Prevalence and predictors of airflow obstruction in an HIV tertiary care clinic in Montreal, Canada: a cross-sectional study.

OBJECTIVES: The reported prevalence of chronic obstructive pulmonary disease (COPD) in people living with HIV (PLWHIV) varies widely. Our objective was to estimate the prevalence of airflow obstruction and COPD in unselected PLWHIV and identify characteristics that increase the risk of nonreversible airflow obstruction in order to guide case finding strategies for COPD. METHODS: All adults attending the Chronic Viral Illness Service were invited to participate in the study, regardless of smoking status or history of known COPD/asthma. Individuals underwent spirometric testing both before and after use of a salbutamol bronchodilator. Airflow obstruction was defined as forced expiratory volume in 1 s (FEV1 )/forced vital capacity (FVC) < 0.7 post-bronchodilation, whereas COPD was defined as FEV1 /FVC < 0.7 post-bronchodilation and Medical Research Council (MRC) score > 2. Multivariate logistic regression was used to evaluate risk factors associated with airflow obstruction, reported as adjusted odds ratios (aORs). RESULTS: Five hundred and three participants successfully completed spirometry testing. The median (Q1; Q3) age was 52 (44; 58) years. The median (Q1; Q3) CD4 count was 598 (438; 784) cells/µL and the median (Q1; Q3) nadir CD4 count was 224 (121; 351) cells/µL. There were 119 (24%) current smokers and 145 (29%) former smokers. Among those screened, 54 (11%) had airflow obstruction whereas three (1%) of the participants had COPD. Factors that were associated with airflow obstruction included a history of smoking [aOR 2.2; 95% confidence interval (CI) 1.1; 4.7], older age (aOR 1.6; 95% CI 1.2; 2.2), and lower CD4 count (aOR 0.8; 95% CI 0.7; 1.0). CONCLUSIONS: Airflow obstruction was relatively uncommon. Our findings suggest that PLWHIV who are ≥50 years old, smokers and those with nadir CD4 counts ≤ 200 cells/µL could be targeted to undergo spirometry to diagnose chronic airflow obstruction.

Histoplasmosis and subcutaneous nodules in a kidney transplant recipient: erythema nodosum versus fungal panniculitis.

Erythema nodosum (EN)-like lesions are a rare occurrence after solid organ transplantation. Differential diagnosis includes infective panniculitis, which can be a feature of progressive disseminated histoplasmosis (PDH), an uncommon but severe form affecting primarily immunocompromised hosts. We report on a fatal case of PDH, which presented as fungal panniculitis masquerading as EN in a renal allograft recipient 25 years after transplantation. We discuss the clinical, histopathological, and microbiological characteristics of this rare complication, with focus on its distinction from EN. This case emphasizes the central role of biopsy in transplant recipients presenting with cutaneous lesions, and the importance of clinicopathologic correlation and complementary microbiological investigations.

Real world data on outcomes of anti-CD38 antibody treated, including triple class refractory, patients with multiple myeloma: a multi-institutional report from the Canadian Myeloma Research Group (CMRG) Database.

Multiple myeloma (MM) remains incurable despite the availability of novel agents. This multi-center retrospective cohort study used the Canadian Myeloma Research Group Database to describe real-world outcomes of patients withanti-CD38 monoclonal antibody (mAb) refractory MM subsequently treated with standard of care (SoC) regimens. Patients with triple class refractory (TCR) disease (refractory to a proteasome inhibitor, immunomodulatory drug, and anti-CD38 mAb) were examined as a distinct cohort. Overall, 663 patients had disease progression on anti-CD38 mAb therapy, 466 received further treatment (346 with SoC regimens were included, 120 with investigational agents on clinical trial and were excluded). The median age at initiation of subsequent SoC therapy of 67.9 (range 39.6-89.6) years with a median of 3 prior lines (range 1-9). The median PFS and OS from the start of subsequent therapy was 4.6 (95% CI 4.1-5.6) months and 13.3 (95% CI 10.6-16.6) months, respectively. The median PFS and OS of patients with TCR disease (n = 199) was 4.4 (95% CI 3.6-5.3) months and 10.5 (95% CI 8.5-13.8) months. Our results reinforce that real-world patients with relapsed MM, particularly those with TCR disease, have dismal outcomes. There remains an urgent unmet need for the development of and access to effective therapeutics for these patients.

Accurate, noninvasive diagnosis of human brain tumors by using proton magnetic resonance spectroscopy.

Although conventional proton magnetic resonance imaging has increased our ability to detect brain tumors, it has not enhanced to nearly the same degree our ability to diagnose tumor type. Proton magnetic resonance spectroscopy is a safe, noninvasive means of performing biochemical analysis in vivo. Using this technique, we characterized and classified tissue from normal brains, as well as tissue from the five most common types of adult supratentorial brain tumors. These six tissue types differed in their pattern across the six metabolites measured. 'Leaving-one-out' linear discriminant analyses based on these resonance profiles correctly classified 104 of 105 spectra, and, whereas conventional preoperative clinical diagnosis misclassified 20 of 91 tumors, the linear discriminant analysis approach missed only 1. Thus, we have found that a pattern-recognition analysis of the biochemical information obtained from proton magnetic resonance spectroscopy can enable accurate, noninvasive diagnosis of the most prevalent types of supratentorial brain tumors.

Cyst formation following radiosurgery for AVMs: report of 3 cases.

BACKGROUND: Stereotactically-focused radiosurgery (SRS) for the treatment of arteriovenous malformations (AVM) has been in widespread use for over two decades. Over this timeframe the indications for treatment, standardization of radiation dosage, and the results expected from treatment have been elaborated. Less well known are the long-term complications associated with SRS. We report three patients who had SRS for the treatment of AVM who developed a cyst at the site of treatment as a late complication. METHODS: From 201 patients treated by SRS for an AVM, three developed a cyst at the treatment site. Their clinical presentation, the characteristics of the AVMs and the treatment were reviewed, as well as similar cases gleaned from the literature. RESULTS: Three women, aged 28-43 years, had an AVM treated by: craniotomy and clipping of arterial feeders followed by SRS, by craniotomy for resection followed by SRS or by endovascular embolization and SRS. The patients did well following treatment but two of them developed a symptomatic and the other an asymptomatic cyst at the treatment site 3-19 years later. The symptomatic patients underwent marsupialization of the cyst and the other is under observation. CONCLUSION: Stereotactic radiosurgery is an established and safe treatment for patients with AVMs. Delayed cyst formation can occur many years after treatment and long term follow-up is indicated in patients whose AVM has been treated with SRS.

White matter-Maximien Parchappe and the integration of articulate language.

The Imperial Academy of Medicine of Paris met in the spring of 1865 to discuss the localization of speech. One of the participants was Maximien Parchappe (1800-1866), an alienist whose research interests lay in the cerebral cortex. This article addresses Maximien Parchappe's concept that the cognitive elements of language-such as the translation of thoughts into words, the will to express them, and the means to do so-reside within the cortical gray matter, and that they are integrated through white-matter fibers. In so doing, Parchappe anticipated Carl Wernicke's linking of the posterior aspects of the dominant frontal and temporal lobes in verbal expression, and Jules Dejerine's linking of the angular gyrus and Wernicke's area in the understanding of written language. Functional imaging has revived interest in language as a network of neuronal aggregates and has given new relevance to Parchappe's concept of the functional organization of language.

Pharmacological inhibition of syntenin PDZ2 domain impairs breast cancer cell activities and exosome loading with syndecan and EpCAM cargo.

Exosomes support cell-to-cell communication in physiology and disease, including cancer. We currently lack tools, such as small chemicals, capable of modifying exosome composition and activity in a specific manner. Building on our previous understanding of how syntenin, and its PDZ partner syndecan (SDC), impact on exosome composition we optimized a small chemical compound targeting the PDZ2 domain of syntenin. In vitro , in tests on MCF-7 breast carcinoma cells, this compound is non-toxic and impairs cell proliferation, migration and primary sphere formation. It does not affect the size or the number of secreted particles, yet it decreases the amounts of exosomal syntenin, ALIX and SDC4 while leaving other exosomal markers unaffected. Interestingly, it also blocks the sorting of EpCAM, a bona fide target used for carcinoma exosome immunocapture. Our study highlights the first characterization of a small pharmacological inhibitor of the syntenin-exosomal pathway, of potential interest for exosome research and oncology.

Updates from the 2019 American Society of Clinical Oncology and European Hematology Association annual meetings: a Canadian perspective on high-risk cytogenetics in multiple myeloma.

The 2019 annual meetings of the American Society of Clinical Oncology and the European Hematology Association took place, respectively, in Chicago, Illinois, 31 May-4 June, and in Amsterdam, Netherlands, 13-16 June. At the meetings, results from key studies on the treatment of patients with relapsed or refractory multiple myeloma with high-risk cytogenetics were presented. Our meeting report describes those studies and includes interviews with investigators and commentaries by Canadian hematologists about the potential impact on Canadian practice.

Hypofractionated stereotactic radiotherapy for low grade glioma at McGill University: long-term follow-up.

Small, well-defined, unresectable low-grade gliomas are attractive targets for stereotactic irradiation. Fractionated stereotactic irradiation of these targets has the theoretical benefit of increased normal tissue sparing beyond that provided by the physical characteristics of stereotactic radiosurgery. From July 1987 to November 1992, 21 patients were treated for low-grade glioma at our institution using a hypofractionated regimen of stereotactic radiotherapy. All patients had well-circumscribed, < 40 mm tumors. No patient had had prior radiotherapy. All lesions were histologically proven WHO grade I or II glial tumors. Lesions involved sensitive brain structures and were deemed unresectable. A typical dose of 42 Gy was delivered in 6 fractions over a two-week period using rigid immobilization and a linac-based dynamic stereotactic radiosurgical technique. Patients had a median age of 23 years (9-74) and were predominantly female (60%). Median tumor diameter was 20 mm. With a median follow-up for living patients of 13.3 years, the actuarial 5, 10, and 15-year overall survival rates are 76%, 71%, and 63%, respectively. Treatment was acutely well tolerated although three patients experienced late post-therapy complications. Our results and those of 241 patients treated in nine other institutional series are reviewed. Despite some examples of favorable short-term outcomes, all reported series are highly selected and thus likely biased. The data regarding the use of SRS is limited and, in our opinion, insufficient to claim a clear therapeutic advantage to SRS in the initial management of low-grade glioma. Our own results with hypofractionated stereotactic radiotherapy are similar to those expected with standard therapy.

A unique, environmentally sustainable and cost-effective programme to re-vegetate military training lands utilising composted wastewater biosolids at a large Canadian military training centre.

The Greater Moncton Sewerage Commission has developed, in concert with National Defence Canada, an environmentally sustainable and cost effective biosolids management and land reclamation programme at the Canadian Forces Base (CFB) Gagetown, New Brunswick, Canada (the second largest land based Military Training Facility in the British Commonwealth). The use of composted biosolids to revegetate military training lands is thought to be a unique application for the beneficial use of biosolids. Results and practical experience gained from this approach to successfully re-vegetate initial sections of extremely large and vast tracts of these lands are described. The paper also overviews the Commission's modern 115000 m3 x d(-1) advanced, chemically assisted primary wastewater treatment facility and associated alkaline (lime) sludge stabilisation process. Planning strategies, security aspects, special and unique challenges in operating adjacent to an active military training facility, costs, spreading techniques, monitoring, next steps and conclusions are also presented.

Canadian cost analysis comparing maintenance therapy with bortezomib versus lenalidomide for patients with multiple myeloma post autologous stem cell transplant.

BACKGROUND: Multiple myeloma (MM) is a cancer caused by malignant plasma cells that accumulate mostly in the bone marrow. In Canada, the most common maintenance therapy options after autologous stem cell transplant (ASCT) are bortezomib and lenalidomide. OBJECTIVE: To determine the incremental cost between bortezomib and lenalidomide maintenance therapies for patients with MM post ASCT. METHODS: Analyses were conducted to compare the annual costs of bortezomib and lenalidomide maintenance treatments for patients with MM post ASCT in Canada. The base case analysis included the acquisition costs of the drugs and administration costs. Additional analyses were conducted which considered the cost of experiencing adverse events (AEs) and the cost of treating second primary malignancies (SPMs). RESULTS: In the Canadian healthcare system, the total annual per patient cost was $33,967 for bortezomib maintenance therapy versus $131,765 for lenalidomide maintenance therapy. One-way sensitivity analyses demonstrated that both AEs and SPMs had little impact on the incremental cost, and that differences between the two maintenance therapies were mainly due to the acquisition costs of the drugs. CONCLUSIONS: Bortezomib is significantly less costly than lenalidomide, and is an economically reasonable maintenance treatment option for patients with MM post ASCT.

Favorable long-term outcome of patients with multiple myeloma using a frontline tandem approach with autologous and non-myeloablative allogeneic transplantation.

Despite survival improvement with novel agents and use of autologous hematopoietic stem cell transplantation (HSCT), cure of patients with multiple myeloma (MM) remains anecdotal. Initial observations suggested that chronic GvHD was accompanied by an anti-myeloma effect after myeloablative HSCT, but unfortunately this procedure was hampered by high non-relapse mortality (NRM). To maximize the anti-myeloma effect and minimize NRM, we developed a non-myeloablative (NMA) regimen associated with a high incidence of chronic GvHD and tested its efficacy on patient survival and disease eradication. From 2001 to 2010, 92 patients aged ⩽ 65 years with a compatible sibling donor received autologous HSCT followed by an outpatient NMA allogeneic HSCT using a conditioning of fludarabine and cyclophosphamide. Patient median age was 52 years and 97% presented Durie-Salmon stages II-III disease. After a median follow-up of 8.8 years, probability of 10-year progression free and overall survival were 41% and 62%, respectively. Although the cumulative incidence of extensive chronic GvHD was high (at 79%), the majority of long-term survivors were off immunosuppressive drugs by year 5 and NRM was low (at 10%). Together, our results suggest that potential MM cure can be achieved with NMA transplantation regimens that maximize graft-versus-myeloma effect and minimize NRM.

Molecular recognition of concanavalin A on mannoside diacetylene lipid monolayer at the air-water interface.

The interaction of p-10,12-pentacosadiyne-1-n-phenylamide alpha-D-mannopyranoside (MPDA) with protein concanavalin A (Con A) was studied at the air/water interface. The expansion of molecular area of PDA (10,12-pentacosadiynoic acid)/MPDA mixed monolayer after injection of Con A in subphase shows strong interaction between Con A and the monolayer. The maximum expansion of molecular area decreases as the molar ratio of MPDA increases due to the steric hindrance effect. By using enzyme mannosidase to cut-off the mannoside headgroup of MPDA, expansion of molecular area was greatly reduced, indicating that the binding of Con A is specific to the mannoside headgroup. The kinetics of the binding fits to the first order bimolecular reaction model. Fluorescence quenching of fluorescein isothiocyanate labeled Con A after injection into the subphase gives a direct proof of the molecular recognition.

Monolayer study of plastoquinones, alpha-tocopherol quinone, their hydroquinone forms and their interaction with monogalactosyldiacylglycerol. Charge-transfer complexes in a mixed monolayer.

The surface pressure-area isotherms of pure plastoquinone-9 (PQ-9), plastoquinone-3 (PQ-3), alpha-tocopherol quinone (alpha-TQ), their reduced (hydroquinone) forms and mixtures of these molecules with monogalactosyldiacylglycerol (MGDG) have been studied by a monolayer technique. The collapse pressures of all hydroquinones (QH2) were higher than those of the corresponding quinones (Q), the difference being highest between PQ-9 and PQH2-9. The limiting molecular areas of hydroquinones were higher than those of the corresponding quinones except for alpha-TQH2. All Q-QH2 mixtures showed miscibility throughout the whole range of the components' ratios. There was no deviation from the additivity rule observed for any of the Q-QH2 mixture, as well as for the mixtures of MGDG with PQ-3, PQH2-9, alpha-TQ and alpha-TQH2. On the other hand, PQ-9/MGDG and PQH2-3/MGDG mixtures showed positive and negative deviations, respectively. All the isotherms of Q-MGDG and QH2-MGDG mixtures showed a kink point above the collapse pressure of the Q or QH2 examined, indicating that with the increase in surface pressure, Q or QH2 were gradually squeezed out from the monolayer. The percent content of Q and QH2 in the monolayer as a function of surface pressure was also calculated. The hydroquinones were more difficult to remove from monolayers than the corresponding quinones, and among the investigated quinones, PQ-9 was most easily and alpha-TQ most difficulty squeezed out. The surface pressure-area isotherms of the three-component mixtures of PQ-9/PQH2-9/MGDG showed a shift to lower molecular areas in comparison with the corresponding two-component mixtures, especially at higher surface pressures. This indicates that the presence of PQ-9 lowered the PQH2-9 content in the monolayer, especially at higher pressures, which was explained by charge-transfer complex formation upon interaction of PQ-9 with PQH2-9. The comparison of surface potential-area isotherms of PQ-9/PQH2-9/MGDG mixtures with those of the corresponding binary mixtures also suggest charge-transfer interaction between PQ-9 and PQH2-9. The orientation and localization of the investigated quinones and quinols in the thylakoid membrane and significance of charge-transfer interactions in functioning of PQ-9 has been discussed.

Linear dichroism and molecular orientation in Langmuir-Blodgett films of plastoquinones and alpha-tocopherol quinone.

The linear dichroism of monolayers of plastoquinone-9, plastoquinone-3 and alpha-tocopherol quinone has been measured. The angle between the transition moments and the plane of the solid support was found to lie between 24 degrees and 28 degrees for the investigated prenylquinones. The possible orientation of quinone rings in a monolayer state has been discussed.

Interactions in mixed monolayers between distearoyl-L-phosphatidylethanolamine, rod outer segment phosphatidylethanolamine and all-trans retinal. Effect of pH.

The interactions in mixed monolayers between distearoyl-L-phosphatidylethanolamine, natural phosphatidylethanolamine purified from bovine rod outer segments and all-trans retinal have been studied at the nitrogen/water interface at 21.0 +/- 0.5 degrees C. Seven mixtures of each phospholipid with all-trans retinal, covering the whole range of molar fractions, were studied. The monolayers were spread on a 1 X 10(-3) M phosphate buffer subphase at three different pH values, 5.5, 7.1 and 8.2. The results for the two series of mixtures are strikingly different. The surface phase rule shows that all-trans retinal is miscible with the natural phospholipid at the interface. Small, negative deviations with respect to the additivity rule are observed in this case. The excess free energies of mixing were also calculated as a function of concentration for this system at four different surface pressures, 5, 7, 10 and 13 mN X m-1. They are negative for the four surface pressures considered and symmetrical with respect to the mole fraction. On the other hand, when distearoyl-L-phosphatidylethanolamine is mixed with all-trans retinal, the components are no longer miscible at the interface. This marked difference in behaviour between the two lipids reflects the importance of hydrophobic interactions in the mixed monolayers of phospholipids with retinals. Furthermore, for the two series of mixtures, the surface pressure isotherms do not show any significant shift when the subphase pH is changed from 5.5 to 8.2. This behaviour raises questions about the formation of a Schiff base between phosphatidylethanolamine and retinal at the interface. It is suggested that, owing to the nature of the disk membranes, such an effect would also be observed in vivo. The possible implications of this are discussed, particularly with respect to questions pertaining to the stability of the retinal chromophore.

Action Spectra of Photosystems I and II in State 1 and State 2 in Intact Sugar Maple Leaves.

Photochemical activity, measured as energy storage of photosystems I (PSI) and II (PSII) together and individually, is studied in sugar maple (Acer saccharum Marsh.) leaves in the spectral range between 400 and 700 nm in state 1 and state 2. Total photochemical activity remains the same in both state 1 and state 2 between 580 and 700 nm, but it is lower in state 2 between 400 and 580 nm. Both PSI and PSII activities change significantly during the state transition due to the migration of light-harvesting chlorophyll a/b protein complex of PSII (LHCII). In the action spectra of PSI and PSII, peak positions vary depending on the association or dissociation of LHCII, except for the peak at 470 nm in the PSII spectrum. PSII activity is about 3 times higher than or equal to PSI in state 1 or state 2, respectively, over most of the spectrum except in the blue and far-red regions. At 470 nm, PSII activity is 8 or 1.6 times higher than PSI in state 1 or state 2, respectively. The amplitude of LHCII coupling-induced change is the same in both PSI and PSII between 580 and 700 nm, but it is less in PSI than in PSII between 400 and 580 nm, which explains the lower photochemical activity of the leaf in state 2 than in state 1. This may be due to a decrease in energy transfer efficiency of carotenoids to chlorophylls in LHCII when it is associated with PSI.

Central corneal thickness and progression of the visual field and optic disc in glaucoma.

AIMS: To determine whether central corneal thickness (CCT) is a significant predictor of visual field and optic disc progression in open angle glaucoma. METHODS: Data were obtained from a prospective study of glaucoma patients tested with static automated perimetry and confocal scanning laser tomography every 6 months. Progression was determined using a trend based approach called evidence of change (EOC) analysis in which sectoral ordinal scores based on the significance of regression coefficients of visual field pattern deviation and neuroretinal rim area over time are summed. Visual field progression was also determined using the event based glaucoma change probability (GCP) analysis using both total and pattern deviation. RESULTS: The sample contained 101 eyes of 54 patients (mean (SD) age 56.5 (9.8) years) with a mean follow up of 9.2 (0.7) years and 20.7 (2.3) sets of examinations every 6 months. Lower CCT was associated with worse baseline visual fields and lower mean IOP in the follow up. In the longitudinal analysis CCT was not correlated with the EOC scores for visual field or optic disc change. In the GCP analyses, there was a tendency for groups classified as progressing to have lower CCT compared to non-progressing groups. In a multivariate analyses accounting for IOP, the opposite was found, whereby higher CCT was associated with visual field progression. None of the independent factors were predictive of optic disc progression. CONCLUSIONS: In this cohort of patients with established glaucoma, CCT was not a useful index in the risk assessment of visual field and optic disc progression.

Immunomodulatory analogs of thalidomide inhibit growth of Hs Sultan cells and angiogenesis in vivo.

We have previously shown that thalidomide and its potent immunomodulatory derivatives (IMiDs) inhibit the in vitro growth of multiple myeloma (MM) cell lines and patient MM cells that are resistant to conventional therapy. In this study, we further characterize the effect of these drugs on growth of B cell malignancies and angiogenesis. We established a beige-nude-xid (BNX) mouse model to allow for simultaneous in vivo measurement of both anti-tumor and anti-angiogenic effects of thalidomide and its analogs. Daily treatment (50 mg/kg/d) with thalidomide or IMiDs was nontoxic. The IMiDs were significantly more potent than thalidomide in vivo in suppressing tumor growth, evidenced by decreased tumor volume and prolonged survival, as well as mediating anti-angiogenic effects, as determined by decreased microvessel density. Our results therefore show that the IMiDs have more potent direct anti-tumor and anti-angiogenic effects than thalidomide in vivo, providing the framework for clinical protocols evaluating these agents in MM and other B cell neoplasms.