Myeloid sarcoma of uterine cervix: A case report with review of the literature.

Myeloid sarcoma is a rare clinical entity, characterised by the extramedullary presence of myeloblasts. It can occur de novo or signify disease recurrence. Involvement of the female reproductive tract is uncommon, with most cases involving the uterine corpus or ovary. Patients with non-leukaemic myeloid sarcoma are treated with acute myeloid leukaemia (AML) regimens, but the optimal therapy is unclear due to the relative rarity of the condition and lack of clinical trial data. We present an unusual case of myeloid sarcoma of the uterine cervix diagnosed incidentally in a patient with cervical-intraepithelial neoplasia grade 2 (CIN2), followed by a literature review.

A pediatric case of SAPHO-CNO syndrome with clinical correlation between cutaneous and osteoarticular features.

Synovitis acne pustulosis hyperostosis osteitis (SAPHO) and chronic nonbacterial osteomyelitis (CNO) represent overlapping osteoarticular autoinflammatory syndromes, with a minority displaying neutrophilic skin features at the time of diagnosis. The pathophysiological link and chronological timeframe between skin and osteoarticular findings remain ambiguous, which in turn can manifest in diagnostic delay. We present a rare pediatric case of SAPHO-CNO with a clear association between cutaneous and osteoarticular symptoms, treated with nonsteroidal anti-inflammatory medications, corticosteroids, and intravenous pamidronate. By raising physician awareness of these syndromes, we hope that appropriate management will be initiated in a more timely fashion avoiding unnecessary investigations and treatment.

Change in troponin concentrations in patients with macrotroponin: An in vitro mixing study.

INTRODUCTION: Macrotroponin is a complex formed between endogenous cardiac troponin autoantibodies (cTnAABs) and circulating cardiac troponin (cTn). The potential effect of macrotroponin on current high sensitivity cTn assays has not been fully explored but has recently been identified as a major cause of discrepancy in cTn results between assays. In this study we investigated the effects of mixing troponin (cTn) standards to specimens with and without macrotroponin. METHOD: Macrotroponin was identified in specimens by a recovery of cTnI < 40% following protein A immunoglobulin depletion. Troponin standards containing cTn-IC and cTn-TIC complexes were mixed with serum samples, with (n = 20) and without (n = 10) the presence of macrotroponin. Specimens were tested for cTn before and after mixing by three commercially available high sensitivity cTn assays. Gel filtration chromatography was carried out on five specimens with macrotroponin and each fraction was analzyed by multiple cTn assays. FINDINGS: Following mixing with cTn-TIC standard, all specimens with macrotroponin had a markedly reduced absolute increase in cTnI, indicating negative analytical interference due to macrotroponin. Following mixing with the cTn-IC standard, specimens with macrotroponin demonstrated highly variable changes in cTnI, suggesting significant heterogeneity in macrotroponin complex reactivity between individuals. When the ratio of change, calculated by dividing the absolute change between two cTn assays, was compared between specimens with and without macrotroponin, significant differences were observed (p < 0.001). These findings were supported by variable migration of peak cTn activity on gel filtration chromatography. CONCLUSION: Macrotroponin leads to assay dependent analytical interference affecting current high sensitivity troponin I assays. Furthermore, endogenously occurring cTnAABs are conformationally specific and the analytical effects vary between assays and individuals.

The impact of a national COVID-19 lockdown on acute coronary syndrome hospitalisations in New Zealand (ANZACS-QI 55).

BACKGROUND: Countries with a high incidence of coronavirus 2019 (COVID-19) reported reduced hospitalisations for acute coronary syndromes (ACS) during the pandemic. This study describes the impact of a nationwide lockdown on ACS hospitalisations in New Zealand (NZ), a country with a low incidence of COVID-19. METHODS: All patients admitted to a NZ Hospital with ACS who underwent coronary angiography in the All NZ ACS Quality Improvement registry during the lockdown (23 March - 26 April 2020) were compared with equivalent weeks in 2015-2019. Ambulance attendances and regional community troponin-I testing were compared for lockdown and non-lockdown (1 July 2019 to 16 February 2020) periods. FINDINGS: Hospitalisation for ACS was lower during the 5-week lockdown (105 vs. 146 per-week, rate ratio 0•72 [95% CI 0•61-0•83], p = 0.003). This was explained by fewer admissions for non-ST-segment elevation ACS (NSTE-ACS; p = 0•002) but not ST-segment elevation myocardial infarction (STEMI; p = 0•31). Patient characteristics and in-hospital mortality were similar. For STEMI, door-to-balloon times were similar (70 vs. 72 min, p = 0•52). For NSTE-ACS, there was an increase in percutaneous revascularisation (59% vs. 49%, p<0•001) and reduction in surgical revascularisation (9% vs. 15%, p = 0•005). There were fewer ambulance attendances for cardiac arrests (98 vs. 110 per-week, p = 0•04) but no difference for suspected ACS (408 vs. 420 per-week, p = 0•44). Community troponin testing was lower throughout the lockdown (182 vs. 394 per-week, p<0•001). INTERPRETATION: Despite the low incidence of COVID-19, there was a nationwide decrease in ACS hospitalisations during the lockdown. These findings have important implications for future pandemic planning. FUNDING: The ANZACS-QI registry receives funding from the New Zealand Ministry of Health.

Identification and Analysis of Mouse Erythroid Progenitor Cells.

The most common cell type in the human body, the red blood cell or erythrocyte, has a life span of approximately 3 months. To compensate for this massive cellular requirement and short life span, the major blood producing tissues contain vast numbers of erythroid progenitor cells. Erythroid progenitors differentiate progressively from hematopoietic stem cells to committed erythroid progenitors to reticulocytes lacking a nucleus and finally to functionally mature erythrocytes in the circulation. Different erythroid progenitor activity, representative of distinct stages of erythropoiesis, can be observed using semisolid colony assays. Distinct stages of erythroid maturation can also be monitored by flow cytometry. Here, we discuss the range of different technical approaches that are used to identify and quantify erythroid progenitors, with particular focus on the mouse as a model system.

Splenomegaly: Pathophysiological bases and therapeutic options.

The spleen is the largest immune organ in the human body and is also essential for red blood cell homeostasis and iron recycling. An average human spleen is approximately 10 centimetres in length and weighs 150g. Pathological conditions can result in the spleen weighing in excess of 2000g and extending over 30 centrimetres in length. This remarkable property of the spleen to expand is termed splenomegaly. Splenomegaly can occur as a physiological response to stress or as a chronic process that is often detrimental to the wellbeing of the individual. Here, we will discuss the normal function and physiology of the spleen, the pathophysiological bases of splenomegaly and the commonly available therapeutic options. Additionally we will address experimental systems to determine the regulatory mechanisms underlying splenomegaly.

Low-dose naltrexone: a novel treatment for Hailey-Hailey disease.

Hailey-Hailey disease (chronic benign familial pemphigus) is a rare inherited dermatosis typically characterized by erosions at intertriginous sites preceded by minor trauma or stress. We report a case of treatment-resistant Hailey-Hailey disease having failed topical and oral steroids, prophylactic aciclovir and doxycycline, and systemic therapies including dapsone, acitretin and ciclosporin. Low-dose naltrexone 4·5 mg once daily was commenced following an incidental benefit in this patient's similarly affected sister. The clinical and psychological response to date has been considerable.

The effect of Rapid Response System revision on standard and specific intensive care unit outcomes in a regional hospital.

Hospital systems for the recognition (afferent limb) and management (efferent limb) of deteriorating patients, or Rapid Response Systems (RRSs), are being mandated worldwide, in spite of conflicting evidence regarding their efficacy. We have evaluated the impact of an Adult Deterioration Detection System (Q-ADDS)-based RRS specifically on illness severity at intensive care unit (ICU) admission and ICU length of stay (LOS), as well as previously studied endpoints. We undertook a retrospective, single-centre observational study comparing equivalent 18-month periods before the Q-ADDS-based RRS, and after implementation. The primary endpoints of the study were illness severity of unplanned ICU admissions from the ward, ICU length of stay, and ICU mortality. Secondary endpoints were RRS call numbers, rate of unplanned ICU admissions, and ward-based cardiorespiratory arrests. Following the introduction of the new RRS, Acute Pain and Chronic Health Evaluation (APACHE) II (17 versus 21, P <0.001), APACHE III (64 versus 68, P=0.011) and Simplified Acute Physiology Score (35 versus 38, P=0.044) scores at ICU admission from the ward were reduced. Fewer patients were in the >50% predicted mortality range of APACHE II (16% versus 32%, P <0.001), APACHE III (18% versus 28%, P=0.012) and Simplified Acute Physiology Score (14% versus 24%, P=0.006). ICU mortality was unchanged (13.7% versus 13.8%, P=0.93). ICU LOS was reduced (3 versus 4 days, P=0.02); prolonged stay (>7 days) was not significantly changed (19% versus 27%, P=0.055). Unplanned ICU admissions, cardiorespiratory arrests and hospital mortality were unchanged. The frequency of RRS activation (48 versus 11 per 1,000 admissions, P <0.001) was markedly increased. This Q-ADDS form-based RRS has resulted in lower illness severity at ICU admission from the ward, and fewer patients with scores associated with a >50% predicted mortality. Overall, ICU length of stay was reduced. These specific outcomes may reliably reflect RRS efficacy, even in smaller centres.

A novel frameshift mutation in the lipoprotein lipase gene is rescued by alternative messenger RNA splicing.

BACKGROUND: Type I hyperlipoproteinemia, manifesting as chylomicronemia and severe hypertriglyceridemia, is a rare autosomal recessive disorder usually caused by mutations in the lipoprotein lipase gene (LPL). OBJECTIVE: We sought to determine whether mutations in LPL could explain the clinical indications of a patient presenting with pancreatitis and hypertriglyceridemia. METHODS: Coding regions of LPL were amplified by polymerase chain reaction and analyzed by nucleotide sequencing. The LPL messenger RNA transcript was also analyzed to investigate whether alternative splicing was occurring. RESULTS: The patient was homozygous for the mutation c.767_768insTAAATATT in exon 5 of the LPL gene. This mutation is predicted to result in either a truncated nonfunctional LPL, or alternatively a new 5' donor splice site may be used, resulting in a full-length LPL with an in-frame deletion of 3 amino acids. Analysis of messenger RNA from the patient showed that the new splice site is used in vivo. CONCLUSION: Homozygosity for a mutation in the LPL gene was consistent with the clinical findings. Use of the new splice site created by the insertion mutation rescues an otherwise damaging frameshift mutation, resulting in expression of an almost full-length LPL that is predicted to be partially functional. The patient therefore has a less severe form of type I hyperlipoproteinemia than would be expected if she lacked any functional LPL.

The influence of cannabinoids on generic traits of neurodegeneration.

UNLABELLED: In an increasingly ageing population, the incidence of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and Huntington's disease are rising. While the aetiologies of these disorders are different, a number of common mechanisms that underlie their neurodegenerative components have been elucidated; namely neuroinflammation, excitotoxicity, mitochondrial dysfunction and reduced trophic support. Current therapies focus on treatment of the symptoms and attempt to delay the progression of these diseases but there is currently no cure. Modulation of the endogenous cannabinoid system is emerging as a potentially viable option in the treatment of neurodegeneration. Endocannabinoid signalling has been found to be altered in many neurodegenerative disorders. To this end, pharmacological manipulation of the endogenous cannabinoid system, as well as application of phytocannabinoids and synthetic cannabinoids have been investigated. Signalling from the CB1 and CB2 receptors are known to be involved in the regulation of Ca(2+) homeostasis, mitochondrial function, trophic support and inflammatory status, respectively, while other receptors gated by cannabinoids such as PPARγ, are gaining interest in their anti-inflammatory properties. Through multiple lines of evidence, this evolutionarily conserved neurosignalling system has shown neuroprotective capabilities and is therefore a potential target for neurodegenerative disorders. This review details the mechanisms of neurodegeneration and highlights the beneficial effects of cannabinoid treatment. LINKED ARTICLES: This article is part of a themed section on Cannabinoids 2013. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-6.

Smoking is a major risk factor for anastomotic leak in patients undergoing low anterior resection.

AIM: To examine modifiable risk factors for anastomotic leak in patients undergoing low anterior resection. METHOD: In total 233 patients undergoing low anterior resection for benign and malignant disease over a 10-year period at a single surgical unit were identified from a prospective database. The relationships between anastomotic leak and 17 variables were examined, including patient demographics, operative technique, tumour pathology, preoperative physiological function and smoking status. RESULTS: The majority (91%) of operations were carried out for rectal cancers, and 24 procedures (10%) were performed with laparoscopic assistance. The overall anastomotic leak rate was 14% (33/233). Patients with anastomotic leak had higher 30-day mortality (6%vs 1%, P<0.05) and stayed significantly longer in hospital (median 23 vs 10 days, P<0.001). On multivariate analysis, current smokers (OR 3.68, 95% CI 1.38-9.82, P=0.009) and patients with evidence of metastatic malignant disease (OR 3.43, 95% CI 1.29-9.13, P=.013) were at increased risk of anastomotic leak. CONCLUSION: Smoking and the presence of metastatic disease are major risk factors for the development of anastomotic leak following low anterior resection.

Tensile strain as a regulator of mesenchymal stem cell osteogenesis.

A role for mechanical stimulation in the control of cell fate has been proposed and mechanical conditioning of mesenchymal stem cells (MSCs) is of interest in directing MSC behavior for tissue engineering applications. This study investigates strain-induced differentiation and proliferation of MSCs, and investigates the cellular mechanisms of mechanotransduction. MSCs were seeded onto a collagen-coated silicone substrate and exposed to cyclic tensile mechanical strain of 2.5% at 0.17 Hz for 1-14 days. To examine mechanotransduction, cells were strained in the presence of the stretch-activated cation channel (SACC) blocker, gadolinium chloride (GdCl(3)); the extracellular regulated kinase (ERK) inhibitor, U0126; the p38 inhibitor, SB203580; and the phosphatidylinosito1 3-kinase (PI3-kinase) inhibitor, LY294002. Following exposure to strain, the osteogenic markers Cbfalpha1, collagen type I, osteocalcin, and BMP2 were temporally expressed. Exposure to strain in the presence of GdCl(3) (10 microM) reduced the induction of collagen I expression, thus identifying a role for SACC, at least in part, as mechanosensors in strain-induced MSC differentiation. The strain-induced synthesis of BMP2 was found to be reduced by inhibitors of the kinases, ERK, p38, and PI3 kinase. Additionally, mechanical strain reduced the rate of MSC proliferation. The identification of the mechanical control of MSC proliferation and the molecular link between mechanical stimulation and osteogenic differentiation has consequences for regenerative medicine through the development of a functional tissue engineering approach.

Blood lactate concentrations in anesthetized dogs with intracranial disease.

BACKGROUND: The importance of blood lactate concentrations in dogs with intracranial disease has not been established, despite frequently observed hyperlactatemia in dogs undergoing general anesthesia for advanced imaging, surgery, or both. HYPOTHESIS: Blood lactate concentrations are elevated in anesthetized dogs with intracranial disease, compared with dogs with intervertebral disc disease (IVDD). ANIMALS: Eighty-five hospitalized dogs undergoing advanced imaging, surgery, or both for primary neurologic disease; 30 with intracranial disease; 55 with IVDD. METHODS: Retrospective study. Age, breed, neurologic diagnosis, time from anesthesia induction to measurement of blood lactate, blood lactate concentration under anesthesia, and concurrently measured heart rate, mean arterial pressure, PCV, arterial hemoglobin oxygen saturation, and arterial partial pressure of oxygen were included in a multivariable linear regression analysis. RESULTS: Dogs with meningioma (adjusted mean lactate 2.99 mmol/L, 95% CL 2.21-4.05, P < 0.0001) and hydrocephalus (adjusted mean lactate 1.5 mmol/L, 95% CL 0.99-2.27, P= 0.003) had higher blood lactate concentrations compared with dogs with IVDD (adjusted mean lactate 0.79 mmol/L, 95% CL 0.6-1.04). Only dogs with meningioma had clinically important hyperlactatemia (>2.5 mmol/L). CONCLUSIONS: Prospective studies are warranted to determine the degree and clinical importance of high blood lactate concentrations in dogs with intracranial disease.

A study of pullout forces of the components of modular multi-manufacturer hybrid endografts used for aortic aneurysm repair.

OBJECTIVES: Aorto-iliac angulations may be challenging for modular stent-graft systems (SGSs) from a single manufacturer. This study aims to define the pullout forces (POFs) of SGSs derived from the same (non-hybrid) or different manufacturers (hybrid). METHODS: The POFs were tested in a vertical position in air and 5% albumin. We studied the POFs between legs from Anaconda (Vascutek), Excluder (Gore), Talent (Medtronic) and Zenith (Cook) with the contralateral limb of bifurcated aortic bodies from Zenith (12 mm), Anaconda and Excluder. RESULTS: For non-hybrid SGSs, the POFs decreased in the following order: Anaconda (11.2+/-0.6N), Talent (6.25+/-0.6N), Zenith (3.5+/-0.01 N) and Excluder (2.5+/-0.5 N). The Zenith body with the Anaconda limb (15 mm) registered the greatest POF (13.083+/-0.821 N); the Zenith and Excluder bodies combined with the Excluder limb (16 mm) registered the weakest POFs (2.397+/-0.22 N and 2.500+/-0.479 N, respectively). The Zenith body combined with the Excluder limb (16 mm) had a POF similar to the Zenith non-hybrid; combined with Talent 14 mm and Anaconda limb exhibited POFs greater than the Zenith non-hybrid system. For the limb-to-limb POFs, the greatest was registered for the Anaconda limb, 13 mm within a 12-mm extension for 40-mm overlaps (23.06+/-0.480 N); the weakest POFs were recorded for the Excluder limbs at 30-mm overlaps (1.09+/-0.167 N and 1.11+/-0.250 N). CONCLUSIONS: The hybrid SGSs performed as well as or better than the non-hybrid systems, and should be considered for clinical testing in patients whose unique anatomy warrants the flexibility that the use of hybrids provides.

Mechanisms of strain-mediated mesenchymal stem cell apoptosis.

Mechanical conditioning of mesenchymal stem cells (MSCs) has been adopted widely as a biophysical signal to aid tissue engineering applications. The replication of in vivo mechanical signaling has been used in in vitro environments to regulate cell differentiation, and extracellular matrix synthesis, so that both the chemical and mechanical properties of the tissue-engineered construct are compatible with the implant site. While research in these areas contributes to tissue engineering, the effects of mechanical strain on MSC apoptosis remain poorly defined. To evaluate the effects of uniaxial cyclic tensile strain on MSC apoptosis and to investigate mechanotransduction associated with strain-mediated cell death, MSCs seeded on a 2D silicone membrane were stimulated by a range of strain magnitudes for 3 days. Mechanotransduction was investigated using the stretch-activated cation channel blocker gadolinium chloride, the L-type voltage-activated calcium channel blocker nicardipine, the c-jun NH(2)-terminal kinase (JNK) blocker D-JNK inhibitor 1, and the calpain inhibitor MDL 28170. Apoptosis was assessed through DNA fragmentation using the terminal deoxynucleotidyl transferase mediated-UTP-end nick labeling method. Results demonstrated that tensile strains of 7.5% or greater induce apoptosis in MSCs. L-type voltage-activated calcium channels coupled mechanical stress to activation of calpain and JNK, which lead to apoptosis through DNA fragmentation. The definition of the in vitro boundary conditions for tensile strain and MSCs along with a proposed mechanism for apoptosis induced by mechanical events positively contributes to the development of MSC biology, bioreactor design for tissue engineering, and development of computational methods for mechanobiology.

Dynamic compression can inhibit chondrogenesis of mesenchymal stem cells.

The objective of this study was to investigate the influence of dynamic compressive loading on chondrogenesis of mesenchymal stem cells (MSCs) in the presence of TGF-beta3. Isolated porcine MSCs were suspended in 2% agarose and subjected to intermittent dynamic compression (10% strain) for a period of 42 days in a dynamic compression bioreactor. After 42 days in culture, the free-swelling specimens exhibited more intense alcian blue staining for proteoglycans, while immunohistochemical analysis revealed increased collagen type II immunoreactivity. Glycosaminoglycan (GAG) content increased with time for both free-swelling and dynamically loaded constructs, and by day 42 it was significantly higher in both the core (2.5+/-0.21%w/w vs. 0.94+/-0.03%w/w) and annulus (1.09+/-0.09%w/w vs. 0.59+/-0.08%w/w) of free-swelling constructs compared to dynamically loaded constructs. This result suggests that further optimization is required in controlling the biomechanical and/or the biochemical environment if such stimuli are to have beneficial effects in generating functional cartilaginous tissue.