Letermovir in lung transplant recipients with cytomegalovirus infection: A retrospective observational study

Letermovir is a new antiviral drug approved for the prophylaxis of CMV infection in allogeneic stem cell transplants. The aim of the study was to assess the therapeutic efficacy of letermovir in difficult to treat CMV infections in lung transplant recipients. All lung transplant recipients between March 2018 and August 2020, who have been treated with letermovir for ganciclovir-resistant or refractory CMV infection were included in the study and analysed retrospectively. In total, 28 patients were identified. CMV disease was present in 15 patients (53.6%). In 23 patients (82.1%), rapid response was noticed, and CMV-viral load could be significantly decreased (>1 log₁₀) after a median of 17 [14–27] days and cleared subsequently in all of these patients. Five patients (17.9%) were classified as non-responder. Thereof, development of a mutation of the CMV UL56 terminase (UL-56-Gen: C325Y) conferring letermovir resistance could be observed in three patients (60%). Common side effects were mild and mostly of gastrointestinal nature. Mild adjustments of the immunosuppressive drugs were mandatory upon treatment initiation with letermovir. In addition to other interventions, letermovir was effective in difficult to treat CMV infections in lung transplant recipients. However, in patients with treatment failure mutation conferring letermovir, resistance should be taken into account.     

Inhibition of uptake1 by (+)-oxaprotiline reveals a differential central regulation of noradrenaline and adrenaline release

Summary Inhibition of uptake, in the central nervous system leads to a decrease of sympathetic outflow to many tissues; central a2-adrenoceptors are involved in this decrease. The aim of the present study was to compare the effects of the selective uptake, inhibitor (+)-oxaprotiline on the plasma kinetics of noradrenaline and adrenaline in anaesthetized and in conscious rabbits. [³H]Noradrenaline and [^3H]adrenaline were infused iv. The arterial plasma concentrations of endogenous and radiolabelled noradrenaline and adrenaline were measured, and the clearance from and spillover into the plasma of noradrenaline and adrenaline were calculated.Results obtained in conscious and anaesthetized rabbits were similar. (+)-Oxaprotiline 0.2, 0.6 and 1.8 mg kg^–1 iv. dose-dependently reduced the clearance of [³H]noradrenaline from the plasma. The clearance of [³H]adrenaline was reduced less. The spillover of endogenous noradrenaline was decreased by up to 35%. In contrast, the spillover of adrenaline tended to be enhanced. Prazosin 0.1 and 1 mg kg^–1 was injected iv. in a second part of each experiment. It lowered the blood pressure and caused a marked increase in noradrenaline spillover but no increase or even a decrease in adrenaline spillover.The results are compatible with the following hypothesis. The sympathetic outflow from the central nervous system is subject to a twofold a-adrenoceptor-mediated modulation: -adrenoceptor-mediated inhibition and ₁-adrenoceptor-mediated excitation. In the control of the sympathetic outflow to many extra-adrenal tissues, the ₂-adrenergic inhibition prevails. Uptake₁ inhibitors depress sympathetic outflow to such tissues by enhancing the ₂-adrenergic inhibition. In the regulation of the sympathetic outflow to the adrenal medulla, in contrast, ₂-adrenergic inhibition and ₁-adrenergic excitation have a similar impact. Uptake, inhibitors, hence, cause little change in adrenaline release: the two opposing influences cancel out. Prazosin produces an increase in noradrenaline but not adrenaline release because the loss of the central ₁ sympathoexcitation attenuates at best slightly the baroreflex to most extra-adrenal tissues but dampens markedly the baroreflex to the adrenal medulla. Correspondence to B. Szabo at the above address     

Continuous regional anaesthesia in infants

Physiological immaturity of the respiratory musculature and central respiratory control centres leads to an increased risk of apnoea and respiratory complications following general anaesthesia in neonates. Regional anaesthetic techniques may obviate the need for general anaesthesia and lessen the risks of perioperative morbidity. Although these techniques have been described in infants, previous reports have dealt with singleshot techniques for brief surgical procedures (< 60 min). Experience with prolonged operative cases using regional anaesthesia via indwelling catheters in infants is limited. We present our experience with four infants in whom either caudal epidural or spinal anaesthesia was administered via indwelling catheters for operative procedures that lasted 90 to 180 min. We believe this technique is an alternative to general anaesthesia in these patients. A cause de l’immaturité physiologique de sa musculature et de son centre respiratoires, le nouveau-né est plus sujet à l’apnée et aux complications après une anesthésie générale. L’anesthésie régionale peut remplacer en partie l’anesthésie générale et diminuer ainsi la morbidité périopératoire. Les techniques régionales sont bien décrites pour l’enfant mais elles sont utilisées en doses uniques pour des interventions brèves (< 60 min). L’expérience d’interventions sous régionale avec des cathéters en place est limitée. Nous présentons ici notre expérience avec quatre enfants auxquels on a administré une caudale ou une rachianesthésie continue pour des interventions de 90 à 180 min. Nous croyons que ces techniques sont des alternatives valables à l’anesthésie générale chez ces patients.     

Enolase 1 of Candida albicans binds human CD4+ T cells and modulates naïve and memory responses

To obtain a better understanding of the biology behind life-threatening fungal infections caused by Candida albicans, we recently conducted an in silico screening for fungal and host protein interaction partners. We report here that the extracellular domain of human CD4 binds to the moonlighting protein enolase 1 (Eno1) of C. albicans as predicted bioinformatically. By using different anti-CD4 monoclonal antibodies, we determined that C. albicans Eno1 (CaEno1) primarily binds to the extracellular domain 3 of CD4. Functionally, we observed that CaEno1 binding to CD4 activated lymphocyte-specific protein tyrosine kinase (LCK), which was also the case for anti-CD4 monoclonal antibodies tested in parallel. CaEno1 binding to naïve human CD4⁺ T cells skewed cytokine secretion toward a Th2 profile indicative of poor fungal control. Moreover, CaEno1 inhibited human memory CD4⁺ T-cell recall responses. Therapeutically, CD4⁺ T cells transduced with a p41/Crf1-specific T-cell receptor developed for adoptive T-cell therapy were not inhibited by CaEno1 in vitro. Together, the interaction of human CD4⁺ T cells with CaEno1 modulated host CD4⁺ T-cell responses in favor of the fungus. Thus, CaEno1 mediates not only immune evasion through its interference with complement regulators but also through the direct modulation of CD4⁺ T-cell responses.     

Pharmacokinetics of 4′-O-tetrahydropyranyladriamycin given on a weekly schedule in patients with advanced breast cancer

Improved quality of life has gained importance over shortly lasting remissions in yet incurable metastatic breast cancer. Fractionation of drug administration is one of the possible approaches to reduce the concentration-dependent toxicity of anthracyclines. We evaluated the pharmacokinetics of 4-O-tetrahydropyranyladriamycin (THP-ADM) under weekly administration in patients with advanced breast cancer (dose escalation, from 20 to 27 mg/m₂ THP-ADM). The concentration-time curves of THP-ADM in plasma were best described by an open three-compartment model [half-life of the first disposition phase (t_1/2), 3.15 min; terminal elimination half-life (t _1/2), 13.9 h] with a mean area under the curve (AUC) of 12.2 ng h ml^–1mg^–1m^–2, resulting in a mean plasma clearance of 86.91 h^–1m^–2. Metabolism included the formation of Adriamycin (ADM), Adriamycinol (ADM-OH), 13-dihydro-4-O-tetrahydropyranyladriamycin (THP-OH), 7-deoxyadriamycinone (7H-ADn), and 7-deoxy-13-dihydroadrimycinone (7H-ADn-OH), with maximal plasma concentrations ranging from 2.8 to 5.5 ng/ml. The mean total amount of cytotoxic anthracyclines excreted into urine, mainly as the parent drug, was 5% of the delivered dose. ADM and ADM-OH, but not the parent drug, were observed in urine at up to 4 weeks after the last therapeutic cycle. There was a significant correlation between the leukocyte nadir under therapy and the AUC of ADM-OH (r=0.800,P<0.05). Since no shift in the plasma kinetics was observed from the first to the sixth cycle, the favorable ratio of the AUCs of THP-ADM and ADM after fractionation of THP-ADM suggests lower toxic side effects attributable to ADM. This hypothesis was confirmed in a clinical study, where no severe cardiotoxicity and only mild alopecia were observed in 19 patients. Thus, pharmacokinetics studies might be helpful in both individualization of therapy with THP-ADM and optimization of the administration schedule.     

Analgesia after inguinal herniorrhaphy with laparoscopic inspection of the peritoneum in children. Caudal block versus ilioinguinal/iliohypogastric block

The authors prospectively evaluated the efficacy of caudal epidural block versus local infiltration combined with ilioinguinal/iliohypogastric block for analgesia after inguinal herniorrhaphy with laparoscopic inspection of the peritoneum. During standardized anesthetic care, 24 children were randomized to Group I (caudal epidural block with 1.2 mL/kg of 0.25% bupivacaine) or to Group II (local infiltration with an ilioinguinal/iliohypogastric block). Postoperative pain scores were significantly lower at all four evaluation points in Group I than in Group II. Patients in Group I had a significantly decreased requirement for supplemental intravenous fentanyl. Intra-operative requirements for isoflurane were decreased in Group I. The expired concentration of isoflurane was 0.4 +/- 0.1 (mean +/- SEM) in Group I and 1.5 +/- 0.3 in Group II. Time to extubation was 3.8 +/- 0.5 minutes in Group I and 8.2 +/- 1.1 minutes in Group II. The time from arrival in the postanesthesia care unit until discharge home was 113 +/- 3 minutes in Group I and 152 +/- 11 minutes in Group II. Caudal epidural block was more effective than local infiltration in controlling pain after herniorrhaphy with laparoscopy in children and resulted in earlier discharge home.     

The short-term effects of air pollution on mortality. The results of the EMECAM project in the city of Barcelona, 1991-1995. Estudio Multicéntrico Espa?ol sobre la Relación entre la Contaminación Atmosférica y la Mortalidad]

BACKGROUND: Most of the studies which demonstrate the existence of a short-term relationship between air pollution and morbidity and the Mortality analyze the impact of "classic" pollutants which are by-products of combustion. However, the changes in the sources of these emissions, shifting basically toward road traffic, has made a change in air pollution, heightening the importance of the photochemical components, such as ozone (O3) and nitrogen dioxide (NO2). Barcelona is a city located in a mild climate zone, and its air pollution comes mainly from vehicle emissions. The main objective of this article is that of analyzing the relationship between the photochemical pollutants, NO2 and O3 and the death rate for different causes in the city of Barcelona throughout the 1991-1995 period, using the procedure for analysis set out as part of the EMECAM Project. METHODS: Daily changes in the number of deaths resulting from all causes, of the number of deaths for all causes of those over age 70, of the number of deaths resulting from cardiovascular diseases, and of the number of deaths resulting from respiratory-related causes are related to the daily changes in the photochemical pollutants using autoregressive Poisson models, controlling confusion-causing variables such as the temperature, the relative humidity, the systematic time structure and the autoregressive structure. RESULTS: Except for the relationship between O3 and the mortality for causes involving respiratory diseases, the relationships between photochemical pollutants and the mortality for all the causes considered were statistically significant. The risks related to dying as a result of rises in O3 were greater than as a result of rises in NO2, almost triple among cardiovascular diseases. The risks related to dying for all the causes are lower than for specific causes and than for those individuals over age 70. The results of the analysis by six-month periods are quite similar to the overall results, revealing, in any event, relative risks somewhat greater during the warm months (May to October). CONCLUSIONS: Photochemical pollution, especially that which is caused by O3, comprises a health risk. In the case of NO2, this might not be more than an indicators of the suspended particles or of other pollutants stemming from city traffic. There may be a certain adjustment between six-month periods of the impact of O3 on the mortality for causes of the circulatory system.     

Prevalence and frequency of microembolic signals in 105 patients with extracranial carotid artery occlusive disease

Besides the established factors "presence of symptoms" and "degree of stenosis", plaque echolucency is considered to be associated with increased risk of stroke in patients with carotid artery disease. An evaluation was carried out as to whether the prevalence and number of microembolic signals (MES) detected by transcranial Doppler ultrasound were higher in patients with echolucent carotid plaques. One hundred and five patients with carotid artery stenosis from 20%-99% or occlusion underwent clinical investigations, duplex ultrasound of the carotid arteries, and a 1 hour recording from the middle cerebral artery downstream to the carotid artery pathology using the four gate technique. The presence of MES was more frequent and the number greater in symptomatic patients (21 out of 64 patients (33%); mean number of MES in all 64 patients 3.1) than in asymptomatic patients (four out of 41 patients (10%); mean number of MES in all 41 patients 0.3) (p=0.007, and p=0.006, respectively). Echogenicity of the lesions did not affect either number or presence of MES. Positivity for MES and the number of MES increased with increasing degree of stenosis (both p=0.002). Four out of 12 patients with carotid artery occlusion showed MES. No MES could be detected in carotid artery stenosis below 80%. There was a decline in positivity of MES and of the number of MES with the time after the ischaemic event. After 80 days or more after the index event, only one patient showed MES. In conclusion, increasing degree of stenosis and presence of symptoms similarly affect macroembolic and microembolic risk. Thus MES may be a surrogate parameter for risk of stroke. The presence of MES in a few asymptomatic patients suggests that clinically silent circulating microemboli may give additional information on the pending embolic potential of carotid artery stenoses. Echolucency of the plaque was not related to an increased number of MES.