Nano-bio interactions of upconversion nanoparticles at subcellular level: biodistribution and cytotoxicity.

Background: Modern medicine requires intensive research to find new diagnostic and therapeutic solutions. Recently, upconverting nanoparticles (UCNPs) doped with lanthanide ions have attracted significant attention. Methods: The efficient internalization of UCNPs by cells was confirmed, and their precise cellular localization was determined by electron microscopy and confocal studies. Results: UCNPs colocalized only with specific organelles, such as early endosomes, late endosomes and lysosomes. Furthermore, experiments with chemical inhibitors confirmed the involvement of endocytosis in UCNPs internalization and helped select several mechanisms involved in internalization. Exposure to selected UCNPs concentrations did not show significant cytotoxicity, induction of oxidative stress or ultrastructural changes in cells. Conclusion: This study suggests that UCNPs offer new diagnostic options for biomedical infrared imaging.

Case report: third-degree atrioventricular block secondary to septic coronary artery embolism following infective endocarditis.

BACKGROUND: Coronary artery emboli can occur from a number of rare causes such as arterial thrombo-embolus or septic embolus. This diagnosis generally requires multi-modal imaging including echocardiography, computed tomography, or invasive coronary angiography. Septic coronary emboli is an extremely rare consequence of infective endocarditis (IE), having been reported in <1% of all cases. CASE SUMMARY: A 54-year-old previously healthy Tibetan monk presented feeling generally unwell and lethargic. Electrocardiogram demonstrated sinus rhythm, third-degree atrioventricular block with a left bundle branch escape. Initial transthoracic and transoesophageal echocardiography demonstrated vegetations on the aortic and tricuspid valve as well as intra-myocardial abscess. Coronary angiography revealed septic embolus involving the septal perforator coronary artery. He underwent surgical replacement of the infected valves and debridement and repair of a ventricular septal defect. DISCUSSION: Infective endocarditis can predispose to a range of cardiac pathology. This case demonstrates that patients can present with cardiac conduction disease from a septic embolus involving a coronary artery as a complication of IE.

Open-Label, Crossover Study to Determine the Pharmacokinetics of Fluticasone Furoate and Batefenterol When Administered Alone, in Combination, or Concurrently.

The study aim was to investigate the pharmacokinetics of single high doses and repeated therapeutic doses of fluticasone furoate (FF) and batefenterol (BAT; a bifunctional muscarinic antagonist and ß2 -agonist) administered in combination (BAT/FF) or as monotherapy. In this open-label, 6-period, crossover study of 48 subjects, the treatment sequences were (1) single high-dose BAT/FF 900/300 µg followed by repeated therapeutic doses of BAT/FF 300/100 µg (once daily for 7 days); (2) single high-dose BAT 900 µg administered concurrently with FF 300 µg; (3) single high-dose BAT 900 µg followed by repeated therapeutic-dose BAT 300 µg; (4) single high-dose FF 300 µg followed by repeated therapeutic-dose FF 100 µg; (5) single high-dose FF 300 µg (magnesium stearate); and (6) single high-dose FF/vilanterol 300/75 µg. Plasma FF area under the plasma drug concentration-time curve (AUC) was reduced after single high-dose BAT/FF versus FF alone (ratio of geometric least squares means: 0.79; 90% confidence interval: 0.75-0.83). After repeat dosing, FF AUC at the lower therapeutic dosage was similar for BAT/FF and FF (primary endpoint; AUC geometric least squares means: 1.03). Adverse events were minor, the most common being cough. These data support the feasibility of developing BAT/inhaled corticosteroid triple therapy in a single inhaler.

Pharmacokinetics, Excretion, and Mass Balance of [14 C]-Batefenterol Following a Single Microtracer Intravenous Dose (Concomitant to an Inhaled Dose) or Oral Dose of Batefenterol in Healthy Men.

Inhaled batefenterol is an investigational bifunctional molecule for the treatment of chronic obstructive pulmonary disease. The excretion balance and pharmacokinetics of batefenterol using [14 C]-radiolabeled drug administered orally and as intravenous (IV) infusion were assessed. In this 2-period, open-label study, 6 healthy male subjects received a single IV microtracer 1-hour infusion of 4 µg [14 C]-batefenterol concomitant with inhaled nonradiolabeled batefenterol (1200 µg) followed by oral [14 C]-batefenterol (200 µg) in period 2 after a 14-day washout. The primary end points included: the area under the concentration-time curve from time zero to last time of quantifiable concentration (AUC0-t ); maximum observed concentration (Cmax ); and time of occurrence of maximum observed concentration. Following IV administration, the geometric mean AUC0-t of [14 C]-batefenterol was 121.9 pgEq • h/mL; maximum observed concentration and time of occurrence of maximum observed concentration were 92.7 pgEq/mL and 0.8 hours, respectively; absolute oral bioavailability was 0.012%. The mean AUC0-t ratio indicated that [14 C]-batefenterol accounted for 85% of total circulating radioactivity in the plasma initially and declined rapidly following IV administration, but only ∼0.2% of total circulating radioactivity following oral administration. Cumulative mean recovery of total radioactive [14 C]-batefenterol in urine and feces was 6.31% and 77.6%, respectively. Overall, batefenterol exhibited low systemic bioavailability after inhaled and oral administration, and high fecal excretion and low urinary excretion following IV and oral administration.

Subadventitial stenting around occluded stents: A bailout technique to recanalize in-stent chronic total occlusions.

OBJECTIVES: To evaluate the outcomes of subadventitial stenting (SS) around occluded stents for recanalizing in-stent chronic total occlusions (IS-CTOs). BACKGROUND: There is little evidence on the outcomes of SS for IS-CTO. METHODS: We examined the outcomes of SS for IS-CTO PCI at 14 centers between July 2011 and June 2017, and compared them to historical controls recanalized using within-stent stenting (WSS). Target-vessel failure (TVF) on follow-up was the endpoint of this study, and was defined as a composite of cardiac death, target-vessel myocardial infarction, and target-vessel revascularization. RESULTS: During study period, 422 IS-CTO PCIs were performed, of which 32 (7.6%) were recanalized with SS, usually when conventional approaches failed. The most frequent CTO vessel was the right coronary artery (72%). Mean J-CTO score was 3.1 ± 0.9. SS was antegrade in 53%, and retrograde in 47%. Part of the occluded stent was crushed in 37%, while the whole stent was crushed in 63%. Intravascular imaging was used in 59%. One patient (3.1%) suffered tamponade. Angiographic follow-up was performed in 10/32 patients: stents were patent in six cases, one had mild neointimal hyperplasia, and three had severe restenosis at the SS site. Clinical follow-up was available for 29/32 patients for a mean of 388 ± 303 days. The 24-month incidence of TVF was 13.8%, which was similar to historical controls treated with WSS (19.5%, P = 0.49). CONCLUSIONS: SS is rarely performed, usually as last resort, to recanalize complex IS-CTOs. It is associated with favorable acute and mid-term outcomes, but given the small sample size of our study additional research is warranted.

Intrasellar cavernous hemangioma presenting as pituitary adenoma: A report of two cases and review of the literature.

Cavernous hemangioma in the sellar region is quite rare with only a handful of cases being reported in the English literature. Its clinical manifestations and imaging characteristics can mimic those of a pituitary adenoma. We report two cases of recurrent sellar lesions, both of which were clinically suspected of being pituitary adenomas but histologically confirmed as cavernous hemangiomas. The first case is of a 67-year-old female whose initial resection was diagnosed as "venous angioma". Neuroimaging performed 27 years later demonstrated significant growth of the lesion involving the right cavernous sinus and encasing the right internal carotid artery. The patient then underwent transsphenoidal endoscopic resection of the mass. At the time of the surgery, the lesion was noted to be quite vascular. The second case is a 48-year-old female who underwent emergency resection of a pituitary mass following an apoplectic event. On follow-up 4 years later, the patient reported recurrence of galactorrhea, and MRI had demonstrated regrowth of the mass. She subsequently underwent subtotal resection of the mass. At the time of surgery, brisk bleeding was noted in the operative area. The above two cases demonstrate that cavernous hemangiomas in the sellar region can clinically and radiologically mimic pituitary adenoma and should be considered in the differential diagnosis of hemorrhagic sellar mass.
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Pathology of toxic leucoencephalopathy in drug abuse supports hypoxic-ischemic pathophysiology/etiology.

The histopathological features of leucoencephalopathy caused by illicit drugs (such as opioids and cocaine) are well documented in acute cases but not in long-survival cases. There are several hypotheses about the pathogenesis of this disorder, including hypoperfusion, direct drug toxicity resulting from the neurotoxic effects of the drug itself or contaminants in the illicit drug vehicle. We reviewed the post mortem findings in five males (aged 24 to 56 years, with survival intervals ranging from 7 days to 5 months) with a history of illicit drug use and concomitant fatal white matter changes. The histological characteristics of leucoencephalopathy vary with survival period. Prominent axonal injury and axonal spheroids were observed with shorter survival and spongiform changes becoming apparent with longer survival (acute and chronic incomplete infarct pattern). Necrosis was present in all cases and its appearance changed with longer survival (acute and chronic complete infarct pattern). Significant primary demyelination was not observed. These observations suggest that the primary defect in this leucoencephalopathy is hypoxic-ischemic injury, predominantly in the white matter. Spongiform leucoencephalopathy likely represents the longer-survival incomplete infarct pattern and is observed with polydrug abuse.

Late Double-Barrel Lumen Following Successful CTO-PCI Using the Crossboss Stingray System.

There remains limited randomized controlled trials on long-term clinical outcomes after chronic total occlusion percutaneous coronary intervention (CTO-PCI). New techniques involving dissection of the subintimal space and reentry into the true lumen increase success rates in CTO-PCI. However, their longer-term safety and efficacy remain unknown and poorly studied. We present a case of double-lumen formation seen at 1 year post CTO-PCI using subintimal dissection reentry with late restoration of major side branches.

Selective anti-scatter grid removal during coronary angiography and PCI: a simple and safe technique for radiation reduction.

Objectives The aim of this study was to quantify the radiation dose reduction during coronary angiography and percutaneous coronary intervention (PCI) through removal of the anti-scatter grid (ASG), and to assess its impact on image quality in adult patients with a low body mass index (BMI). Methods A phantom with different thicknesses of acrylic was used with a Westmead Test Object to simulate patient sizes and assess image quality. 129 low BMI patients underwent coronary angiography or PCI with or without the ASG in situ. Radiation dose was compared between both patient groups. Results With the same imaging system and a comparable patient population, ASG removal was associated with a 47% reduction in total dose-area product (DAP) (p < 0.001). Peak skin dose was reduced by 54% (p < 0.001). Operator scatter was reduced to a similar degree and was significantly reduced through removal of the ASG. Using an image quality phantom it was demonstrated that image quality remained satisfactory. Conclusions Removal of the ASG is a simple and effective method to significantly reduce radiation dose in coronary angiography and PCI. This was achieved while maintaining adequate diagnostic image quality. Selective removal of the ASG is likely to improve the radiation safety of cardiac angiography and interventions.

Reduction of falls and fractures after permanent pacemaker implantation in elderly patients with sinus node dysfunction.

AIMS: Elderly patients with sinus node dysfunction (SND) are at increased risk of falls with possible injuries. However, the incidence of these adverse events and its reduction after permanent pacemaker (PPM) implantation are not known. METHODS AND RESULTS: Eighty-seven patients (mean [SD] age 75.4 [8.3] years, 51% women) with SND and an indication for cardiac pacing were included and were examined by a standardized interview targeting fall history. The incidence and total number of falls, falls with injury, falls requiring treatment, and falls resulting in a fracture were assessed for the time period of 12 months before (retrospectively) and after PPM implantation (prospectively). Furthermore, symptoms such as syncope, dizziness, and dyspnea were evaluated before and after PPM implantation. The implantation of a PPM was associated with a reduced proportion of patients experiencing at least one fall by 71% (from 53 to 15%, P < 0.001) and a reduction of the absolute number of falls by 90% (from 127 to 13, P < 0.001) during the 12 months before vs. after PPM implant. Falls with injury (28 vs. 10%, P = 0.005), falls requiring medical attention (31 vs. 8%, P < 0.001), and falls leading to fracture (8 vs. 0%, P = 0.013) were similarly reduced. Notably, fewer patients had syncope (4 vs. 45%, P < 0.001) and dizziness after PPM implantation (12 vs. 45%, P < 0.001). CONCLUSION: Falls, fall-related injuries, and fall-related fractures are frequent in SND patients. Permanent pacemaker implantation is associated with a significantly reduced risk of these adverse events, although no causal relationship could be established due to the study design.

Balo's concentric lesions with concurrent features of Schilder's disease in relapsing multiple sclerosis: neuropathological findings

Atypical inflammatory demyelinating syndromes are rare neurological diseases that differ from multiple sclerosis (MS), owing to unusual clinicoradiological and pathological findings, and poor responses to treatment. The distinction between them and the criteria for their diagnoses are poorly defined due to the lack of advanced research studies. Balo's concentric sclerosis (BCS) and Schilder's disease (SD) are two of these syndromes and can present as monophasic or in association with chronic MS. Both variants are difficult to distinguish when they present in acute stages. We describe an autopsy case of middle-aged female with a chronic history of MS newly relapsed with atypical demyelinating lesions, which showed concurrent features of BCS and SD. We also describe the neuropathological findings, and discuss the overlapping features between these two variants.

Real-time colour pictorial radiation monitoring during coronary angiography: effect on patient peak skin and total dose during coronary angiography.

AIMS: The aim of this study was to evaluate whether a real-time (RT) colour pictorial radiation dose monitoring system reduces patient skin and total radiation dose during coronary angiography and intervention. METHODS AND RESULTS: Patient demographics, procedural variables and radiation parameters were recorded before and after institution of the RT skin dose recording system. Peak skin dose as well as traditionally available measures of procedural radiation dose were compared. A total of 1,077 consecutive patients underwent coronary angiography, of whom 460 also had PCI. Institution of the RT skin dose recording system resulted in a 22% reduction in peak skin dose after accounting for confounding variables. Radiation dose reduction was most pronounced in those having PCI but was also seen over a range of subgroups including those with prior coronary artery bypass surgery, high BMI, and with radial arterial access. This was associated with a significant reduction in the number of patients placed at risk of skin damage. Similar reductions in parameters reflective of total radiation dose were also demonstrated after institution of RT radiation monitoring. CONCLUSIONS: Institution of an RT skin dose recording reduced patient peak skin and total radiation dose during coronary angiography and intervention. Consideration should be given to widespread adoption of this technology.

Cerebellar liponeurocytoma: a rare intracranial tumor with possible familial predisposition. Case report.

The biological origin of cerebellar liponeurocytomas is unknown, and hereditary forms of this disease have not been described. Here, the authors present clinical and histopathological findings of a young patient with a cerebellar liponeurocytoma who had multiple immediate family members who harbored similar intracranial tumors. A 37-year-old otherwise healthy woman presented with a history of progressive headaches. Lipomatous medulloblastoma had been diagnosed previously in her mother and maternal grandfather, and her maternal uncle had a supratentorial liponeurocytoma. MRI revealed a large, poorly enhancing, lipomatous mass emanating from the superior vermis that produced marked compression of posterior fossa structures. An uncomplicated supracerebellar infratentorial approach was used to resect the lesion. Genetic and histopathological analyses of the lesion revealed neuronal, glial, and lipomatous differentiation and confirmed the diagnosis of cerebellar liponeurocytoma. A comparison of the tumors resected from the patient and, 22 years previously, her mother revealed similar features. Cerebellar liponeurocytoma is a poorly understood entity. This report provides novel evidence of an inheritable predisposition for tumor development. Accurate diagnosis and reporting of clinical outcomes and associated genetic and histopathological changes are necessary for guiding prognosis and developing recommendations for patient care.

Balo's concentric lesions with concurrent features of Schilder's disease in relapsing multiple sclerosis: neuropathological findings.

Atypical inflammatory demyelinating syndromes are rare neurological diseases that differ from multiple sclerosis (MS), owing to unusual clinicoradiological and pathological findings, and poor responses to treatment. The distinction between them and the criteria for their diagnoses are poorly defined due to the lack of advanced research studies. Balo's concentric sclerosis (BCS) and Schilder's disease (SD) are two of these syndromes and can present as monophasic or in association with chronic MS. Both variants are difficult to distinguish when they present in acute stages. We describe an autopsy case of middle-aged female with a chronic history of MS newly relapsed with atypical demyelinating lesions, which showed concurrent features of BCS and SD. We also describe the neuropathological findings, and discuss the overlapping features between these two variants.

Primary cutaneous smoldering adult T-cell leukemia/ lymphoma.

HTLV-1 is a virus that is endemic in southwesternJapan and the Caribbean and has been implicatedin the development of ATLL. ATLL, which is anuncommon malignant condition of peripheralT-lymphocytes, is characterized by four clinicalsubtypes, which include acute, lymphomatous,chronic, and smoldering types, that are based onLDH levels, calcium levels, and extent of organinvolvement. We present a 52-year- old woman withpruritic patches with scale on the buttocks and withtender, hyperpigmented macules and papules oftwo-years duration. Histopathologic examinationwas suggestive of mycosis fungoides, laboratoryresults showed HTLV-I and II, and the patient wasdiagnosed with primary cutaneous ATLL. We reviewthe literature on HTLV-1 and ATLL and specifically theprognosis of cutaneous ATLL. The literature suggeststhat a diagnosis of ATLL should be considered amongpatients of Caribbean origin or other endemicareas with skin lesions that suggest a cutaneousT-cell lymphoma, with clinicopathologic features ofmycosis fungoides. Differentiation between ATLLand cutaneous T-cell lymphoma is imperative as theyhave different prognoses and treatment approaches.

Molecular subgroups of atypical teratoid rhabdoid tumours in children: an integrated genomic and clinicopathological analysis.

BACKGROUND: Rhabdoid brain tumours, also called atypical teratoid rhabdoid tumours, are lethal childhood cancers with characteristic genetic alterations of SMARCB1/hSNF5. Lack of biological understanding of the substantial clinical heterogeneity of these tumours restricts therapeutic advances. We integrated genomic and clinicopathological analyses of a cohort of patients with atypical teratoid rhabdoid tumours to find out the molecular basis for clinical heterogeneity in these tumours. METHODS: We obtained 259 rhabdoid tumours from 37 international institutions and assessed transcriptional profiles in 43 primary tumours and copy number profiles in 38 primary tumours to discover molecular subgroups of atypical teratoid rhabdoid tumours. We used gene and pathway enrichment analyses to discover group-specific molecular markers and did immunohistochemical analyses on 125 primary tumours to evaluate clinicopathological significance of molecular subgroup and ASCL1-NOTCH signalling. FINDINGS: Transcriptional analyses identified two atypical teratoid rhabdoid tumour subgroups with differential enrichment of genetic pathways, and distinct clinicopathological and survival features. Expression of ASCL1, a regulator of NOTCH signalling, correlated with supratentorial location (p=0·004) and superior 5-year overall survival (35%, 95% CI 13-57, and 20%, 6-34, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·033) in 70 patients who received multimodal treatment. ASCL1 expression also correlated with superior 5-year overall survival (34%, 7-61, and 9%, 0-21, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·001) in 39 patients who received only chemotherapy without radiation. Cox hazard ratios for overall survival in patients with differential ASCL1 enrichment treated with chemotherapy with or without radiation were 2·02 (95% CI 1·04-3·85; p=0·038) and 3·98 (1·71-9·26; p=0·001). Integrated analyses of molecular subgroupings with clinical prognostic factors showed three distinct clinical risk groups of tumours with different therapeutic outcomes. INTERPRETATION: An integration of clinical risk factors and tumour molecular groups can be used to identify patients who are likely to have improved long-term radiation-free survival and might help therapeutic stratification of patients with atypical teratoid rhabdoid tumours. FUNDING: C17 Research Network, Genome Canada, b.r.a.i.n.child, Mitchell Duckman, Tal Doron and Suri Boon foundations.

Chronic total occlusions - Current techniques and future directions.

Chronic total occlusions (CTOs) of coronary arteries represent a common and significant challenge to interventional cardiology. Medical therapy is often regarded as an adequate long term strategy in the management of these lesions with surgical intervention for refractory symptoms. Extensive collateralisation is used as a marker of distal coronary perfusion, further reinforcing non-invasive strategies. This together with relatively low percutaneous success rates outside of specialised centres has meant that rates of percutaneous intervention have remained low. Increasing evidence suggests that CTOs are not a benign entity. Further, symptom control and quality of life improve significantly with successful percutaneous revascularisation. Both factors have reignited interest in percutaneous modalities. The Japanese have been pioneers in the field of CTO intervention although their success rates have been difficult to replicate. New techniques and equipment developed in North America offer an alternative to the Japanese approach. These techniques focus on time, radiation and contrast minimisation. This review will assess the histopathology of CTO and shifting paradigms in CTO treatment strategies.

Case of multiple sulfatase deficiency and ocular albinism: a diagnostic odyssey.

BACKGROUND: Multiple sulfatase deficiency (MSD) is a rare autosomal recessive inborn error of lysosomal metabolism. The clinical phenotypic spectrum encompasses overlapping features of variable severity and is suggestive of individual single sulfatase deficiencies (i.e., metachromatic leukodystrophy, mucopolysaccharidosis, and X-linked ichthyosis). CASE REPORT: We describe a 3-year-old male with severe hypotonia, developmental regression and progressive neurodegeneration, coarse facial features, nystagmus (from ocular albinism), and dysmyelinating motor sensory neuropathy. Ethics approval was obtained from the Western University Ontario. RESULTS: Extensive investigative work-up identified deficiencies of multiple sulfatases: heparan sulfate sulfamidase: 6.5 nmoles/mg/protein/17 hour (reference 25.0-75.0), iduronate-2-sulfate sulfatase: 9 nmol/mg/protein/4 hour (reference 31-110), and arylsulfatase A: 3.8 nmoles/hr/mg protein (reference 22-50). The identification of compound heterozygous pathogenic mutations in the SUMF1 gene c.836 C>T (p.A279V) and c.1045C>T (p.R349W) confirmed the diagnosis of MSD. CONCLUSION: The complex clinical manifestations of MSD and the unrelated coexistence of ocular albinism as in our case can delay diagnosis. Genetic counselling should be provided to all affected families.