Ramsay Hunt Syndrome (RHS), also known as herpes zoster oticus, is caused by the reactivation of varicella zoster virus (VZV) in the geniculate ganglion of the facial nerve. Herein, we report a case of Ramsey Hunt Syndrome in a patient after antimonial treatment for Cutaneous Leishmaniasis. The patient presented with microvesicles grouped on an erythematous base, starting in the neck and ascending towards the scalp margin on the right side of the head. The patient also developed grade V peripheral facial palsy the day after initiating the herpes zoster treatment, this outcome corroborated the assumption of Ramsey Hunt Syndrome. Ramsay Hunt Syndrome (RHS) was first described by James Ramsay Hunt in 1907. The syndrome is characterized by a vesicular rash on the pinna, ipsilateral otalgia, and peripheral facial palsy on the same side of the headA 55-year-old male patient who was born in Manaus metropolitan area, in the Brazilian state of Amazonas, with no comorbidities, sought medical help at the leishmaniasis service of the Doctor Heitor Vieira Dourado Foundation for Tropical Medicine (FMT-HVD) in Manaus. He had completed treatment with a pentavalent antimonial drug for cutaneous leishmaniasis (CL) 40 days prior. A history and physical examination detected an active lesion with satellite papule in the patient’s right upper limb. He received outpatient treatment with a second cycle of antimonial application for 30 days. microvesicles grouped on anerythematous base, starting in the neck and ascended towards the scalp margin on the right side of the head. The microvesicles affected the patient’s pinna, external auditory canal, and right ear lobe, and were associated with severe torticollis-like pain in the nerve path (Ten days after the end of treatment, the patient’s leishmaniasis lesion was healed . Howeverrve path . The patrve path . SerologThe patient reported improvement in the cervical pain at the end of the acyclovir-based treatment; however, he continued to have persistent headache and peripheral facial palsy symptoms. Following the gradual reduction of these symptoms, he was referred to another hospital in Manaus County for motor physical therapy treatment. The eye lubricant applications and analgesic medication were maintained, and the patient was referred to the neurology service for an outpatient follow-up where he presented with full neurological recovery. RHS, is the second most common cause of non-traumatic facial palsy in adultsClinical diagnosis of RHS is based on the signs and symptoms although VZV-specific serology can be indicated in atypical casesRHS should be diagnosed as early as possible to enable the fast implementation of appropriate treatment and to avoid sequelaeHerpes zoster association with antimonial treatment for leishmaniasis has also been reported with a possible secondary link to transient lymphopeniaAny individual who has had chickenpox is susceptible to RHS. The syndrome is not contagious; however, VZV reactivation can cause chickenpox in contacts who were not previously immunized against the virus. The infection in immunodeficient patients can be severe; therefore, recommendations include avoiding physical contact with individuals in the infection stage or those who have not been vaccinated, as well as with immunosuppressed individuals, newborns, and pregnant womenThis report presented the case of a previously healthy patient who developed a rare VZV-associated facial palsy after treatment with antimonial drugs for cutaneous leishmaniasis. The patient’s condition improved following the use of antiviral drugs and systemic corticosteroids. Early diagnosis and effective intervention resulted in the manifestation of his disease and the primary outcome was similar to the ones described in the literature.


Juvenile ossifying fibroma (JOF) is a controversial and uncommon lesion that has been distinguished from the larger group of ossifying fibromas because of distinct clinical features and some morphological peculiarities. Furthermore, JOF shows an aggressive biological behavior that has led researchers to consider it a benign neoplasm, resulting in its differential diagnosis with important benign and malignant bone neoplasms.This study describes a case of synchronous presentation of JOF in the mandible and maxilla of a young patient. In addition, the literature was reviewed to identify clinical-pathologic features and possible factors that could help establish the correct diagnosis. A 26-year-old male patient presented simultaneously a lesion affecting the body, angle and ramus of the left mandible and another lesion in the left maxilla. Both lesions were well delimited and radiolucent, being unilocular in the maxilla and multilocular in the mandible. The mandibular lesion was partially resected and the maxillary lesion was submitted to curettage. The diagnosis was JOF.A delay in seeking medical care and a late diagnosis can have serious consequences for the postoperative functional and esthetic outcome. Much care should be taken during establishment of this diagnosis since an equivocal diagnosis can have serious consequences for the patient in terms of treatment.After 1 year, the patient shows no signs or symptoms of recurrence of the lesions and was referred for reconstructive surgery of the mandible. An early and correct diagnosis is necessary to permit the best therapeutic management. Clinical, radiographic and microscopic features are discussed, highlighting the main criteria used for its differential diagnosis.2A 26-year-old black male patient with 2-year history of a painless swelling involving the left mandibular body. No reports of drug use, underlying diseases or harmful habits. Family history without relevant associated information. Extraoral clinical examination showed an asymmetry in the left lower third of the face A. IntraoHistopathologic analysis of the two lesions revealed characteristics of JTOF. 3Sixteen cases of synchronous manifestation of conventional ossifying fibroma are reported in the literature Although JOF is a benign neoplasm, it can manifest as an aggressive lesion because of its rapid growth, expansion of cortical bones and possible displacement of adjacent structures, leading to the suspicion of a malignant neoplasm in some cases JPOF, commonly found in the craniofacial skeleton, can affect the frontal, orbital and zygomatic bones and paranasal sinuses of young people and adults between 16 and 33 years of age. On the other hand, JTOF is a purely gnathic lesion that preferentially affects the maxilla of children aged 8 to 12 years The radiographic and imaging features of the present case agree with those commonly reported in the literature The clinical and imaging findings of the mandibular tumor and the rarity of JOF led to the diagnostic hypotheses of ameloblastoma, followed by KOT and myxoma. The maxillary lesion did not cause swelling or cortical bone expansion and was discovered during radiography for diagnosis of the mandibular lesion. Its radiographic appearance was suggestive of KOT. The detection of hyperdense foci in computed tomography also suggests the calcifying odontogenic cyst (COC).The criteria available in the present case were sufficient for the diagnosis of JTOF. The lesion was characterized by intensely cellularized fibrous connective tissue associated with the presence of mineralized tissue at different stages of maturation and calcification that appeared as irregular trabeculae, some of them lined by osteoblasts The initial microscopic diagnosis of myxoma obtained by incisional biopsy of the mandibular lesion highlights the importance of a careful differential diagnosis. Clinical, radiographic and histopathologic findings should always be correlated since lesions with a different etiopathogenesis, behavior and prognosis can exhibit clinical and pathologic similarities. In the present case, the material collected during the incisional biopsy may have corresponded exactly to the myxoid areas found in JOF, resulting in the diagnosis consistent with myxoma.The differential diagnosis of JOF includes fibrous dysplasia, COD, conventional ossifying fibroma, and even low-grade osteosarcoma JOF have been distinguished from the large group of conventional ossifying fibroma based on the age of the patient, the site affected, and biological behavior The greater cellularity and the presence of myxomatous foci and abundant osteoid material favored the diagnosis of JOF in the present study. A useful intraoperative finding that helps distinguish conventional ossifying fibroma and JOF from COD is the fact that ossifying fibromas can be separated easily from the adjacent normal bone tissue The therapeutic approach to treating JOF must consider the aggressiveness, size and potential of recurrence (30% to 58%) of this tumor. Consequently, surgical resection with safety margins seems to be the preferential treatment Recurrence of JOF is related to the difficulty in performing an adequate resection due to the location of the borders of the tumor and its infiltrative nature. It would therefore be more prudent to determine the therapeutic approach based on the location, extent and biological behavior of the tumor This study reported the synchronous presentation of a rare lesion. The aggressive biological behavior of this lesion indicates the need for an early diagnosis so that the best therapy can be instituted for the patients, preferentially conservative treatments that do not compromise function or esthetics. In the case reported a extension lesion in the mandibular body, a fact justifying the hemimandibulectomy performed. The maxillary lesion that measured approximately 5 cm and in view of the diagnostic hypothesis, a more conservative approach of surgical curettage was adopted. After 1 year, the patient shows no signs or symptoms of recurrence of the lesions and was referred for reconstructive surgery of the mandible. Despite radical treatment, the patient was well accepted with the prospect of future mandibular reconstruction.Based on the literature review, we recognize that, despite major diagnostic difficulty, some clinical and pathologic features favor the diagnosis of JOF. Thus, the knowledge and combination of clinical, radiographic and histopathologic features of JOF are extremely important for its accurate diagnosis. The presente work has been reported in line with the SCARE 2018 criteria We declare no conflict of interest.This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectores.Ethical approval exempted by our institution.Written informed conset was obtained from patient. A copy of a signed document stating this is avaliable for review by the Editor-in-Chief of this journal on request.Vildeman Almeida Júnior: performed sugery, manuscript writing, revision and submission.Joaquim Dultra: performed sugery and manuscript writing.Paloma Cerqueira: manuscript writing and revision.Tarcísio Fernandes: performed sugery and manuscript writing.Flávia Xavier: manuscript writing, revision and histopathologic analysis.Jean dos Santos: manuscript writing, revision and histopathologic analysis.Águida Henriques: histopathologic analysis, manuscript writing, revision and submission.NA.Vildeman Almeida Júnior.Águida Henriques.Not commissioned, externally peer-reviewed.


Retinal structural and microvascular damages reflect damage to cerebral microvasculature and neurons. We aimed to investigate neovascular unit abnormalities among patients with large-artery atherosclerosis (LAA) or small-vessel occlusion (SAA) and control subjects.  Twenty-eight LAA patients, forty-one SAA patients, and sixty-five age- and gender-matched controls were recruited. Based on optical coherence tomography angiography (OCTA), retinal capillary vessel density was assessed in the general and local sectors, and the thickness of individual retinal layer was extracted from retinal structural images. The differences between structural and microvascular were analyzed. P < 0.05), and the fractal dimension in C2 and C4 regions of deep retina was significantly lower in the LAA group (P < 0.05). Discussion. Compared with superficial microvascular network, deep microvascular network is more sensitive to ischemic stroke. In addition, we have demonstrated quadrant-specific pRNFL abnormalities in LAA and SAA patients. Superior quadrant pRNFL thickness differences between stroke subgroups may suggest that changes in retinal nerve fiber layer are more sensitive to subtype identification than changes in retinal microvascular structure. All in all, the alteration in retinal structural and microvascular may further elucidate the role of the neovascular unit in ischemic stroke, suggesting that the combination of these two indicators could be used for subtype identification to guide prognosis and establish a risk prediction model. The superior peripapillary retinal nerve fiber layer (pRNFL) thickness was significantly different among the three groups, and the LAA group had the thinnest thickness. Compared to the control group, the deep retinal capillary vessel density in other two stroke subgroups were significantly reduced in all regions except in the inferior region ( Stroke is the most common cause of serious disability in adults, and China bears the biggest burden globally . As therPrevious studies based on fundus photography have revealed an independent correlation between retinal vascular parameters and stroke –6. AdditThe concept of the neurovascular unit (NVU) was proposed in 2003 , which iIn this study, we aimed to find the retinal microvascular and microstructural changes in the subtypes of initial acute stroke patients.In this study, a total of 85 patients with initial ischemic stroke within 14 days of an acute period were prospectively recruited from the neurology unit at the Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University from Jan 2017 to December 2018. One neurologist (Zhao Han) assessed the stroke severity with the National Institutes of Health Stroke Scale (NIHSS) . Br. Br29]. In addition, we also acknowledge the limits in this study. The cross-sectional study with a small sample limits our ability to identify the different pathogenesis of the capillaries and microstructures of the stroke. The outer structure of the retina which is mainly supplied by the choroid has not been analyzed. Due to the practical difficulty of recruiting and examining the patients, milder patients may be recruited, which may be more likely with milder vascular lesions to differentiate the two subtypes. Despite the weakness, there are several strengths in our study. We recruited different ischemic stroke subtypes with strict inclusion and exclusion criteria. Otherwise, to minimize the confounding of stroke, the patients with a history of previous stroke were excluded. We completed the detailed ophthalmic and clinical examinations within two weeks after the onset of the stroke and maintained the blinding of retinal and brain images to each other. Finally, this is the first attempt to simultaneously observe retinal microvascular and neurological changes in different stroke subtypes in vivo.Moreover, further longitudinal studies with a larger sample size are required to show differences in the characteristics of retinal microstructure and capillaries. It remains to be seen whether the retinal signs are indicative of cerebrovascular risk beyond the conventional risk indicators and whether the retinal imaging technique will be a surrogate or accessory examination system in clinical settings and ultimately become a part of the routine stroke risk or evaluation of treatment assessment.


In children with Transposition of the Great Arteries (TGA), the pulmonary artery, and aorta are connected to the heart abnormally resulting in blue blood (deoxygenated) recirculating to the body and red blood (oxygenated) recirculating to the lungs. The arterial switch operation (ASO) is the standard of care for transposition of the great arteries (TGA), and given the low risk of early mortality and satisfactory long-term outcomes, focus is now on managing longer term complications such as neo-aortic root dilatation, and pulmonary artery stenosis. Since May 2016, we have used 2-ply extracellular matrix  for reconstruction of the coronary button defects using a pantaloon patch. We present histology of implanted 2-ply ECM (Tyke) from a patient who went back to surgery for development of subaortic stenosis ~12 months after ASO. In a normal heart, there are two large arteries that carry blood out of the heart, the pulmonary artery which carries blood to the lungs, and the aorta which carries blood to the body. In children with Transposition of the Great Arteries (TGA), these arteries are connected to the heart abnormally resulting in blue blood (deoxygenated) recirculating to the body and red blood (oxygenated) recirculating to the lungs. This happens because the aorta is attached to the right-sided pumping chamber instead of the left, and the pulmonary artery is attached to the left-sided pumping chamber instead of the right.The arterial switch operation (ASO) is the standard of care for transposition of the great arteries (TGA). The arterial switch operation involves cutting off the aorta and pulmonary arteries just above the point where they leave the heart, and reconnecting them to the proper ventricle. The valve stays attached to the ventricle, so what was once the pulmonary valve is now the aortic valve and vice versa. Since the coronary arteries must stay with the aorta, they must be taken off the area above the valve and reimplanted separately above the new aortic valve. This leaves a defect in the vessel from where they were removed, and this requires patching the defect with some type of material .Given the low risk of early mortality and satisfactory long-term outcomes, focus is now on managing longer term complications such as neo-aortic root dilatation, and pulmonary artery stenosis . The incThe original surgery was performed in a patient with prenatal diagnosis born at 37 weeks with no intrapartum complications. Postnatal echocardiographic diagnosis of double outlet right ventricle with TGA , sub pulmonic ventricular septal defect (VSD) with overriding pulmonary artery was made. Patient underwent repair at 11 days old where an arterial switch procedure and closure of VSD was performed. A LeCompte maneuver was performed and the posterior neo-pulmonary artery root where the coronary buttons were harvested was reconstructed using a pantaloon shaped patch of 2-ply ECM core porcine xenograft (Tyke) with running 7-0 Prolene suture. The patient did well and was discharged at 18 days postoperatively.Post-operatively the patient was evaluated by the genetics service and a diagnosis of Sotos syndrome (chromosome disorder 5q35.2q35.3 duplication that interrupts NSD1 gene) was made which is associated with congenital cardiac defects. At 11 months of age, a follow up echocardiogram revealed significant sub-aortic stenosis. The patient was referred for cardiac catheterization which revealed significant outflow tract gradient of 92 mmHg and the patient was referred for surgical repair.During this procedure, the aorta and pulmonary arteries were separated easily. The pulmonary artery was transected allowing access to the aorta which was also transected. This allowed for inspection of the left ventricular outflow tract through the aortic valve which revealed an exceedingly tight opening in the left ventricular outflow tract measuring ~3 mm in diameter. A longitudinal incision was carefully made down into the left ventricle and connected with a transverse incision excising a large chunk of septal left ventricular outflow tract muscle, now allowing a 10 mm dilator to pass easily. Before re-anastomosing the pulmonary artery, the pantaloon patch was examined from the inside and could not be distinguished from the native tissue except for the suture line. The tissue looked and felt like normal pulmonary artery. A small 1 mm sample of the pulmonary artery anastomosis was therefore taken from the rim of pantaloon patch for histology to evaluate the destiny of the inserted ECM patch. The patient recovered well, without any complications, and was discharged uneventfully.The specimen was dehydrated in a graded series of ethanol and infiltrated with paraffin. The block was sectioned at 4–6 microns, mounted on a glass slide, and stained with hematoxylin and eosin and Masson's trichrome stains. In addition, immunohistochemistry for CD31 was performed on the paraffin block.Microscopic evaluation of the graft at the pulmonary anastomosis showed a small region of acellular laminated Cormatrix collagen with surrounding spindle cells and collagen deposition with re-endothelialization of the surface demonstrated by CD31 staining. Overall, inflammation was mild and consisted predominantly of lymphohistiocytic inflammation around suture material, nerve fiber, and at the interface with the ECM patch material. Postoperative echocardiography performed more than year and half after initial switch operation demonstrated nicely functioning pulmonary valve with trivial pulmonary insufficiency and 18 mmHg peak pulmonary gradient .in vivo migration and proliferation of endothelial cells, recruitment and differentiation of mural cells, culminating in the formation of a bio integrated tissue (Decellularized matrices are biological grafts capable of stimulating d tissue . CorMatrd tissue , 4. Cormd tissue . Howeverd tissue . Longer-d tissue . Neointid tissue . In our de novo growth of true histologic three layered arteries or valves resembling native cardiac structures in human explants. At ~1 year post-implantation in a pediatric patient, we report incorporation of the Cormatrix scaffold by collagen deposition, re-endothelialization, and mild chronic inflammation, reflecting a typical healing response for implant duration similar to other reports. Additional studies evaluating longer term explants may further elucidate the mechanisms of tissue incorporation and potential for reconstitution of native structures.Bioscaffolds such as Cormatrix become incorporated by host tissue cells with eventual collagen deposition characteristic of wound healing . There hThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Memorial Healthcare System Office of Human Research. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.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 worldwide emergence of microbial resistance to available antibiotics presents a global threat to public health and health systems. This special issue aimed to gather papers describing novel antibiotics, originating form chemical synthesis, repurposing of existent drugs, or from natural sources like plant extracts, herbs and spices. A total of 13 papers were published, covering a wide range of topic, including antimicrobial resistance surveillance studies; synthesis of novel molecules with antimicrobial activities; modification or repurposing of already existing molecules, plant-derived active extracts, and molecules; the effects of antimicrobial therapy on microbiota; and the investigation of novel formulations for human and veterinary uses. After decades of antibiotics discovery decline, antibiotics discovery is boosting. Recent developments of post genomics approaches and bioinformatics tools will most certainly turn the tide in the discovery and development of antimicrobials in this exciting field. The worldwide emergence of microbial resistance to available antibiotics is a threat to public health and health systems at a global scale, leading organizations like the World Health Organization (WHO) to announce a global crisis of antibiotics resistance and to publish a list of priority pathogens in 2017 [Surveillance studies carried out to understand how the resistance patterns are evolving in specific groups and regions are critical to understand the trends of antibiotic resistance in both hospital and community-acquired infections and to establish new guidelines for the correct use of existing antibiotics. An example of such studies is illustrated by Folliero et al. in their paper published in this Special Issue, reporting a two-year surveillance study on the antibiotic susceptibility patterns of bacterial pathogens from patients with urinary tract infections attended in a university hospital .Escherichia coli dihydroorotase [The steady increase and spread of resistance to antibiotics among human pathogens has not been accompanied by the introduction in the market of novel antibiotics. The main reasons for the exodus of pharma and biotech companies from antimicrobial research and development rely on the low investment return and demanding regulatory requirements . This laoorotase . In ordeoorotase . The autoorotase .Lactobacillales and Staphylococcaceae including methicillin-resistant Staphylococcus aureus (MRSA) strains, was previously found by an ultrahigh-throughput screening approach to identify high Bacillus pumilus strains producers [Bacteria remain a useful source of compounds with antimicrobial activity. Terekhov et al. report the use of omics approaches to boost amicoumacin biosynthesis by cultivation under optimized conditions for high-scale production. The compound, active against roducers . Amicoumroducers .12 or C14 linear alkyl substituents were serendipitously found to strongly inhibit reverse transcriptase. The authors show evidence that these compounds act by binding nucleic acids with high affinity, forming high-molecular-weight complexes [The chemical modification of already existing antimicrobials has achieved some success, such as the chemical modifications introduced in the β-lactam ring of penicillin to prevent its hydrolysis by penicillinases. Ying et al. have synthesized aminoglicosides variants containing different alkyl substituents . The automplexes . The comomplexes .Staphylococcus aureus [Acinetobacter baumanni [Repurposing encompasses the finding of novel uses to already approved and available drugs . Variouss aureus . In theibaumanni , one of baumanni .Erythrina lysistemon bark and the screening of their antimicrobial activity against an extensive panel of bacterial skin pathogens [Erythrina as antimicrobials by demonstrating the antimicrobial activity of isoflavone derivatives as the active principles [Callitris and Widdringtonia (Cupressaceae) were studied [Widdringtonia and compare their chemistry with that of the genus Callitris from the Australian clade sister [Nymphaea alba methanolic extracts [N. alba and the evaluation of the above-mentioned properties. Both leaf and root extracts present high fungistatic activity against C. glabrata [N. alba extracts could be used as an immune booster to prevent infection in immunosuppressed cancer patients [The search for plant extracts and molecules with antimicrobial activities is an intense area of research. Sadgrove et al. describe in their paper the extraction and isolation of seven isoflavone derivatives from athogens . Resultsinciples . In anot studied . The aute sister . The papextracts . The autglabrata . In addipatients . The pappatients . Variouspatients .S. aureus and P. aeruginosa [Antimicrobial peptides (AMP) are promising alternatives for therapeutic interventions to eradicate both human and animal infections. In their paper, Gomes et al. evaluated the antibacterial potential of combinations of 2 AMP, the synthetic pexiganan, and the natural nisin to control the growth of co-cultured diabetic foot clinical isolates of ruginosa . The autruginosa . The sturuginosa . In anotruginosa . The resruginosa .The development and validation of antimicrobials also encompass the evaluation of their in vivo efficacy and side effects. In the paper of Kaji et al., the effects of rifaximin on the gut microbiome were investigated . RifaximAfter a Golden Age that lasted roughly form the 1930s to the 1950s, antibiotic discovery has declined. The emergence of multi-resistant microbial pathogens, as well as the rise of old and new pathogens like SARS-COV2, poses tremendous challenges to the field of antibiotics discovery and development. The discovery of novel antimicrobials is now empowered with post genomics approaches and bioinformatics tools that will most certainly turn the tide in this exciting field of antimicrobials discovery and development.


Rapid development of nanotechnology has been in high demand, especially for silver nanoparticles (AgNPs) since they have been proven to be useful in various fields such as medicine, textiles, and household appliances. AgNPs are very important because of their unique physicochemical and antimicrobial properties, with a myriad of activities that are applicable in various fields, including wound care management. This review aimed to elucidate the underlying mechanisms of AgNPs that are responsible for their antiviral properties and their antibacterial activity towards the microorganisms. AgNPs can be synthesized through three different methods—physical, chemical, and biological synthesis—as indicated in this review. The applications and limitations of the AgNPs such as their cytotoxicity towards humans and the environment, will be discussed. Based on the literature search obtained, the properties of AgNPs scrutinizing the antibacterial or antiviral effect shown different interaction towards bacteria which dependent on the synthesis processes followed by the morphological structure of AgNPs. Silver (Ag) is a chemical element that has provided promising results in various fields such as medicine, electronics, and household applications, e.g., silver sulfadiazine has been used as a standard treatment for burn wounds to prevent the formation of biofilm on the wound area, thus enhancing the wound recovery progress . Silver −1, ultraviolet visible spectroscopy (UV–vis spectroscopy) at the range of 400–500 nm, transmission electron microscopy (TEM), scanning electron microscopy (SEM), dynamic light scattering (DLS) at scattering angle of 173°, and localized surface plasma resonance (LSPR) at wavelength of 300 nm to 1100 nm [Evaluation of silver nanoparticles (AgNPs) involves various types of analytical techniques which includes X-ray diffractometry (XRD) at wavelength (λ) = 1.54056 Å, X-ray photoelectron spectroscopy (XPS) usually between 300–400 eV, Fourier transform infrared spectroscopy (FTIR) in wavelength range of 400–4000 cmThe size, morphology, surface, and particle distribution of nanoparticles have proven to influence the physicochemical properties of AgNPs which can be altered through various synthesis methods, reducing agents, and stabilizers . Size haSilver nanoparticles (AgNPs) are already in high demand in various fields which includ health care, medical, and industrial purposes, due to their unique physical and chemical properties. Their unique properties have been influenced by their surface-to-volume ratio which enables modification of their physical, chemical, and biological properties . AgNPs cAdditional insights into the characteristics of AgNPs are discussed in this review. This review presents comprehensive and detailed information on the synthesis of AgNPs by various methods as well as the antibacterial of a AgNP. In addition, the review also focuses on the antiviral effect, application, safety, and limitation of AgNPs.There are various methods that have been done to synthesize silver nanoparticles (AgNPs) consist of physical, chemical, and biological methods which is also known as green synthesis. Physical synthesis of AgNPs excels in producing a uniform and fair distribution of AgNPs prepared on a thin film due to the absence of solvent contamination. Vapor condensation method and laser ablation are the widely used physical approaches in the synthesis of AgNPs . Vapor cAnother example of the physical synthesis of AgNPs is done by the laser ablation method that results in the average size of AgNPs between 10 nm to 30 nm. In brief, the process includes laser ablation of bulk metallic silver salts or materials in solution phase . Pure coChemical synthesis has been widely used as an alternative method in preparing silver nanoparticles in colloidal dispersion. The chemical method of preparing AgNPs involves water or organic solvents in order to reduce the silver metal salts. This process involves three components which are reducing agents, metal precursors, and stabilizing or capping agents. Reducing and capping agents is an important step in producing AgNPs because it can alter the characteristics of AgNPs according to its applications and purposes e.g., AgNPs in dental applications required particles size of 15–20 nm. The selection of reducing agents is a rate-limiting process used to achieve the specific characteristics of AgNPs in terms of size, physicochemical properties as well as prevent the coagulation of AgNPs . The dis2O (Equation (3)) which then reduced by glucose causing generation of silver particles (Equation (4)). The reaction between glucose and silver ion in PVP solution can be written as follows:The productions of silver nanoparticles with different morphologies and sizes have already been reported in various articles. To overcome the disadvantages of the chemical synthesis of AgNPs, biological methods have been preferred and are thus well studied as an alternative method in preparing silver nanoparticles. The application of biologically-mediated synthesis is proven to be cost-effective, simple, and environmentally friendly as it does not use hazardous or toxic chemicals . This apPycnoporus sp. [A previous study had extensively discussed the differences between chemical and biological methods of producing AgNPs . The cheorus sp. . The stuorus sp. . Table 3Silver has become one of the most widely studied oligodynamic materials due to its range of bactericidal activities, effectiveness, low toxicity, and various application as disinfectant. The oligodynamic effect is the biocidal effects of metals, especially heavy metals, which could occur in low concentrations of heavy metals. Silver nanoparticles (AgNPs) have proven to have oligodynamic effect due to their large surface areas with its ability to bind with bacterial biomolecules, the ability to penetrate the cells, generation of reactive oxygen species (ROS) and free radicals, and act as modulators in signal transduction pathways of microorganisms . The broE. coli and Bacillus [Escherichia coli and Staphylococcus aureus as well as prevent formation of film [The surface modification of AgNPs can also affect the oligodynamics effect of nanoparticles as surface modification can stabilize these nanoparticles e.g., modification of AgNPs with polyimide. There is a study that has proven half encapsulation of AgNPs with loosely polyimide can increase the antibacterial activity of these nanoparticles as well as improve the silver stability . CoatingBacillus . Thus, p of film .The antibacterial effects of AgNPs are more complex compare with other metallic nanoparticles and shows lower toxicity toward cells. Some metallic nanoparticles show higher antibacterial activity than AgNPs but are toxic towards cell, e.g., copper nanoparticles (CuNPs). CuNPs show greater ability to inhibit bacterial growth than AgNPs as their mechanism of action involve rupture of bacterial membrane and electron transfer by photocatalytic process . Even thSilver nanoparticles (AgNPs) have caught the attention of researchers due to its broad spectrum of antifungal and antibacterial properties. New developments of antibacterial products or agents are in dire need due to resistance of microbial towards antibiotics through mutation. Moreover, the low reactivity of AgNPs compared to the silver ions made them suitable for clinical and therapeutic application . There aE. coli and S. typhimurium) membrane by depolarization and destabilization of membrane [When the microbes are exposed to AgNPs, the nanoparticles tend to stick or adhere to the cell wall or membrane of microbes due to the electrostatic attraction between the positive charge of silver ions which is generated from oxidation of AgNPs and the negatively charged cell membrane of microorganisms . AgNPs amembrane .E. coli. After penetration of AgNPs into the cells, these nanoparticles will start to bind with cellular structures and biomolecules such as proteins, lipids, and DNA, thus damaging the internal structure of the bacteria. The silver ions that have been released into the environment will bind to negatively charge protein which altering the protein structurally and eventually result in deactivation the proteins. The result from Li et al. (2010) proved that the AgNP inhibits the respiratory chain dehydrogenase by conversion of various enzymes such as glycerol-3-phosphate dehydrogenase into dihydroxyacetone in S. aureus (Gram-positive bacteria), and thus interfere with normal growth and metabolism of the bacteria cells [As the AgNPs bind to the surface of the microbial membrane, they can also penetrate the cells and affect important biomolecules and cellular activity. AgNPs can enter the bacterial cells through a water-filled channel called porins in the outer membrane of Gram-negative bacteria such as ia cells . Additioia cells . AgNPs cia cells . Sadoon ia cells .B. sublitis and E. coli by increasing the formation of ROS which leads to membrane damage and is followed by cell death [A. vinelandii and N. europaea which were treated with 10 mg/L and 50 mg/L of AgNP.Another mechanism of action in AgNPs is the production of reactive oxygen species (ROS) which normally causes cellular oxidative stress in microbes. ROS is a general term for oxygenated compounds that involved in various cellular biological events such as superoxide, hydrogen peroxide and hydroxyl radicals. The antibacterial potential of AgNPs is usually related to the ability of nanoparticles to produce ROS and free radicals and eventually increase the oxidative stress in cells. Productions of intercellular ROS have become the most important indicator towards toxicity related to nanoparticles as they may induce lipid damage, leakage of cellular biomolecules and eventually lead to cell apoptosis . Song etll death . The TEMll death . The stuThe mechanism of signaling pathway depends on the phosphorylation and dephosphorylation cascade of protein or enzymes which are essential for cellular activity and bacterial growth. Due to unique physicochemical properties of AgNPs, there is a possibility for these nanoparticles to act as modulators of signal transduction in microbial cells . Jena etThe recent outbreaks of an infectious disease caused by a newly evolving pathogenic virus, which has developed resistance towards available antiviral drugs, has encouraged numerous researchers in the search for new antiviral agents. The viral disease depends on the entry and attachment of the virus onto the host cells by binding of viral surface components with ligands and proteins on the cell membrane. The best strategy in developing new antiviral agents is to interfere with the interactions of virus ligand and cell membrane, thereby blocking the attachment and entry of the virus into the cells. By considering the metal nanoparticles mechanism of action in microbes, silver nanoparticles (AgNPs) have become one of the strongest candidates as antiviral agents. The broad attack ranges of AgNPs towards its target have made resistance of microbes towards these nanoparticles become futile. There are a few types of research on the effects of AgNPs towards viruses. However, the details of the interaction are limited. The complexity of virus structures can contribute to the limited knowledge of nanoparticles mechanism towards the viruses. There are two ways the AgNP interacts with the pathogenic virus: (1) the AgNP will bind to the outer coat of the virus thus inhibit the attachment of virus towards cell receptors and (2) the AgNP will bind to the DNA or the RNA of the virus thus inhibiting the replication or propagation of the virus inside the host cells. A virus often triggers a cell’s apoptosis when it undergoes the viral replication process. The apoptosis of cells causes the host to have severe symptoms and could cause fatality if not treated. Mitochondrial-mediated apoptosis pathway is an example of signaling pathway that could induce cell apoptosis involving depolarization of mitochondrial membrane potential (MMP). This pathway involves 2 different protein which are Bax and Bcl-2. Bax is the pro-apoptotic protein causing permeabilization of mitochondrial membrane which allow proteins in mitochondrial intermembrane space to escape to the cytosol to induce cell apoptosis while Bcl-2 is the anti-apoptotic protein which inhibit Bax mechanism . Lv et aCoronaviridae in Nidovirales order. Coronaviridae often associate with infection in the upper part of respiratory system and the gastrointestinal tract of host. The term “corona” represents morphological structure of the protein spikes on the outer surface of the virus which resemble a crown. The size of coronaviruses are in the range of 65 to 125 nm in diameter which only contain a single-stranded RNA (size range from 26 to 32 kbs in length) as nucleic material [The Coronavirus disease 19 pandemic, commonly known as COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The coronaviruses belong to family material . With thmaterial . The hypE. coli) and non-toxic to epidermal cells [Silver nanoparticles (AgNPs) have been useful in different industrials, e.g., textiles, biomedicines, foods, and electronic applications, due to their unique physicochemical and biological properties. AgNPs are applied as antibacterial agents in disinfectants to water treatment. Moreover, the uses of AgNPs in the textile industry have gained quite a lot of attention due to the greater ion release and increasing catalytic activity as a result of the large surface area per mass of AgNP. The AgNPs are embedded into the fabric by two primary methods: (1) inserting the substrates with pre-formed nanoparticles and (2) inserting the substrates into a solution with silver salts and treating with reducing agents in order to convert silver salts into AgNPs . A silveal cells . Other tConjugations of AgNPs with other types of polymers have shown beneficial results especially stabilizing the nanoparticles as well as providing a chemically stable system . FunctioFunctionalization can also increase the antimicrobial activity of these nanoparticles. Addition of platinum can enhance the formation of silver ions through galvanic action thus enhance the efficiency of anti-bacterial activity without affecting cytoxicity . GalvaniDrosophila melanogaster [Silver nanoparticles (AgNPs) have been very useful towards many fields especially the medical field due to their wide range of applications in disinfection. However, there have been a couple of issues regarding AgNPs that are still highly debatable between researchers involving the toxicity and the environmental impact of AgNPs. These nanoparticles are viewed as potential hazards due to its ability to induce cytotoxic mechanisms such as production of reactive oxygen species (ROS), DNA damage, and heighten pro-inflammation progress in cells. Due to the unique physicochemical properties of AgNPs, especially production of reactive oxygen (ROS), these nanoparticles can cause sublethal adverse effects when the concentration or production of ROS is not controlled properly . There anogaster . There wnogaster . Argyrianogaster . This shSilver nanoparticles (AgNPs) are known for their advantages in physicochemical properties in comparison with their bulk structure. However, these nanoparticles have their own limitations whereas one of the limitations is fast reaction with oxygen called oxidation. AgNPs are very sensitive with oxygen as the silver ion will bind to oxygen and form a strong bond called an ionic bond. The formation of this ionic bond will alter the structure of nanoparticles, thus changing the physicochemical properties of nanoparticles. The oxidized AgNPs also reduce the antibacterial properties of AgNPs due to its dependence towards silver ions . AnotherThe occurrence of nanoparticles, particularly metallic nanoparticles, have been deemed very useful in numerous fields and have been acknowledged worldwide. This inclusive research on silver nanoparticles has been discussed in this review to have a better understanding on the characterization of physicochemical properties, synthesis, mechanisms of action, application, safety, and limitation of AgNPs. The unique physicochemical properties of the AgNP are dependent on various parameters of AgNPs such as size, surfactant, and structure morphology of these nanoparticles. Even though there are various methods in producing AgNPs, biological method or green synthesis have high yield and biocompatibility as it uses natural agents and nontoxic chemicals. In this review, we provide an inclusive discussion on the mode of action of AgNPs that have drawn attention as antimicrobial agents covering the antibacterial and antiviral properties of AgNPs towards various types of pathogenic viruses. Topics on the safety and limitation of AgNPs were also highlighted in this review where the aggregation and cytotoxicity of these nanoparticles have becoming the main concerns of AgNP applications. Lastly, research on a better understanding in cytotoxic mechanisms of AgNPs towards the environment by breaking the technologies limit could benefit the future prospects of AgNPs.


The Hall technique for placement of preformed metal crowns is widely used in the UK for the management of decayed primary molar teeth. The creation of space is achieved by the placement of orthodontic separators adjacent to the tooth requiring restoration. Highlighting the first reported case of an abrasion caused by dental floss, this communication describes the clinical findings of an 8-year-old patient following placement of orthodontic separators.An 8-year old boy attended the University Dental Hospital of Manchester for placement of orthodontic separators prior to restoration URE, ULE, LLE, and LRE with preformed metal crowns using the hall technique. The following week he presented with a 2cm abrasion to his right cheek, which had been caused by dental floss used in placement of the orthodontic separators.Conservative advice was given and the lesion had resolved completely at a 2-week review. This case is a timely reminder of the importance of adequate lip retraction and soft tissue management during placement of orthodontic separators. We wish to highlight a case of an iatrogenic facial abrasion caused by dental floss during the placement of an orthodontic separator. An 8-year-old boy attended the undergraduate student clinic for placement of separators, prior to the placement of preformed metal crowns using the Hall technique URE, ULE, LLE and LRE. The procedure was uneventful. However, the following week the patient presented with a 2 cm abrasion to his right cheek which was healing Fig. . His motTreatment of an abrasion involves cleaning the area, application of petroleum jelly and careful follow-up to assess for infection or scarring. In this case, the lesion had resolved completely at a 2-week review.Preformed metal crowns are the gold standard restoration for extensively decayed primary molar teeth (Kindelan et al.


Psoriasis (PsO) is one of the common chronic inflammatory skin diseases. Approximately 3% of the European Caucasian population is affected. Psoriatic arthritis (PsA) is a chronic immune-mediated disease associated with PsO characterized by distinct musculoskeletal inflammation. Due to its heterogeneous clinical manifestations , early diagnosis of PsA is often difficult and delayed. Approximately 30% of PsO patients will develop PsA. The responsible triggers for the transition from PsO only to PsA are currently unclear, and the impacts of different factors  on disease development are currently discussed. There is a high medical need, recently unmet, to specifically detect those patients with an increased risk for the development of clinically evident PsA early to initiate sufficient treatment to inhibit disease progression and avoid structural damage and loss of function or even intercept disease development. Increased neoangiogenesis and enthesial inflammation are hypothesized to be early pathological findings in PsO patients with PsA development. Different disease states describe the transition from PsO to PsA. Two of those phases are of value for early detection of PsA at-risk patients to prevent later development of PsA as changes in biomarker profiles are detectable: the subclinical phase  and the prodromal phase . To target the unmet need for early detection of this at-risk population and to identify the subgroup of patients who will transition from PsO to PsA, imaging plays an important role in characterizing patients precisely. Imaging techniques such as ultrasound (US), magnetic resonance imaging (MRI), and computerized tomography (CT) are advanced techniques to detect sensitively inflammatory changes or changes in bone structure. With the use of these techniques, anatomic structures involved in inflammatory processes can be identified. These techniques are complemented by fluorescence optical imaging as a sensitive method for detection of changes in vascularization, especially in longitudinal measures. Moreover, high-resolution peripheral quantitative CT (HR-pQCT) and dynamic contrast-enhanced MRI (DCE-MRI) may give the advantage to identify PsA-related early characteristics in PsO patients reflecting transition phases of the disease. Psoriasis (PsO) is one of the common chronic inflammatory skin diseases. Approximately 3% of the European Caucasian population is affected. Psoriatic arthritis (PsA) is a chronic immune-mediated disease associated with PsO characterized by distinct musculoskeletal inflammation. Due to its heterogeneous clinical manifestations , and the fact that only classification criteria are available [ClASsification for Psoriatic ARthritis (CASPAR) criteria], early diagnosis of PsA is often difficult to set and frequently delayed. Approximately 30% of PsO patients will develop PsA in their lifetime. Moreover, many patients develop a destructive form of arthritis with substantial morbidity and disability . ReasonsThe underlying molecular mechanisms for the transition from PsO to PsA are still poorly defined but better understood due to the use of biologic treatments addressing different target molecules for both PsO and PsA. Similar to the predictive value of anti-citrullinated peptide antibodies (ACPAs) for the development of rheumatoid arthritis (RA) in patients with arthralgia, the medical condition of PsO as an underlying disease describes an at-risk population to develop PsA. There is a high medical need, recently unmet, to identify early those patients with an increased risk for PsA development and first signs of musculoskeletal inflammatory changes for clinically evident PsA development. Only by early detection, sufficient treatments to inhibit disease progression and avoid structural damage and loss of function can be initiated. Moreover, here, the interception of PsA may be targeted with sufficient treatment when initiated in a very early stage of the PsO patients at risk for PsA development (principle of disease interception). However, ~50% of patients with PsO present with subclinical imaging enthesopathy, and only a subgroup of them will develop PsA . So, evePsA mostly develops in patients with established PsO; only in 15% of patients PsO occurs in parallel or after PsA development . The incScher et al.  recentlySo, the subclinical and prodromal phases are linked by changes that might be detectable by established biomarkers or a specific biomarker profile including imaging techniques predicting later clinical development of PsA. In the clinical care setting, patients will mainly be presented to a specialist rheumatologist in the prodromal phase, when clinical symptoms such as arthralgia and fatigue occur. The subclinical identification of PsA will be necessary for dermatologists or general practitioners (GPs) to select the patients being presented to the rheumatologist or change treatment strategy.In both scenarios, the biomarker to detect either patient in the subclinical or prodromal phase must be sensitive for detection of musculoskeletal inflammatory changes but also specific to identify those changes as PsA-related and highly predictive for later development of clinically evident PsA. Imaging studies of early PsA suggest that inflammatory enthesopathy is an early sign that is presented in PsA development . HoweverDifferent imaging techniques are available in clinical routine care to determine inflammatory musculoskeletal changes and increase in angiogenesis . DiffereIncrease in micro-vascularization is identified as an early marker for PsA and of higher value than in other inflammatory joint diseases such as RA and may be a parameter to distinguish PsO from PsA in the subclinical phase of transition . FOI is First studies to validate FOI were performed by assessment of its ability to detect synovitis/arthritis compared to the US and MRI examination  . ThuermeThe different morphologic patterns can be identified in PsA patients that might be specific for the disease : in 94% In the XCITING study, FOI was performed in patients with PsO and at risk for PsA development . In ~46% of the patients, FOI showed an increase of micro-vascularization defined as related to subclinical PsA (with the determination of inflammatory changes in MRI in 37%). Here, longitudinal data will show how many of those patients develop PsA in a 24-month follow-up period  to indicFOI is assessed with the use of a manual assessment algorithm published by Werner et al. . To use To visualize the micro-vascularization of the hands with the FOI technique, a time-dependent data set of 360 images is acquired. Each image shows the current state of the proceeding distribution of the contrast agent ICG. To objectively evaluate the status of the subject's joints individually, the micro-vascularization at each joint position is evaluated.k ∈ {3, 5, 7, 9}. Furthermore, each pixel is assigned a shade of red–blue, where the brightest (red) corresponds to the highest cluster indicating highest dynamics and the darkest to the lowest indicating the smallest dynamics  is represented by a time series containing 360 values. For each time series, three different features are extracted: the amplitude, the mean value during the signal increasing time, and the maximal gradient. Then, each of the three sets is clustered by k-means clustering, with dynamics .ks) are generated. Finally, scores for the defined joint areas are calculated based on the assigned cluster values, number of pixels in the joint area and the number of clusters k.Therefore, 12 heatmaps  labeled patients with 6,426 healthy joints and 1,162 affected joints  results in a clear distinction between the scores for healthy and affected labeled joints. The summarized results for Ultrasound (US) is used to identify structural and inflammatory changes in the joints and the musculoskeletal system . In diffAs it was shown that inflammatory enthesopathy is a subclinical sign in the transition from PsO to PsA, the US may be a sensitive and feasible method to detect early inflammatory changes at entheses. Savage et al.  showed tMRI is a very sensitive method for visualization of musculoskeletal structures that are involved in inflammatory processes. There are only little data on the detection of early PsA as the main studies on the detection of early arthritis were performed for the indication field of RA . With thDifferences between PsA and other inflammatory diseases classified by MRI are reported. In PsA, enthesitis is not related to a focal inflammation but to a wider “synovio-enthesal complex” , includiAssessments in PsO patients without evident arthritis revealed subclinical inflammation in both joints and entheses. Moreover, it was found that PsO patients with subclinical inflammation in MRI and arthralgia had a high risk (55.5%) for the later development of PsA, whereas patients without arthralgia had a low risk (15.3%) for PsA development . The speNew methods of MRI such as whole-body MRI (WB-MRI) and dynamic contrast-enhanced MRI (DCE-MRI) are used in the research of PsO and PsA discrimination and prediction of PsA development. DCE-MRI allows semiautomated quantification of inflammation based on the measurement of contrast enhancement pattern over time in the selected region of interest. A recent report reports differences in RA and PsA in the pattern of enhancement of the synovial membrane with higher inflamed tissue in RA but a higher degree of inflammation in PsA . WB-MRI Conventional radiographic imaging methods such as x-ray  or conveInnovative methods, such as high-resolution peripheral quantitative CT (HR-pQCT) are available to sensitively detect early changes in bone metabolism in PsO patients compared to PsA and other joint diseases. Bone erosions can be detected early in the disease state of PsA , and theBesides HR-pQCT, dual-energy CT (DECT) with iodine mapping to improve iodine contrast resolution may be a sensitive method to discriminate early inflammatory arthritis  but restBone scintigraphy is an established method displaying an increase of metabolism of the tracer as a sign for abnormal metabolism rates, e.g., in the inflammatory state. It is used to detect inflammatory changes in the whole body, especially if other imaging techniques are not available. It has poor specificity and is limited by the use of the radioactive isotopes (tracers). In PsA, it was used in different cohorts to detect subclinical signs of inflammation in PsO patients without evident clinical PsA. The results were compared to the findings in US examination and clinical examination . It was 18F-FDG-PET) is a very sensitive imaging method for detection of changes in metabolism, e.g., inflammation-dependent early musculoskeletal changes indicating PsA-related changes. Takata et al. , demonstrating its high sensitivity in the detection of inflammation at the entheses.Fluorine-18-labeled fluorodeoxyglucose positron emission tomography . In only two of those phases, early changes in soluble biomarkers/imaging can be detected  or first unspecific clinical symptoms  occur . These two phases may be useful in early discrimination of the PsO patients at risk to develop overt PsA to prevent its occurrence .In the transition model, the subclinical phase includes early musculoskeletal inflammatory changes in PsO patients without musculoskeletal complaints. In this phase of the disease, MRI, HR-pQCT, and high-frequency ultrasonography might have the highest potential to distinguish inflammatory changes in the defined at-risk-population with the limitation of the specificity to be PsA-related. By a combination of these techniques, patients are deeply characterized in focus on first musculoskeletal inflammatory changes and early changes in bone structure/bone metabolism. This characterization is completed by the use of FOI to generate additional information on early changes in vascularization as signs of increased angiogenesis, reported as an early marker in PsA progress . In diffThe prodromal phase of the disease is classified as unspecific clinical symptoms such as arthralgia and/or fatigue combined with the occurrence of inflammatory changes in imaging. A recent study showed that, in this phase, tenosynovitis was the most significant contributor to the reported musculoskeletal symptoms . In the US, in a high proportion of patients, tenosynovitis especially of the flexor tendon of the hands was detected  , whereasPsO is one of the common chronic inflammatory skin diseases, affecting ~3% of the European Caucasians. PsA is a chronic immune-mediated disease associated with PsO characterized by distinct musculoskeletal inflammation. Due to its heterogeneous clinical manifestations , early diagnosis of PsA is often difficult and delayed. PsO patients are of high risk for PsA development as ~30% of PsO patients will be affected by (chronic) musculoskeletal inflammation.The main events for the transition from PsO to PsA are currently unclear: the combination of genetic and clinical–demographic risk factors  may promote PsA development and its progression. The underlying molecular mechanisms for the transition from PsO to PsA are still poorly defined. The increase of neoangiogenesis  and the Different phases were defined to describe the transition from PsO to PsA . Three pThe potential of the available imaging techniques to detect patients in one of these two phases differs widely as all of these techniques characterize different pathophysiologic states of the inflammatory process that might have the highest value by being combined for deep characterization of the patients .Besides sensitivity and specificity in the detection of anatomical and pathophysiological changes by use of advanced imaging techniques, standardized assessment tools are needed to bring innovative imaging methods in context to the suspected indications and process results to enable detection of coherence between saliences and the underlying disease. Technological advances should be integrated into assessment algorithms to use its full potential to be beneficial in the detection of at-risk patients especially in context to PsO and PsA patients.FOI as an ICG-tailored imaging technique visualizes changes in micro-vascularization of the hands . It is aMRI and US are the recent widely used methods for sensitive detection of inflammation in the joints and musculoskeletal structures . Bone marrow edema, enthesitis, and changes in vascularization as early indicators of inflammation of the joints, entheses, and spine in the subclinical and prodromal phases can be visualized with high sensitivity by both . The US HR-pQCT, developed from CT technique, might be of high value to detect early changes in bone metabolism and structure in PsO and PsA patients (compared to other inflammatory diseases), but the value for discrimination of PsO or PsO transient to PsA is recently not clear. Simon et al.  showed tEstablished methods such as x-ray or CT are not sensitive enough to detect early inflammatory changes of the musculoskeletal disease but changes in bone structure.PET/CT and scintigraphy have established methods with a focus on metabolism and its changes in the inflammatory disease state. Both methods are limited by their poor specificity but sensitive to illustrate changes early and with focus on the whole body not restricted by use in one region of interest.For US, MRI, and HR-pQCT, the relevance of the early findings of enthesophytes (HR-pQCT) or detection of enthesopathy  as signs for early musculoskeletal inflammation without clinical symptoms  in PsO patients is still unclear. In a longitudinal study, it was found that although these findings were detectable in 50% of the PsO patients, only a part of them developed overt PsA later in their disease state , 45. So,The potential of these imaging techniques increases in the prodromal phase when clinical symptoms appear, even if they are non-specific. Here, the at-risk population is enriched, and the combination of both imaging findings and arthralgia predicts the development of PsA significantly.Overall, different imaging techniques are available with various methods to sensitively quantify vascularization and early signs of musculoskeletal inflammation in PsO and PsA patients. Advanced methods adapted from conventional techniques are of advantage to illustrate early changes in bone metabolism or quantify inflammation in the anatomical structure. With the use of these techniques, pathophysiological backgrounds of PsO and PsA are explored and can be characterized more precisely. New methods such as FOI might be able to complement other imaging techniques by quantification of changes in micro-vascularization as a very early sign of inflammation . Nevertheless, by now, it is not possible to specifically discriminate between PsO patients and those who will develop PsA by solely using imaging as a biomarker. So, further studies are needed to explore the impact of different characteristics/biomarkers  and their impact in predicting PsA to characterize the at-risk patients precisely and explore their impact of PsO patient selection for a longitudinal follow-up to assess the development of PsA or its interception.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.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 terminology of cerebellar dysmetria embraces a ubiquitous symptom in motor deficits, oculomotor symptoms, and cognitive/emotional symptoms occurring in cerebellar ataxias. Patients with episodic ataxia exhibit recurrent episodes of ataxia, including motor dysmetria. Despite the consensus that cerebellar dysmetria is a cardinal symptom, there is still no agreement on its pathophysiological mechanisms to date since its first clinical description by Babinski. We argue that impairment in the predictive computation for voluntary movements explains a range of characteristics accompanied by dysmetria. Within this framework, the cerebellum acquires and maintains an internal forward model, which predicts current and future states of the body by integrating an estimate of the previous state and a given efference copy of motor commands. Two of our recent studies experimentally support the internal-forward-model hypothesis of the cerebellar circuitry. First, the cerebellar outputs (firing rates of dentate nucleus cells) contain predictive information for the future cerebellar inputs (firing rates of mossy fibers). Second, a component of movement kinematics is predictive for target motions in control subjects. In cerebellar patients, the predictive component lags behind a target motion and is compensated with a feedback component. Furthermore, a clinical analysis has examined kinematic and electromyography (EMG) features using a task of elbow flexion goal-directed movements, which mimics the finger-to-nose test. Consistent with the hypothesis of the internal forward model, the predictive activations in the triceps muscles are impaired, and the impaired predictive activations result in hypermetria (overshoot). Dysmetria stems from deficits in the predictive computation of the internal forward model in the cerebellum. Errors in this fundamental mechanism result in undershoot (hypometria) and overshoot during voluntary motor actions. The predictive computation of the forward model affords error-based motor learning, coordination of multiple degrees of freedom, and adequate timing of muscle activities. Both the timing and synergy theory fit with the internal forward model, microzones being the elemental computational unit, and the anatomical organization of converging inputs to the Purkinje neurons providing them the unique property of a perceptron in the brain. We propose that motor dysmetria observed in attacks of ataxia occurs as a result of impaired predictive computation of the internal forward model in the cerebellum.  Lesions of the cerebellum elicit inaccuracy and clumsiness in limb movements and instability in posture and gait and ocular saccades, collectively termed as “ataxia”, the diseases being gathered under the umbrella of cerebellar ataxias (CAs) . The terAmong a wide range of manifestations of cerebellar ataxias, dysmetria is a core symptom in cerebellar motor ataxias  and alsoAtaxic movements are typically slow and inaccurate and accompanied by excessive movement corrections. Movement deviation becomes more significant for actions performed as fast as possible , where pRecent computational and physiological studies have shown that the cerebellum predicts current and future states of the body and environments by integrating an estimate of the previous state and a given efference copy of motor commands ,9,10. ThThis review will focus on pathomechanisms underlying dysmetria in cerebellar motor ataxias. We will evaluate the hypothesis that dysmetria is a result of impairments in an internal forward model. For this aim, we first review, in Several physiological classifications of the cerebellum have been advanced in the last years with the demonstration that the cerebellum contributes to non-motor functions, in addition to the motor functions . The mosThe cerebellar cortex is characterized by the homogeneous “crystal-like” organization. Nevertheless, the parallel loop organization mentioned above suggests functional localization of the cerebellar cortex. Indeed, there are two known gradients in the cerebellar cortex: rostrocaudal and mediolateral.Anterior cerebellar lobe (lobule I-VI) and lobule VIII relate to sensorimotor regions of the cerebral cortex and participate in motor tasks . Lobule Besides these rostrocaudal compartments, the mediolateral axis separates cerebellar functions. The medial and intermediate cerebellar cortex controls gait and stance, and the intermediate and lateral cerebellar cortex control limb movements . In terms of somatomotor maps, recent studies with 7T fMRI confirms that multiple representations of the distal body parts are found in the human cerebellum and organized in an orderly fashion B–D 14]..14]. TheA recent study also reported functional compartmentalization of the cerebellum for different associative learning. The medial and lateral zones contribute to fear conditioning, whereas the intermediate zone handles eyeblink conditioning . Several4) in primates . A. Aθ(t) amponent) C. In theA theory in neuroscience should guide what an experiment must investigate and what consequences the experiment should yield to support or falsify the theory. One of the prime examples is the Marr-Albus-Ito theory of the cerebellar cortex; the prediction of plasticity in the synapses from parallel fibers to a Purkinje cell set the stage for the subsequent experimental endeavors . In a si5. Second, there is a population of granule cells and Golgi cells between MFs and PCs, which may enable a complex nonlinear transformation of MF inputs. So, we expected that models with some nonlinearities could provide much better fitting for the activities of PCs. We then compared the linear model with a thresholded nonlinear model, a quadratic nonlinear model, and a finite-impulse model. A statistical comparison test revealed that the linear model explained the firing rate most parsimoniously. Subsequently, we proceeded to reconstruct the firing rates of DCs as a linear weighted sum of those of MFs and PCs, considering the anatomical connectivity that DCs receives inhibitory inputs from PCs and excitatory inputs from collaterals of MFs. The linear-model fitting was again most distinguished, where the median value of goodness-of-fit was as much as 0.94. Overall, our analysis revealed the linear transformation of cerebellar activities across populations. The dataset we analyzed contained activities of 94 MFs, 83 PCs, and 73 DCs recorded from a behaving monkey performing the wrist step-tracking task toward one of the eight targets ,65. We ft + t1 as a linear weighted sum of the firing rates of DCs at time t. The time advance t1 was a parameter to determine how much future the cerebellar output should predict the cerebellar input. When t1 ranged from 20 ms to 200 ms, the median goodness-of-fit decreased only moderately from 0.89 to 0.86. A statistical permutation test confirmed that these values were statistically significant, rejecting a null hypothesis that the linear prediction was caused just by a statistical coincidence. Our result of linear prediction affirms empirically that the cerebellum as a whole operates as an internal predictive model, which outputs a prediction of future inputs. We finally note that the linear relationship between the MF, PC, and DC activities resemble those of an optimal estimator known as the Kalman filter , i.e., when the trajectory was adjusted using oscillations, dysmetria became small. The compensatory feedback corrections in our recordings correspond with discontinuities in movements by Hore and Flament [A series of studies from our group has supported this predictive origin of muscle activity. We identified the receipt of motor commands in humans by analyzing the components of muscle activity in terms of movement kinematics of the wrist joint in smooth tracking task see [59,60,6 Flament . Discont Flament . The traImportantly, the tremorous movements observed in ataxic patients are highly irregular and different from regular oscillations that are generated as an inherent problem in the reflex controller or as potentiation of a central oscillator ,85. For These behavioral observations indicate that EMG and kinematic features of the goal-directed tracking tasks in ataxic patients are related to the impairment of continuous predictive controls substituted by intermittent step-wise corrections. It should be noted that these step-wise corrections themselves are controlled with the impaired predictive controller and therefore result in irregular tremorous oscillations.Although there have been a number of studies suggesting that the cerebellum serves as a predictive controller , the preHolmes proposed that impaired movements in the nose-finger test are attributed to the delay in initiation (asthenia) and deficit in postural fixation (adventitious movements) ,88. He aIn parallel with the timing-control theory of the cerebellum, another theory stresses the coordinative function of the cerebellum, which we refer to as the synergy-control theory. Thach  emphasizA study on neuronal activities in monkeys showed that a vast majority of PCs, with somatosensory receptive fields (RFs) in the forearm, was suppressed strongly before the onset of wrist movements. In contrast, a vast majority of DNs with the same RFs showed a concurrent increase in the activity . The cenBased on these neural mechanisms, altered timing and amplitude of disinhibition will provide not only delayed timing of activities of agonist and/or antagonist muscles , but also reduced rates of the rise with altered amplitudes . In fact, noninvasive cerebellar stimulation reinforced activities of the chained inhibitory neurons, resulting in improvement in the relative timing of agonist/antagonist bursts . On the seeDespite their apparent differences, the timing theory and the synergy theory could be two aspects of an impairment of the predictive control using the internal forward model. It should be emphasized that even a synergic control requires adjustments of both timing and amplitude of individual muscle activities. Taken together, we believe that the cerebellum contributes prediction of proper temporal and spatial parameters of the body and its environment for coordinated compound movements and that both timing and synergy are essential aspects of the prediction see.An impairment of the predictive computation explains a range of characteristics manifested in cerebellar ataxia, as reviewed above. The finding that the prediction of the internal forward model underlies not only compensation of sensory delay but also motor learning indicates that the internal forward model administers motor control and learning in multiple time scales. In this regard, a theory of the internal forward model could provide a comprehensive framework for dysmetria not only for episodic ataxias but also for chronic and permanent ataxias. The attacks of ataxia would represent recurrent impairments in the update/building of the internal model. In conclusion, EMG and kinematic features associated with dysmetria can be explained without contradiction by inappropriate timing and synergy controls in cerebellar prediction. This review article proposes that the prediction of the internal forward model is critical both for motor control and learning and that the neural circuitry of the cerebellum is befitting for implementing the neural computation of the internal-forward-model prediction. The two recent studies from our group support the forward-model hypothesis of the cerebellum from behavioral and neurophysiological perspectives. Recent progress in clinical neurophysiology evinces that dysmetria in cerebellar motor ataxias is a result of impairments in an internal forward model embedded in the cerebellum. Although there have been historical arguments whether dysmetria can be attributed to deficits in timing or impediments in synergy, timing anomalies and asynergy could be two aspects of an elementary impairment of the predictive control using the internal forward model. The cerebellum forms reciprocal connections with both (a) the cortical motor areas and the prefrontal areas and (b) basal ganglia, indicating that the cerebellum coordinates with those cortical areas for motor and non-motor functions. The uniform anatomical circuit in the cerebellum suggests that the predictive computation in the cerebrocerebellum contributes to not only motor controls but also to non-motor, so-called ‘cognitive’ functions, not only for episodic ataxias but also for chronic ataxias. We expect that future studies will advance our understanding of the predictive nature and its impairment underlying dysmetria in the cerebellar cognitive affective syndrome (Schmahmann’s syndrome).


The deposition of a multicomponent alloy—Inconel 625—on a basic substrate such as structural steel is presented. The authors propose a new approach for stopping carbon and iron diffusion from the substrate, by using the Semi-Hybrid Deposition Method (S-HDM) developed by team members. The proposed semi-hybrid method was compared with alternative wire and powder deposition using laser beam. Differences of S-HDM and classic wire deposition and powder deposition methods are presented using metallographic analysis, within optic and electron microscopy. Significant differences in the obtained results reveal advantages of the developed method compared to traditional deposition methods. A comparison of the aforementioned methods performed using nickel based super alloy Inconel 625 deposited on low carbon steel substrate is presented. An alternative prototyping approach for an advanced high alloy materials deposition using CO2 laser, without the requirement of using the same substrate was presented in this article. This study confirmed the established assumption of reducing selected components diffusion from a substrate via buffer layer. Results of metallographic analysis confirm the advantages and application potential of using the new semi-hybrid method for prototyping high alloy materials on low alloy structural steel substrate.This article presents the results of the metal deposition process using additive materials in the form of filler wire and metal powder. An important problem in wire deposition using a CO Microstructure of the upper layers is similar and consists of pillar-dendritic structure ,31. HoweThe manufactured materials have a dominating pillar-dendritic structure; however, in fusion regions in this method, regions with a cellular dendritic structure can also be observed .A chemical composition analysis of the fusion region where deposited materials are mixed with the substrate was performed  based onDistribution of the measured alloying elements shows a higher mixing factor for S-HDM; meanwhile, in wire deposition, non-uniform distribution is reveled. The deposition method using filler wire without a buffer zone affected the appearing of local areas, where both the substrate and deposited material are not fully mixed, and clear boundaries can be indicated . The bufDifferences in iron concentration between the second and third layers reveal a more intense migration of iron from the substrate to the upper layers for the deposition method using filler wire alone, while for the developed semi-hybrid method, iron diffusion is limited to the buffer zone, similar to the powder deposition method.The materials used for deposition have important differences in chemical composition compared to the substrate material . The afoDeposition parameters were developed according to a separate preliminary study. Therefore, for the filler wire deposition method, output power was equal to 3 kW with deposition speed  of 1.5 m/min for wire deposition alone. However, those parameters were corrected, and for deposition of the first two layers for the semi-hybrid method, output power reduction was performed (to 2.8 kW), and deposition speed was increased (to 2 m/min). The buffer layer as well as powder deposition method was obtained with output power equal to 2.25 kW and deposition speed combining process head movement speed of 0.8 m/min and powder delivery feed rate of 15 g/min.Global observation showed significant differences in the fusion zone between the substrate and the deposited materials depending on the deposition process. Moreover, macroscopic analysis showed a potentially non-uniform structure in the fusion zones for the wire deposition method and cavity with partially molten powder for the powder deposition method . TherefoPrototyping using the proposed new semi-hybrid method combines advantages of powder and wire deposition, where the fusion zone of the substrate and deposited material is narrow, and is related to the thin film of the substrate surface melted by deposited material in liquid state. This phenomenon allows obtaining a permanent bonding between the substrate and first layers of the deposited material; however, diffusion between them is limited . In the The ferritic-pearlitic structure of the substrate material consisted of a substantial iron amount, and diffusion of this element combined with migration of carbon to Inconel 625 layers can reduce its properties, especially high temperature resistance and corrosion resistance. The wire deposition alone method via keyhole deep penetration affects intensive mixing of deposited material with the substrate, when the keyhole penetrates the bottom workpiece. The influence of the flow field is clearly evident from the corresponding solidified structure. In the case of substrate penetration, discrete growth bands occur in the entire solidified padding beads, suggesting severe fluctuations in the flow field and the growth process  38]..38].xOy oxides detection was located in a buffer zone. This type of precipitation most likely appears in materials when temperature of the buffer zone reaches 700 °C (973 K). The γ” phase precipitates (A3 B type) and a tetragonal crystal structure begins to form, often in a disk-shaped morphology, coherent with respect to the matrix . SE. SE39]. e matrix .The homogenous structure of manufactured materials is related to the uniform distribution of chemical elements. Therefore, an analysis of the defined regions in the cross-section was performed based on the linear and map distribution of Mo, Fe, and Ni. The performed study shows greater differences in the wire deposition method without a buffer zone. Distribution of alloying elements in the material deposited using the wire alone method fluctuates, and uniform composition and structure do not occur a. The maThe obtained uniform composition and structure of the deposited material provide good mechanical properties, as well as corrosion and temperature resistance, which is crucial in power plant construction, especially for components of nuclear installation. While using the proposed method, reduction in material costs  can be achieved. While restraining of iron and carbon diffusion from the substrate can be obtained using powder deposition alone or proposed semi-hybrid methods, better material density can be provided by the wire deposition method. Even trace amounts of iron and carbon from the substrate or buffer zone affect the properties of the deposited material, which change with the subsequent layers. Applying a buffer zone with similar chemical composition allows to obtain materials with similar composition and properties starting from the first wire deposition layers. Moreover, the deposited additional buffer zone is bonded with the substrate using less power than in the wire deposition method; therefore, stress-strain concentration in the substrate and its deformation are reduced.2 laser wire deposition disadvantages. The requirement of obtaining a keyhole effect with deep penetration affecting high mixing of the substrate and the deposited material was reduced by the buffer layer. Similar composition of the buffer and deposited layers allows the development of materials with good characteristics. This new approach to wire deposition and CO2 lasers enables the use of this type of machine and the wire deposition method to manufacture high alloy materials on the substrate made of inexpensive structural steel. The present study confirms the established assumption of reducing iron diffusion from inexpensive substrate by using buffer layers. The deposition of a two-layer buffer zone using selective melting of metal powder having a composition similar to that of the inexpensive filler wire makes it possible to use wire deposition and CO2 laser in order to manufacture an advanced structure of uniform composition and good properties. Further study of the developed S-HDM is planned and will be aimed at comparing the mechanical properties of materials prototyped using the proposed new method, filler wire deposition, and metal powder deposition methods.A new developed semi-hybrid deposition method, consisting of combining selective metal deposition of metal powder with deposition using filler wire was performed. The proposed method was compared with filler wire and metal powder deposition methods. The presented results show significant differences in bonding mechanism between the substrate and deposited materials. Deep material penetration via the keyhole effect leads to a high mixing ratio of deposited layers with the substrate. However, using S-HDM, where the first two layers are deposited using metal powder causes diffusion of alloy components from the substrate to be restrained, similar to the powder alone deposition method. Some inclusions occur for the three mentioned methods, i.e., wire deposition is related to solidification between the substrate and the lower layers, while for the proposed method, complex oxides containing Nb, Ti, and Al were identified in the deposited buffer zone. Combination of the two deposition methods makes it possible to overcome CO