Rationale of using the dual chemokine receptor CCR2/CCR5 inhibitor cenicriviroc for the treatment of COVID-19

Coronavirus Disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has created a global pandemic infecting over 230 million people and costing millions of lives. Therapies to attenuate severe disease are desperately needed. Cenicriviroc (CVC), a C-C chemokine receptor type 5 (CCR5) and C-C chemokine receptor type 2 (CCR2) antagonist, an agent previously studied in advanced clinical trials for patients with HIV or nonalcoholic steatohepatitis (NASH), may have the potential to reduce respiratory and cardiovascular organ failures related to COVID-19. Inhibiting the CCR2 and CCR5 pathways could attenuate or prevent inflammation or fibrosis in both early and late stages of the disease and improve outcomes of COVID-19. Clinical trials using CVC either in addition to standard of care (SoC; e.g., dexamethasone) or in combination with other investigational agents in patients with COVID-19 are currently ongoing. These trials intend to leverage the anti-inflammatory actions of CVC for ameliorating the clinical course of COVID-19 and prevent complications. This article reviews the literature surrounding the CCR2 and CCR5 pathways, their proposed role in COVID-19, and the potential role of CVC to improve outcomes.     

Prophylaxis and treatment of bacterial infections: do we need new strategies?

Bacterial infections in patients with hematologic malignancies still represent a severe and life-treating problem. Several observational studies during the last decade have revealed that neutropenic patients with fever are a heterogeneous population with various differences regarding response to initial therapy, development of serious complications and mortality. The role of neutropenia as main risk factor for infections in hematologic patients and the definition of different level of risk related to neutrophils count and duration of neutropenia have been extensively studied and different categories of patients based on the risk of infection, mostly the condition of neutropenia, have been clearly defined. The strategies on antimicrobial therapy and supportive care in hematologic patients need to be continuously assessed, in fact new conditions favouring the occurrence of infectious complications in patients with hematologic malignancies have progressively emerged. The use of oral prophylactic antibiotics in neutropenic cancer patients is still a matter of debate. Before 2005, several trials showed how the prevention of infection can be extremely important in this setting of patients but none was conclusive. In 2005 two meta-analysis and two large randomized clinical trials gave new evidence that antibacterial prophylaxis can reduce in neutropenic patients several important outcomes including mortality. The use of the empiric antibacterial therapy represents the cornerstone of the antimicrobial strategies in the febrile neutropenic patients leading, over the span of 20 years, to a dramatic decrease of deaths: Actually beta-lactam monotherapy is commonly used for the empiric treatment of febrile neutropenia. Recently, large randomized clinical trials and meta-analysis showed that the addition of an aminoglycoside and/or a glycopeptides results in a more favourable outcome only in selected severe infections. The use of antibiotics should be prudent and safe also in neutropenic hematologic patients to prevent emergence of microbial resistance, to save costs, to reduce toxicity. For this reasons, according to the evidence, antibacterial prophylaxis should be restricted to high risk hematologic patients and empiric parenteral antibiotic monotherapy should be recommended in case of febrile neutropenia limiting the use of amynoglicosides and glycopeptides. In the next future, a major effort should be made to state in hematologic patients new risk factors which could more accurately define subgroups for targeted anti-infective strategies.     

Central and peripheral venous lines-associated blood stream infections in the critically ill surgical patients

ABSTRACT: Critically ill surgical patients are always at increased risk of actual or potentially life-threatening health complications. Central/peripheral venous lines form a key part of their care. We review the current evidence on incidence of central and peripheral venous catheter-related bloodstream infections in critically ill surgical patients, and outline pathways for prevention and intervention. An extensive systematic electronic search was carried out on the relevant databases. Articles were considered suitable for inclusion if they investigated catheter colonisation and catheter-related bloodstream infection. Two independent reviewers were engaged in selecting appropriate articles in line with the above protocol. Our search protocol retrieved 8 articles published from 1999 to 2011. Outcomes on CVC colonisation and infections were investigated in six studies; four of which were prospective cohort studies, one prospective longitudinal study and one retrospective cohort study. Outcomes relating only to PICCs were reported in one prospective randomised trial. We identified only one study that compared CVC- and PICC-related complications in surgical intensive care units. Although our search protocol may not have yielded an exhaustive list we have identified a key deficiency in the literature, namely a paucity of studies investigating the incidence of CVC- and PICC-related bloodstream infection in exclusively critically ill surgical populations. In summary, the diverse definitions for the diagnosis of central and peripheral venous catheter-related bloodstream infections along with the vastly different sample size and extremely small PICC population size has, predictably, yielded inconsistent findings. Our current understanding is still limited; the studies we have identified do point us towards some tentative understanding that the CVC/PICC performance remains inconclusive.     

New medical approaches in pituitary adenomas

Recently, the medical approach to patients with secreting and clinically non-functioning pituitary adenomas has received great impulse thanks to the availability of new, selective and long-lasting compounds with dopaminergic activity, such as cabergoline, and of somatostatin analogues provided in slow-release formulations, such as lanreotide and octreotide long acting release (LAR). In particular, the use of cabergoline has induced control of hyperprolactinaemia and tumour shrinkage in the great majority of patients with micro- and macroprolactinomas. Cabergoline treatment restores fertility both in women and men, and partially improves osteoporosis, one of the major complications of hyperprolactinaemia. In acromegaly, disease control (growth hormone [GH] <2.5-1.0 microg/l as a fasting or glucose-suppressed value, respectively, together with age-normalised insulin-like growth factor [IGF]-I) is achievable in more than half of patients receiving treatment with lanreotide or octreotide-LAR. Improvement in cardiomyopathy, sleep apnoea and arthropathy has been reported during GH/IGF-I suppression after pharmacotherapy. A synthetic GH analogue, B2036-PEG, that antagonises endogenous GH binding to its receptor-binding sites and a GH-releasing hormone antagonist that blocks the effect of this releasing factor on the hypothalamus and pituitary are presently under investigation in acromegaly. Preliminary studies have clearly demonstrated the effectiveness of the GH receptor antagonist in suppressing IGF-I levels in acromegalic patients previously unresponsive to somatostatin analogues. Beneficial effects of subcutaneous octreotide and lanreotide have also been reported in adenomas secreting thyroid-stimulating hormone, while the results of treatment with dopamine agonists or somatostatin analogues remain disappointing in patients with clinically non-functioning adenomas. In these patients the possibility of visualising in vivo the expression of D(2) receptors using specific radiotracers such as (123)I-methoxybenzamide has allowed selection of patients likely to respond to cabergoline. Scant effects of pharmacotherapy have also been reported in patients with adenomas secreting adrenocorticotropic hormone. However, some preliminary data suggest a potential use of cabergoline in combination with ketoconazole, or alone, in selected cases of Cushing's disease or Nelson's syndrome.     

Cultivation of Marine Sponges

There is increasing interest in biotechnological production of marine sponge biomass owing to the discovery of many commercially important secondary metabolites in this group of animals. In this article, different approaches to producing sponge biomass are reviewed, and several factors that possibly influence culture success are evaluated. In situ sponge aquacultures, based on old methods for producing commercial bath sponges, are still the easiest and least expensive way to obtain sponge biomass in bulk. However, success of cultivation with this method strongly depends on the unpredictable and often suboptimal natural environment. Hence, a better-defined production system would be desirable. Some progress has been made with culturing sponges in semicontrolled systems, but these still use unfiltered natural seawater. Cultivation of sponges under completely controlled conditions has remained a problem. When designing an in vitro cultivation method, it is important to determine both qualitatively and quantitatively the nutritional demands of the species that is to be cultured. An adequate supply of food seems to be the key to successful sponge culture. Recently, some progress has been made with sponge cell cultures. The advantage of cell cultures is that they are completely controlled and can easily be manipulated for optimal production of the target metabolites. However, this technique is still in its infancy: a continuous cell line has yet to be established. Axenic cultures of sponge aggregates (primmorphs) may provide an alternative to cell culture. Some sponge metabolites are, in fact, produced by endosymbiotic bacteria or algae that live in the sponge tissue. Only a few of these endosymbionts have been cultivated so far. The biotechnology for the production of sponge metabolites needs further development. Research efforts should be continued to enable commercial exploitation of this valuable natural resource in the near future. Received November 5, 1998; accepted June 20, 1999.     

Factors affecting engraftment of allogeneic hematopoietic stem cells after reduced-intensity conditioning

Several factors influence the engraftment of allogeneic hematopoietic stem cells (HSC). Recently, there has been increased utilization of transplant-conditioning regimens that use reduced doses of chemotherapy and radiation that are considered to be non-myeloablative. These non-myeloablative (or reduced-intensity) allogeneic HSC transplants (RIST) decrease early post-transplant complications, but they are associated with higher incidences of mixed chimerism and graft rejection compared with transplantation after myeloablative condition-ing. RIST provides a unique opportunity to study allogeneic HSC engraftment. In particular, host immune status and stem cell graft composition have emerged as important factors affecting engraftment after RIST Based on these observations, it has been hypothesized that conditioning regimens and allograft composition can be tailored to an individual patients immune and disease status prior to transplant.     

脂肪因子Chemerin与妊娠相关疾病的关系展望

<正>1 Introduction Recurrent pregnant loss,gestational diabetes,premature delivery,intrauterine growth restriction,preeclampsia and other pregnancy-related complications have severe impact on the fetus development and the health and life quality of the mother.These diseases are also causes of unstability and huge economic burden for the family as well as the     

Two major metabolites of 8-prenylnaringenin are estrogenic in vitro

8-prenylnaringenin (8-PN) and preparations containing 8-prenylnaringenin have been suggested for use in medicinal and cosmetic applications like hormone replacement or bust enhancement. However, the safety of application is still under considerable debate. Recently it has been shown that human liver microsomes are converting 8-prenylnaringenin to 12 metabolites, with (E)-8-(4'-hydroxyisopentenyl)naringenin (8-PN-OH) and (E)-8-(4'-oxoisopentenyl)naringenin (8-PN=O) being among the most abundant. Applying two independent in vitro test systems we demonstrate that these two metabolites of 8-prenylnaringenin are estrogenic in vitro. These results represent an important piece of information towards the discussion of safety of use of preparations containing 8-prenylnaringenin.     

Do bacteria differentiate between degrees of nanoscale surface roughness?

Whereas the employment of nanotechnology in electronics and optics engineering is relatively well established, the use of nanostructured materials in medicine and biology is undoubtedly novel. Certain nanoscale surface phenomena are being exploited to promote or prevent the attachment of living cells. However, as yet, it has not been possible to develop methods that completely prevent cells from attaching to solid surfaces, since the mechanisms by which living cells interact with the nanoscale surface characteristics of these substrates are still poorly understood. Recently, novel and advanced surface characterisation techniques have been developed that allow the precise molecular and atomic scale characterisation of both living cells and the solid surfaces to which they attach. Given this additional capability, it may now be possible to define boundaries, or minimum dimensions, at which a surface feature can exert influence over an attaching living organism.This review explores the current research on the interaction of living cells with both native and nanostructured surfaces, and the role that these surface properties play in the different stages of cell attachment.     

Tunnelled central venous catheters yield a low incidence of septicaemia in interleukin-2-treated patients

 A retrospective study on the incidence of catheter-related complications and catheter indwelling time (t _CI) during treatment with continuous interleukin-2 (IL-2) infusion in patients with metastatic renal cell cancer, who were equipped with tunnelled central venous catheters (CVC). A group of 72 patients were treated with IL-2-based immunotherapy. Two induction treatment cycles of 35 days each were used. Treatment consisted of IL-2 as a continuous intravenous infusion (c.i.v.) with lymphokine-activated killer cells and interferon α intramuscularly. A tunnelled CVC was inserted at the start of treatment and was kept in place for the duration of the therapy or until the occurrence of complications. Out of 72 CVC, 30 (42%) functioned uneventfully for a median t _CI of 64 days. In another 12 clinically uncomplicated cases (16%), catheter tips were positive in routine culture after a median t _CI of 33 days. In 18 patients (25%), CVC-related infections were noted, including 8 (11%) local tunnel infections and 10 (14%) septic episodes. These complications occurred at a median t _CI of 28 and 20 days respectively. In 15 (83%) of these 18 catheter infections, Staphylococcus aureus was isolated, whereas in the remaining 3 (17%) Staphylococcus epidermidis was found. Subclavian vein thrombosis was noted in 12 (17%) CVC at a median t _CI of 31 days; 5 (36%) of these were diagnosed in the first 14 patients. This prompted us to administer prophylactic heparin 15 000 IU c.i.v. daily during IL-2 treatment. Thereafter the incidence of thrombosis dropped to 7 (12%) in the subsequent 58 CVC inserted (P = 0.03). In conclusion, in contrast to previous reports on the high incidence of CVC-related septicaemia and thrombosis, we observed a relatively low incidence of these complications, which we ascribe to the use of tunnelled catheters and prophylactic heparin. Received: 9. January 1997 / Accepted: 13. March 1997     

A regulatory view on adaptive/flexible clinical trial design

Recently there is growing interest in use of adaptive or flexible designs for development of pharmaceutical products. Statistical methodology has been greatly advanced in the literature. However, there are still some important issues with the methodology and application. In addition, there are many other challenges with these designs, including efficiency of these designs in the entire development program, trial conduct and logistics, the infrastructure of an adaptive trial, the regulatory evaluation of trial results and trial conduct, etc. Up till now, regulatory experience in these designs is very limited. We share some of the challenges.     

MDM2 inhibitors for cancer therapy

The tumor suppressor p53 is a powerful antitumoral molecule frequently inactivated by mutations or deletions in cancer. However, half of all human tumors express wild-type p53, and its activation by antagonizing its negative regulator murine double minute 2 (MDM2) might offer a new therapeutic strategy. Proof-of-concept experiments have demonstrated the feasibility of this approach in vitro but the development of pharmacological inhibitors has been challenging. Recently, potent and selective small-molecule MDM2 inhibitors have been identified. Studies with these compounds have strengthened the concept that selective, non-genotoxic p53 activation is a viable alternative to current cytotoxic chemotherapy but clinical validation is still pending. Here, the new developments in the quest for pharmacological p53 activators are reviewed with an emphasis on small-molecule inhibitors of the p53-MDM2 interaction.     

Biocompatibility of hydrogel-based scaffolds for tissue engineering applications

Recently, understanding of the extracellular matrix (ECM) has expanded rapidly due to the accessibility of cellular and molecular techniques and the growing potential and value for hydrogels in tissue engineering. The fabrication of hydrogel-based cellular scaffolds for the generation of bioengineered tissues has been based on knowledge of the composition and structure of ECM. Attempts at recreating ECM have used either naturally-derived ECM components or synthetic polymers with structural integrity derived from hydrogels. Due to their increasing use, their biocompatibility has been questioned since the use of these biomaterials needs to be effective and safe. It is not surprising then that the evaluation of biocompatibility of these types of biomaterials for regenerative and tissue engineering applications has been expanded from being primarily investigated in a laboratory setting to being applied in the multi-billion dollar medicinal industry. This review will aid in the improvement of design of non-invasive, smart hydrogels that can be utilized for tissue engineering and other biomedical applications. In this review, the biocompatibility of hydrogels and design criteria for fabricating effective scaffolds are examined. Examples of natural and synthetic hydrogels, their biocompatibility and use in tissue engineering are discussed. The merits and clinical complications of hydrogel scaffold use are also reviewed. The article concludes with a future outlook of the field of biocompatibility within the context of hydrogel-based scaffolds.     

Anesthetic implications of laparoscopic surgery

Minimally invasive therapy aims to minimize the trauma of any interventional process but still achieve a satisfactory therapeutic result. The development of "critical pathways," rapid mobilization and early feeding have contributed towards the goal of shorter hospital stay. This concept has been extended to include laparoscopic cholecystectomy and hernia repair. Reports have been published confirming the safety of same day discharge for the majority of patients. However, we would caution against overenthusiastic ambulatory laparoscopic cholecystectomy on the rational but unproven assumption that early discharge will lead to occasional delays in diagnosis and management of postoperative complications. Intraoperative complications of laparoscopic surgery are mostly due to traumatic injuries sustained during blind trocar insertion and physiologic changes associated with patient positioning and pneumoperitoneum creation. General anesthesia and controlled ventilation comprise the accepted anesthetic technique to reduce the increase in PaCO2. Investigators have recently documented the cardiorespiratory compromise associated with upper abdominal laparoscopic surgery, and particular emphasis is placed on careful perioperative monitoring of ASA III-IV patients during insufflation. Setting limits on the inflationary pressure is advised in these patients. Anesthesiologists must maintain a high index of suspicion for complications such as gas embolism, extraperitoneal insufflation and surgical emphysema, pneumothorax and pneumomediastinum. Postoperative nausea and vomiting are among the most common and distressing symptoms after laparoscopic surgery. A highly potent and selective 5-HT3 receptor antagonist, ondansetron, has proven to be an effective oral and IV prophylaxis against postoperative emesis in preliminary studies. Opioids remain an important component of the anesthesia technique, although the introduction of newer potent NSAIDs may diminish their use. A preoperative multimodal analgesic regimen involving skin infiltration with local anesthesia. NSAIDs to attenuate peripheral pain and opioids for central pain may reduce postoperative discomfort and expedite patient recovery/discharge. There is no conclusive evidence to demonstrate clinically significant effects of nitrous oxide on surgical conditions during laparoscopic cholecystectomy or on the incidence of postoperative emesis. Laparoscopic cholecystectomy has proven to be a major advance in the treatment of patients with symptomatic gallbladder disease.     

生长素与乙烯信号途径及其相互关系研究进展

长期的研究表明,生长素在调节植物生长发育的各种生理活动中起关键作用,但对它如何调控这些生理活动却缺乏系统和深入的了解。最近,细胞核内生长素信号途径的发现为揭示其作用机制带来了曙光。乙烯参与果实成熟及植物对逆境的反应等生理活动,其信号途径也已得到部分阐明。越来越多的证据表明,乙烯的作用与生长素对植物生长发育的调控之间有密切的联系。该文概述了生长素与乙烯信号途径的研究进展及其相互关系,讨论了生长素在植物三重反应中的作用;并对生长素与乙烯相互关系研究中存在的问题及研究前景进行了探讨。     

Advancement in high dose therapy and autologous stem cell rescue in lymphoma

Although advanced stage aggressive non-Hodgkin’s lymphomas and Hodgkin’s disease are thought to be chemotherapy-responsive cancers, a considerable number of patients either relapse or never attain a remission. High-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) is often the only possibility of cure for most of these patients. However, many controversial issues still remain with respect to HDT/ASCT for lymphomas, including its role for, the optimal timing of transplantation, the best conditioning regimen and the potential use of localized radiotherapy or immunologic methods to decrease post-transplant recurrence. Recently, mainly due to the unavailability of carmustine, several novel conditioning protocols have been clinically developed, with the aim of improving the overall outcome by enhancing the anti-lymphoma effect and, at the same time, by reducing short and long-term toxicity. Furthermore, the better safety profiles of novel approaches would definitively allow patients aged more than 65-70 years to benefit from this therapeutic option. In this review, we will briefly discuss the most relevant and recent data available regarding HDT/ASCT in lymphomas.     

Rehabilitación geriátrica multidisciplinar en el paciente con fractura de cadera y demencia

Hip fracture and dementia rates increase with age, and both groups of patients suffer increased morbidity and mortality and functional impairment. The management of these patients is a challenge for the orthogeriatric and rehabilitation team process, as despite the evidence on the benefit, the results analysed are still worse than in patients without cognitive impairment. For this reason, and due to the limitation in health resources, many of them have problems in accessibility to them, or are limited to a less intense rehabilitation. There are insufficient studies on the best rehabilitation interventions in this group of patients, but it is suggested: 1) to use a multidisciplinary rehabilitation model adapted to the patient with dementia, and 2) to redefine results of the rehabilitation of these patients not only in terms of functional improvement, without highlighting other concepts, such as quality of life, decrease in complications or improved social support.     

Candidiasis invasora en el paciente crítico quemado

BackgroundThe advances in burn care therapy have extended considerably the survival of seriously burned patients, exposing them to infectious complications, notably fungal infections. Due to the difficulty in the diagnosis of invasive mycoses and their high associated mortality rates, approaches to prophylactic or pre-emptive antifungal therapy in high-risk burned patients have been proposed, although these guidelines remain controversial. On the other hand, the management of these conditions is a serious problem, especially in critically ill patients with multiorgan failure, including severely ill burn patients due to the shortage of available antifungal agents. However, in the last several years, the range of antifungal agents has been significantly extended, which have led to an improvement in the treatment of invasive fungal infection in this population.Clinical caseWe report a case of invasive candidiasis in a severelly ill burns patient successfully treated with an echinocandin. In this case report, current treatment options are discussed, and a review of the literature of previously published cases is made.ConclusionsThere are still significant gaps in our knowledge of the optimal diagnostic and management approach for invasive candidiasis in burn patients. Prospective studies are needed in this population to optimise management and improve outcomes in this state of high morbidity and mortality.     

Relationship of obesity and specimen weight to complications in reduction mammaplasty

Obesity and specimen weight have both been associated with a higher incidence of complications for patients undergoing reduction mammaplasty. However, obesity has been arbitrarily and inconsistently defined, and the degree of obesity has not been considered in these previous studies. Because insurance companies are increasingly demanding weight loss before authorizing surgery, the relationship of obesity and breast size to complications is of great importance. Upon critical review of the literature, a number of fundamental questions remain unanswered. If complications are more frequent in the obese patient, are these complications directly proportional to the degree of obesity? Also, if the patient is required to lose weight before surgery, is weight loss effective in reducing complication rates? In an attempt to clarify these issues, 395 patients who underwent reduction mammaplasty over a 10-year period were reviewed retrospectively. Patients were arbitrarily divided into five groups in which, depending on their degree of relative obesity, they were classified as less than 5 percent, 5 to 10 percent, 10 to 15 percent, 15 to 20 percent, or greater than 20 percent above average body weight. To evaluate the relationship of specimen weight to complications, patients were also arbitrarily divided into five groups according to weight of the breast reduction specimen, which was classified as less than 300 g, 300 to 600 g, 600 to 900 g, 900 to 1200 g, and greater than 1200 g reduction per breast. Complications were then divided into local and systemic and major and minor. When bilateral reductions alone were analyzed (n = 267), there was a statistically significant increase in complication rate in the obese (p = 0.01). However, when the obese population was further subdivided according to their degree of obesity (less than 5 percent, 5 to 10 percent, 10 to 15 percent, 15 to 20 percent, and greater than 20 percent above average body weight), no further correlation was found. However, the relationship between specimen weight per breast and complications was much stronger with a direct correlation existing between increasing specimen weight and the incidence of complications. Although this study has shown that patients who are average body weight have fewer complications than obese patients after breast reduction surgery, it has not shown an increasing incidence of complication with increasing degrees of obesity. The implications of these findings and their relationship for denying patients surgery on the basis of weight alone are discussed in detail.