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ID PMID Title PublicationDate abstract
34033819 Nanomedicine-based delivery strategies for nucleic acid gene inhibitors in inflammatory di 2021 Aug Thanks to their abilities to modulate the expression of virtually any genes, RNA therapeutics have attracted considerable research efforts. Among the strategies focusing on nucleic acid gene inhibitors, antisense oligonucleotides and small interfering RNAs have reached advanced clinical trial phases with several of them having recently been marketed. These successes were obtained by overcoming stability and cellular delivery issues using either chemically modified nucleic acids or nanoparticles. As nucleic acid gene inhibitors are promising strategies to treat inflammatory diseases, this review focuses on the barriers, from manufacturing issues to cellular/subcellular delivery, that still need to be overcome to deliver the nucleic acids to sites of inflammation other than the liver. Furthermore, key examples of applications in rheumatoid arthritis, inflammatory bowel, and lung diseases are presented as case studies of systemic, oral, and lung nucleic acid delivery.
34000006 Cefazolin and rifampin: A coagulopathy-inducing combination. 2021 Dec 9 PURPOSE: To identify risk factors that may predispose patients to rifampin- and cefazolin-induced coagulopathy. SUMMARY: An 86-year-old man with a history of rheumatoid arthritis on chronic prednisone and stage 3 chronic kidney disease, notably not on warfarin, presented to the hospital with a 10-day history of right hip pain, swelling, and drainage after a recent right total-hip arthroplasty. The patient underwent a combination of surgical intervention and medication therapy with rifampin and ceftriaxone. After discharge and at postoperative day 9, ceftriaxone was changed to cefazolin due to increasing alkaline phosphatase levels. Four weeks after the initial debridement, antibiotics, and implant retention, the patient underwent a second irrigation and debridement due to persistent infection. Cefazolin and rifampin therapy was extended. Three days later, the patient presented to the emergency room with significant bleeding at the surgical site and a profoundly elevated prothrombin time and international normalized ratio (INR). No potential contributors were identified. The Naranjo adverse drug reaction probability scale identified cefazolin and rifampin as the probable cause of elevated INR. The Liverpool adverse drug reaction avoidability assessment tool classified this adverse event as "definitely avoidable." CONCLUSION: Rifampin-containing regimens are often recommended to treat staphylococcal prosthetic joint infections when the implant is retained. In methicillin-susceptible staphylococcal infections, cefazolin is routinely employed as the β-lactam backbone of definitive antimicrobial regimens. Although rifampin- and cefazolin-induced hypoprothrombinemia seems to be rare, adverse consequences of its occurrence may be prevented with appropriate monitoring.
33955139 Aggregation of autoimmunity in extended families of people with autoimmune Addison disease 2021 May 5 BACKGROUND: Autoimmunity accounts for 90% of cases of primary adrenal insufficiency (Addison disease (AD)). Affected people present a significant co-occurrence of autoimmune conditions; hence, clustering of autoimmunity is also predicted among their relatives. AIMS: To evaluate the burden of autoimmunity in families of people with AD. METHODS: A total of 116 individuals with AD was surveyed regarding the occurrence of 23 autoimmune diseases among their relatives. RESULTS: A total of 74.1% of persons with AD reported at least one relative with an autoimmune disorder - 257 cases were diagnosed in 221 relatives. Hashimoto thyroiditis was found in 100 individuals, followed by Graves disease and vitiligo, in 25 and 24 relatives respectively. Type 1 diabetes was diagnosed in 23 relatives, psoriasis in 15, rheumatoid arthritis in 12, pernicious anaemia in 11, multiple sclerosis in 8, and premature menopause in 8 women. AD was found in seven relatives, alopecia in six and celiac disease in five. Other conditions were rare. Significant correlation was noticed between the number of autoimmune conditions in AD proband and the number of affected relatives (P = 0.031). A total of 66.4% of people with AD had a first-degree relative suffering from autoimmunity. Autoimmune conditions were more frequent among females: sisters (P < 0.001), mothers (P = 0.002) and grandmothers (P = 0.002). CONCLUSIONS: Considerable prevalence of autoimmune conditions in relatives of people with AD confirms substantial risk of autoimmunity, especially in females and relatives of patients affected by multiplex autoimmunity. Our data corroborate the recommendation of active screening for autoimmune disorders, particularly thyroid disease, among AD family members.
33868250 New Insights Into Novel Therapeutic Targets in ANCA-Associated Vasculitis. 2021 Biologics targeting inflammation-related molecules in the immune system have been developed to treat rheumatoid arthritis (RA), and these RA treatments have provided revolutionary advances. Biologics may also be an effective treatment for anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, particularly in patients with resistance to standard treatments. Despite the accumulation of clinical experience and the increasing understanding of the pathogenesis of vasculitis, it is becoming more difficult to cure vasculitis. The treatment of vasculitis with biologics has been examined in clinical trials, and this has also enhanced our understanding of the pathogenesis of vasculitis. A humanized anti-interleukin-5 monoclonal antibody known as mepolizumab was recently demonstrated to provide clinical benefit in the management of eosinophilic granulomatosis with polyangiitis in refractory and relapsing disease, and additional new drugs for vasculitis are being tested in clinical trials, while others are in abeyance. This review presents the new findings regarding biologics in addition to the conventional immunosuppressive therapy for ANCA-associated vasculitis.
33777941 Comparative Analysis of BTK Inhibitors and Mechanisms Underlying Adverse Effects. 2021 The cytoplasmic protein-tyrosine kinase BTK plays an essential role for differentiation and survival of B-lineage cells and, hence, represents a suitable drug target. The number of BTK inhibitors (BTKis) in the clinic has increased considerably and currently amounts to at least 22. First-in-class was ibrutinib, an irreversible binder forming a covalent bond to a cysteine in the catalytic region of the kinase, for which we have identified 228 active trials listed at ClinicalTrials.gov. Next-generation inhibitors, acalabrutinib and zanubrutinib, are approved both in the United States and in Europe, and zanubrutinib also in China, while tirabrutinib is currently only registered in Japan. In most cases, these compounds have been used for the treatment of B-lymphocyte tumors. However, an increasing number of trials instead addresses autoimmunity and inflammation in multiple sclerosis, rheumatoid arthritis, pemphigus and systemic lupus erythematosus with the use of either irreversibly binding inhibitors, e.g., evobrutinib and tolebrutinib, or reversibly binding inhibitors, like fenebrutinib. Adverse effects (AEs) have predominantly implicated inhibition of other kinases with a BTKi-binding cysteine in their catalytic domain. Analysis of the reported AEs suggests that ibrutinib-associated atrial fibrillation is caused by binding to ERBB2/HER2 and ERBB4/HER4. However, the binding pattern of BTKis to various additional kinases does not correlate with the common assumption that skin manifestations and diarrhoeas are off-target effects related to EGF receptor inhibition. Moreover, dermatological toxicities, diarrhoea, bleedings and invasive fungal infections often develop early after BTKi treatment initiation and subsequently subside. Conversely, cardiovascular AEs, like hypertension and various forms of heart disease, often persist.
33714267 Cerebral metastasis of Merkel cell carcinoma following resection with negative margins and 2021 Mar 14 BACKGROUND: Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine tumor of the skin. It is associated with advanced age, ultraviolet (UV) radiation, and Merkel cell polyomavirus. It has a predilection for the lymphatic system, but rarely spreads to the central nervous system. CASE PRESENTATION: A 71-year-old Caucasian man with a history of rheumatoid arthritis and MCC of the right lower eyelid and cheek presented with left-sided hemineglect and word-finding difficulty. Twenty months earlier he had undergone local excision of a 3 cm lesion with negative margins, negative sentinel lymph node biopsy, and external beam radiation. On presentation he was found to have a 6.3 cm mass in the right frontotemporal region. He underwent prompt resection, with pathological analysis consistent with metastatic MCC. He subsequently underwent stereotactic radiosurgery (SRS) and adjunctive immunotherapy with pembrolizumab. He has since tolerated the therapy well and is currently without neurological symptoms or evidence of recurrence. CONCLUSIONS: Cerebral metastasis of MCC is a rare event and should be considered when a patient with a history of MCC presents with neurological symptoms. Optimal treatment regimens of these rare cases are unclear; however, prompt resection, stereotactic radiosurgery, and adjunctive immunotherapy have shown an initial positive response in this patient.
33627288 Whole-body cryostimulation application with age: A review. 2021 Feb In this review we examine studies exploring the effects of whole-body cryostimulation (WBC) from the perspective of applications with age with subjects over the age of 55 years old. Blood based factors such as Erythropoietin and Il-3 increased in exercised trained and normal subjects after WBC while other parameters did not change. WBC treatment of patients with Rheumatoid Arthritis decreased levels of the inflammatory markers IL-6 and TNF-α with a in the elasticity of erythrocytes. In older subjects with Mild Cognitive Impairment (MCI) a significant improvement of short-term memory was noted with reduced levels of IL-6 with an increase in BDNF release when whole blood was challenged with Aβ42. WBC appears to be an exciting non-pharmacological treatments with pleiotropic action. It has potential in enhancing performance and alleviating chronic conditions in older subjects as part of an active rest programme in combination with regular physical exercise. In conditions associated with cognitive dysfunction including Alzheimer's and other forms of dementia the many properties of WBC as an affordable treatment has exciting therapeutic potential.
33532105 A Case of Cardiac Arrest during C1 Laminectomy for Irreducible Atlantoaxial Subluxation. 2021 We report a case of cardiac arrest, which occurred during C1 laminectomy for irreducible atlantoaxial subluxation, with return of spontaneous circulation (ROSC) upon interruption of the laminectomy. A 60-year-old woman with rheumatoid arthritis presented with neck pain, bilateral finger numbness, and bladder-rectal disturbance. Simple radiograph images showed that the atlantodental interval (ADI) was enlarged to 8 mm, and magnetic resonance imaging revealed severe spinal stenosis at C1. She was diagnosed with cervical spondylotic myelopathy due to atlantoaxial subluxation. Cardiac arrest occurred twice during the C1 laminectomy and occipito-cervical fusion (Occ-C3), and ROSC occurred without any treatment. There was no postoperative worsening of neurological symptoms, and the improvement of sensory and motor palsy was favorable. The pathogenic mechanism was presumed to be trigeminocardiac reflex. Cardiac arrest during upper cervical spine surgery is an important intraoperative complication of which operators should be made aware.
33422443 The Association of Gastrocnemius Tightness, Genu Valgum and Hallux Valgus: A Prospective C 2021 Mar There has been much debate regarding the aetiology and pathogenesis of hallux valgus and it appears to be multifactorial with contracture or tightness of the Achilles tendon and more specifically the gastrocnemius being implicated as an intrinsic factor. The purpose of this study was to look at the association of gastrocnemius tightness, genu valgum and hallux valgus. A prospective case-control study with 25 patients in each group was carried out over a 12-month period. The case group observed adult patients who were referred primarily because of symptomatic hallux valgus and were assessed for the following: hallux valgus stage; presence or absence of isolated gastrocnemius tightness; presence or absence of genu valgum. The control group excluded those with pre-existing hallux valgus, genu valgum and rheumatoid arthritis and were assessed for isolated gastrocnemius tightness. There was a statistically significant association between the presence of genu valgum and hallux valgus when comparing both groups with a p < .001. There was also a statistically significant association between the Silfverskiöld test and the presence of hallux valgus, as well as the Silfverskiöld test and the presence of genu valgum with a p < .001. This study is the first to describe the association of gastrocnemius tightness, genu valgum and hallux valgus. Further studies are required to assess this relationship but knowledge and awareness of it can be applied by clinicians when considering the most appropriate management options with patients.
33127557 Emerging role of ficolins in autoimmune diseases. 2021 Jan Ficolins are pattern-recognition molecules (PRMs) that could form complexes with mannose-binding lectin-associated serine proteases (MASPs) to trigger complement activation via the lectin pathway, thereby mediating a series of immune responses including opsonization, phagocytosis and cytokine production. In the past few decades, accumulating evidence have suggested that ficolins play a major role in the onset and development of several autoimmune diseases (ADs), including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), Type 1 diabetes (T1D), inflammatory bowel disease (IBD), etc. In this review, we synthesized previous literatures and recent advances to elucidate the immunological regulations of ficolins and discuss the potential diagnostic ability of ficolins in ADs, as well as giving an insight into the future therapeutic options for ficolins in ADs.
33096106 Regulatory B cells and T cell Regulation in Cancer. 2021 Jan 8 Recent researches shed light on B cell role on various autoimmune diseases, including autoantibody-mediated diseases as well as T cell-mediated autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. B cells play a critical role in the immune response beyond the production of antibodies through mechanisms such as antigen presentation and cytokine production. Furthermore, B cells have recently been recognized to play a role in promoting tumor immunity against cancer. However, not all B cells positively regulate immune responses. Regulatory B cells negatively regulate immune responses by the production of anti-inflammatory cytokines such as interleukin (IL)-10, IL-35, and transforming growth factor-beta. Thus, a balance between effector and regulatory B cells regulates the immune response through the release of cytokines. In this review, we highlight the main emerging roles of B cells in tumor immunity with a focus on the T cell response. These findings can guide a protocol for selectively depleting regulatory B cells as a potential therapeutic strategy for patients with cancer.
32840657 Total laparoscopic multi-compartment native tissue repair of pelvic organ prolapse and str 2021 Apr AIM OF THE VIDEO: In this video we present the surgical management of a 59-year-old woman with stress urinary incontinece (SUI) and pelvic organ prolapse (POP) who had a history of rheumatoid arthritis and endometrial hyperplasia with atypia. METHODS: A concomitant laparoscopic hysterectomy with bilateral oophorectomy and a multi-compartment laparoscopic native tissue repair of the POP, combined with a Burch urethropexy, was performed to restore pelvic floor defects and treat the underlying endometrial pathology. CONCLUSION: Total laparoscopic multi-compartment repair of POP and/or SUI using native tissue appears to be a viable alternative to both laparoscopic procedures using synthetic meshes and vaginal native tissue repairs. Although not a routine option for the majority of patients with POP and SUI, this procedure may be offered in selected cases, where native tissue repair of the pelvic floor is preferred.
30924367 Multistate Comparison of Cost, Trends, and Complications in Open Versus Endoscopic Carpal 2021 Jan Background: Surgical carpal tunnel release is performed by either open carpal tunnel release (OCTR) or endoscopic carpal tunnel release (ECTR). The purpose of this study was to assess differences in intraoperative and postoperative complications, trends, and costs between OCTR and ECTR. Methods: State Ambulatory Surgery and Services Databases (SASD) files for California, Florida, and New Jersey were queried for patients who underwent OCTR and ECTR between 2000 and 2014. Patient demographics, comorbidities, intraoperative and postoperative complications, and cost were compared between OCTR and ECTR. The frequency of each procedure was used to formulate trends in OCTR and ECTR. Results: A total of 571 403 patients were included in this study. Sex was significantly different by a small percentage (OCTR = 64.8% female, ECTR = 65.4% female). A higher proportion of Hispanic patients underwent ECTR (P < .001). The patients who underwent OCTR had a greater comorbidity burden in terms of diabetes and rheumatoid arthritis (P < .001). None of the aforementioned complication rates were statistically significant between the 2 procedures. Endoscopic carpal tunnel release was significantly more costly by almost $2000. Open carpal tunnel release has remained stable over the years studied, whereas ECTR increased 3-fold. Conclusions: Our findings demonstrate no significant differences between OCTR and ECTR regarding intraoperative and postoperative complications and patient outcomes. Endoscopic carpal tunnel release was found to be significantly more costly.
35415128 Effective Treatment for Breakage of a Solid Long Cementless Stem with a Distal Locking Scr 2021 Nov INTRODUCTION: Fractures around the femoral stem are difficult complications to treat. In revision surgery, good results can be obtained by a long cementless stem with a distal locking screw. However, there are few reports of treatment for cases where the stem itself is broken. CASE REPORT: The case of a 69-year-old woman in which the femoral stem that was broken 5 years after performing revision surgery for a right periprosthetic femoral fracture was repaired using a solid long stem with a distal locking screw is presented. Her past history included osteoporosis and rheumatoid arthritis. She fell due to sudden right thigh pain and was then taken to the emergency department of our hospital. X-ray examination showed breakage of the stem itself at the position of the distal locking screw hole closest to the previous fracture. Revision total hip arthroplasty using a larger diameter stem of the same model was performed. The previous fracture site had been a fibrous non-union, and the femur proximal to the previous fracture site had severe atrophy and bone loss due to stress shielding. Two years after surgery, the patient can walk without pain, and progression of stress shielding, loosening of the stem, and breakage of the implants have not occurred. CONCLUSION: In the present case, non-union, proximal bone atrophy, the location of the hole of the distal locking screw, and insufficient stem strength were the causes of stem breakage. It is necessary to take measures such as bone grafting and select a stem as long as possible for the position of the distal locking screw to be as far as possible from the fracture line when using a narrow long stem with a distal locking screw.
35146055 Movement Disorders and Musculoskeletal System: A Reciprocal Relationship. 2022 Feb The association of movement disorders (MDs) with musculoskeletal (MSK) disorders is observed in two principal scenarios. First, MDs patients may present with MSK issues. This phenomenon is primarily observed in parkinsonian syndromes, but may also be seen in patients with dystonia, Tourette syndrome, and some gene-related MDs. Second, there are MSK disorders that may produce or mimic MDs. Important primary MSK disorders producing MDs are joint hyperlaxity syndrome, non-traumatic craniovertebral junction anomalies, congenital muscular torticollis, and rheumatoid arthritis. Peripheral trauma to the MSK system may also lead to MDs commonly referred to as peripherally induced MDs. The exact pathogenesis of these disorders is not clear, however many patients have associated sensory phenomena such as complex regional pain syndrome. Herein, we provide an overview of disorders that may manifest with a combination of MSK and MDs, as detailed above. The most common MDs are discussed in each section, along with important clinical points, suggested diagnostic workups, and possible differential diagnoses.
34936547 The relationship of ADAMTSL2 and LRPAP1 gene methylation level with rheumatoid arthritis a 2021 Dec 22 OBJECTIVES: The role of epigenetic mechanisms in the pathogenesis and course of RA as well as response to treatment is increasingly being emphasised. The aim of our study was to determine the ADAMTSL2 and LRPAP1 gene methylation levels in RA patients' serum divided according to disease activity and in comparison with the results with the control group. METHODS: Quantitative real-time methylation-specific PCR was used to analyse the methylation status of the investigated genes. RESULTS: We observed a significant difference in the methylation levels of both the ADAMTSL2 and the LRPAP1 genes in patients with high RA activity compared to patients in remission. CONCLUSIONS: ADAMTSL2 methylation status was inversely correlated with DAS28. High disease activity was associated with lower methylation levels than in remission as well as in the control group. Different results were obtained for the methylation levels of the LRPAP1 gene. High disease activity and the control group were characterised by a higher level of LRPAP1 gene methylation compared to patients in remission. We have proven that methylation may play an important role in the course and severity of RA. The level of ADAMTSL2 and LRPAP1 gene methylation might impact the development of disease and reflect the activity of RA.
34843075 A Review on the Role of Endogenous Neurotrophins and Schwann Cells in Axonal Regeneration. 2021 Nov 29 Injury to the peripheral nerve is traditionally referred to acquired nerve injury as they are the result of physical trauma due to laceration, stretch, crush and compression of nerves. However, peripheral nerve injury may not be completely limited to acquired physical trauma. Peripheral nerve injury equally implies clinical conditions like Guillain-Barré syndrome (GBS), Carpal tunnel syndrome, rheumatoid arthritis and diabetes. Physical trauma is commonly mono-neuropathic as it engages a single nerve and produces focal damage, while in the context of pathological conditions the damage is divergent involving a group of the nerve causing polyneuropathy. Damage to the peripheral nerve can cause a diverse range of manifestations from sensory impairment to loss of function with unpredictable recovery patterns. Presently no treatment option provides complete or functional recovery in nerve injury, as nerve cells are highly differentiated and inert to regeneration. However, the regenerative phenotypes in Schwann cells get expressed when a signalling cascade is triggered by neurotrophins. Neurotrophins are one of the promising biomolecules that are released naturally post-injury with the potential to exhibit better functional recovery. Pharmacological intervention modulating the expression of these neurotrophins such as brain-derived neurotrophic factor (BDNF) and pituitary adenylyl cyclase-activating peptide (PACAP) can prove to be a significant treatment option as endogenous compounds which may have remarkable innate advantage showing maximum 'biological relevance'.
34826845 [COVID-19 and inflammatory rheumatic diseases]. 2021 Nov Older age, cardiovascular comorbidities, chronic lung diseases, and GC use were identified as independent risk factors for severe courses of COVID-19 resulting in the need of hospitalization. Glucocorticoid dosis of > 10 mg over a longer period of time should be very carefully used as there are various immunomodulatory alternatives. Of particular note, disease activity of inflammatory rheumatic diseases (IRD) was also identified as an independent predictor of COVID-19 related hospitalization.Already in the early phase of the pandemic case reports of fatal courses of IRD patients under treatment with rituximab were reported. Meanwhile, several data could demonstrate higher rates of hospitalization and COVID-19-related deaths. Whether a similar effect is detectable regarding Janus kinase inhibitors in patients with rheumatoid arthritis is currently under investigation.Preliminary data indicate that all available COVID-19 vaccines in Europe are not associated with higher rates of disease flares or differences of side effect profiles compared to the general population. There is no recommendation to discontinue or reduce immunomodulatory treatment in general to achieve better immune response. In the case of Rituximab, consideration should be given to postponing or switching to alternative therapies, taking into account the risk of reactivation of the underlying disease on the one hand and the improvement of a potential vaccine response on the other.
34772213 Diflunisal Targeted Delivery Systems: A Review. 2021 Nov 6 Diflunisal is a well-known drug for the treatment of rheumatoid arthritis, osteoarthritis, primary dysmenorrhea, and colon cancer. This molecule belongs to the group of nonsteroidal anti-inflammatory drugs (NSAID) and thus possesses serious side effects such as cardiovascular diseases risk development, renal injury, and hepatic reactions. The last clinical data demonstrated that diflunisal is one of the recognized drugs for the treatment of cardiac amyloidosis and possesses a survival benefit similar to that of clinically approved tafamidis. Diflunisal stabilizes the transthyretin (TTR) tetramer and prevents the misfolding of monomers and dimers from forming amyloid deposits in the heart. To avoid serious side effects of diflunisal, the various delivery systems have been developed. In the present review, attention is given to the recent development of diflunisal-loaded delivery systems, its technology, release profiles, and effectiveness.
34680614 Strategies Targeting Type 2 Inflammation: From Monoclonal Antibodies to JAK-Inhibitors. 2021 Oct 19 Bronchial asthma and its frequent comorbidity chronic rhinosinusitis (CRS), are characterized by an inflammatory process at lower and upper respiratory tract, with a variability in terms of clinical presentations (phenotypes) and distinct underpin pathophysiological mechanisms (endotypes). Based on the characteristics of inflammation, bronchial asthma can be distinguished into type 2 (eosinophilic) or nontype 2 (noneosinophilic) endotypes. In type 2 asthma endotype, the pathogenic mechanism is sustained by an inflammatory process driven by Th2 cells, type 2 innate lymphoid cells (ILC2) and type 2 cytokines, which include interleukin (IL)-4, IL-5, IL-9 and IL-13. The definition of asthma and chronic rhinusinusitis phenotype/endotype is crucial, taking into account the availability of novel biologic agents, such as monoclonal antibodies targeting the classical type 2 cytokines. Recently, new therapeutic strategies have been proposed and analyzed in preliminary clinical trials. Among them Janus kinase (JAK) inhibitors, now largely used for the treatment of other chronic inflammatory diseases such as rheumatoid arthritis and inflammatory bowel diseases, is receiving great relevance. The rationale of this strategy derives from the data that JAK is a tyrosine kinase involved in the signaling of T cell receptor and of several cytokines that play a role in allergic respiratory disease, such as IL-2, IL-4 and IL-9. In this review, we discuss whether treatment with biological agents and JAK inhibitors may be equally effective in controlling type 2 inflammatory process in both asthma and CRS.