ENPP1 in the Regulation of Mineralization and Beyond.

ENPP1 is well known for its role in regulating skeletal and soft tissue mineralization. It primarily exerts its function through the generation of pyrophosphate, a key inhibitor of hydroxyapatite formation. Several previous studies have suggested that ENPP1 also contributes to a range of human diseases including diabetes, cancer, cardiovascular disease, and osteoarthritis. In this review, we summarize the pathological roles of ENPP1 in mineralization and these soft tissue disorders. We also discuss the underlying mechanisms through which ENPP1 exerts its pathological effects. A fuller understanding of the pathways through which ENPP1 acts may help to develop novel therapeutic strategies for these commonly diagnosed morbidities.

Primary orbital sarcoma in adults: a case series with emphasis on post-irradiation sarcoma.

PURPOSE: To describe a series of eight adult patients with primary orbital sarcoma and to review the existing literature on orbital sarcoma and post-irradiation sarcoma. METHODS: Report of eight cases and literature review. RESULTS: We report eight cases of primary orbital sarcoma, three of which were radiation-induced. Only one patient had a history of retinoblastoma. The most common presentations were painful proptosis and reduced vision. Most tumours arose in the extraconal compartment. The overall median age at diagnosis was 50 years. The pathology comprised a diverse group of tumours. Treatment and outcome varied between patients and their clinical circumstances. CONCLUSIONS: Adult primary orbital sarcomas are rare. They can comprise a variety of tumour types and are difficult to treat. Irradiation is a significant risk factor, and the incidence of post-irradiation sarcoma of the orbit may be increasing due to the widespread use of radiotherapy and improved survival of patients with cancer. Post-irradiation sarcoma should be considered in the differential diagnosis of an orbital space-occupying lesion in a patient with a history of radiotherapy.

Osteoblast-specific deficiency of ectonucleotide pyrophosphatase or phosphodiesterase-1 engenders insulin resistance in high-fat diet fed mice.

Supraphysiological levels of the osteoblast-enriched mineralization regulator ectonucleotide pyrophosphatase or phosphodiesterase-1 (NPP1) is associated with type 2 diabetes mellitus. We determined the impact of osteoblast-specific Enpp1 ablation on skeletal structure and metabolic phenotype in mice. Female, but not male, 6-week-old mice lacking osteoblast NPP1 expression (osteoblast-specific knockout [KO]) exhibited increased femoral bone volume or total volume (17.50% vs. 11.67%; p < .01), and reduced trabecular spacing (0.187 vs. 0.157 mm; p < .01) compared with floxed (control) mice. Furthermore, an enhanced ability of isolated osteoblasts from the osteoblast-specific KO to calcify their matrix in vitro compared to fl/fl osteoblasts was observed (p < .05). Male osteoblast-specific KO and fl/fl mice showed comparable glucose and insulin tolerance despite increased levels of insulin-sensitizing under-carboxylated osteocalcin (195% increase; p < .05). However, following high-fat-diet challenge, osteoblast-specific KO mice showed impaired glucose and insulin tolerance compared with fl/fl mice. These data highlight a crucial local role for osteoblast NPP1 in skeletal development and a secondary metabolic impact that predominantly maintains insulin sensitivity.

Impact of the COVID-19 pandemic on anaesthesia trainees and their training.

Coronavirus disease 2019 (COVID-19; severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] has dislocated clinical services and postgraduate training. To better understand and to document these impacts, we contacted anaesthesia trainees and trainers across six continents and collated their experiences during the pandemic. All aspects of training programmes have been affected. Trainees report that reduced caseload, sub-specialty experience, and supervised procedures are impairing learning. Cancelled educational activities, postponed examinations, and altered rotations threaten progression through training. Job prospects and international opportunities are downgraded. Work-related anxieties about provision of personal protective equipment, and risks to self and to colleagues are superimposed on concerns for family and friends and domestic disruption. These seismic changes have had consequences for well-being and mental health. In response, anaesthetists have developed innovations in teaching and trainee support. New technologies support trainer-trainee interactions, with a focus on e-learning. National training bodies and medical regulators that specify training and oversee assessment of trainees and their progression have provided flexibility in their requirements. Within anaesthesia departments, support transcends grades and job titles with lessons for the future. Attention to wellness, awareness of mental health issues and multimodal support can attenuate but not eliminate trainee distress.

Scottish healthcare student's perceptions of an interprofessional ward simulation: An exploratory, descriptive study.

The most memorable learning occurs during placement. Simulated interprofessional learning is a logical learning opportunity to help healthcare professionals work beyond their professional silos. In this qualitative study, we investigated the perceived learning of students from six health professions (adult nursing, diagnostic radiography, occupational therapy, physiotherapy, dietetics, and pharmacy) from their participation in a 45 min interprofessional ward simulation. Semistructured focus groups were undertaken, and data were analyzed using framework analysis. Two overarching themes were evident, each of which had subthemes: (i) the ward simulation as an interprofessional education opportunity (subthemes: reality of situations and interactions); and (ii) the perceived learning achieved (subthemes: professional roles, priorities, respect, communication, teamwork, and quality of care). The results indicated that a short interprofessional ward simulation, unsupported by additional learning opportunities or directed study, is a useful and engaging interprofessional learning opportunity. Students appear to have learnt important key messages central to the interprofessional education curricula to help develop practitioners who can effectively work together as an interprofessional team, and that this learning is partly due to simulation allowing things to go wrong.

Primary Transitional Cell Carcinoma of the Conjunctiva.

A 77-year-old male presented with a large papillomatous conjunctival lesion on his lower eyelid. Biopsy and extensive systemic investigation revealed this to be a primary conjunctival transitional cell carcinoma. Patient preference and coexisting medical problems dictated conservative management with surgical debulking, topical mitomicin, and radiotherapy. Local control has been maintained for 4 years to date.

Macroscopic techniques for ophthalmic tumor specimens.

This article explores the range of tumor specimens that may be submitted to ophthalmic pathology. The handling of complex enucleation and exenteration is described along with smaller eyelid, conjunctival and corneal specimens. The importance of a good understanding of the unique anatomy of the ocular region and detailed clinical information is emphasized as this results in the taking of appropriate blocks for histology and consequently clinically helpful reports. Recommendations for handling specimens where further tissue is required for molecular studies is discussed.

Educational report: A case of lacrimal sac rhinosporidiosis.

This article reports a presentation of lacrimal sac rhinosporidiosis and informs the reader of this uncommon but important diagnosis. A 36-year-old man from Pakistan presented with a 3-month history of swelling at the nasal aspect of the left lower lid. This was associated with occasional crepitus and slight localised discomfort, but no epiphora. There was a palpable fullness near the left medial canthus associated with telecanthus but a normal sac washout and normal eye examination otherwise. Previous medical history included an ipsilateral nasal polypectomy and inferior meatal antrostomy around 10 years previously, whilst living in Pakistan. Various imaging modalities were useful in identifying a soft tissue mass within the left nasolacrimal duct. Following excision biopsy, histological examination confirmed the presence of rhinosporidiosis, likely caused by the organism Rhinosporidium seeberi. Rhinosporidiosis should be considered as a potential cause in any case of lacrimal sac pathology. Imaging studies may be helpful in measuring the extent of disease, although histological examination is required to confirm the diagnosis. Although rare, the complications of rhinosporidiosis can be potentially blinding or fatal. As discussed in this case, the presence of telecanthus may represent a lacrimal system tumour, either malignant or benign, and should always prompt further investigation.

Ocular Lichen Planus: A clinicopathologic review.

Lichen planus is a chronic inflammatory dermatosis that can affect the skin, mucous membranes and nails. Cutaneous lichen planus lesions are best described by the "six Ps" - purple pruritic polygonal planar papules and plaques. Mucous membrane lesions are commonly associated with cutaneous lichen planus. Ocular involvement with lichen planus is rare and conjunctival involvement usually predominates, it can however be visually devastating. Ocular lichen planus often progresses to extensive conjunctival scarring which can be impossible to distinguish clinically from other cicatrising conjunctivitis, requiring histopathological confirmation. Here we review the ocular pathology of this condition.

Deletion of Hsd11b1 suppresses caloric restriction-induced bone marrow adiposity in male but not female mice.

Bone marrow adipose tissue (BMAT) comprises >10% of total adipose mass in healthy humans. It increases in diverse conditions, including ageing, obesity, osteoporosis, glucocorticoid therapy, and notably, during caloric restriction (CR). BMAT potentially influences skeletal, metabolic, and immune functions, but the mechanisms of BMAT expansion remain poorly understood. Our hypothesis is that, during CR, excessive glucocorticoid activity drives BMAT expansion. The enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) amplifies glucocorticoid activity by catalysing intracellular regeneration of active glucocorticoids from inert 11-keto forms. Mice lacking 11ß-HSD1 resist metabolic dysregulation and bone loss during exogenous glucocorticoid excess; thus, we hypothesised that 11ß-HSD1 knockout mice would also resist excessive glucocorticoid action during CR, thereby restrining BMAT expansion and bone loss. To test this, we first confirmed that 11ß-HSD1 is expressed in mouse and human bone marrow. We then investigated the effects of CR in male and female control and 11ß-HSD1 knockout mice from 9 to 15 weeks of age. CR increased Hsd11b1 mRNA in adipose tissue and bone marrow. Deletion of Hsd11b1 did not alter bone or BMAT characteristics in mice fed a control diet and had little effect on tibial bone microarchitecture during CR. Notably, Hsd11b1 deletion attenuated the CR-induced increases in BMAT and prevented increases in bone marrow corticosterone in males but not females. This was not associated with suppression of glucocorticoid target genes in bone marrow. Instead, knockout males had increased progesterone in plasma and bone marrow. Together, our findings show that knockout of 11ß-HSD1 prevents CR-induced BMAT expansion in a sex-specific manner and highlights progesterone as a potential new regulator of bone marrow adiposity.

Pleomorphic adenomas of the lower eyelid: a case series.

Pleomorphic adenomas are well-recognized tumors usually arising within the main lacrimal gland. Their occurrence, however, is not limited to the main lacrimal gland. There have been cases reported in the eyebrow, upper eyelid, lateral lower eyelid, lacrimal sac, and even intraocularly. The medial aspect of the lower eyelid is a very rare site of occurrence because it is largely devoid of accessory lacrimal glands. We describe 2 cases of pleomorphic adenomas arising in the medial aspect and 1 case arising in the middle of the lower eyelid, respectively. The likely origin of these tumors at this location is from ectopic lacrimal gland.

Monoamines' role in islet cell function and type 2 diabetes risk.

The two monoamines serotonin and melatonin have recently been highlighted as potent regulators of islet hormone secretion and overall glucose homeostasis in the body. In fact, dysregulated signaling of both amines are implicated in ß-cell dysfunction and development of type 2 diabetes mellitus (T2DM). Serotonin is a key player in ß-cell physiology and plays a role in expansion of ß-cell mass. Melatonin regulates circadian rhythm and nutrient metabolism and reduces insulin release in human and rodent islets in vitro. Herein, we focus on the role of serotonin and melatonin in islet physiology and the pathophysiology of T2DM. This includes effects on hormone secretion, receptor expression, genetic variants influencing ß-cell function, melatonin treatment, and compounds that alter serotonin availability and signaling.

Post-enucleation outcomes of patients with uveal melanoma in Scotland.

BACKGROUND/OBJECTIVES: To investigate post-enucleation outcomes and assess the effect of extrascleral extension (ESE) on these outcomes for patients with uveal melanoma (UM) managed at a tertiary referral centre in Scotland. SUBJECTS/METHODS: Retrospective review of all cases of UM managed by the Scottish Ocular Oncology Service for which enucleation was undertaken between 13/03/2008 and 31/12/2020. Primary outcomes were length of survival, time-to-metastasis (TTM) and local recurrence rate. Secondary outcomes were the effects of the presence of ESE, ESE size, and the use of adjuvant external beam radiotherapy (EBRT) on the primary outcomes. RESULTS: Of 172 enucleated UMs, 32 (18.6%) had ESE. Over a median follow-up period of 33.7 months (range = 1.1-163.7 months), 91 (52.9%) patients died. The median length of all-cause survival of 54.1 months (range = 1.1-163.7 months). One-year, 5-year, and 10-year survival rates were 84.8%, 49.1%, and 30.9%, respectively. Eighty-four (49.7%) patients had metastatic disease. The median TTM of 42.2 months (range = 0.4-106.8 months). Proportions of patients who developed metastases within 1-year, 5-years and 10-years post-enucleation were 22.7%, 52.8%, and 71.8%, respectively. There was one instance of local orbital recurrence. ESE was associated with a significantly shorter length of survival (p = 0.03). There was a trend towards a shorter length of survival and TTM with ESE > 5 mm and those who received adjuvant EBRT. CONCLUSIONS: ESE was present in one-sixth of our cohort and was associated with a significantly shorter length of survival, particularly in the presence of ESE > 5 mm or high-risk characteristics warranting adjuvant EBRT. This data will aid prognostication of the patients in our service.

Development of a tool to assess core cardiorespiratory physiotherapy skills: a Delphi study.

PURPOSE: This study reports on the development of an outcome measure designed to evaluate pre-registration physiotherapy students' ability in performing core cardiorespiratory skills. METHOD: A four round, e- Delphi study using an international panel of expert cardiorespiratory physiotherapists involved in pre-registration student education was undertaken. In round one participants identified what they look for in students competently performing core cardio-respiratory physiotherapy assessment and treatment skills. These items were refined in rounds two and three. Item content validity score (iCVI) of ≥ 0.8 at round four identified consensus. Scale content validity index (SCVI) was calculated. RESULTS: Response rate for round one was 46% (6/13). Additional experts were invited to participate and response rates increased to 71% (round 2), 88% (round 3) and 100% (round 4). Of the 207 items across the seven skills identified in round one, 140 were presented in round four. Of these, consensus was achieved for 128 items, with 12 being excluded. The SCVI was 0.907. CONCLUSION: This e-Delphi study enabled the development of a draft outcome measure, which aims to assess performance of seven cardiorespiratory physiotherapy skills. This tool will enable rigorous evaluation of different education methods to establish their effectiveness. However, it is first necessary to establish construct validity and assess inter and intra-rater reliability.

The impact of macronutrient composition on metabolic regulation: An Islet-Centric view.

AIM: The influence of dietary carbohydrates and fats on weight gain is inconclusively understood. We studied the acute impact of these nutrients on the overall metabolic state utilizing the insulin:glucagon ratio (IGR). METHODS: Following in vitro glucose and palmitate treatment, insulin and glucagon secretion from islets isolated from C57Bl/6J mice was measured. Our human in vivo study included 21 normoglycaemia (mean age 51.9 ± 16.5 years, BMI 23.9 ± 3.5 kg/m2 , and HbA1c 36.9 ± 3.3 mmol/mol) and 20 type 2 diabetes (T2D) diagnosed individuals (duration 12 ± 7 years, mean age 63.6 ± 4.5 years, BMI 29.1 ± 2.4 kg/m2 , and HbA1c 52.3 ± 9.5 mmol/mol). Individuals consumed a carbohydrate-rich or fat-rich meal (600 kcal) in a cross-over design. Plasma insulin and glucagon levels were measured at -30, -5, and 0 min, and every 30 min until 240 min after meal ingestion. RESULTS: The IGR measured from mouse islets was determined solely by glucose levels. The palmitate-stimulated hormone secretion was largely glucose independent in the analysed mouse islets. The acute meal tolerance test demonstrated that insulin and glucagon secretion is dependent on glycaemic status and meal composition, whereas the IGR was dependent upon meal composition. The relative reduction in IGR elicited by the fat-rich meal was more pronounced in obese individuals. This effect was blunted in T2D individuals with elevated HbA1c levels. CONCLUSION: The metabolic state in normoglycaemic individuals and T2D-diagnosed individuals is regulated by glucose. We demonstrate that consumption of a low carbohydrate diet, eliciting a catabolic state, may be beneficial for weight loss, particularly in obese individuals.

IL-33 receptor (T1/ST2) signalling is necessary to prevent the development of encephalitis in mice infected with Toxoplasma gondii.

T1/ST2 is an immunoregulatory protein of the IL-1 receptor family that has recently been reported as being a component of the IL-33 receptor. IL-33 is a newly described cytokine known to amplify the Th2 response and reduce production of Th1 cytokines. The function of T1/ST2 during Toxoplasma gondii infection is as yet undescribed. Given the requirement of a balanced type 1/type 2 response for effective control of parasite number and immunopathology, it is likely that T1/ST2 may play a part in aiding this process. Accordingly, we have shown that T1/ST2 mRNA transcripts are upregulated in the brains of mice infected with T. gondii and that mice deficient in T1/ST2 demonstrated increased susceptibility to infection with T. gondii that correlated with increased pathology and greater parasite burden in the brains. Real-time PCR analysis of cerebral cytokine levels revealed increased mRNA levels of iNOS, IFN-gamma and TNF-alpha in infected T1/ST2(-/-) mice. These effects were independent of changes in IL-10 production. This study provides the first evidence of a specific role for IL-33 receptor signalling in the brain as well as highlighting the requirement of this mechanism in limiting infection with an intracellular parasite.

Corneal perforation due to limbal involvement in Sézary syndrome.

BACKGROUND: The majority of lymphomas involving the eye and ocular adnexa are B-cell lymphomas. Ocular involvement by T-cell lymphoma is rare. We report a case of corneal perforation due to direct involvement of the corneal limbus by lymphoma in a patient with Sézary syndrome. METHODS: A 58-year-old male with cutaneous T-cell lymphoma presented with painful, left-sided corneal ulceration, a dense infiltrate, severe epitheliopathy, hypopyon and a diffuse confluent dermatitis involving the lids. He had a history of Sézary syndrome. Despite maximal treatment, this severe ulcerative keratitis progressed to central corneal perforation. The eye was subsequently enucleated and submitted for histopathological examination. RESULTS: Histopathological examination confirmed corneal ulceration with perforation. There was an infiltrate of large atypical cells at the limbus, with tropism for the overlying epithelium. Immunohistochemical staining of these cells was positive for CD2, CD3, CD5, CD4 and CD7. Staining for CD8, CD30 and CD56 was negative. The appearances were those of an epitheliotrophic T-cell lymphoma, and were considered to represent spread from the patient's underlying Sézary syndrome. The patient died 2 months later from bronchopneumonia. CONCLUSIONS: Ocular involvement by cutaneous T-cell lymphoma usually occurs in advanced disease, and carries a poor prognosis. This patient was immunocompromised due to advanced malignancy, and there was a high suspicion of infection as the primary cause of corneal ulceration. This case highlights that it is important to consider direct tumour infiltration as an initiating or contributing factor for corneal ulceration in such patients.

Caliber persistent artery of the eyelid.

BACKGROUND: To report three cases of caliber persistent artery presenting in the eyelid. METHODS: A case series describing three patients with vascular lesions of the eyelid that were biopsied. One case was bilateral. RESULTS: All three patients presented with a painless red lesion on the eyelid. These were on the lower eyelid in two patients and the upper eyelid in one patient. For the bilateral case, the lesions were both on the lower eyelid. Histological examination of all four biopsies showed a large caliber artery within the dermis extending almost at right angles to the skin surface and consistent with caliber persistent artery. CONCLUSIONS: These are the first reports of caliber persistent artery of the eyelids, an entity that is most commonly recognized on the lips. Clinicians should consider this entity in the differential diagnosis of patients presenting with a painless, vascular lesion of the eyelid.

Balloon cell naevus of the conjunctiva: clinicopathological features and management.

A 7-year-old Caucasian girl presented with a pigmented lesion on the left bulbar conjunctiva that increased in size from 1 mm to 4 mm over a 12-month period. She underwent excision biopsy and reconstruction of the ocular surface with amniotic membrane graft. Histopathology showed the naevus was composed of somewhat swollen naevus cells with clear cytoplasm and central nucleus. These vacuolated naevus cells were approximately 40 µm in diameter. Over 90% of the cells in the naevus were composed of these swollen cells. Immunohistochemical staining was positive for S100 and Melan-A. This case illustrates that balloon cells may be observed in conjunctival naevi at a previously unreported pre-pubescent age. Awareness of ballon cell naevus is important to avoid clinical and histological pitfalls in diagnosis.

New Insights into Molecular Mechanisms Mediating Adaptation to Exercise; A Review Focusing on Mitochondrial Biogenesis, Mitochondrial Function, Mitophagy and Autophagy.

Exercise itself is fundamental for good health, and when practiced regularly confers a myriad of metabolic benefits in a range of tissues. These benefits are mediated by a range of adaptive responses in a coordinated, multi-organ manner. The continued understanding of the molecular mechanisms of action which confer beneficial effects of exercise on the body will identify more specific pathways which can be manipulated by therapeutic intervention in order to prevent or treat various metabolism-associated diseases. This is particularly important as exercise is not an available option to all and so novel methods must be identified to confer the beneficial effects of exercise in a therapeutic manner. This review will focus on key emerging molecular mechanisms of mitochondrial biogenesis, autophagy and mitophagy in selected, highly metabolic tissues, describing their regulation and contribution to beneficial adaptations to exercise.