The magnitude of the COVID-19 pandemic is unprecedented, causing lots of apprehension among scientists, industry actors, politicians, and the general populace. Adverse health, social and economic effects of the pandemic have triggered an urgency among policy makers to seek an effective panacea. In this commentary, we examine the covert outbreak of a demand for alternative remedies with limited scientific evidence on their effectiveness to manage COVID-19 in Africa. Similar demands have been displayed in previous epidemics, though the ubiquity of social media in this current clime fuels such demands even more. We describe the attendant consequences of this demand surge on ongoing public health efforts to mitigate the spread of COVID-19 and highlight its future repercussions which may continue to plague health systems beyond the present outbreak. Going forward, governments must be proactive in surveillance of this covert epidemic, actively engage community influencers in knowledge transfer and implement targeted health promotion interventions. The unprecedented magnitude of the Coronavirus Disease (COVID-19) pandemic is significantly shifting the dynamics of the pharmaceutical industry, including the supply and demand for unorthodox remedies. The recent adverse health, social and economic effects of the ongoing pandemic have triggered a sense of urgency to seek an effective panacea by governments, with a ripple effect on health seeking behavior of the populace. Africa is the last continent to be affected by the outbreak. This gave ample time for the various governments, organizations like the African Union, and people to prepare ahead, learning from the experiences of other countries. Emergency operations centers were activated in various countries to coordinate response, laboratories were upgraded, public health communication strategies were designed, amongst other measures. But for a novel disease whose epidemiology and clinical characteristics are still being studied, no country can be prepared enough. Consequently, Africa has been battling to control the spread of the contagion since it arrived the continent early February 2020. However, another covert epidemic is brewing in Africa as a collateral effect of COVID-19, and the apprehension it has generated both within the leadership of African countries, and among its populace. This has to do with the abuse of untested ‘cures’, a ripple effect of the perceived confusion within the scientific community, and among political actors, as to which of the numerous proposed measures and therapies are truly effective. In this article, we examine the demand for alternative cures in Africa. We also warn about an imminent surge in abuse of presumed alternatives resulting from the ongoing political and social dynamics of the COVID-19 pandemic.Plurality of voices and alternatives from all and sundry: the pressure to mitigate the morbidity and mortality of COVID-19, with the need to restore socioeconomic normalcy, has led to increased political interference in medical processes. For example, Donald Trump´s political pressure on regulatory bodies to accelerate approval of hydroxychloroquine (HCQ) for the treatment of COVID-19 [COVID-19 . This urCOVID-19 . But theArtemisia annua by the Malagasy Institute of Applied Research [Recently, the president of Madagascar, Andry Rajoelina, announced a breakthrough herbal medicine for COVID-19 developed from the Research . COVID OResearch . In GhanResearch .Increasing demand for alternative remedies and its attendant consequences: in Africa, this increase in demand is not a new phenomenon. Previous epidemics triggered widespread demand for speculative therapies. During the 2014 West African Ebola virus disease (EVD) crisis, there was an ‘epidemic’ salt toxicity occasioned by rumors that ingesting or bathing with concentrated salt solutions could prevent or cure the disease. A recent survey of survivors of the outbreak revealed that over 70% resorted to self-medication, and almost half of them used TCMs for post-EVD care [EVD care . LikewisEVD care .Psychosocial untoward effects reported with the use of either tested or speculative preventive therapies include a false sense of immunity. The abuse of alcohol, cannabis sativa and other psychoactive substances believed to prevent or cure the contagion can further aggravate this ‘superhuman’ grandeur, leading to deliberate exposure or undermining of public health measures, such as social distancing and the use of facemasks . In addiGoing forward, governments must be proactive in surveillance for this covert epidemic, and other collateral effects of the pandemic. Regulatory systems must be enhanced to mitigate abuse of controlled substances. Further, clinical trials must be strongly encouraged for TCMs to provide evidence of safety and efficacy. Efforts must be intensified to bridge the gap between knowledge producers and consumers, particularly policy makers, community influencers, and the general populace. Such knowledge brokerage must be incorporated into awareness campaigns about COVID-19 through traditional public and social media platforms to dispel existing and emerging rumors. Targeted health promotion interventions that recognize the motivations of diverse sub-groups of the population to seek alternative cures will be critical in stemming the demand. This needs to be done while providing the best available evidence in a manner and language that the target populations understand and can relate with. Community and religious leaders must also be involved in this process, given their strong influence and the established relationship between TCM, culture and religion. These efforts will go a long way to mitigate unintended consequences of COVID-19 and accelerate the restoration of society to post-pandemic normalcy.


The human gut microbiome is a complex ecosystem that can mediate the interaction of the human host with their environment. The interaction between gut microbes and commonly used non-antibiotic drugs is complex and bidirectional: gut microbiome composition can be influenced by drugs, but, vice versa, the gut microbiome can also influence an individual’s response to a drug by enzymatically transforming the drug’s structure and altering its bioavailability, bioactivity or toxicity (pharmacomicrobiomics). The gut microbiome can also indirectly impact an individual’s response to immunotherapy in cancer treatment. In this review we discuss the bidirectional interactions between microbes and drugs, describe the changes in gut microbiota induced by commonly used non-antibiotic drugs, and their potential clinical consequences and summarise how the microbiome impacts drug effectiveness and its role in immunotherapy. Understanding how the microbiome metabolises drugs and reduces treatment efficacy will unlock the possibility of modulating the gut microbiome to improve treatment. There is a complex bidirectional interaction between commonly used non-antibiotic drugs and the gut microbiome.Commonly used drugs such as proton pump inhibitors, metformin, selective serotonin reuptake inhibitors and laxatives influence gut microbiome composition and function.Clostridium Difficile infections.Proton pump inhibitor-induced changes in the gut microbiome can lead to decreased colonisation resistance and the development of enteric infections, including Gut microbiome composition is associated with antitumour response and the clinical efficacy of treatment with immune checkpoint inhibition.Gut microbes can contribute to drug efficacy and safety by enzymatically transforming drug structure and altering drug bioavailability, bioactivity or toxicity.Insights into how the gut microbiome interacts with commonly used drugs enable interventions to modulate the gut microbiome and optimise treatment efficacy.In the past decade we have witnessed exciting discoveries linking the composition and function of the human gut microbiome to numerous common diseases and phenotypes. Association studies have documented changes in the abundance of various gut bacteria in individuals with gastrointestinal phenotypes, including inflammatory bowel disease, irritable bowel syndrome and colorectal cancer, and with diseases of other systems and organs, including cardiovascular and metabolic conditions, autoimmune conditions and psychiatric disorders.One very important recent finding is that many commonly used non-antibiotic drugs—such as proton pump inhibitors (PPIs) and metformin—change microbiome composition and function.Just a few decades ago our ability to analyse the role of the gut microbiome in relation to human health was mainly defined by large technical challenges. Historically, microbiome studies were performed using culturing methods in which one, or a few, bacterial species were isolated and studied in relation to a disease. This research produced numerous important findings, but our ability to analyse other components of the gut ecosystem was limited. The development of the technique to sequence the bacterial 16S ribosomal RNA gene allowed overall taxonomic assessment of the gut microbiome, and this has dramatically increased our knowledge of the broad variations in microbial composition. More recently, whole genome shotgun sequencing, or metagenomic sequencing (MGS), has become a powerful methodology for studying the microbiome. MGS allows identification of not only bacteria, but also viruses, protozoa and fungi, and it enables focussed analysis of bacterial genes and predicted biological pathways. However, as with all sequencing-based methods, MGS results are very dependent on the method used to isolate DNA from stool samples, and this is the major source of the technical variability in the results of microbiome studies.With the aid of next-generating sequencing, gut microbiome analysis has been applied to several human cohorts. One important finding is the large interindividual variability of the gut ecosystem: only a minority of gut microbes are shared across the majority of individuals. For example, in a European data set of 3000 samples, only 17 bacteria were identified as a core microbiome present in >95% of all samples.Human cohort-based analysis has further shown that the dynamic nature of the gut ecosystem reflects a complex interaction of the host with lifestyle, dietary, ecological and other factors. Hundreds of intrinsic and environmental factors influence the gut microbiome in healthy individuals, including diet, medication, smoking, lifestyle, host genetics and diseases.Several human cohort studies have reported associations between use of specific drugs and altered microbial composition and functional profiles  now use either pantoprazole or omeprazole by prescription, and similar usage percentages have been reported for other countries such as the UK.The large population-based study from the Netherlands showed that PPIs were the drugs most associated to a decreased diversity and taxonomical changes in the gut microbiome.Rothia dentocariosa and Rothia mucilaginosa, the genus Actinomyces and the family Micrococcaceae.Overall, the taxonomic changes in faecal samples of PPI users show a decrease in abundance of commensal bacteria of the intestine and an increase of bacteria from the oral cavity. These changes include an increase in the families Enterobacteriaceae, Enterococcaceae and Lactobacillaceae and a decrease in Ruminococcaceae and Bifidobacteriaceae, while the shift toward typical oral bacteria is reflected by increases in the species Bifidobacterium and Ruminococcus species, are predicted to contribute to these pathways, statistical analyses showed that only the changes in Streptococcus mutans contributed to the predicted pathway changes due to PPI use.A recent study that used metagenomic sequence data, allowing for both high resolution taxonomy and predicted pathway analysis, studied the effect of 41 commonly used drugs on the gut microbiome and again observed that PPIs accounted for the largest number of associations.Clostridium difficile, Campylobacter and Salmonella, which are similar to the ones now observed in PPI users.C. difficile and 2.0 to 4.0 for the other pathogenic bacteria.C. difficile infections develop in the altered gut microbial environment following the administration of antibiotics,It is important to recognise that PPI-induced changes in the microbiome might actually be contributing to clinically important diseases. For example, previous studies defined changes in the gut microbiome that lead to a decreased colonisation-resistance to enteric infections, including While the efficacy and safety profiles of PPIs are still very favourable when they are prescribed for evidence-based indications, the medical community should start to rethink their widespread and chronic use and their over-the-counter availability. We have come to the point where we need to carefully assess the long-term effects of PPI-induced changes in the microbiome in up to one-fifth of the population in western society, a shift that has taken place in a relative short period of time in human history, and specifically examine the effects of changing the developing gut microbiome in early life and its influence on health and disease in later life.Metformin is an oral blood glucose-lowering compound used in the treatment of type 2 diabetes (T2D). While its exact working mechanism is complex, and not fully understood, metformin does inhibit liver gluconeogenesis, and studies increasingly suggest that some of its beneficial effects are mediated by the gut microbiota.Escherichia coli and lowers Intestinibacter abundance, which is in line with findings from cross-sectional cohorts that compared untreated patients to metformin-treated patients with T2D.Akkermansia muciniphila, as well as through common biological pathways and genes encoded in different metformin-affected bacteria, for example, metalloproteins or metal transporters. Moreover, it is clinically well known that up to one-third of patients taking metformin report gastrointestinal side effects like diarrhoea, bloating and nausea, and the identified metformin-induced changes, including the increase of virulence factors and gas metabolism genes (mainly derived from an increase of E. coli species), can contribute to these side effects.In an additional intervention study in healthy volunteers, use of metformin resulted in a change in >80 species compared with a control group receiving placebo. Notably, metformin treatment significantly increase The intertwined relationship between metformin and the gut microbiome shows how a commonly used drug can change the gut microbiome and explain part of the drug’s therapeutic function, as well as some of its side effects. It also emphasises the need to rigorously control for confounders like drug use  when performing microbiome studies looking at specific diseases or conditions.Large population-based microbiome studies using cross-sectional data from cohorts from the UK, the Netherlands and Belgium have assessed hundreds of factors, including drug use. In addition to PPIs and metformin, these studies have shown that other commonly used drugs, including laxatives, statins, antidepressants and opioids, can explain some of the variability in gut microbiome composition.Bacteroides species are observed in individuals taking laxatives, but also in low consistency stool samples. However, in an independent study of mice exposed to polyethylene glycol (PEG) showed a similar increase in Bacteroides. In this study, the induction of mild osmotic diarrhoea by administration of PEG induced long-term changes in the gut microbiome, transient disruption of the mucus barrier and subsequent innate and adaptive immune responses.When considering microbial changes induced by the use of laxatives, one should take into account the fact that intestinal transit time, stool consistency and bacterial quantities  all influence microbiome features.Over the past few decades, pharmacogenomics has become a well-established field that studies how human genome variations affect drug disposition and action. With the increasing recognition of the gut microbiome as the second human genome, the concept of pharmacomicrobiomics has been introduced as a natural expansion of pharmacogenomics. While this field is attracting new attention, the idea that the gut microbiome can impact drug efficacy can be dated back to 1937 and the discovery of the impact of gut microbes on the activation of the antibacterial drug prontosil.In parallel with the gut-microbe associations observed in humans, several in vitro and animal studies have revealed the action modes of drug-microbe interactions and the potential consequences for drug efficacy and safety.Drug usage may influence gut microbial compositions in different ways, and at least two action modes have been proposed. The first mode is that drugs can result in the translocation of the microbiome from other body sites to the gut. As described above, PPIs can reduce the acidity barrier of the stomach, which allows oral microbes pass through the stomach to the gut, thereby inducing microbial dysbiosis. The second action mode, which might be the dominant one, is that drugs can change intestinal microenvironments and directly affect bacterial growth. For instance, metformin has been found to promote the growth of short-chain fatty acid producers in the gut, with these bacteria ultimately contributing to the therapeutic effect of metformin in improving insulin resistance and glucose homoeostasis. This second action mode can be bidirectional. Instead of promoting growth of certain bacteria, drugs can also inhibit the growth of specific bacteria, for example, showing antimicrobial activities as antibiotics. This was demonstrated by a landmark high-throughput studyet al determined that 70% of brivudine toxicity is attributable to gut microbes, particularly to Bacteroides thetaiotaomicron and Bacteroides ovatus.Bacteroides dorei (strain DSM17855) and Clostridium sp, which could metabolise 164 and 154 drugs, respectively.It has been shown that gut microbes can contribute to drug efficacy and safety by enzymatically transforming drug structure and altering drug bioavailability, bioactivity or toxicity. For instance, the oral antiviral drug brivudine can be metabolised to bromovinyluracil by both the host and the gut microbiota, with the latter exerting hepatic toxicity. By comparing the plasma and liver concentrations of brivudine and bromovinyluracil between conventional and germ-free mice, Zimmermann All in all, the results of these two independent studies, one assessing the antimicrobial effect of drugsEnterococcus faecalis.E. faecalis can block this bacterial L-dopa-to-dopamine metabolism, thereby improving drug efficacy. In addition to Enterococcus species, tyrDCs are also present in Lactobacillus species, although Enterococcus and Lactobacillus species show considerable differences in the efficiency of their L-dopa metabolism.Eggerthella lenta and 10 other bacterial species were found to contain the dopamine-dehydroxylating enzyme, which can further convert bacterial-derived dopamine to m-tyramine and thereby induce hypertensive crisis.Levodopa, used for the treatment of Parkinson disease, is an intriguing example of microbial impact on drug efficacy. After oral administration, levodopa needs to be absorbed via the small intestine so it can cross the blood-brain barrier and enter the brain, where the human enzyme aromatic amino acid decarboxylase converts levodopa to the therapeutically active dopamine. The bioavailability of levodopa to the brain is a key factor for drug efficacy, and levodopa is often co-administered with catechol metabolism inhibitors, for example, carbidopa and entacapone, to inhibit its off-site metabolism. In recent years, research has shown that the microbial decarboxylases that are part of gut microbial organisms appear to be able to metabolise levodopa. Novel bacterial L-dopa metabolism by tyrosine decarboxylases (tyrDCs) has been identified, dominantly driven by E. faecalis, for instance, metabolises both levodopa and entacapone at an efficiency of 98.9%.Ruminococcus torques, which in turn metabolises entacapone at 84% efficiency.Interestingly, in vitro, there is also a direct metabolising effect of bacteria on the catechol metabolism inhibitors carbidopa and entacapone that are often co-administered with levodopa. Numerous microbes can metabolise entacapone. We have described how commonly used non-antibiotic drugs can influence the gut microbiome composition and how the gut microbiome composition can influence drug availability and efficacy. In addition, there is also increasing evidence that the gut microbiome is involved in modulating the clinical response to cancer therapy. This occurs specifically in the setting of treatment with immunotherapy using monoclonal antibodies that target programmed cell death protein 1 (PD-1) and its ligand (PD-L1) or the cytotoxic T lymphocyte antigen 4 (CTLA-4).B. fragilis, combined with Burkholderia cepacia or B. thetaiotaomicron, which induced a Th1-mediated immune response and maturation of intratumorous dendritic cells. This, in turn, yielded improved antitumour reactivity to anti-CTLA-4 therapy. In the following phase, the authors transferred faecal material of patients with high levels of B. fragilis into mice, and this indeed resulted in improved antitumour response to anti-CTLA-4 therapy.The first breakthrough studies that provided compelling evidence that the gut microbiome influences tumour response were conducted in mice, and these findings were later substantiated in human clinical and microbiome data. It was observed that the efficacy of anti-CTLA-4 therapy was reduced in germ-free mice and in specific pathogen-free mice that were treated upfront with antibiotics.Bifidobacterium species in mice resulted in better efficacy of PD-L1 blockade.Bifidobacterium-containing probiotics, again through maturation of dendritic cells and increased T-cell reactivity. A more recent study showed similar beneficial results after supplementation with A. muciniphila.At the same time, similar results were published in the setting of another anticancer drug that induces PD-L1 blockade. In this case a higher relative abundance of Bifidobacterium longum, Enterococcus faecium and B. thetaiotaomicron, which were positively correlated with response to checkpoint inhibitors, and E. coli, which was negatively correlated.A series of subsequent papers have reported the baseline gut microbial composition and specific taxa associated to response or non-response to checkpoint inhibitors. These included, among many others, The precise mechanisms by which the gut microbiome influences immunotherapy response still have to be elucidated. It is thought that the microbiome is partially responsible for general peripheral immune homoeostasis and that microbial antigens induce exaggerated T-cell reactivity, which can support tumour-specific responses. In mouse models it has been shown that both innate and adaptive immune cells exposed to specific gut microbes can infiltrate the tumour microenvironment and produce chemotactic factors like CXCL9, CXCR3, CCR9 and CXCL10, which induce trafficking of immune cells to the tumour site.The finding that the gut microbiome influences clinical responses implies that modulating the gut microbiome could potentially improve, or worsen, survival after treatment with checkpoint inhibitors. Intriguingly, both the use of antibiotics and of PPIs has been associated with shorter survival and disease-free survival after treatment with immune checkpoint inhibitors.Recognition that the microbiome plays a role in antitumour efficacy is a major scientific breakthrough that has changed our thinking on how to predict and improve cancer immunotherapy. Understanding the underlying mechanisms will be crucial, and results of interventional trials will aid in optimising immunotherapy treatment.We have described the complex bidirectional interaction between commonly used non-antibiotic drugs and the gut microbiome and described different examples to highlight specific mechanisms. Clinicians need to be aware that it is not only antibiotics that influence the gut microbiome, non-antibiotic drugs can also change the gut microbiome and ultimately lead to impaired health outcomes. At the same time, the pharmacomicrobiomics field is emerging, and a deeper understanding of how the microbiome metabolises drugs or ameliorates the efficacy of, for example, anticancer treatment, will open up the possibility of modulating the gut microbiome to improve treatment efficacy. Clinical trials are already underway, and their results will influence clinical practice in the foreseeable future.


The main challenges in drug delivery systems are to protect, transport and release biologically active compounds at the right time in a safe and reproducible manner, usually at a specific target site. In the past, drug nano-carriers have contributed to the development of precision medicine and to a lesser extent have focused on its inroads in agriculture. The concept of engineered nano-carriers may be a promising route to address confounding challenges in agriculture that could perhaps lead to an increase in crop production while reducing the environmental impact associated with crop protection and food production. The main objective of this review is to contrast the advantages and disadvantages of different types of nanoparticles and nano-carriers currently used in the biomedical field along with their fabrication methods to discuss the potential use of these technologies at a larger scale in agriculture. Here we explain what is the problem that nano-delivery systems intent to solve as a technological platform and describe the benefits this technology has brought to medicine. Also here we highlight the potential drawbacks that this technology may face during its translation to agricultural applications, based on the lessons learned so far from its use for biomedical purposes. We discuss not only the characteristics of an ideal nano-delivery system, but also the potential constraints regarding the fabrication including technical, environmental, and legal aspects. A key motivation is to evaluate the potential use of these systems in agriculture, especially in the area of plant breeding, growth promotion, disease control, and post-harvest quality control. Further, we highlight the importance of a rational design of nano-carriers and identify current research gaps to enable scale-up relevant to applications in the treatment of plant diseases, controlled release of fertilizers, and plant breeding. The potency and efficacy of an exogenously administrated bioactive molecule heavily depend on the extent of its prolonged availability in the intended final site of action. In turn, its availability depends on the intrinsic factors related to the nature of the molecule itself, such as its solubility  enters the target cell at a proper time. The challenge of drug delivery is to accomplish the release of the drug agents at the right time in a safe and reproducible manner, usually to a specific target site.Drug delivery systems are engineered devices used to transport a pharmaceutical compound throughout the body in order to release its therapeutic cargo in a controlled manner NIH, . By encain vitro such as engineered antibodies, growth factors , time-controlled release, and less eco-toxicity is not only an expanding area of research but a potential growth market  water decontamination through adsorption of radioactive pollutants   are spheSLN have been successfully implemented in a wide range of applications. In the biomedical field, for instance, it has been used to increase both the solubility of several poorly soluble drugs,  is an example of a repurposed drug with poor aqueous solubility which requires a sophisticated delivery system such as nano-encapsulation for topical application as a promising, safe and complementary alternative to the treatment of cutaneous candidiasis  communication and curli-related gene expression  vector assisted by ultrasound has been used for DNA delivery. Amani et al.  demonstrDendrimers are also useful for agricultural purposes. They may improve the delivery of agrochemicals intended to either promote growth or discourage diseases. For instance, in 2016, a crop protection company (Adama) licensed Starpharma's (ASX:SPL) Priostar dendrimer technology for the development of an enhanced 2,4-D herbicide for the US market. According to the manufacturer, some of the potential benefits from the use of dendrimer technology in crop protection include improved efficacy, more concentrated formulations to reduce transport costs, reduction in solvent requirements and increased adhesion. Stapharma's lysine dendrimer based Vivagel® managed to achieve clinical approval . Thus, drug nanocrystals possess the merits of improving the oral bioavailability of water-insoluble compounds, reducing administered dose, avoiding abnormal absorption thus minimizing utilization of large excipients, increasing dissolution velocity, increasing adhesiveness to surface cell membranes, and increasing particle stability . The details on the roles of ssCO2 as solvent, co-solvent and as an additive for the production of drug nanocrystals are comprehensively reviewed elsewhere  or physical crosslinks, such as entanglements or crystallites, are responsible for their characteristic conformational structure and size  may improve the way we grow crops. Nano-delivery systems enable the controlled release of agrochemicals  and target-specific delivery of biomolecules  Reg. No. 67760-104-53883) with 5.9% γ-cyhalothrin; and an EPA registered capsule suspension insecticide with 22.8% λ-cyhalothrin  are two examples of nano-pesticides currently available in the market under this reformulation scheme  anchoring using zinc, calcium phosphate, silica, gold, magnetite, strontium phosphate, magnesium phosphate, and manganese phosphate  reaches the targeted site due to leaching of chemicals, drift, runoff, evaporation, hydrolysis by soil moisture, and photolytic and microbial degradation losses. Thus, nano-delivery systems for controlled release emerge as a highly valuable technology with the potential to strengthen the responsive capabilities of a sustainable food chain supply.The application of nanotechnology for fertilizer delivery is encouraging. Patent applications related to nano-fertilizers are growing consistently according to the world intellectual property organization database. a 10% increment in patent filings related to nano-fertilizers from China, in a period of fewer than 3 years (01/2014–11/2016). This is consistent with data reported by Mastronardi et al.  who note2-NPs were shown to increase the activity of several enzymes and promote the adsorption of nitrate, which accelerated the transformation of inorganic nitrogen into organic nitrogen  Nanoscale fertilizer inputs, which describe examples of nano-sized reformulation of fertilizer input in such a way that the size of the fertilizer or supplement is reduced down to the nano-scale. (2) Nanoscale additives, which include the additives presented as nanoparticles and added to bull materials. And 3, nanoscale coatings or host materials for fertilizers, which include nano-thin films or nanoporous materials used to encapsulate fertilizers for the controlled release of nutrients in crops  each year, but only 0.1% of this reach its desired target to effectively eliminate pests . Given the lack of experimental standardization and the divergent responses, even within similar plant species, it is challenging to foresee the challenges on the use of ENMs in plants (Zuverza-Mena et al., The initial framework and idea were conceptualized by PV-V and JI. All authors contributed toward the writing of this article.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The clinical diagnosis of Kyrle's disease may sometimes be challenging, due to the clinical similarity of lesions to other pruritic dermatosis. Although the dermoscopy is being increasingly used in daily practice, there is insufficient data in literature describing the dermoscopic patterns of Kyrle's disease, since only one report has been published to date. Herein we report our dermoscopic observation with additional diagnostic tips in a case who was diagnosed with Kyrle's disease histopathologically. The clinical diagnosis of Kyrle's disease may sometimes be challenging, due to the clinical similarity of lesions to other pruritic dermatosis. With the increasing use of dermoscopy in daily practice, some dermoscopic patterns are useful for the recognition of this spectrum of skin disorders in recent publications.A 61-year-old women presented with a 1 month history of pruritic lesions over the whole body. Her past medical history included type 2 diabetes mellitus and end stage renal disease on peritoneal dialysis. Physical examination revealed multiple, erythematous, excoriated umbilicated papules with central adherent keratotic plugs . LaboratKyrle's disease is one of the rare variants of primary perforating disorders, characterized by transepidermal elimination of abnormal endogenous materials. The disease affects more commonly 30–50-year-old females, presents with pruritic hyperkeratotic and ulcerated nodules, and papules with a central keratotic plug mostly located on extensor surface of upper and lower limbs, and on the trunk. Although the exact pathogenesis remains unknown, its association has been reported sparsely with renal disorders, uremic patients on dialysis, diabetes mellitus, liver disease and paraneoplastic syndromes, tuberculosis and some fungal diseases.Over the last few years, dermoscopy has been shown to facilitate the clinical recognition of several dermatological disorders, thus reducing the number of biopsies. Recently, Russo et al. reported the dermoscopic findings of Kyrle's disease describing a 3-zonal concentric pattern, characterized by bright whitish-brownish scales in the center, a structureless whitish-gray area surrounding the central crusts, and a peripheral, brown, delicate pigmentation.In conclusion, we report an additional case of Kyrle's disease with its detailed dermoscopic features showing a strong correlation with the histological aspect of the disease. Although histopathology is still the gold standard exam for this dermatosis, the familiarity with the dermoscopic findings of perforating diseases should be increased with such reports to get more reliable clinical interpretation.None declared.Ozlem Ozbagcivan: Approval of the final version of the manuscript; elaboration and writing of the manuscript; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.Banu Lebe: Approval of the final version of the manuscript; obtaining, analysis, and interpretation of the data; critical review of the manuscript.Emel Fetil: Approval of the final version of the manuscript; critical review of the manuscript.None declared.


Malunions of the upper extremity can result in severe functional problems and increase the risk of osteoarthritis. The surgical reconstruction of complex malunions can be technically challenging. Recent advances in computer-assisted orthopedic surgery provide an innovative solution for complex three-dimensional (3-D) reconstructions. This study aims to evaluate the clinical applicability of 3-D computer-assisted planning and surgery for upper extremity malunions. Hence, we provide a summary of evidence on this topic and highlight recent advances in this field. Further, we provide a practical implementation of this therapeutic approach based on three cases of malunited forearm fractures treated with corrective osteotomy using preoperative three-dimensional simulation and patient-specific surgical guides. All three cases, one female (56 years old) and two males (18 and 26 years old), had painful restrictions in range of motion (ROM) due to forearm malunions and took part in clinical and radiologic assessments. Postoperative evaluation of patient outcomes showed a substantial increase in range of motion, reduction of preoperatively reported pain, and an overall improvement of patients' satisfaction. The therapeutic approach used in these cases resulted in an excellent anatomical and functional reconstruction and was assessed as precise, safe, and reliable. Based on current evidence and our results, the 3-D preoperative planning technique could be the new gold standard in the treatment of complex upper extremity malunions in the future. The forearm is a complex anatomical and functional unit, including the radius, the ulna, the interosseous membrane (IOM), the triangular fibrocartilage complex (TFCC), the proximal (PRUJ) and the distal (DRUJ) radioulnar joint. Forearm malunions represent a disruption of this functional system, which could lead to limited forearm range of motion, loss of power, visible cosmetic changes, painful forearm rotations due to bony impingement of the IOM, and instability of the DRUJ , 2. FurtHere, we provide evidence from recent advances and present three cases of forearm malunions treated with corrective osteotomy using preoperative three-dimensional planning and patient-specific surgical guides to evaluate the outcomes of this innovative technique and close the present evidence gap.n = 6), postoperative screw loosening (n = 2), a persistent distal radioulnar subluxation (n = 2), and partial laceration of the extensor pollicis longus tendon (n = 1). The authors argued that especially corrective osteotomies of distal radius malunions tend to show higher percentages of complications compared to less complex elective wrist surgery . Based on patients' CT data, three-dimensional bone models were created to assess the deformity and plan the corrective osteotomy. Malunions of the affected bones were further evaluated with the contralateral non-affected bone as a mirrored and precisely aligned ideal template for the correction. The planning of the corrective osteotomy was conducted with a clinical engineer to superimpose the contralateral template and simulate the corrective osteotomy. For both bones, ulna and radius, a closing osteotomy after removing a wedge of bone and consecutive plate fixation was simulated. According to the simulation, we determined the plate bending angle for the radius and the ulna, to fixate the fragments in the desired position, appropriately. One patient-specific drilling guide and one patient-specific combined drilling and cutting guide were designed for radius and ulna, respectively, to reproduce the simulation to the surgery. Guides' cutting slots were designed to orient the saw blade, and guiding holes served to orient K-wires as a reference during fragment reduction. Furthermore, drilling holes helped predrilling screw holes as an additional reference during fragment reduction and plate fixation. Fixation was performed with screws on each side of the osteotomy line. Follow-up of up to 9 months revealed a significant improvement of range of motion, which reached the level of the non-affected side in the first 2 months. The patients reported a significant improvement in pain and satisfaction compared to the preoperative situation. Fist closure and finger spreading were possible without restriction. No sensorimotor deficits were observed in clinical examination.All three cases, one female (56 years old) and two males (18 and 26 years old), had painful restrictions in range of motion (ROM) due to forearm malunions and took part in clinical and radiologic assessments . Based oIn the three presented cases, three-dimensional corrective osteotomy of forearm malunions resulted in excellent results. There is currently limited evidence from studies comparing three-dimensional surgical planning techniques with conventional planning methods with regards to forearm malunions to the best of our knowledge. One important reason is that three-dimensional planning techniques are often used for more complex cases, therefore making it difficult to compare cohorts . VroemenPatient-specific guides based on preoperative three-dimensional techniques have been reported to be accurate and easier to handle, and integration into the surgical workflow is simple to implement with structured training and the help of clinical engineers , 31. AnoThree-dimensional corrective osteotomy based on preoperative computerized planning and patient-specific surgical guides resulted in excellent results in this case series. The promising evidence from the current literature and our case series suggest that preoperative computer-assisted three-dimensional planning techniques for corrective osteotomies of complex upper extremity malunion could be the new gold standard in the future.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.The studies involving human participants were reviewed and approved by Local institutional review board at the University Medical Center Freiburg, Freiburg, Germany. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.BS and GL did the literature search and wrote the first draft of the manuscript. JZ performed the surgery of the three cases, designed the study, proofread the manuscript, and made corrections. RS and AV did the literature search, proofread the manuscript, designed figures, and edited the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Opioids are the main group of pharmacological agents used during the perioperative period and provide a sedative and analgesic component. The observations of opioid consumption in West Europe indicate that this group of drugs is widely used in chronic noncancer pain therapy.Nearly 20 years ago, the first publications indicating that opioids, as an element of perioperative pharmacotherapy in oncologic patients, increase the risk of tumor recurrence and affect further prognosis were presented. The actual publications suggest that there are multifactorial, complex mechanisms underlying the immunological impact and carcinogenesis promotion of opioids and that the intensity varies depending on the type of opioid. There are also questions about the immunosuppressive effects among patients receiving opioids in the treatment of chronic noncancer pain.The aim of the review article is to present information about the action of opioids on the immune system in carcinogenic settings and to define the clinical usefulness of this pharmacological phenomenon. Opioids are the main group of pharmacological agents used during general anesthesia and provide a sedative and analgesic component. In addition to these two effects, it should also be emphasized that these substances cause an immunosuppressive effect and exacerbate this effect in the perioperative period. Opioid-induced immunosuppression, especially in oncologic patients, is a hot topic of current perioperative pharmacology research. This is a new trend in complex oncologic treatment: not only does the surgical resection of the lesion begin the therapeutic process, but the whole perioperative period, including the pharmacological aspects of the method of anesthesia and postoperative analgesia, is of great importance ,2.Nearly 20 years ago, the first publications indicating that opioids affect prognosis in oncologic therapy were presented. Many authors demonstrated a reduced risk of tumor recurrence connected with the use of regional anesthetic techniques and limitation of opioid use in the perioperative period. It has also been suggested that the intensity of these effects varies depending on the type of opioid. This is particularly important in cancer-related pain and in the perioperative period, especially in patients with early-stage cancer. The observations of opioid consumption in West Europe indicate that this group of drugs is widely used in chronic noncancer pain therapy. There are also questions about the effects of the immunosuppressive mechanisms among patients receiving opioids in the treatment of chronic noncancer pain. The influence of opioids on the immune system and carcinogenesis has not been fully explained. In view of the increasing use of opioid drugs and their important place in multimodal oncologic therapy, the connection of opioids with the immune system and cancer has a crucial role ,4.It has also been suggested that the intensity of immunosuppressive effects varies depending on the type of opioid. It was also described that in many tumor tissues, increased expression of opioid receptors was observed, and their accumulation was also associated with an increased risk of cancer progression with metastasis. The presented reports are a very important element of multidirectional cancer therapy. With respect to such publications, the question should be asked as to whether to limit the use of opioid drugs in oncologic patients -5.The aim is to present information about the mechanisms underlying the influence of opioid drugs on the immune system in a cancer setting and determine the clinical usefulness of this phenomenon in multimodal oncologic treatment.The first publications regarding the location of opioid receptors and the endogenous opioid peptide system in the 1970s and 1980s indicated that these substances were associated with the nervous system. However, subsequent experimental studies have indicated that the opioid receptor system is widely distributed in both peripheral and central nervous system structures, in structures of ascending  and descending pain transmission pathways, in organs of the autonomic nervous system and in the immune system. Recent publications indicate that opioid receptors are also found in tissues involved in the inflammatory process as well as in cancerous tissues ,6.Opioid receptors are classified into the following groups: the classic naloxone-sensitive receptors, mi opioid receptor (MOR), delta opioid receptor (DOR), and kappa opioid receptor (KOR), and nonclassic naloxone-insensitive receptors (NORs). Receptor-specific interactions induce analgesic effects; however, many authors have emphasized that only MORs are associated with the effects leading to respiratory depressive, tolerance-inducing and immunosuppressive effects -10.The effects of immunomodulation have been related to interactions with MORs and NORs. The functions and significance of MORs have been well understood and described. The most important aspect related to NOR activation is analgesic effects at the spinal cord level, and unlike other opioid receptors, NORs do not contribute to the development of respiratory depression and have minimal risk of tolerance or addiction -14.In terms of elements of innate immunity, the activation of opioid receptors results in a decrease in the number of macrophages, reduced leukocyte migration to inflammatory sites, decreased phagocytotic activity of macrophages, decreased chemotaxis and superoxide production by neutrophils and macrophages, accelerated apoptosis of macrophages, weakened microbiological protection, and reduced adhesion of leukocytes and endothelial cells. Other negative effects have also been described in relation to mast cells, dendritic cells, and natural killer (NK) cells. Opioids impair intestinal barrier function and promote systemic infections by increasing the sensitivity of gut epithelial cells to Toll-like receptor activation with bacterial translocation. In addition, opioid treatment changes the gut microbial composition and induces the expansion of gram-positive pathogens. These mechanisms promote the translocation of harmful pathogens and result in the risk of systemic infection -8,12. ReOther publications have also confirmed the multidirectional role opioids play in carcinogenesis by regulating the transcription of tumor growth factors and promoting capillary formation and neovascularization of cancerous tissue. It has been shown that the MORs regulate the proliferation and migration of non-small-cell lung cancer cells through interactions at the level of gene transcription: nonreceptor tyrosine kinase (Src), associated binding protein 1 (Gab-1/GRB 2), phosphatidylinositol-4,5-biphosphate 3-kinase catalytic subunit alpha (PI3CA), signal transducer and activator of transcription 3 (STAT 3), serine/threonine kinase 1 (Akt) ,19. ConnAnother mechanism of opioid-regulated carcinogenesis is connected with microRNA function (miRNA), which are endogenous factors, including noncoding RNAs, which regulate gene expression and posttranscriptional modification. It was described that opioids induce upregulation of miRNA 221 and the let-7 family, which are important factors in carcinogenesis and apoptosis, and downregulation of miRNA-92, which is crucial for proliferation, invasion, and migration ,24.The next mechanism of opioid-induced immunosuppression is connected with oxidative stress and reactive oxygen species (ROS) function. ROS are known as the most important mutagenic factor, causing DNA damage and contributing to malignant transformation. The ROS concentration is a final balance of oxidative and antioxidative processes. Their low stability and high diversity of reactions complicate their intracellular and fluid measurements, and many other biochemical markers have been described as predictors of oxidative balance . The newest laboratory measures are total oxidative capacity and total antioxidative capacity, which present a summary of all mechanisms ,6.The opioid-induced immunosuppression phenomenon in anesthesia and acute postoperative pain is a current topic. Although no relevant recommendations have been developed yet, methods of low-dose opioid or even nonopioid anesthesia, multimodal perioperative analgesia with the use of local anesthetics and regional analgesia are performed. It seems that in the perioperative period, many pharmacological substances used during general anesthesia cause immunosuppression through modulation of the oxidative balance and activation of HPA and the sympathomimetic system. These mechanisms have been reported to increase ROS concentration and release catecholamines and prostaglandins, which in turn induce the secretion of chemokines, immunosuppressive cytokines and proinflammatory cytokines that promote angiogenesis in tumor tissues and metastases ,14,16.The clinical effects of opioid-induced immunosuppression have been described in many aspects. It was shown that opioid analgesia deprived the cytotoxic function of NK lymphocytes more than ketorolac did, and the immunosuppressive effect assessed by the cytotoxicity of NK lymphocytes was stronger after using morphine and had a smaller effect after using oxycodone than after using opioids ,26. CombThe phenomenon of increased expression of opioid receptors in gynecologic cancers and the effect of opioid use in the perioperative period on prognosis have also been described. Levins et al. showed that MOR expression on breast cancer cells was higher in patients who underwent combined volatile anesthesia with perioperative opioid analgesia. Authors suggested that administration of propofol, a paravertebral anesthetic, without opioids decreased MOR expression. A retrospective analysis of the course of treatment of patients with ovarian cancer demonstrated that nonopioid analgesia, epidural anesthesia and the continuation of this method in the perioperative period may reduce mortality after 3 and 5 years of observation .An important aspect of immunosuppression associated with the use of opioids in cancer patients is the risk of infection. Total daily opioid dose was an independent factor that influenced the development of infection in opioid monotherapy in cancer patients, and the risk for developing infection increased by 2% per 10 mg increase in an oral morphine equivalent .Opioid therapy is also used as an element in pharmacotherapy for neuropathic pain, which very often persists as a consequence of chemotherapy, radiotherapy or cancer-related neuropathy. The pathogenesis of neuropathic pain points to multifactorial influences with a strongly expressed component of excessive immune activation. In these clinical situations, the opioid-induced immunosuppression phenomenon has a crucial and beneficial effect ,15.A separate issue is the risk of developing cancer in natural opioid users and among patients with chronic noncancer pain. Prolonged use of opium or its derivatives has been reported to be an important risk factor for oral cavity cancers, upper gastrointestinal tract cancers, pancreatic cancers, and bladder, kidney, larynx, pharynx and lung cancers -33.The role of opioid administration on the human immune system and cancer progression cannot be unequivocally assessed. Despite many observational and experimental studies, these conclusions are contentious. A serious limitation of the assessment of the clinical usefulness is the biological diversity of tumors. Most publications presenting the topic of the influence of opioid drugs on the course of cancer are based on studies of gastrointestinal tract, lung, prostate and breast cancer. In connection with epidemiological data, it is extremely important to assess the data of opioid influence on the progression of the most frequently occurring and poorest prognosis cancers -37.Opioid tolerance is another important clinical aspect of immunosuppression. Approximately 60% of patients develop drug tolerance during opioid therapy. However, the crucial mechanisms are not completely understood, and the role of microglia and astrocyte activation is the newest theory. A key point is that opioids have direct effects on non-neuronal cells, in particular, mast cells, astrocytes, and microglia. Mast cell activation releases numerous cytokines  and pronociceptive substances, such as substance P, that contribute to the exacerbation of proinflammatory processes and nociception. Indeed, glial cell-produced chemokines decrease the expression of receptors to antinociceptive mediators (gamma-aminobutyric acid - GABA) and increase the number of pronociceptive mediators , decrease glutamate transporter proteins, and decrease outward potassium currents. Many authors have shown that both acute and chronic opioid administration, due to microglia and astrocyte activation and increased levels of pronociceptive stimulation mediators, require an increased demand for opioid consumption and lead to the development of opioid tolerance ,39.6 carbonyl substitution, together with the presence of a C7-C8 single bond, potentiates the antinociceptive effect but minimizes immunosuppression. This chemical construction is characteristic of hydromorphone and oxycodone. Indeed, the single substitution of an allyl on the piperidine ring resulted in a molecule that antagonized the antinociceptive effect but maintained the immunosuppressive effect. Wodehouse et al. (Opioids lead to immunosuppression via many mechanisms, but not all of them induce the same immune profile. A strong modulating effect has been demonstrated for codeine, methadone, morphine, fentanyl, sufentanil, and remifentanil, and a weak modulating effect has been demonstrated for oxycodone, tramadol, and hydromorphone. The smallest immunomodulatory effect was noted for buprenorphine ,41. Moste et al.  presentee et al. . Buprenoe et al. .Another important clinical issue associated with the opioid-induced immunosuppression is the formation of hyperalgesia. Classically, analgesic doses of morphine activate G molecules of opioid receptor, and inhibite adenylyl cyclase activity. Suprisingly, morphine administration at very low doses induces a parodoxical effect with increase neuronal excitability with creation of hyperalgesia. It was explained that specific activation of non-neural cells in low-doses opioid therapy increases level of pronociceptive stimulation mediators. Inadequate postoperative pain control resulting from the use of inappropriate doses of opioids results in persistent postoperative chronic pain . CurrentThe topic of opioid influence on the immune system and carcinogenesis is an important point of acute and chronic pain pharmacotherapy. It should be assumed that this issue is less relevant for patients with cancer at the stage of palliative medicine, when multidirectional medical activities, including pharmacological treatments, are aimed to ensure quality of life. The subject of opioid influence on the development and progression of neoplastic disease is a very new topic, and at the moment, most publications concern the use of these substances during surgical procedures and as perioperative pharmacotherapy. At present, no precise recommendations have been made to limit opioids in the perioperative period in oncologic patients or during any other period of oncologic therapy. However, methods of low-opioid and nonopioid anesthesia have already been developed, and a number of studies indicate that there are possibilities to provide an adequate level of analgesia with proper perioperative safety while limiting the use of opioids. Knowledge about the relationships between long-term opioid intake in noncancer chronic pain pharmacotherapy and the development of cancer is incomplete, but current publications increasingly indicate that patients in these settings are at risk of developing cancer.In conclusion, knowledge about the immunosuppressive effects and carcinogenesis associated with the use of opioids suggests that there are multifactorial, complex mechanisms underlying the immunological and oxidative stress impacts and carcinogenesis promotion of opioids and that the intensity varies depending on the type of opioid. It should be emphasized that current publications point to limiting the use of opioids in acute and chronic pain treatment. In light of the presented publications, it can be stated that there are valid premises for modifying clinical practice.Kosciuczuk U and Lotowska-Cwiklewska AM conceived and designed the study and were responsible for the data acquisition, analysis and interpretation. Knapp P was responsible for the manuscript drafting and critical revision for important intellectual content. All of the authors approved the manuscript final version submitted and all of the authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.


Spinal cord injury (SCI) is a major cause of physical disability and leads to patient dissatisfaction with their quality of life. Patients with SCI usually exhibit severe clinical symptoms, including sensory and motor dysfunction below the injured levels, paraplegia, quadriplegia and urinary retention, which can exacerbate the substantial medical and social burdens. The major pathological change observed in SCI is inflammatory reaction, which induces demyelination, axonal degeneration, and the apoptosis and necrosis of neurons. Traditional medical treatments are mainly focused on the recovery of motor function and prevention of complications. To date, numerous studies have been conducted to explore the cellular and molecular mechanism of SCI and have proposed lots of effective treatments, but the clinical applications are still limited due to the complex pathogenesis and poor prognosis after SCI. Endocrine hormones are kinds of molecules that are synthesized by specialized endocrine organs and can participate in the regulation of multiple physiological activities, and their protective effects on several disorders have been widely discussed. In addition, many studies have identified that endocrine hormones can promote nerve regeneration and functional recovery in individuals with central nervous system diseases. Therefore, studies investigating the clinical applications of endocrine hormones as treatments for SCI are necessary. In this review, we described the neuroprotective roles of several endocrine hormones in SCI; endocrine hormone administration reduces cell death and promotes functional repair after SCI. We also proposed novel therapies for SCI. Spinal cord injury (SCI) is a devastating nerve injury caused by severe trauma to the spinal cord, leading to temporary or permanent somatosensory, and motor dysfunction . The majAccording to the severity of clinical symptoms, SCI can be divided into complete injury and incomplete injury. Complete SCI is characterized by the loss of sensory and motor function below the injured section, while incomplete SCI refers to the incomplete loss of motion and sensory function of the lowest sacral segment below the injury plane. In addition, contusion of spinal segments elicits distinct disabilities. For instance, quadriplegia occurs when the cervical vertebra segment is injured, and paraplegia occurs when the lower thoracic segment is injured . The cliDuring the early stage of injury, primary mechanical compression of the spinal cord causes oedema, ischaemia and hypoxia of adjacent tissues and stimulates immune activity that can aggravate tissue damage . The perSpinal cord injury is a long-standing pathological state and primary SCI tends to progress into chronic SCI. Both primary and secondary injuries stimulate a series of cellular and molecular processes that subsequently induce the accumulation of proinflammatory chemokines and cytotoxic factors at injured site and cause significant sensorimotor dysfunction, neuromuscular injury, and muscle loss at the injured site . For insin vivo and in vitro studies have explored the cellular and molecular mechanisms of SCI, and several therapies have been identified as achieving good therapeutic effects on SCI animal models, the number of efficient treatments applied in the clinic is limited  on the surface of the cell membrane.Estrogen has been traditionally identified as a reproductive hormone that is involved in the development of the female reproductive system and maintaining secondary sexual characteristics in humans. However, in recent years, the neuroprotective effects of estrogen have been widely discussed, and similar to brain-derived neuroprotective factor (BDNF) which is synthesized by the brain tissue, estrogen ameliorates several neurodegenerative diseases to maintain cerebral homeostasis . EstrogeThe neuroprotective effect of estrogen has been widely recognized, and estrogen plays an important role in brain development and CNS inflammation mainly by binding to ERs ERα and Erβ . ERs canAdditionally, estrogen activates BDNF signaling in the brain to exert neurotrophic effects . BDNF fuEstrogen has versatile neurological functions. The spontaneous synthesis of oestradiol and several neuroprotective factors is induced in damaged sites of the CNS to alleviate inflammation and cell destruction , while vBased on the neuroprotective effects of estrogen, many studies have explored the therapeutic effects of estrogen on SCI. As shown in the study by Lee et al., the administration of a single dose of 17β-oestradiol (100 or 300 μg/kg) to rats ameliorated neuropathic pain, including mechanical allodynia and thermal hyperalgesia, in the late phase after SCI compared to the littermates . The phoGenerally, the protective effects of estrogen in neurodegeneration and SCI animal models are remarkable, while controversies still exist in individuals with SCI. Greenwald et al. reported that no gender-associated differences was found in the Functional Independence Measure (FIM) motor scores and American Spinal Injury Association (ASIA) scores on acute-care admission and rehabilitation discharge in SCI patients . While aRecently, novel drug delivery systems have exhibited more favorable treatment effects in SCI animal models. By the focal delivery of estrogen to the injured spinal cord, desired therapeutic effect may be achieved while systemic levels of estrogen can be kept in a normal physiological range. For instance, Studies have reported that approximately 50% men suffer from lower levels of testosterone after SCI, who are usually accompanied by significant impairments in muscle mass, locomotor function and hypogonadism , and patAn insufficient level of testosterone has also been observed in rat models of chronic SCI, in which the serum testosterone level was 49–55% lower than in sham animals at 4 weeks after injury, and the levator ani and bulbocavernosus (LABC) muscle mass was also 13% lower in the SCI group than in controls . HoweverAndrogen is an anabolic protein that plays a pivotal role in the development of the body composition and the quality of life. Androgen promotes the synthesis of muscle, protein and bone, and increases lean body mass in males after SCI ; it can Since skeletal muscle function is governed by somatic motor neurons, the degeneration of the dendrites and axons of neurons in lesions after SCI represent the dominant factors contributing to an insufficient muscle mass and skeletal muscle atrophy, but androgen can preserve both muscle mass and motoneuron dendrites by suppressing the degeneration of dendrites . AdditioThe neuroprotective effect of testosterone on nerve diseases has mainly been confirmed by the activation of androgen receptors in neurons throughout the CNS, and the activated androgenic pathways are involved in the regulation of multiple functional proteins that can inhibit inflammatory and oxidation reactions to improve neuroprotection and attenuate nerve degeneration. Mechanistically, testosterone passes through the blood-brain barrier and binds to androgen receptors in neurons to influence neuronal differentiation and growth . TestostErythropoietin is a pleiotropic hormone with remarkable neuroprotective effect. EPO also known as a hematopoietic growth factor is secreted from the kidney and is named for its ability to promote the formation of red blood cells. The traditional application of EPO is mainly focused on the treatment of anemia caused by chronic renal failure (CRF) or an advanced malignant disease . RecentlA large number of studies have reported the neuroprotective effect of EPO in neurological disorders. In addition to inhibiting apoptosis and necrosis in injured neuronal tissues, EPO also participates in the mechanism regulating autophagy dysfunction. Physiological autophagy plays a pivotal role in the maintenance of physiological homeostasis. However, abnormal autophagy is pathologically induced after SCI, and the disruption of autophagy is a significant factor that exacerbates secondary injury . Jang etin vivo experiment, bFGF administration rescues 66–74% of neurons from death and reduces the necrosis of cholinergic neurons in the medial septum and diagonal band of Broca after axonal transection (Basic fibroblast growth factor is a member of the fibroblast growth factor (FGF) family that is involved in regulating various biological functions, including nerve regeneration, angiogenesis, the suppression of cell apoptosis and glial scar formation . bFGF isnsection . In addinsection . TBI is In addition to increasing neuronal survival after SCI, bFGF can also ameliorate secondary injury to restore motor function. As a macromolecular protein involved in physiological processes, the systemic administration of bFGF after SCI appears to be unacceptable due to the persistence of several limitations, such as the inability to cross the blood-spinal cord barrier or the short circulating half-life that is responsible for its unstable biological activity . HoweverThyroid hormones are important for the development of the CNS in mammals, particularly during the embryonic and fetal stages of brain development . THs proStudies have observed lower levels of T3 and testosterone in men with SCI . Thyroidin vitro, and the T3-induced activation of KLF9 promotes oligodendrocyte differentiation and myelination.Under physiological conditions, THs bind to nuclear receptors in target cells to regulate biological functions, and nuclear thyroid hormone receptors are widely expressed on oligodendrocytes. According to Oligodendrocytes participate in cellular metabolism in the CNS and ensure the generation of myelin membrane and the integrity of axons. Oligodendrocytes provide neurotrophic support for axon growth in the microenvironment and reduce axonal injury and myelin degradation, which are very important for the maintenance and conduction of action potentials in axons . The spo–1, which are much higher levels than the circulating level of T3 in patients with hyperthyroidism. A hydrogel containing T3 had the ability to locally deliver T3 to the lesion, with a completely effective dose for oligodendrocyte differentiation and maturation, as well as myelination (The systemic administration of T3 poses a risk of hyperthyroidism, with little efficiency in the treatment of the injured spinal cord tissue. lination . Bighinalination . TherefoSpinal cord injury is the main cause of physical disability and is responsible for the overuse of medical care and increased socioeconomic burdens. The chronic, progressive loss of the myelin sheath and neuroinflammation increase the apoptosis and necrosis of neurons, which inhibit nerve regeneration and motor function recovery after SCI, and are also verified as risk factors for many refractory complications. Clinically, no effective therapy exists for the treatment of SCI. Although numerous studies have reported significant functional recovery in SCI after pharmacotherapy, the treatments for clinical application in patients with SCI are still limited. Therefore, a difficult but meaningful task is to exploit or develop a reliable and effective treatment. Endocrine hormones are regulatory molecules with the potential to treat SCI because of their non-toxic properties and ability to promote nerve regeneration. Several different hormones, including estrogen, testosterone, EPO, bFGF and THs, have been reported to play important roles in nerve regrowth and neuroprotection. With an understanding of the physical and chemical properties of those hormones and advances in endocrine therapy theory and clinical practice, the application of endocrine therapy to the treatment of SCI shows promise. At the same time, the methods for choosing the appropriate hormone or multiple hormones and for controlling the amount and balance of hormones undoubtedly require further study. In conclusion, endocrine therapy for SCI is a therapeutic approach with broad prospects that deserved further attention from researchers.HW and A-mW designed the study. HW, X-qZ, J-fH, W-xZ, H-jT, BW, W-lF, and A-mW conducted literature collection and summary. HW and A-mW drafted the manuscript. All authors critically revised the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Mycobacterium tuberculosis, and colonoscopy revealed multiple shallow ulcers. Disseminated tuberculosis associated with reactive Poncet arthritis was diagnosed, with an improvement of the clinical and skin condition after appropriate treatment.Cutaneous tuberculosis is a rare extrapulmonary manifestation of tuberculosis which, like disseminated tuberculosis, commonly occurs in immunocompromised patients. Poncet reactive arthritis is a seronegative arthritis affecting patients with extrapulmonary tuberculosis, which is uncommon even in endemic countries. We report a previously healthy 23-year-old male patient with watery diarrhea associated with erythematous ulcers on the lower limbs and oligoarthritis of the hands. Histopathological examination of the skin showed epithelioid granulomatous process with palisade granulomas and central caseous necrosis. AFB screening by Ziehl–Neelsen staining showed intact bacilli, the culture was positive for  Mycobacterium tuberculosis)Although tuberculosis (TB) is one of the most common diseases in humans, its cutaneous form is rare and represents about 1–2% of cases of extrapulmonary TB, which corresponds to 10% of the total cases.Tuberculosis is considered multifocal when there is involvement of at least two extrapulmonary sites, with or without pulmonary involvement. It accounts for one-third of the mortality among patients infected with the human immunodeficiency virus (HIV), but it can also affect immunocompetent patients.Poncet's reactive arthritis was described by Antonin Poncet in 1897 as a TB-associated polyarthritis and is currently defined by polyarthritis or oligoarthritis in the presence of TB, usually visceral. Despite the involvement of the joints, no bacilli are found in the joint fluid of the symptomatic patients,M. tuberculosis, confirming the diagnostic hypothesis of cutaneous TB. The histopathological analysis of the intestinal biopsy revealed a mild inflammatory infiltrate without the presence of bacilli. After the beginning of the RIPE treatment regimen, the patient evolved with complete healing of the ulcers (A 23-year-old male patient, previously healthy, started with watery diarrhea, abdominal pain and weight loss of 6 kg, associated with nocturnal episodes of fever, 9 months before admission. He denied the consumption of alcohol or illicit drugs. The patient evolved with multiple ulcers with necrotic crust, some with granular floor and raised borders, associated with soft erythematous painful nodules on the lower limbs and ulcers of the fibrinous floor in the glans . In addie ulcers  and gradTuberculosis is an important public health problem, especially in underdeveloped countries. In the last decades, it has been reclassified as a re-emerging disease due to increased poverty, malnutrition, increased coinfection with HIV, use of immunosuppressive drugs and cases resistant to the drugs used in treatment.Multifocal forms are rare and account for 9–10% of cases of extrapulmonary disease. It accounts for one-third of the mortality among HIV-infected patients, but may also affect immunocompetent individuals, with mortality rates ranging from 16% to 25%, although the risk of developing extrapulmonary lesions is proportional to the degree of immunodeficiency.There are hypotheses trying to justify the occurrence of multifocal TB in immunocompetent patients, such as the intensity of transmission in the community, Mendelian susceptibility syndrome to mycobacterial infections due to the existence of defects of interleukin-12, and malnutrition, among others.The diagnosis of cutaneous TB should be differentiated from leishmaniasis, leprosy, cat scratch disease and deep fungal infections. The concomitant presence of pulmonary TB or in other organs increases the diagnostic probability, which can be confirmed by PPD, microbiological examination with culture and/or PCR.Intestinal TB may have a variable and nonspecific clinical picture, and anatomopathological examination may not indicate AFB infection in up to 29% of cases. However, colonoscopy may reveal shallow ulcers in the ileocecal region, with improvement after treatment, as occurred with the patient reported.M. tuberculosis. In this case, the rheumatology team chose hydroxychloroquine, avoiding prolonged immunosuppression, with good control of the disease during RIPE scheme and resolution of oligoarthritis at the end of treatment. This case alerts us to the possibility of severe, multifocal, cutaneous expression, requiring special care and multidisciplinary care, making it necessary to be recognized by the dermatologist in countries where TB remains endemic.The description of Poncet's reactive arthritis consists in polyarthritis or oligoarthritis associated with active TB, without the presence of bacilli in the joints.None declared.Juliana Alves Calado: Approval of the final version of the manuscript; elaboration and writing of the manuscript; critical review of the literature; critical review of the manuscript.Anna Carolina Miola: Approval of the final version of the manuscript; elaboration and writing of the manuscript; critical review of the literature; critical review of the manuscript.Maria Regina Cavariani Silvares: Approval of the final version of the manuscript; critical review of the literature; critical review of the manuscript.Silvio Alencar Marques: Approval of the final version of the manuscript; critical review of the literature; critical review of the manuscript.None declared.


To the Editor,The improved survival impact of achieving residue zero cytoreduction were proven in many studies for ovarian carcinoma ,2. In thTM (TM) were placed transversally to diaphragm, under the full thickness implant which had been displaced by traction; (iii) in order to avoid lung parenchymal injury, the ventilator was temporarily turned off after exhalation, while the stapler was locked up; (iv) the stapler was locked up to place the sutures automatically; (v) the full thickness implant above the staplers was resected via manual scalpel for thoraco-abdominal stapler or by the integrated automated scalpel for gastro-intestinal anastomosis stapler, and the stapler was opened; (vi) the resection was completed without entrance to pleural space; and (vii) final control for air leakage using a bubble test, was performed. There were either no, or minimal, asymptomatic pleural effusion, and no pneumothorax. There was also no need for thoracentesis during the postoperative period in both patients in our institution. Diaphragmatic muscle invasion of a high-grade, serous ovarian carcinoma was reported in pathologic results [institutional review board ].Therefore, we would like to describe a technique for resection of diaphragm full thickness implants without entrance to the pleural space. Firstly, the liver was mobilized. Diaphragm striping was performed up to the full thickness implant. When an unresectable area was reached, the following technique was performed to resect the full thickness implant. The steps of the technique were: (i) after identification of the full thickness implant borderlines, sutures were placed to the medial, middle and lateral edges of the full thickness implant to more easily perform traction ; (ii) anTM  or gastrOne of the concerns when undertaking diaphragmatic full thickness implant resection is pulmonary complication. Additionally, entrance to the pleural cavity increases the possibility of prophylactic chest tube application ,5. The tTo the best of our knowledge, this is the first report of the usage of a thoraco-abdominal stapler for resection of diaphragmatic full thickness implant without entrance to the pleural space. Diaphragmatic full thickness implant resection with stapler appears to be safe, practical and an easy to learn surgical technique. There is a need for large scale studies to evaluate the conclusions of this technique.


Trypanosoma cruzi glycosomes have located, in addition to enzymes of the glycolytic pathway, enzymes of several other metabolic processes in the organelles. These analyses revealed many aspects in common with glycosomes from other trypanosomatids as well as features that seem specific for T. cruzi. Their enzyme content indicates that T. cruzi glycosomes are multifunctional organelles, involved in both several catabolic processes such as glycolysis and anabolic ones. Specifically discussed in this minireview are the cross-talk between glycosomal metabolism and metabolic processes occurring in other cell compartments, and the importance of metabolite translocation systems in the glycosomal membrane to enable the coordination between the spatially separated processes. Possible mechanisms for metabolite translocation across the membrane are suggested by proteins identified in the organelle's membrane—homologs of the ABC and MCF transporter families—and the presence of channels as inferred previously from the detection of channel-forming proteins in glycosomal membrane preparations from the related parasite T. brucei. Together, these data provide insight in the way in which different parts of T. cruzi metabolism, although uniquely distributed over different compartments, are integrated and regulated. Moreover, this information reveals opportunities for the development of drugs against Chagas disease caused by these parasites and for which currently no adequate treatment is available.Glycosomes are peroxisome-related organelles that have been identified in kinetoplastids and diplonemids. The hallmark of glycosomes is their harboring of the majority of the glycolytic enzymes. Our biochemical studies and proteome analysis of  Trypanosoma cruzi contains peroxisome-related organelles called glycosomes  comprising pyruvate phosphate dikinase (PPDK) and enzymes of the succinate production/utilization pathway, the pentose-phosphate pathway (PPP), biosynthesis of sugar-nucleotides, purines, and pyrimidines, sterols and ether-lipids and β-oxidation of fatty acids as well as enzymes involved in detoxification of oxygen radicals , galactokinase (GALK) and a unique form of phosphoglycerate kinase (PAS-PGK) with at its N-terminus a PAS domain, known to possess signaling and regulatory functions , as well as pore-forming proteins  into glycosomes, while smaller molecules, with an estimated Mr of approximately 400 Da, such as glycolytic intermediates and inorganic ions pass through pores  transporters as in T. brucei  was found . The addition of a single free H+ would result in an intraglycosomal pH drop of ~0.4. It is important to realize that such calculations provide averaged values: averaged in time and space, over the total number of glycosomes in a trypanosome. Establishment of a pH is a dynamic process, involving metabolic reactions and the continuous protonation/deprotonation of many groups . One may thus wonder if the apparent response of the probes is affected by specific properties of the organelles, such as the high density of proteins with relatively high pI values—both considerably higher than in cytosol, the relatively high membrane/matrix ratio and/or the presence of inorganic polyphosphate  across the membrane, i.e., slightly different concentrations on both sides, responsible for a  membrane potential and/or pH gradient. Furthermore, as argued by Antonenkov and Hiltunen  budding from special parts of the endoplasmic reticulum (ER) after insertion of some  peroxisomal membrane proteins (PMPs), followed by fusion with pre-existing peroxisomes and maturation involving matrix protein import, or (ii) PMPs and matrix proteins are directly sorted to existing peroxisomes. Lipids for growing and proliferating peroxisomes are provided by the vesicular transport from the ER, but may also be delivered via not yet well-studied non-vesicular routes involving contact sites between the organelles and the ER  , but with a somewhat different C-terminal sequence  that may not be able to sort the protein to the organelles. Therefore, further research is required to establish if Nudix proteins are involved in glycosomal polyP hydrolysis. Whether polyP serves as glycosomal storage of PPi that is known to regulate the activity of several glycosomal enzymes seems questionable if PPi may easily pass through the pores in the membrane.Docampo and coworkers have shown that trypanosomes synthesize and store inorganic polyphosphate (polyP) in their acidocalcisomes. Recently, they also reported the presence of important amounts of long-chain polyP in the nucleolus and glycosomes of T. cruzi, like other dixenous trypanosomatid parasites, undergoes an elaborate life cycle involving extracellular replicative epimastigotes in the triatomine digestive tube, non-replicative extracellular metacyclic and bloodstream trypomastigotes in the insect and mammalian host, respectively, and replicative amastigotes intracellularly in the cytosol of the mammalian cells. The different developmental stages differ importantly in morphology, but also in metabolism to adapt to the large nutritional conditions encountered in the different niches , provides further information to the question to what extent quantitative and/or qualitative differences occur in the glycosomal proteome during in vivo differentiation between life-cycle stages , phosphofructokinase (PFK) and PPDK, the cytosolic PYK, 6-phosphofructo-2-kinase/fructose-2-bisphosphatase (PFK2/FBPase2) and alanine transferase (ALT), and PGK that is present in both compartments, whereas phosphorylation of glycosomal fumarate reductase (FRD) was increased. These changes correlated with a decrease of activities of HK and PYK, as well as changes in the concentration of various intermediates of carbon metabolism. Together, the data indicate that phosphorylation of these enzymes, both glycosomal and cytosolic, plays an important role to control their activity and that the interaction of trypomastigotes with ECM components serves as trigger for the cells to prepare for intracellular life as amastigotes, by decreasing the glycolytic activity through dephosporylation of the enzymes. Previously, differential phosphorylation of proteins, including glycosomal enzymes, has also been demonstrated when bloodstream-form and procyclic T. brucei were compared  at its C-terminus. This protein is part of a protein phosphatase cascade that regulates the differentiation of the non-replicating short-stumpy bloodstream forms to the proliferating procyclic forms in the tsetse fly  that was detected in the proteome of epimastigote glycosomes  and other cofactors. It is therefore unlikely that they form a permeability barrier for H+ and inorganic ions. Import and efflux of metabolites occurs probably by diffusion through the pores and is dependent on their gradients, rather than transmembrane H+ or ion gradients, and on the control of the fluxes by the enzymes within and outside the organelles. Moreover, the notion of a separate matrix pH for small organelles as glycosomes is doubtful. Glycosomal function(s) should therefore rather be sought in other aspects such as assembly of enzymes in functional, efficient complexes and/or the coordinated turnover of major units of metabolic machinery by autophagy and biogenesis of the organelles during life-cycle differentiation (Herman et al., Glycosomes are authentic members of the peroxisome-organelle family, but have as distinguishable feature the sequestering of enzymes of glycolysis and other core processes of carbon metabolism. Although glycolysis is important, and in some trypanosomatid life-cycle stages essential for ATP production, there are several reasons why these organelles should not be considered as the cells “ATP factories” or as “energy-transducing organelles” comparable to mitochondria. First, ATP production and hydrolysis by all processes together—catabolic and anabolic ones—within the organelles seem to be kept in balance, net ATP production occurs outside the organelles. Contrary to mitochondria, there is no evidence for ATP delivery, in exchange for ADP, from the matrix to the cytosol. Also intraglycosomal NADAn as yet unsolved question is how long-chain polyP is sequestered within glycosomes. There are no indications for its synthesis in these organelles. It is probably “piggyback” imported in association with the positively charged matrix proteins through the transient pores formed by peroxins which have the ability to transport proteins, even when folded, in multimeric form or with bound, large artificial ligands (Häusler et al., Although the origin of peroxisomes and glycosomes is unrelated to that of mitochondria, it is important to realize that recent research has established contact sites, vesicular traffic, coordinated proliferation, and sharing of physiological functions between peroxisomes and mitochondria (Fransen et al., Finally, although glycosomes are evolutionarily related to peroxisomes, and share some functions, there are also considerable differences in enzyme content and aspects of their biogenesis. The large evolutionary distance between human and trypanosomes has resulted in large differences in the proteins involved. These differences, together with the essentiality of glycosomes and several of its metabolic processes make a variety of the trypanosomatid enzymes and peroxins promising drug targets. Indeed, selective, potent inhibitors of some glycosomal proteins have been developed that interfere with metabolic processes like sterol biosynthesis and glycosome biogenesis or function and kill the parasites (Buckner and Urbina, The experiments to create The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.