Current Pharmaceutical Design - Volume 24, Issue 12, 2018

Factors strongly related to the risk of developing diabetic foot infections include vascular, neuropathic and hyperglycemic complications of long-standing diabetes mellitus. These infections are common and serious, posing a worldwide burden on administrative providers of healthcare, patients and physicians. The most appropriate approach to these infections is with a multidisciplinary team. This subchapter summarizes the current state-of the-art concerning therapy, and scientific knowledge, for peripheral arterial insufficiency, hyperglycemia, and peripheral neuropathy of the diabetic foot, with an emphasis on the infectious complications.

Background: Diabetes Mellitus (DM) is a common medical condition affecting more than 6% of the world population. Besides well-known pathology like diabetic retinopathy and renal insufficiency, it carries important orthopedic implications, especially around the foot and ankle (diabetic foot). Focus: This article focusses on the three major areas confronting the orthopedist: 1) changes in foot statics and biology leading to ulceration with or without osteomyelitis, 2) ankle fractures, particularly complications after a fracture and 3) Charcot foot. Their pathophysiology, clinical features, classification, diagnostic dilemmas and treatment options are discussed. Conclusion: DM is very common and is often associated with foot problems. Diabetic foot is a special condition that needs special attention. This article aims to provide the necessary knowledge to a better understanding and treatment of the diabetic foot.

Background: Diagnosing diabetic foot infection is often difficult, despite several available diagnostic methods. Amongst these, several imaging modalities exist to evaluate the diabetic foot in case of a suspected osteomyelitis. Nuclear Medicine, in particular, offers a variety of radiopharmaceuticals and techniques. Nowadays the gold standard radionuclide procedure, when an osteomyelitis is suspected, is represented by the use of radiolabelled leukocytes with either 99mTc-HMPAO or 111In-oxine. Methods: In this review, we describe the correct acquisition and interpretation of white blood cell scintigraphy and we provide an overview of the existing literature data of the use of this technique in the infected diabetic foot. If images are correctly acquired, displayed and interpreted, this modality reaches very high diagnostic accuracy (>95%) in detecting osteomyelitis and it allows the differential diagnosis with a soft tissue infection or inflammation. Single-photon emission computed tomography/computed tomography (SPECT/CT) in addition to planar images is mandatory to determine the extent and exact location of the infective process in both fore foot and midhint foot. With the addition of bone marrow scintigraphy using radiolabelled nanocolloids, radiolabelled white blood cell scintigraphy is also able to differentiate between Charcot neuroarthropathy and osteomyelitis, which is a challenge in the evaluation of diabetic foot. Radiolabelled anti-granulocyte monoclonal antibodies and their fragments can also be used instead of white blood cells although there is a limited experience on their usefulness in diabetic foot infection.

Osteomyelitis in the diabetic foot can be difficult to diagnose and has serious consequences. Although 2-deoxy-2-[18F]-fluoro-D-glucose (FDG) positron emission tomography (PET) was traditionally used in oncology, it is emerging as a useful method in inflammatory and infectious entities. In this chapter, original research articles, meta-analyses, and reviews on the performance of FDG PET in diagnosing osteomyelitis in the diabetic foot will be discussed. In addition, PET available data in comparison to different imaging methods, different analysis methods, and impact of other co-existing conditions such as hyperglycemia, and long-term antibiotic treatment on the performance of FDG PET will be reviewed. Studies published in the last two decades showed variable performance of FDG PET in the assessment of diabetic foot infection with a relatively high specificity (67-93%) but a wide range of sensitivity (29-100%). More recent studies showed better sensitivity, probably due to improved imaging technology and analysis methods and use of hybrid imaging with positron emission tomography/ computed tomography (PET/CT). FDG PET/CT has several advantages compared to other anatomical and functional imaging methods, including short acquisition time, high resolution, low radiation dose, and better tolerability. Further research is required to establish its role in the clinical practice.

Diabetic Foot Infections (DFIs) are associated with increased morbidity, an economic burden on patients, their families and healthcare systems and increased mortality. Early diagnosis with prompt, appropriate and adequate treatment of the infected diabetic foot is crucial. The determination of DFIs, however, may be quite perplexing and invasive. Imaging is useful in the evaluation of certain cases of DFIs, especially in suspected instances with no overt clinical features, or in the diagnosis of osteomyelitis. Nuclear medicine imaging is currently used in the evaluation of DFIs; however, like all the imaging techniques now available, it has its limitations. Several radiopharmaceuticals presently available play useful roles in the management of DFIs, while new ones are being evaluated. Optical imaging techniques have recently demonstrated promising results in the evaluation of many infections including DFIs. Using the same molecule, a tracer can be labeled with a radioisotope or an optical imaging dye. This enables infections to be evaluated both pre- and intra-operatively when surgery is required in their management. In some cases, tracers have been simultaneously labeled with both a radioisotope and an optical imaging dye to produce a hybrid tracer. These new tracers potentially provide powerful and new opportunities in the management of DFIs. In this review, we briefly examine tracers that have been used in the evaluation of the infected diabetic foot. We then explore the potential of new imaging tracers currently under development for infection that may be useful in the management of DFIs.

Background: The most severe diabetic foot ulcers are those related with critical ischemia, which is primarily diagnosed with non-invasive diagnostics. However, these diagnostics have several disadvantages. For example, they only provide global indications of the (macro)level of ischemia. A potential solution can be found in novel optical imaging techniques for local assessment of the microcirculation in diabetic foot ulcers. This review provides an overview of these imaging techniques (Laser Doppler Perfusion Imaging, Laser Speckle Contrast Imaging, Photoacoustic Imaging and Hyperspectral Imaging) and their applicability for the diagnostic assessment of microcirculation in diabetic foot ulcers. Method: For each technique, the following parts are described: a) their technical background; b) general clinical applications; and, c) its application for microcirculation assessment in diabetic foot ulcers. Parts a-b are based on a narrative review of the literature, part c on a systematic review that was performed in the database Scopus, covering the period from January 1, 2000 to November 31, 2017. Results: Each of these techniques has specific advantages and disadvantages for imaging microcirculation. Potential clinical use depends on measurement aims, and clinical relevance. However, none of the techniques has a strongly established clinical relevance yet: we found a limited number of publications describing clinical outcomes. Future research is needed to determine which technique is the most clinically relevant for the assessment of microcirculation in diabetic foot ulcers. Conclusion: Although promising, the currently available novel optical techniques need to be further improved technically and prospective trials are necessary to evaluate their clinical value.

Background: Influenza is a widely distributed infection that almost annually causes seasonal epidemics. The current egg-based platforms for influenza vaccine production are facing a number of challenges and are failing to satisfy the global demand in the case of pandemics due to the long production time. Recombinant vaccines are an alternative that can be quickly produced in high quantities in standard expression systems. Methods: Plants may become a promising biofactory for the large-scale production of recombinant proteins due to low cost, scalability, and safety. Plant-based expression systems have been used to produce recombinant vaccines against influenza based on two targets; the major surface antigen hemagglutinin and the transmembrane protein M2. Results: Different forms of recombinant hemagglutinin were successfully expressed in plants, and some plantproduced vaccines based on hemagglutinin were successfully tested in clinical trials. However, these vaccines remain strain specific, while the highly conserved extracellular domain of the M2 protein (M2e) could be used for the development of a universal influenza vaccine. In this review, the state of the art in developing plant-produced influenza vaccines based on M2e is presented and placed in perspective. A number of strategies to produce M2e in an immunogenic form in plants have been reported, including its presentation on the surface of plant viruses or virus-like particles formed by capsid proteins, linkage to bacterial flagellin, and targeting to protein bodies. Conclusion: Some M2e-based vaccine candidates were produced at high levels (up to 1 mg/g of fresh plant tissue) and were shown to be capable of stimulating broad-range protective immunity.

Heterocyclic N-oxides have emerged as promising agents against a number of diseases and disorders, especially infectious diseases. This review analyzes the emergence and development of this scaffold in the medicinal chemistry, focusing mainly on the discovery of new heterocyclic N-oxide compounds with potent activity against tuberculosis, malaria and neglected tropical diseases (i.e. leishmaniasis and Chagas disease). A number of heterocyclic N-oxides are described herein, nevertheless, the following chemical classes deserve to be highlighted due to a large number of reports in the literature about their promising pharmacological effects: furoxan, benzofuroxan, quinoxaline 1,4-di-N-oxide, indolone N-oxide and benzimidazole N-oxide. In order to describe those most promising compounds, we included in this review only those most biologically active heterocyclic Noxide published since 2000.