color flow cytometry technique. FCR induced a profound and sustained depletion of all T-cell populations, Tgammadelta being the most affected, whereas NK cells were relatively preserved. Both basal and interleukin-2-stimulated nonleukemic PBL/CTC against MEC-2, a CLL cell line, increased during the post-FCR period. There was no correlation between immune recovery parameters and MRD progression profile, except that patients with high post-FCR CD4(+) counts experienced rapid MRD progression. MRD at M12 predicts clinical relapse. The limited data show RTX-mediated LBL/CTC activity against autologous B-cell cells in individuals with <1% residual disease at M12, opening avenues for immunomodulation post-FCR with anti-CD20 antibodies. To conclude, our study suggests that MRD increase at M12 precedes disease evolution post-FCR, and should be assessed as a surrogate marker for proactive management of CLL relapse.

Begging calls support offspring individual identity and recognition by zebra finch parents.

In colonial birds, the recognition between parents and their offspring is essential to ensure the exclusivity of parental care. Although individual vocal recognition seems to be a key component of parent-chicks recognition, few studies assessed the period when the emergence of the vocal signature takes place. The present study investigated the acoustic cues of signaler identity carried in the begging calls at three stages of development in zebra finches (Taeniopygia guttata castanotis), a colonial species which experiences food-dependence after fledging. Testing parents with playback of begging calls recorded the day before fledging, we found that the offspring recognition was based on acoustic cues. Begging calls showed a highly individualized vocal signature well before fledging. The individual identity coding was multi-parametric and encoded in both spectral and temporal domains. These results suggest that the successful recognition process of offspring might be strongly dependent on the receiver's abilities to use multi-parametric acoustic cues. The precocity of the vocal signature in chicks could enable parents to familiarize with the call features of their offspring at the pre-fledging period through a learning process.

Prisoners and skin diseases in Toulouse, France: epidemiological analysis and evaluation of life impact.

BACKGROUND: Dermatology in a penitentiary environment is an under-researched field. OBJECTIVES: To study the prison population seeking medical advice for skin diseases and to assess among detainees the life impact of these diseases, an approach that to the best of our knowledge has not previously been reported. METHODS: This prospective study was carried out in the male population of two penal institutions in the region of Toulouse, south-western France. RESULTS: One hundred seventy-eight men were seen, for a total of 234 diagnoses and 281 consultations. The five most frequent diagnoses, in order of decreasing frequency, were disorders of the pilosebaceous follicle, fungal diseases, benign skin tumours, warts and eczemas, which are common skin diseases. However, 72% of inmates believed their skin disease was directly related to detention. This belief was related to the conditions of life in prison (seclusion and its effects) and to frequent psychological problems. CONCLUSIONS: The disorders observed were generally benign skin conditions that could be expected in a population of young men living in a closed community. They led to a high demand for care and treatment: skin diseases represented the largest specialist consultation in our institutions. Skin problems can easily be managed in an outpatient unit, which confirms the usefulness of a dedicated dermatology clinic within the outpatient consultation units of penal institutions in order to provide care of equivalent quality to that available in a free environment. The dermatologist can have an important role in the medical management and the health education of prisoners.

Exposure to antimony from polyethylene terephthalate (PET) trays used in ready-to-eat meals.

Antimony residues, a result of the use of a polycondensation catalyst in the production of polyethylene terephthalate (PET) oven-proof trays, were analysed in ready-to-eat meals. The toxicity of antimony has raised concerns about consumer safety; therefore, the migration of small fractions of these residues into ready meals and foods as a result of cooking directly in the PET trays was studied. A straightforward approach of measuring real samples was selected to obtain accurate exposure data. Background antimony concentration was determined separately from a series of lunch meals, which ranged from not detectable to 3.4 microg kg(-1). Microwave and conventional oven-cooking caused a distinct increase in the concentration of antimony in food and ready meals of 0-17 and 8-38 microg kg(-1), respectively, depending, to a certain extent, on the industrial preparations. The migrated quantities of antimony corresponded to 3-13 microg. For comparison, PET roasting bags and ready-made dough products in PET baking dishes were also evaluated. About half of the products prepared at a temperature of 180 degrees C exceeded the specific migration limit set for food contact material by the European Commission. However, the migrated amounts of antimony relative to the accepted tolerable daily intake (TDI) show that exposure from this type of food is currently not of toxicological concern.

New [99mTc]bombesin analogues with improved biodistribution for targeting gastrin releasing-peptide receptor-positive tumors.

AIM: Bombesin (BBS) receptors are potential targets for diagnosis and therapy of breast and prostate tumors. To overcome the rapid degradation of natural BBS some modifications were introduced at positions 13 and 14. Additionally, a spacer was inserted between the chelator and the binding sequence in order to further improve the in vivo uptake. The analogues were labeled with the [(99m)Tc(CO)(3)]-core and tested. METHODS: Stability was analyzed in vitro in human plasma. Binding affinity and internalization were determined in vitro in prostate carcinoma PC-3 cells. Biodistribution studies and single photon emission computed tomography/X-ray computed tomography (SPECT/CT) imaging were performed in nude mice with PC-3 tumor xenografts. RESULTS: The changes introduced in the BBS(7-14) sequence substantially increased plasma stability. Affinity for gastrin releasing-peptide (GRP) receptors on PC-3 cells was comparable to that of the unmodified analogue with Kd<1 nM. The presence of a spacer in the molecule induced an increment in the in vivo uptake in pancreas and PC-3 xenografts (GRP receptor-positive tissues). The increase in pancreas and tumor uptake was higher when both spacer and stabilization are present in the same molecule. Moreover, in vivo uptake was highly specific. The tumor was clearly visualized by SPECT/CT. CONCLUSIONS: The modifications in the BBS(7-14) sequence led to a higher plasma stability while binding affinity remained unaffected. Stabilization resulted in improved biodistribution with better tumor to non-tumor ratios. However, the insertion of a spacer had a greater influence on the biodistribution. Analogues with both spacer and stabilization are the most promising radiopharmaceuticals for targeting GRP receptor-positive tumors.

[Pleural effusion complicating a totally implanted venous device]. / Un épanchement pleural liquidien compliquant une chambre à cathéter implantable.

INTRODUCTION: Totally implanted venous devices (TIVD) are an essential tool for repeated intravenous treatments such as chemotherapy for cancer and antibiotics for cystic fibrosis. CASE REPORT: A woman of 76 years was treated for bronchiectasis, colonised by Pseudomonas aeruginosa, with courses of intravenous antibiotics. On account of poor peripheral veins a TIVD was implanted. The implantation and subsequent antibiotic injections were uncomplicated. Three years later a further course of antibiotics was prescribed. As no reflux of blood was obtained on puncturing the device the position of the catheter was checked radiologically. The patient complained of right shoulder pain following each infusion. The chest x-ray showed a pleural effusion. The sudden onset of the effusion, the absence of signs of infection and the patient's good clinical condition suggested pleural extravasation of the antibiotic infusion from the TIVD. Pleural aspiration yielded 1400 mls of watery fluid. Injection of contrast into the TIVD confirmed intra-pleural extravasation. CONCLUSION: When using a TIVD it is important to bear in mind the possibility of late pleural complications.