Design, synthesis and anticancer activity of constrained sphingolipid-phenoxazine/phenothiazine hybrid constructs targeting protein phosphatase 2A.

Inspired by the cytotoxicity of perphenazine toward cancer cells and its ability to activate the serine/threonine protein phosphatase 2A (PP2A), we prepared series of ether-carbon linked analogs of a constrained synthetic sphingolipid analog 3, known for its cytotoxicity, nutrient transporter down-regulation and vacuolation properties, incorporating the tricyclic neuroleptics phenoxazine and phenothiazine to represent hybrid structures with possible synergistic cytotoxic activity. While the original activity of the lead compound 3 was diminished by fusion with the phenoxazine or phenothiazine tethered moieties, the corresponding 3-pyridyltetryl ether analog 10 showed cytotoxicity and nutrient transporter down-regulation similar to the lead compound 3, although it separated these PP2A-dependent phenotypes from that of vacuolation.

Emerging Treatments and Novel Pathways in Pruritus.

Itch treatment is a major challenge in the dermatologist's practice. We encounter patients suffering from pruritus on a regular basis, and often lack diverse treatment options to adequately respond to the patients' needs. In the last 20 years, novel pathways have been investigated that were beyond the scope of histamine. Although most did not result in a molecule available on the Canadian market, it is interesting and important as health care providers to stay up to date with new neuronal pathways involved in itch transmission and potential new therapeutic options. In this review, we will discuss pathways targeted in new topical treatments such as antagonist of proteinase-activated receptor-2, the endocannabinoid system, neurotrophins and tropomyosin-related kinase A receptor, the transient receptor potential-vanilloid or transient receptor potential-melastatine ion channels. New systemic therapies are now focusing on antagonizing the neurokinin receptor, modulating the opioidergic system, or targeting itch cytokines such as interleukin-31.

An interesting case of pyoderma gangrenosum with immature hystiocytoid neutrophils.

We present a unique case of a 36-year-old male who developed more than 20 pyoderma gangrenosum (PG) ulcers showing on histopathology a dense inflammatory infiltrate composed of histiocytoid mononuclear immature cells with a strong positivity for myeloperoxidase and Leder stain, suggesting a myeloid lineage in the absence of a concomitant myeloproliferative disorder. Histiocytoid Sweet syndrome (SS) is now recognized as a histological subtype of SS. Although PG and SS belong to the spectrum of neutrophilic diseases, to the best of our knowledge, this is the first case of a "Histiocytoid pyoderma gangrenosum" encompassing immature granulocytes in the absence of leukemia cutis.

Tazarotene 0.1% Cream as Monotherapy for Early-Stage Cutaneous T-Cell Lymphoma.

BACKGROUND: Numerous treatments are available for cutaneous T-cell lymphoma (CTCL), including systemic retinoids. Very few data are available on topical retinoids. OBJECTIVES: The aim of this study was to evaluate the safety and efficiency of tazarotene as monotherapy for early-stage CTCL. METHODS: An open-label, prospective study of tazarotene as monotherapy for stages IA to IIA CTCL was conducted. Index lesions on 10 patients were followed for 6 months on treatment, plus at least 6 months off treatment. RESULTS: Six patients (60%) showed complete response (CR). Erythema, scaling, thickness, and lesion area decreased progressively throughout treatment. The mean time to CR was 3.8 months; CR was durable for at least 6 months in 83%. Of the 4 patients (40%) without CR, 2 (20%) had stable disease and 2 (20%) stopped the medication because of local side effects; none showed progression. CONCLUSIONS: This is the first Canadian trial providing evidence that topical tazarotene has excellent potential as a monotherapy agent for stages I to IIA CTCL.

Is health-related quality of life trajectory associated with dialysis modality choice in advanced chronic kidney disease?

BACKGROUND: Patients with advanced chronic kidney disease have lower health-related quality of life (HRQOL) than the general population. There is uncertainty regarding patterns of HRQOL changes before dialysis initiation. This study aimed to characterise HRQOL trajectory and assess its potential association with intended dialysis modality. METHODS: This prospective single-centre cohort study followed adults with an estimated glomerular filtration rate ≤15 mL/min/1.73 m2 for one year. Patients were allocated into one of two groups based on their intended treatment modality, 'home dialysis' (peritoneal dialysis or home haemodialysis (HD)) and 'other' (in-centre HD or conservative care). Follow-up was for up to 1 year or earlier if initiated on kidney replacement therapy or died. Kidney Disease Quality of Life - Short Form (KDQOL-SF) was completed every 6 months. Predictors of changes in KDQOL-SF components were modelled using mixed effect multivariable linear regressions. RESULTS: One hundred and nine patients were included. At baseline, crude physical composite summary (PCS) (45 ± 10 vs. 39 ± 8) was higher in patients choosing home dialysis (n = 41), while mental composite summary (MCS) was similar in both groups. After adjustment, patients choosing home dialysis had an increase in MCS (B = 8.4 per year, p = 0.007) compared to those selecting in-centre HD/conservative care. This translates into an annual increase in MSC by 3 points for the 'home dialysis' group, compared to an annual decline by 5.4 points in the 'other' group. There was no difference in PCS trajectory through time. CONCLUSIONS: Patients choosing home dialysis had improved MCS over time compared to those not selecting home dialysis. More work is needed to determine how differences in processes of care and/or unmeasured patient characteristics modulate this association.

Risk of hospitalization, technique failure, and death with increased training duration in 3-days-a-week home hemodialysis.

INTRODUCTION: Quality training is a core component of successful home hemodialysis (HHD) and training duration varies significantly between dialysis centers as well as at the patient level. This study aimed to assess the adverse outcomes associated with HHD training duration. METHODS: All HHD patients successfully trained in a single dialysis center between January 2005 and July 2017 were included. A multivariable multiple-events (Andersen-Gill) survival model was built to evaluate the association between training time and main adverse events, including hospitalizations, technique failure, and death on HHD. Potential confounding factors were defined a priori (age, diabetes, coronary artery disease, and year of training start). Adjusted risk of vascular interventions (arteriovenous fistula angioplasties and central venous catheter replacements) was assessed as the secondary outcome in a negative binomial regression. FINDINGS: Forty-eight patients were included in the study. Median HHD training duration was 86 (67-108) days, using a thrice weekly training schedule. Over a follow-up median time of 2.0 (0.7-3.3) years, three patients died while on HHD, 10 had a definitive transfer to HD, and 18 experienced a least 1 hospitalization (38 hospitalizations in total). Training duration was associated with a higher risk of hospitalization, technique failure, and death in unadjusted (hazard ratio [HR] 1.16 per month, 95% confidence interval [CI] 1.08-1.24) and adjusted multiple events model (HR 1.21, 95% CI 1.04-1.43). Risk of vascular access intervention was also significantly higher with increased training time (adjusted incidence rate ratio 1.31, 95% CI 1.03-1.64, per training month). DISCUSSION: In this single-center observational study, HHD training duration was associated with a higher risk of adverse events including, death, technique failure, hospitalizations, and vascular access intervention. Enhanced clinical follow-up and home support should be offered to these more vulnerable patients to mitigate this heightened risk.

Chronic itch: emerging treatments following new research concepts.

Until recently, itch pathophysiology was poorly understood and treatments were poorly effective in relieving itch. Current progress in our knowledge of the itch processing, the numerous mediators and receptors involved has led to a large variety of possible therapeutic pathways. Currently, inhibitors of IL-31, IL-4/13, NK1 receptors, opioids and cannabinoids, JAK, PDE4 or TRP are the main compounds involved in clinical trials. However, many new targets, such as Mas-related GPCRs and unexpected new pathways need to be also explored.

Expanding Patch Testing Beyond the Baseline Series: Usefulness of Customized Antimicrobials, Vehicles, and Cosmetics Series.

BACKGROUND: Testing cosmetics and their ingredients is essential to avoid missing relevant allergens and to monitor fluctuating incidence of hypersensitivity. OBJECTIVE: The aim of this study was to review the usefulness of patch testing with a customized antimicrobials, vehicles, and cosmetics (AVC) series over 15 years at a single Canadian site. METHODS: Between January 1, 2005, and December 31, 2019, patients suspected of having cosmetics allergy were patch tested with a 40-allergen AVC series in addition to the North American Contact Dermatitis Group standard screening series. We reviewed the patch test results of 2868 patients. RESULTS: We consecutively patch tested with the baseline series 6103 patients, of which 2868 (47%) were also tested with the AVC series. Of 53 different allergens that were tested at some point, 26 remained in the series throughout the 15-year span. The most common positive allergens were thimerosal (4.52%), polyvidone-iodine (2.25%), propolis (2.06%), sodium metabisulfite (1.94%), dodecyl gallate (1.53%), carmine (1.10%), lauryl glucoside (1.01%), sandalwood oil (0.7%), and tert-butylhydroquinone (0.7%). CONCLUSIONS: Although the expansion of the North American Contact Dermatitis Group standard screening series has decreased the yield from the AVC series from 21.1% to 13.9%, it still remains a useful adjunct for patients suspected of having cosmetics or disinfectants allergy.

[Sense of personal identity and focal brain lesions]. / Sentiment d'identité et lésions cérébrales focales.

The sense of personal identity is an element of the Jasperian definition of self-conscience. Each of us is convinced of being a unique and stable individual, different from other individuals. These properties - stability ad coherence - belong to an image of ourselves that was proposed to us by the Other's look during the mirror phase. Brain focal lesions may threaten this certitude in two ways: 1) brain lesions result in deficiency, disability or handicap, which are experienced as a narcissistic injury. The patient questions himself about the image he offers to the Other's look, and, as a result, his sense of personal identity is unsettled; 2) a variety of focal brain lesions or dysfunctions may alter the activity of areas which are necessary for maintaining a stable image of the patients' body or self. This may lead patients to experience depersonalisation, autoscopy, somatoparaphrenic "delusions" or disturbed agency. The sense of personal identity may be disturbed during brief paroxystic or psychologically traumatic phenomena. However, this is not observed in chronic sequelae of brain lesions (e.g. right hemisphere syndrome or amnesic syndrome), even though the patients may present a broken up image of themselves.

[Medical and social characteristics and treatment plans for brain-damaged patients hospitalized]. / Caractéistiques médicales et sociales et trajectoires de soins des patients cérébro-lésés hospitalisés.

The study objective was to better understand the clinical and social characteristics, and the treatment plans, of brain-damaged patients who were hospitalized longer than one month in acute care units. A 6-month descriptive prospective epidemiological study of 90 patients was carried out. The average length of stay (LOS) was 84 +/- 73 days. Patients were severely disabled: 17.83% of patients showed a Glasgow Outcome Scale (GOS) 2, 70% a GOS 3 and 12.2%, a GOS > or =4. Two-thirds of the patients had social difficulties that influenced their LOS (68.4 days when social difficulties <3, versus 157.4 days when > or =3). An average of 4 rehabilitation settings were solicited per patient. The actual rehabilitation setting matched the patient's and team's wishes in only 63.4% of the cases. Several proposals are discussed to improve overall management of care for brain-damaged patients: the need to establish a mobile steering team, to improve multidisciplinary approaches, and to create acute physical medicine and rehabilitation units.

Identification, purification and characterization of a novel human blood protein with binding affinity for prostate secretory protein of 94 amino acids.

PSP94 (prostate secretory protein of 94 amino acids), an abundant protein within semen, has reported local functions within the reproductive tract and reported systemic functions. Mechanisms of action remain poorly understood, but binding to undefined molecules within the prostate, pituitary, testis and blood may initiate some of these actions. PSP94 serum measurements, especially of bound and free forms, have potential clinical utility in prostate cancer management. Identification of the binding molecules will help in the understanding of PSP94's action, and enable further development of PSP94 serum assays. PSPBP (PSP94-binding protein) was purified from human serum by ammonium sulphate fractionation, ion-exchange and affinity chromatography. The glycosylated protein ran as two bands on SDS/PAGE (70 and 95 kDa). N-terminal sequencing yielded a 30-amino-acid sequence, identical with the translated N-terminal region of a previously published cDNA (GenBank accession number AX136261). Reverse transcriptase PCR and plaque hybridization demonstrated PSPBP mRNA in peripheral blood leucocytes and in a prostate cDNA library. Northern blotting showed 2 kb mRNA species in prostate, testis, ovary and intestine. Immunohistochemistry demonstrated PSPBP in tissues, including pituitary and Leydig cells, supporting a role for PSP94 in hormonal control at the pituitary gonadal axis. ELISA demonstrated that PSPBP levels were significantly lower (P=0.0014) in the serum of a prostate cancer population (n=65) compared with a control population (n=70). PSPBP identification will help the understanding of PSP94's functions and facilitate ELISA development to address the clinical value of PSP94 serum assays.

Adapting and implementing a long-term nutrition and physical activity curriculum to a rural, low-income, biethnic community.

This study adapted an urban-based school nutrition program for delivery in a rural community. Specific aims were to adapt the curriculum; expand it to include physical activity; determine effectiveness on students' attitudes, knowledge, and self-efficacy; and assess teachers' impressions. Three cohorts were established: 173 students taught by a resource teacher, 170 students taught by classroom teachers, and 187 students who did not receive the curriculum. Pre- and posttest surveys measured outcomes, and classroom teachers were observed and interviewed. The curriculum was shown to be effective in enhancing student outcomes for both the resource teacher and classroom teacher cohorts. Teachers reported that lessons needed to be simplified and that children enjoyed them. Findings support the transferability of an urban-based nutrition curriculum to a rural community and the need for students to receive health education annually.

Hypopigmented segmental Darier disease.

BACKGROUND: Darier disease is a genodermatosis caused by a mutation in the ATP2A2 gene. It classically presents as hyperkeratotic greasy papules in a seborrheic distribution. Several variants have been reported, notably the hypopigmented variant, which predominantly targets dark-skinned individuals, and a segmental variant that often follows the lines of Blaschko. METHODS: We report a case of a 41-year-old African-Canadian female with a long-standing history of macular hypopigmented pruritic eruption following the lines of Blaschko on her back. The eruption was persistent and recalcitrant to various treatments. Dyskeratosis with corps ronds and grains, acantholysis, and parakeratosis were observed on histopathology. Those findings were consistent with the diagnosis of segmental hypopigmented Darier disease. RESULTS AND CONCLUSIONS: To our knowledge, this is the first case reporting a combined segmental and hypopigmented variant of Darier disease. We further present a literature review for hypopigmented and segmental variants of Darier disease.