Rhino-orbito-cerebral mucormycosis: patient characteristics in pre-COVID-19 and COVID-19 period.

BACKGROUND: Rhino-orbito-cerebral-mucormycosis (ROCM), a rare and potentially fatal disease was seen in increasing numbers during the COVID-19 pandemic. This study describes and compares the patient characteristics and outcomes in COVID-19 associated mucormycosis (CAM) and non-COVID-19 mucormycosis (non-CAM). METHODOLOGY: CAM patients (24 cases) were recruited from the COVID-19 period and non-CAM (24 controls) from the pre-COVID-19 period. Clinical data of the CAM group was collected retrospectively with 3 month outcomes prospectively. The non-CAM group data was collected retrospectively. Patient characteristics were compared and risk factors for mortality in ROCM were assessed. RESULTS: Orbital symptoms [altered vision, restricted eye movements, ptosis] and intracranial involvement were higher in CAM patients on presentation. Similarly, the radiological involvement of orbit (orbital apex, superior orbital fissure) and intracranial cavity (intracranial thrombosis, cavernous sinus) was also higher in CAM patients. Newly detected diabetes was found only in CAM patients (29.2%). Although univariate analysis suggested an increased mortality risk in ROCM patients with orbital involvement, the multivariate analysis showed no increased risk with any of the parameters assessed, including COVID-19 positivity. CONCLUSIONS: Compared to the non-CAM, the disease presentation was severe in CAM with higher frequency of orbital and intracranial involvement. However, with early detection and treatment, the short term survival was comparable in both groups.

Chronic kidney disease mediates cardiac dysfunction associated with increased resident cardiac macrophages.

BACKGROUND: The leading cause of death in end-stage kidney disease is related to cardiovascular disease. Macrophages are known to be involved in both chronic kidney disease (CKD) and heart failure, however their role in the development of cardiorenal syndrome is less clear. We thus sought to investigate the role of macrophages in uremic cardiac disease. METHODS: We assessed cardiac response in two experimental models of CKD and tested macrophage and chemokine implication in monocytopenic CCR2-/- and anti-CXCL10 treated mice. We quantified CXCL10 in human CKD plasma and tested the response of human iPSC-derived cardiomyocytes and primary cardiac fibroblasts to serum from CKD donors. RESULTS: We found that reduced kidney function resulted in the expansion of cardiac macrophages, in particular through local proliferation of resident populations. Influx of circulating monocytes contributed to this increase. We identified CXCL10 as a crucial factor for cardiac macrophage expansion in uremic disease. In humans, we found increased plasma CXCL10 concentrations in advanced CKD, and identified the production of CXCL10 in cardiomyocytes and cardiac fibroblasts. CONCLUSIONS: This study provides new insight into the role of the innate immune system in uremic cardiomyopathy.

Erectile Dysfunction Is Highly Prevalent in Men With Newly Diagnosed Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Cross-sectional studies on sexual function in men with inflammatory bowel disease (IBD) yield mixed results. Using a prospective incidence cohort, we aimed to describe sexual function at baseline and over time and to identify factors associated with impaired sexual function in men with IBD. METHODS: Men 18 years and older enrolled between April 2008 and January 2013 in the Ocean State Crohn's and Colitis Area Registry (OSCCAR) with a minimum of 2 years of follow-up were eligible for study. Male sexual function was assessed using the International Index of Erectile Function (IIEF), a self-administered questionnaire that assesses 5 dimensions of sexual function over the most recent 4 weeks. To assess changes in the IIEF per various demographic and clinical factors, linear mixed effects models were used. RESULTS: Sixty-nine of 82 eligible men (84%) completed the questionnaire (41 Crohn's disease, 28 ulcerative colitis). The mean age (SD) of the cohort at diagnosis was 43.4 (19.2) years. At baseline, 39% of men had global sexual dysfunction, and 94% had erectile dysfunction. Independent factors associated with erectile dysfunction are older age and lower physical and mental component summary scores on the Short Form Health Survey (SF-36). CONCLUSION: In an incident cohort of IBD patients, most men had erectile dysfunction. Physicians should be aware of the high prevalence of erectile dysfunction and its associated risk factors among men with newly diagnosed IBD to direct multidisciplinary treatment planning.

Potential of iPSC-Derived Mesenchymal Stromal Cells for Treating Periodontal Disease.

Mesenchymal stromal cell-like populations have been derived from mouse-induced pluripotent stem cells (miPSC-MSC) with the capability for tissue regeneration. In this study, murine iPSC underwent differentiation towards an MSC-like immunophenotype. Stable miPSC-MSC cultures expressed the MSC-associated markers, CD73, CD105, and Sca-1, but lacked expression of the pluripotency marker, SSEA1, and hematopoietic markers, CD34 and CD45. Functionally, miPSC-MSC exhibited the potential for trilineage differentiation into osteoblasts, adipocytes, and chondrocytes and the capacity to suppress the proliferation of mitogen-activated splenocytes. The efficacy of miPSC-MSC was assessed in an acute inflammation model following systemic or local delivery into mice with subcutaneous implants containing heat-inactivated P. gingivalis. Histological analysis revealed less inflammatory cellular infiltrate within the sponges in mice treated with miPSC-MSC cells delivered locally rather than systemically. Assessment of proinflammatory cytokines in mouse spleens found that CXCL1 transcripts and protein were reduced in mice treated with miPSC-MSC. In a periodontitis model, mice subjected to oral inoculation with P. gingivalis revealed less bone tissue destruction and inflammation within the jaws when treated with miPSC-MSC compared to PBS alone. Our results demonstrated that miPSC-MSC derived from iPSC have the capacity to control acute and chronic inflammatory responses associated with the destruction of periodontal tissue. Therefore, miPSC-MSC present a promising novel source of stromal cells which could be used in the treatment of periodontal disease and other inflammatory systemic diseases such as rheumatoid arthritis.

Opportunistic screening for bone disease using abdominal CT scans obtained for other reasons in newly diagnosed IBD patients.

Bone disease is prevalent among patients with inflammatory bowel disease (IBD), though bone density screening remains underutilized. We used CT scans performed for other indications in IBD patients to identify and monitor osteopenia using CT attenuation values at the lumbar spine. Significant rates of bone disease were detected which would have otherwise gone undiagnosed. INTRODUCTION: Osteoporosis affects about 14-42% of patients with IBD. Though screening is recommended in IBD patients with risk factors, it remains underutilized. In patients with newly diagnosed IBD, we used CT scans performed for other indications to identify and monitor progression of osteopenia. METHODS: Using the Ocean State Crohn's and Colitis Area Registry, we identified adult patients with one or more abdominal CT scans. Each patient had two age- and gender-matched controls. Radiologists measured attenuation through trabecular bone in the L1 vertebral body recorded in Hounsfield units (HU). Generalized estimating equations were used to measure how HU varied as a function of gender, type of IBD, and age. RESULTS: One hundred five IBD patients were included, and 72.4% were classified as "normal" bone mineral density (BMD) and 27.6% as potentially osteopenic: 8.6% with ulcerative colitis and 19.0% with Crohn's disease. We found a decrease in bone density over time (p < 0.001) and that BMD decreases more in Crohn's disease than in ulcerative colitis (p < 0.004). Sixty patients had two CT scans, and mean loss of 9.3 HU was noted. There was a non-significant decrease in BMD over time in patients exposed to > 31 days of steroids and BMD was stable with < 30 days of steroid exposure (p < 0.09). CONCLUSION: Using CT scans obtained for other indications, we found low rates of osteopenia and osteoporosis that may otherwise have gone undiagnosed. Refinement of opportunistic screening may have advantages in terms of cost-savings and earlier detection of bone loss.

Gingival tissue, an extrasynovial source of malondialdehyde-acetaldehyde adducts, citrullinated and carbamylated proteins.

BACKGROUND AND OBJECTIVE: Postranslational modification of proteins can lead to the production of autoantibodies and loss of immune tolerance. This process has been hypothesised to be a critical factor in the pathogenesis of rheumatoid arthritis. The objective of this study was to demonstrate that inflamed human gingival tissue provides an extrasynovial source of malondialdehyde-acetaldehyde adducts, citrullinated and carbamylated proteins all of which are considered to be linked to the development of rheumatoid arthritis. Identification of such modified proteins in inflamed gingiva may explain, in part, how inflammation of the periodontal tissues may influence the development of rheumatoid arthritis. MATERIAL AND METHODS: Gingival biopsies of healthy, mild and moderate periodontitis were triple stained with antibodies against malondialdehyde-acetaldehyde adducts, citrullinated and carbamylated proteins. RESULTS: Assessment of healthy gingival tissue revealed negligible staining for carbamylated, malondialdehyde-acetaldehyde (MAA), or citrullinated proteins. Mild periodontitis was positive for all three modifications. Furthermore, there was an increase in staining intensity for carbamylated, citrullinated and MAA-modified proteins in moderate periodontitis. Negative staining results were observed for the isotype controls. CONCLUSION: This study provides evidence for the presence of citrullinated, carbamylated and MAA adduct modified proteins in inflamed periodontal tissues. The potential for these proteins to play a role in autoimmunity in a multi-system inflammatory syndromic disease model now needs to be determined.

Induced Pluripotent Stem Cells: A New Frontier for Stem Cells in Dentistry.

Induced pluripotent stem cells (iPSCs) are the newest member of a growing list of stem cell populations that hold great potential for use in cell-based treatment approaches in the dental field. This review summarizes the dental tissues that have successfully been utilized to generate iPSC lines, as well as the potential uses of iPSCs for tissue regeneration in different dental applications. While iPSCs display great promise in a number of dental applications, there are safety concerns with these cells that need to be addressed before they can be used in clinical settings. This review outlines some of the apprehensions to the use of iPSCs clinically, and it details approaches that are being employed to ensure the safety and efficacy of these cells. One of the major approaches being investigated is the differentiation of iPSCs prior to use in patients. iPSCs have successfully been differentiated into a wide range of cells and tissue types. This review focuses on 2 differentiation approaches-the differentiation of iPSCs into mesenchymal stem cells and the differentiation of iPSCs into osteoprogenitor cells. Both these resulting populations of cells are particularly relevant to the dental field.

Is there a link between carbamylation and citrullination in periodontal disease and rheumatoid arthritis?

The remarkable similarity in inflammatory response and pathology of periodontal disease and rheumatoid arthritis has been recognized for several decades. However, how these two disease may be interrelated has been less clear. During the pathogenesis of rheumatoid arthritis there is a preclinical immunological phase which precedes the clinical manifestation of rheumatoid arthritis. During this phase serum autoantibodies appear many years before the clinical signs and symptoms of rheumatoid arthritis become apparent. To date, the two best studied autoantibodies have been rheumatoid factor and anti-citrullinated protein antibodies (ACPA). Of these the production of ACPA has been considered very important due to their high predictive value in future manifestation of rheumatoid arthritis. Citrullination is a common post-translational modification of proteins based on the enzymatic conversion of arginine into citrulline. Extra-articular citrullination and production of ACPA, as a priming immunological experience, is well documented in many tissues including the inflamed gingival tissues associated with periodontal disease. More recently, carbamylation of proteins has also been implicated in the pathogenesis of rheumatoid arthritis in a manner similar to citrullination. Carbamylation is a post translational modification of proteins by an enzyme-independent modification of lysine residues against which autoantibodies are subsequently induced. In this article we hypothesise that, like citrullination, carbamylation of proteins and associated antibody production during the gingival inflammation associated with gingivitis and periodontitis may play a role in the pathogenesis of rheumatoid arthritis.

Periodontal ligament-derived cells for periodontal regeneration in animal models: a systematic review.

BACKGROUND AND OBJECTIVE: Implantation of periodontal ligament stem cells is emerging as a potential periodontal regenerative procedure. This systematic review considers the evidence from animal models investigating the use of periodontal ligament stem cells for successful periodontal regeneration. MATERIAL AND METHODS: PubMed, Embase, MEDLINE and Google Scholar were searched to December 2013 for quantitative studies examining the outcome of implanting periodontal ligament stem cells into experimental periodontal defects in animals. Inclusion criteria were: implantation of periodontal ligament stem cells into surgically created periodontal defects for periodontal regeneration; animal models only; source of cells either human or animal; and published in English. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: From the literature search, 43 studies met the inclusion criteria. A wide variety of surgical defects were created in four species of animal (dog, rat, pig and sheep). Owing to wide variability in defect type, cell source and cell scaffold, no meta-analysis was possible. Outcome measures included new bone, new cementum and new connective tissue formation. In 70.5% of the results, statistically significant improvements of these measures was recorded. CONCLUSION: These results are notable in that they indicate that irrespective of the defect type and animal model used, periodontal ligament stem cell implantation can be expected to result in a beneficial outcome for periodontal regeneration. It is recommended that there is sufficient evidence from preclinical animal studies to warrant moving to human studies to examine the efficacy, safety, feasibility (autologous vs. allogeneic transplantation) and delivery of periodontal ligament stem cells for periodontal regeneration.

Fatigue is highly associated with poor health-related quality of life, disability and depression in newly-diagnosed patients with inflammatory bowel disease, independent of disease activity.

BACKGROUND: Fatigue is common in Crohn's disease (CD) and ulcerative colitis (UC). Data on fatigue in newly diagnosed patients are unavailable. AIM: To report prevalence of fatigue in newly diagnosed CD and UC patients and examine its association with health-related quality of life (HRQOL), depression and disability. METHODS: The Ocean State Crohn's and Colitis Area Registry (OSCCAR) is a statewide cohort of newly diagnosed inflammatory bowel disease patients in Rhode Island. Fatigue was assessed using the Functional Assessment of Chronic Illness Therapy-Fatigue Scale. Patients were administered instruments measuring HRQOL, overall disability and work impairment, and depression. RESULTS: Fatigue was prevalent in 26.4% of 220 subjects. Cohen's d effect sizes for fatigue were large: Short-Form 36 Health Survey mental health component (CD 1.5, UC 1.4) and physical health component (CD 1.4, UC 1.4), EuroQol-5D valuation of current health state (CD 1.2, UC 1.0), Inflammatory Bowel Disease Questionnaire (CD 1.9, UC 1.6) and Patient Health Questionnaire depression scale (CD 1.8, UC 1.7). Fatigued patients reported more work impairment (Score difference: CD 29.5%, UC 23.8%) and activity impairment (score difference: CD 32.3%, UC 25.7%) on the Work Productivity and Activity Impairment Questionnaire. Fatigue's association with all scores remained highly significant despite controlling for disease activity. CONCLUSIONS: Fatigue is strongly associated with poor HRQOL, disability and depression similarly in CD and UC even when controlling for disease activity. Fatigue's association with a wide range of patient-reported outcome measures suggests that monitoring fatigue is a simple way to screen for overall disruption in patient life.

Airway gene transfer in a non-human primate: lentiviral gene expression in marmoset lungs.

Genetic therapies for cystic fibrosis (CF) must be assessed for safety and efficacy, so testing in a non-human primate (NHP) model is invaluable. In this pilot study we determined if the conducting airways of marmosets (n = 2) could be transduced using an airway pre-treatment followed by an intratracheal bolus dose of a VSV-G pseudotyped HIV-1 based lentiviral (LV) vector (LacZ reporter). LacZ gene expression (X-gal) was assessed after 7 days and found primarily in conducting airway epithelia as well as in alveolar regions. The LacZ gene was not detected in liver or spleen via qPCR. Vector p24 protein bio-distribution into blood was transient. Dosing was well tolerated. This preliminary study confirmed the transducibility of CF-relevant airway cell types. The marmoset is a promising NHP model for testing and translating genetic treatments for CF airway disease towards clinical trials.

Nuisance flies on Australian cattle feedlots: immature populations.

Species composition, seasonality and distribution of immature fly populations on a southern Queensland feedlot during 2001-2003 were determined. Similar data were collected on feedlots in central New South Wales and central Queensland. The fly species recovered in the highest numbers were Musca domestica L. (Diptera: Muscidae), Stomoxys calcitrans L. (Diptera: Muscidae) and Physiphora clausa Macquart (Diptera: Ulidiidae). Houseflies were the dominant species at all feedlots. Houseflies preferred the warmer months from October to June, but stable flies preferred the cooler months and peaked in spring (September-November) and autumn (March-May). Larval abundance ratings recorded in the feedlot and numbers of larvae extracted in the laboratory from corresponding samples followed similar trends. Larvae of M. domestica were most abundant in the hospital and induction area and least abundant in horse stables and yards. Pupae of M. domestica were abundant in the hospital and induction area and drains, but least abundant in horse stables and yards. Larvae of S. calcitrans were most abundant in drains and least abundant in horse stables and yards. Pupae of S. calcitrans were most numerous in drains and least numerous in old cattle pens. Feedlot design and management had little effect on fly reduction.

Influenza virus-like particles as pandemic vaccines.

There is an urgent need to develop novel approaches for vaccination against emerging pathogenic avian influenza viruses as a priority for pandemic preparedness. Influenza virus-like particles (VLPs) have been suggested and developed as a new generation of non-egg-based cell culture-derived vaccine candidates against influenza infection. Influenza VLPs are formed by a self-assembly process incorporating structural proteins into budding particles composed of the hemagglutinin (HA), neuraminidase (NA) and M1 proteins, and may include additional influenza proteins such as M2. Animals vaccinated with VLPs were protected from morbidity and mortality resulting from lethal influenza infections. The protective mechanism of influenza VLP vaccines was similar to that of the currently licensed influenza vaccines inducing neutralizing antibodies and hemagglutination inhibition activities. Current studies demonstrate that influenza VLP approaches can be a promising alternative approach to developing a vaccine for pandemic influenza viruses. The first human clinical trial of a recombinant pandemic-like H5N1 influenza VLP vaccine was initiated in July 2007 (Bright et al., unpublished).

Insulinoma in a cat.

A 14-year-old domestic shorthair cat was presented with hypoglycaemia and seizures of several weeks duration. Bloodwork revealed hypoglycaemia (1.83 mmol/l; reference range 4.22-8.05 mmol/l) with concurrent normal insulin levels (171 pmol/l; reference range 72-583 pmol/l). An insulinoma was suspected and medical and dietary management were attempted with minimal success. An exploratory laparotomy was performed and a single, well-defined mass was found within the left lobe of the pancreas. The mass was removed and histologically classified as an islet cell carcinoma, consistent with an insulinoma. The cat had an episode of presumed postoperative pancreatitits, but recovered with appropriate treatment. The cat has had no clinical signs of recurrence of greater than 32 months postsurgery. There are only four cases of insulinoma in cats reported in the literature. All prior insulionomas reported were in older cats and were malignant in character, which is similar to the reports in the dog. This case is unique because of the apparent lack of local recurrence and development of metastatic disease, leading to the prolonged survival.

Paraoesophageal hiatal hernia and megaoesophagus in a three-week-old Alaskan malamute.

Paraoesophageal hiatal hernia was diagnosed in a three-week-old Alaskan malamute. Reduction of the hernia was followed by an oesophagopexy and a bilateral gastropexy. During the early postoperative period, the puppy continued to have signs that were thought to be related to a concurrent megaoesophagus. At nine months of age the dog had gained weight and was well except for occasional episodes of regurgitation. These episodes responded well to medical therapy, and at the time of writing the dog had not required further treatment.

Umbilico-biliary fistula in a dog.

This case report describes a previously unreported congenital malformation, an umbilico-billary fistula, in a dog. A one-year-old male bulldog was diagnosed with umbilico-billary fistula using fistulography. Treatment involving surgical removal of the fistula was straightforward and resulted in clinical resolution of the problem.

Neurological manifestations of avian influenza viruses in mammals.

The H5N1 viruses isolated from humans in Hong Kong directly infected both mice and ferrets without prior adaptation to either host. Two representative viruses, A/Hong Kong/483/97 (HK/483) and A/Hong Kong/486/97 (HK/486) were equally virulent in outbred ferrets but differed in their virulence in inbred mice. Both HK/483 and HK/486 replicated systemically in ferrets and showed neurologic manifestations. In contrast, intranasal infection of mice with HK/483, but not HK/486, resulted in viral spread to the brain, neurologic signs, and death. However, HK/486 was able to replicate in the brain and induce lethal disease following direct intracerebral inoculation.

Mechanisms of pathogenicity of influenza A (H5N1) viruses in mice.

Avian-like H5N1 influenza viruses isolated from humans in 1997 were shown to have two distinct pathogenic phenotypes in BALB/c mice, after intranasal inoculation and without prior adaptation to this host. To further understand the mechanisms of H5N1 pathogenicity, we investigated the consequences of the mute of viral inoculation on morbidity and mortality, viral replication in pulmonary and systemic organs, and lymphocyte depletion. This study demonstrates the importance of extrapulmonary spread and replication, particularly in the brain, for the lethality of H5N1 viruses.