Publications by authors named "Joanne Leung"

27 Publications

  • Page 1 of 1

ILC2s amplify PD-1 blockade by activating tissue-specific cancer immunity.

Nature 2020 03 19;579(7797):130-135. Epub 2020 Feb 19.

Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Group 2 innate lymphoid cells (ILC2s) regulate inflammation and immunity in mammalian tissues. Although ILC2s are found in cancers of these tissues, their roles in cancer immunity and immunotherapy are unclear. Here we show that ILC2s infiltrate pancreatic ductal adenocarcinomas (PDACs) to activate tissue-specific tumour immunity. Interleukin-33 (IL33) activates tumour ILC2s (TILC2s) and CD8 T cells in orthotopic pancreatic tumours but not heterotopic skin tumours in mice to restrict pancreas-specific tumour growth. Resting and activated TILC2s express the inhibitory checkpoint receptor PD-1. Antibody-mediated PD-1 blockade relieves ILC2 cell-intrinsic PD-1 inhibition to expand TILC2s, augment anti-tumour immunity, and enhance tumour control, identifying activated TILC2s as targets of anti-PD-1 immunotherapy. Finally, both PD-1 TILC2s and PD-1 T cells are present in most human PDACs. Our results identify ILC2s as anti-cancer immune cells for PDAC immunotherapy. More broadly, ILC2s emerge as tissue-specific enhancers of cancer immunity that amplify the efficacy of anti-PD-1 immunotherapy. As ILC2s and T cells co-exist in human cancers and share stimulatory and inhibitory pathways, immunotherapeutic strategies to collectively target anti-cancer ILC2s and T cells may be broadly applicable.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-020-2015-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060130PMC
March 2020

Hippo Pathway Kinase Mst1 Is Required for Long-Lived Humoral Immunity.

J Immunol 2019 01 26;202(1):69-78. Epub 2018 Nov 26.

Institut de Recherches Cliniques de Montréal, Montreal, Quebec H2W 1R7, Canada;

The protein kinase Mst1 is a key component of the evolutionarily conserved Hippo pathway that regulates cell survival, proliferation, differentiation, and migration. In humans, Mst1 deficiency causes primary immunodeficiency. Patients with MST1-null mutations show progressive loss of naive T cells but, paradoxically, mildly elevated serum Ab titers. Nonetheless, the role of Mst1 in humoral immunity remains poorly understood. In this study, we found that early T cell-dependent IgG1 responses in young adult Mst1-deficient mice were largely intact with signs of impaired affinity maturation. However, the established Ag-specific IgG1 titers in Mst1-deficient mice decayed more readily because of a loss of Ag-specific but not the overall bone marrow plasma cells. Despite the impaired affinity and longevity of Ag-specific Abs, Mst1-deficient mice produced plasma cells displaying apparently normal maturation markers with intact migratory and secretory capacities. Intriguingly, in immunized Mst1-deficient mice, T follicular helper cells were hyperactive, expressing higher levels of IL-21, IL-4, and surface CD40L. Accordingly, germinal center B cells progressed more rapidly into the plasma cell lineage, presumably forgoing rigorous affinity maturation processes. Importantly, Mst1-deficient mice had elevated levels of CD138Blimp1 splenic plasma cell populations, yet the size of the bone marrow plasma cell population remained normal. Thus, overproduced low-affinity plasma cells from dysregulated germinal centers seem to underlie humoral immune defects in Mst1-deficiency. Our findings imply that vaccination of Mst1-deficient human patients, even at the early stage of life, may fail to establish long-lived high-affinity humoral immunity and that prophylactic Ab replacement therapy can be beneficial to the patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4049/jimmunol.1701407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6310088PMC
January 2019

Synergistic effects of host B7-H4 deficiency and gemcitabine treatment on tumor regression and anti-tumor T cell immunity in a mouse model.

Cancer Immunol Immunother 2017 Apr 10;66(4):491-502. Epub 2017 Jan 10.

Institut de recherches cliniques de Montréal (IRCM), 110 avenue des Pins Ouest, Montréal, QC, H2W 1R7, Canada.

B7-H4 (B7x/B7S1), a B7 family inhibitor of T cell activity, is expressed in multiple human cancers and correlates with decreased infiltrating lymphocytes and poor prognosis. In murine models, tumor-expressed B7-H4 enhances tumor growth and reduces T cell immunity, and blockade of tumor-B7-H4 rescues T cell activity and lowers tumor burden. This implicates B7-H4 as a target for cancer immunotherapy, yet limits the efficacy of B7-H4 blockade exclusively to patients with B7-H4+ tumors. Given the expression of B7-H4 on host immune cells, we have previously shown that BALB/c mice lacking host B7-H4 have enhanced anti-tumor profiles, yet similar 4T1 tumor growth relative to control. Given that T cell-mediated immunotherapies work best for tumors presenting tumor-associated neoantigens, we further investigated the function of host B7-H4 in the growth of a more immunogenic derivative, 4T1-12B, which is known to elicit strong anti-tumor CD8 T cell responses due to expression of a surrogate tumor-specific antigen, firefly luciferase. Notably, B7-H4 knockout hosts not only mounted greater tumor-associated anti-tumor T cell responses, but also displayed reduced tumors. Additionally, B7-H4-deficiency synergized with gemcitabine to further inhibit tumor growth, often leading to tumor eradication and the generation of protective T cell immunity. These findings imply that inhibition of host B7-H4 can enhance anti-tumor T cell immunity in immunogenic cancers, and can be combined with other anti-cancer therapies to further reduce tumor burden regardless of tumor-B7-H4 positivity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00262-016-1950-2DOI Listing
April 2017

Predicting client attendance at further treatment following drug and alcohol detoxification: Theory of Planned Behaviour and Implementation Intentions.

Drug Alcohol Rev 2016 11 30;35(6):678-685. Epub 2015 Sep 30.

Illawarra Institute for Mental Health, School of Psychology, University of Wollongong, Wollongong, Australia.

Introduction And Aims: Despite clinical recommendations that further treatment is critical for successful recovery following drug and alcohol detoxification, a large proportion of clients fail to attend treatment after detoxification. In this study, individual factors and constructs based on motivational and volitional models of health behaviour were examined as predictors of post-detoxification treatment attendance.

Design And Methods: The sample consisted of 220 substance-dependent individuals participating in short-term detoxification programs provided by The Australian Salvation Army. The Theory of Planned Behaviour and Implementation Intentions were used to predict attendance at subsequent treatment.

Results: Follow-up data were collected for 177 participants (81%), with 104 (80%) of those participants reporting that they had either attended further formal treatment (e.g. residential rehabilitation programs, outpatient counselling) or mutual support groups in the 2 weeks after leaving the detoxification program. Logistic regression examined the predictors of further treatment attendance. The full model accounted for 21% of the variance in treatment attendance, with attitude and Implementation Intentions contributing significantly to the prediction.

Discussion And Conclusions: Findings from the present study would suggest that assisting clients to develop a specific treatment plan, as well as helping clients to build positive perceptions about subsequent treatment, will promote greater attendance at further treatment following detoxification. [Kelly PJ, Leung J, Deane FP, Lyons GCB. Predicting client attendance at further treatment following drug and alcohol detoxification: Theory of Planned Behaviour and Implementation Intentions. Drug Alcohol Rev 2016;35:678-685].
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/dar.12332DOI Listing
November 2016

The CD28-B7 Family in Anti-Tumor Immunity: Emerging Concepts in Cancer Immunotherapy.

Immune Netw 2014 Dec 22;14(6):265-76. Epub 2014 Dec 22.

Institut de Recherches Cliniques de Montréal (IRCM), Montreal, QC H2W 1R7, Canada. ; Department of Microbiology and Immunology, McGill University, Montreal, QC H3A 0G4, Canada. ; Department of Medicine; Department of Microbiology, Infectiology, and Immunology, University of Montreal, Montreal, QC H3T 1J4, Canada.

The interactions between B7 molecules and CD28-family receptors are crucial in the regulation of adaptive cellular immunity. In cancer, the aberrant expression of co-inhibitory B7 molecules has been attributed to reduced anti-tumor immunity and cancer immune evasion, prompting the development of cancer therapeutics that can restore T cell function. Murine tumor models have provided significant support for the targeting of multiple immune checkpoints involving CTLA-4, PD-1, ICOS, B7-H3 and B7-H4 during tumor growth, and clinical studies investigating the therapeutic effects of CTLA-4 and PD-1 blockade have shown exceptionally promising results in patients with advanced melanoma and other cancers. The expression pattern of co-inhibitory B7 ligands in the tumor microenvironment has also been largely correlated with poor patient prognosis, and recent evidence suggests that the presence of several B7 molecules may predict the responsiveness of immunotherapies that rely on pre-existing tumor-associated immune responses. While monotherapies blocking T cell co-inhibition have beneficial effects in reducing tumor burden, combinatorial immunotherapy targeting multiple immune checkpoints involved in various stages of the anti-tumor response has led to the most substantial impact on tumor reduction. In this review, we will examine the contributions of B7- and CD28-family members in the context of cancer development, and discuss the implications of current human findings in cancer immunotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4110/in.2014.14.6.265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4275384PMC
December 2014

Chronic psychological stress in high-anxiety rats induces sustained bladder hyperalgesia.

Physiol Behav 2015 Feb 20;139:541-8. Epub 2014 Nov 20.

Department of Urology, University of Southern California, Los Angeles, CA. Electronic address:

Objective: To evaluate whether anxiety-prone rats exposed to chronic water avoidance stress (WAS) develop visceral bladder hyperalgesia in addition to increased voiding frequency and anxiety-related behaviors.

Materials And Methods: Female Wistar-Kyoto (WKY) rats were exposed to chronic (10-day) WAS or sham paradigms. Referred hyperalgesia and tactile allodynia were tested using von Frey filaments applied to the suprapubic region and plantar region of the hindpaw, respectively. To confirm that suprapubic nociception represented referred visceral bladder hyperalgesia, we recorded abdominal visceromotor responses (VMR) to slow (100 μl/min) and fast (1 cc/sec) bladder filling with room temperature or ice-cold saline. We assessed the development of hyperalgesia over the 10-day WAS protocol and the durability of increased pain sensations over time.

Results: Animals exposed to chronic WAS had significantly lower hindpaw withdrawal thresholds post-stress and significant differences in referred hyperalgesia. Rats exposed to chronic WAS demonstrated an increased pain response to suprapubic stimulation and decreased response threshold to mechanical hindpaw stimulation by day 8 of the stress protocol, which persisted for more than one month. Animals exposed to chronic WAS showed increased VMR to fast filling and ice water testing in comparison to sham animals. Cystometry under anesthesia did not show increases in the frequency of non-voiding contractions.

Conclusion: Chronic WAS induces sustained bladder hyperalgesia, lasting over a month after exposure to stress. The urinary frequency demonstrated previously in anxiety-prone rats exposed to chronic WAS seems to be associated with bladder hyperalgesia, suggesting that this is a potential model for future studies of bladder hypersensitivity syndromes such as interstitial cystitis/painful bladder syndrome (IC/PBS).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.physbeh.2014.11.045DOI Listing
February 2015

Cardiovascular effects of acute treatment with the antipsychotic drug olanzapine in rats.

Vascul Pharmacol 2014 Sep 23;62(3):143-9. Epub 2014 Jun 23.

Department of Anesthesiology, Pharmacology & Therapeutics, Faculty of Medicine, 2176 Health Sciences Mall, The University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada; British Columbia Mental Health & Addictions Research Institute, 938 W 28th Ave., Vancouver, British Columbia V5Z 4H4, Canada. Electronic address:

Treatment with antipsychotics is associated with adverse cardiovascular effects such as orthostatic hypotension and arrhythmias. Despite the higher prevalence of cardiovascular complications in patients with schizophrenia, the effects of antipsychotic drugs on vascular tone and cardiac contractility have received little attention. In order to better understand the cardiovascular effects of antipsychotic drugs, we investigated if the atypical antipsychotic olanzapine alters in vivo cardiovascular function in rats. Male Sprague-Dawley rats were prepared with indwelling catheters. After 4 h of recovery from surgery, the mean arterial pressure (MAP), mean circulatory filling pressure (MCFP; index of body venous tone), heart rate, left ventricular peak systolic pressure (LVP) and cardiac contractility (±dP/dt) were measured in conscious, unrestrained rats for 60 min after a single injection of olanzapine (3 or 15 mg/kg, i.p.) or vehicle. Cardiovascular measurements were not altered at any time points in the vehicle-treated rats. Olanzapine did not affect heart rate, but dose-dependently decreased MAP, MCFP, LVP and +dP/dt. Acute olanzapine treatment in rats thus reduced blood pressure and venous tone, as well as cardiac contractile function. Decreased venous tone may be a contributing factor to orthostatic hypotension commonly observed in patients during initiation of antipsychotic therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.vph.2014.06.003DOI Listing
September 2014

Effects of nimesulide, a selective COX-2 inhibitor, on cardiovascular function in 2 rat models of diabetes.

J Cardiovasc Pharmacol 2014 Jul;64(1):79-86

*Department of Anesthesiology, Pharmacology, and Therapeutics, Faculty of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada.

Cyclooxygenase-2 (COX-2) has been found to be activated in diabetes. We investigated whether nimesulide (selective COX-2 inhibitor) alters cardiovascular responses to adrenaline in 2 rat models of diabetes. Wistar rats (5-week old) were continuously fed a normal or high-fructose diet (60% of caloric intake). At week 2, half of the rats in each diet regimen were given streptozotocin (STZ) (60 mg/kg, intravenously). At week 6, cardiovascular effects of adrenaline (6 and 16 × 10 mol·kg·min, intravenously) were measured in 4 groups of thiobutabarbital-anesthetized rats (control, fructose, STZ, and fructose-streptozotocin [F-STZ]) before and after the injection of nimesulide (3 mg/kg, intravenously). Both the STZ and F-STZ groups exhibited hyperglycemia and significantly (P < 0.05) reduced left ventricular contractility, mean arterial pressure, arterial and venous resistance, and mean circulatory filling pressure (index of venous tone) responses to adrenaline, relative to the control and fructose groups. Nimesulide did not affect responses in the control and fructose groups but increased the venous and, to a less extent, arterial constriction to adrenaline in both the groups of diabetic rats. The cardiac contractile responses, however, were not altered after nimesulide treatment. The results show that nimesulide partially restored arterial and venous constriction to adrenaline in rats with STZ- and F-STZ-induced diabetes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/FJC.0000000000000093DOI Listing
July 2014

Inducible costimulator facilitates T-dependent B cell activation by augmenting IL-4 translation.

Mol Immunol 2014 May 31;59(1):46-54. Epub 2014 Jan 31.

Institut de recherches cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada; Department of Microbiology and Immunology, McGill University, Montréal, QC H3A 2B4, Canada; Department of Microbiology and Immunology, Université de Montréal, Montréal, QC H3T 1J4, Canada; Department of Medicine, Université de Montréal, Montréal, QC H3T 1J4, Canada. Electronic address:

The inducible costimulator (ICOS) is highly expressed in follicular helper T (Tfh) cells, a subset of CD4 T cells that migrate into the B cell zone and facilitate germinal center reactions. Although ICOS is known to play a critical role in forming the Tfh cell population during immune responses, its contribution to the effector functions of Tfh cells remains unclear. Using activated mouse splenic CD4 T cells we demonstrate that ICOS assists TCR-mediated signal transduction by potentiating the PI3K-AKT-mTOR signaling cascade that leads to hyper-phosphorylation of p70S6K and 4E-BP1, events that are known to augment cap-dependent mRNA translation. Consequently, ICOS costimulation promotes the formation of polysomes on IL-4 mRNA in a PI3K-dependent manner. Furthermore, we show that the supply of IL-4 becomes a limiting factor for T-dependent B cell activation during in vitro co-culture when the ICOS-PI3K signaling axis is disrupted in T cells. This ICOS costimulation-dependent translational control may ensure targeted delivery of IL-4 to cognate B cells during T-B collaborations in the germinal center.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.molimm.2014.01.008DOI Listing
May 2014

Host B7-H4 regulates antitumor T cell responses through inhibition of myeloid-derived suppressor cells in a 4T1 tumor transplantation model.

J Immunol 2013 Jun 17;190(12):6651-61. Epub 2013 May 17.

Unité de Recherche en Régulation Immunitaire, Institut de Recherches Cliniques de Montréal, Montreal, Quebec H2W 1R7, Canada.

B7-H4, a member of the B7 family of T cell immunomodulatory proteins, has been shown to inhibit T cell responses and neutrophil expansion during bacterial infections. However, the role of B7-H4 in the immune response during tumor growth has been unclear. In this study, we examined the host immune responses in B7-H4-deficient (knockout [KO]) or sufficient (wild-type [WT]) BALB/cJ mice upon transplantation of murine 4T1 carcinoma cells that had little B7-H4 expression. We reveal that host B7-H4 not only dampens the antitumor Th1 responses, but also inhibits the protumor function of myeloid-derived suppressor cells (MDSC). We observed increased expression of both antitumor immune effectors and protumor MDSC-associated transcripts in 4T1 tumors grown in B7-H4 KO mice compared with those grown in WT hosts. Consistently, MDSCs derived from B7-H4 KO mice suppressed T cell proliferation more potently than their WT counterparts. Although the primary growth of 4T1 tumors in B7-H4 KO hosts was similar to that in WT mice, tumors that had grown in B7-H4 KO hosts grew much slower than those from WT mice when subsequently transplanted into WT hosts. Importantly, this differential tumor growth during the secondary transplantation was abrogated when recipient mice lacked T cells, indicating that the immune environment in B7-H4 KO hosts allowed outgrowth of 4T1 tumors with reduced immune-evasive capacities against T cells. Thus, B7-H4 can inhibit both antitumor T cells and protumor MDSCs, influencing the immune-evasive character of the outgrowing tumors. These factors should be considered if B7-H4 blockade is to be used for cancer immunotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4049/jimmunol.1201242DOI Listing
June 2013

Association of social support with quality of life in patients with polyneuropathy.

J Peripher Nerv Syst 2013 Mar;18(1):37-43

Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.

The aim of this study was to examine the impact of social support on quality of life (QoL) in patients with polyneuropathy. One hundred and fifty-four patients with polyneuropathy were enrolled from a neuromuscular clinic. The QoL Instrument and the Medical Outcome Study-Social Support Survey (MOS-SSS) were used to assess QoL and social support, respectively. Disease severity and clinical factors were also assessed. Neuropathy patients had a lower QoL compared to a previously published normative sample (p < 0.0001) and an MOS-SSS comparable to other patients with chronic disease. Social support correlated weakly with the self esteem and emotional well being mental health dimensions (rs :0.20-0.38) but not the physical health QoL (PH-QoL) domains. Physical and mental QoL also correlated significantly with presence of pain (rs : -0.39 and -0.42, respectively) and number of autonomic symptoms (rs : -0.39 and -0.30, respectively). Social support independently predicts MH-QoL when controlling for age, gender, pain, and the Toronto Clinical Neuropathy Score (TCNS; p < 0.0001). TCNS and gender are independently related to PH-QoL (p < 0.05). This study demonstrates that improved social support serves as an independent predictor of MH-QoL when controlling for age, gender, pain, and severity of neuropathy. Future studies examining the effects of improving social support on QoL in patients with polyneuropathy are recommended.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jns5.12005DOI Listing
March 2013

Cardiovascular side-effects of antipsychotic drugs: the role of the autonomic nervous system.

Pharmacol Ther 2012 Aug 27;135(2):113-22. Epub 2012 Apr 27.

Department of Pharmacology, University of British Columbia, 2176 Health Sciences Mall, Vancouver, B.C. V6T1Z3, Canada.

Cardiovascular disease is the leading cause of death in people with severe mental disorders, and rates are proportionally greater than for other diseases such as cancer. Reports of sudden death in patients receiving antipsychotic treatment have raised concerns about the safety of antipsychotic drugs, leading to a number of recent changes in how such drugs are advertised and marketed. The majority of second generation antipsychotic drugs also have significant metabolic side-effects, such as weight gain, insulin resistance and hyperlipidemia, which may contribute indirectly to cardiovascular complications. As the use of antipsychotic drugs continues to expand into new indications and populations such as children and adolescents, a better understanding is needed of how antipsychotic drugs affect the cardiovascular system. Antipsychotic drugs interact with numerous receptors both centrally and peripherally, including monoamine receptors. The direct, non-specific pharmacological actions of antipsychotic drugs can lead to adverse cardiovascular effects, including orthostatic hypotension, tachycardia and ventricular arrhythmias. The mechanisms responsible for these antipsychotic-induced cardiovascular abnormalities have not been fully elucidated, but likely involve blockade of adrenergic or cholinergic receptors and hERG channels, in addition to impaired autonomic function. The direct and indirect effects of antipsychotic drugs on the cardiovascular system and their possible mechanisms of action are discussed in this review, where both preclinical and clinical findings are integrated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pharmthera.2012.04.003DOI Listing
August 2012

The effects of acute and chronic psychological stress on bladder function in a rodent model.

Urology 2011 Oct 24;78(4):967.e1-7. Epub 2011 Aug 24.

Department of Surgery, University of Pennsylvania, Philadelphia, PA, USA.

Objective: Psychological stress plays a role in the exacerbation of functional lower urinary tract disorders, such as painful bladder syndrome and overactive bladder. To better understand the mechanism underlying this relationship, we characterized changes in micturition, anxiety-related behavior, and bladder pathology in rats exposed to repeated water avoidance (WA) stress.

Methods: Twenty-four Wistar rats were subjected to WA stress or sham. Immediately after acute (day 1) and chronic (day 10) stress or sham, rats were placed in a metabolic cage for a 2-hour voiding behavior assessment. Voiding parameters were compared with baseline values obtained before stress. Four animals from each group were sacrificed on day 10 and bladders harvested for histologic and gene expression studies. The remaining 8 animals per group underwent repeated voiding assessment every 3 days for 1 month followed by 10 days of repeat WA stress or sham. Bladder histology and gene expression were studied.

Results: Rats exposed to WA stress developed a significant increase in micturition frequency and decrease in latency to void, voiding interval, and volume of first void compared with sham and baseline. Alterations in micturition persisted for approximately 1 month. Stressed rats showed increased fecal pellet excretion and anxiety-like behavior. In addition, bladder specimens from stressed animals revealed increased angiogenesis, and increased total and activated mast cells.

Conclusion: In rats, repeated psychological stress results in lasting alterations in micturition frequency, interval, and volume. This rodent model may represent a valid tool for studying syndromes characterized by increased urinary frequency.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.urology.2011.06.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3190050PMC
October 2011

Attenuated alpha-adrenoceptor-mediated arterial and venous constrictions in rat models of diabetes.

Eur J Pharmacol 2010 Sep 12;642(1-3):128-33. Epub 2010 Jun 12.

Department of Anesthesiology, Pharmacology & Therapeutics, Faculty of Medicine, University of British Columbia, 2176 Health Sciences Mall, Vancouver, British Columbia, V6T 1Z3 Canada.

Diabetes is associated with metabolic and vascular abnormalities. We investigated if arterial and venous constrictions are impaired in rat models of diabetes. Wistar rats (5 weeks old) were fed a normal or high-fructose diet (60% of caloric intake). On Day 14, half of the animals in each diet regimen were given streptozotocin (60 mg/kg, i.v.). On Day 35, plasma insulin and triglyceride were measured, and on Day 42, insulin sensitivity (via hyperinsulinemic euglycemic clamp), and pressor as well as mean circulatory filling pressure (index of venous tone) responses to noradrenaline were determined. The rats treated with streptozotocin or fructose-streptozotocin were hyperglycemic, hypoinsulinemic and insulin resistant, and they also had reduced potency (increased ED(50)) of pressor response and reduced venoconstriction to noradrenaline compared to the two groups not given streptozotocin. Plasma triglyceride was unchanged in streptozotocin-treated rats, moderately increased in fructose-fed rats, and markedly increased in fructose-streptozotocin-treated rats. Hyperglycemia, insulin resistance and alpha-adrenoceptor-mediated venous contractile dysfunction were more pronounced in the group given fructose-streptozotocin than that given streptozotocin alone. The presence of marked hypertriglyceridemia, insulin resistance and vascular dysfunction makes the fructose-streptozotocin-treated rats a suitable model for study of metabolic and vascular abnormalities in advanced type 2 diabetes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejphar.2010.06.009DOI Listing
September 2010

Effects of age, viewing distance and target complexity on static ocular counterroll.

Vision Res 2009 Jul 3;49(14):1848-52. Epub 2009 May 3.

Department of Ophthalmology and Vision Sciences, University of Toronto, 60 Murray Street, Suite 1-003, Toronto, Ontario, Canada M5G 1X5.

The ocular counterroll (OCR) reflex generates partially compensatory torsional eye movements during static head roll tilt. We assessed the influence of age, viewing distance and target complexity on the OCR across the age span (13-63 years; n=47), by recording eye movements during head-on-body roll tilt (0+/-40 degrees in 5 degrees steps) while subjects viewed simple vs. complex targets at 0.33 and 1m. We found that subjects > or = 31 years had lower gains than those < or =30 years, but only for far targets. Consistent with prior reports, far targets elicited higher OCR gains than near targets, and target complexity had no effect on gains, suggesting that visual input is primarily used to maintain vergence during OCR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.visres.2009.04.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5104536PMC
July 2009

Clonogenic multipotent stem cells in human adipose tissue differentiate into functional smooth muscle cells.

Proc Natl Acad Sci U S A 2006 Aug 31;103(32):12167-72. Epub 2006 Jul 31.

Department of Urology, University of California School of Medicine, Los Angeles, CA 90024, USA.

Smooth muscle is a major component of human tissues and is essential for the normal function of a multitude of organs including the intestine, urinary tract and the vascular system. The use of stem cells for cell-based tissue engineering and regeneration strategies represents a promising alternative for smooth muscle repair. For such strategies to succeed, a reliable source of smooth muscle precursor cells must be identified. Adipose tissue provides an abundant source of multipotent cells. In this study, the capacity of processed lipoaspirate (PLA) and adipose-derived stem cells to differentiate into phenotypic and functional smooth muscle cells was evaluated. To induce differentiation, PLA cells were cultured in smooth muscle differentiation medium. Smooth muscle differentiation of PLA cells induced genetic expression of all smooth muscle markers and further confirmed by increased protein expression of smooth muscle cell-specific alpha actin (ASMA), calponin, caldesmon, SM22, myosin heavy chain (MHC), and smoothelin. Clonal studies of adipose derived multipotent cells demonstrated differentiation of these cells into smooth muscle cells in addition to trilineage differentiation capacity. Importantly, smooth muscle-differentiated cells, but not their precursors, exhibit the functional ability to contract and relax in direct response to pharmacologic agents. In conclusion, adipose-derived cells have the potential to differentiate into functional smooth muscle cells and, thus, adipose tissue can be a useful source of cells for treatment of injured tissues where smooth muscle plays an important role.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.0604850103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1567713PMC
August 2006

Value of statistical life: adults versus children.

Accid Anal Prev 2006 Nov 25;38(6):1208-17. Epub 2006 Jul 25.

Ministry of Transport, Wellington, New Zealand.

Most studies on the value of statistical life (VOSL) and values for prevention of injuries provide only the average values for the overall population. It is often argued that the values for children may be higher than that for adults because parents are usually more concerned about the mortality and morbidity risks of their children than for themselves. However, it is not an easy task to determine separate VOSLs for children and adults. Only a few empirical results are available and they do not show a definite pattern. Using the results of a value of safety survey carried out in New Zealand in 1997-1998, this paper investigates whether the willingness to pay based VOSL is higher or lower for children. Formal statistical tests were carried out to test the differences and also a regression analysis was carried out to estimate the VOSL separately for adults and children, particularly in households with children. The analysis shows that for the whole sample, the value is higher for children. However, when some outliers were removed the results indicate a higher value for adults than for children. A further trimming shows the value of children is slightly higher. Therefore, no definite conclusion could be drawn. Households without children have the highest VOSL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.aap.2006.05.009DOI Listing
November 2006

The yeast lipin Smp2 couples phospholipid biosynthesis to nuclear membrane growth.

EMBO J 2005 Jun 5;24(11):1931-41. Epub 2005 May 5.

WellcomeTrust/Cancer Research UK Gurdon Institute, Cambridge, UK.

Remodelling of the nuclear membrane is essential for the dynamic changes of nuclear architecture at different stages of the cell cycle and during cell differentiation. The molecular mechanism underlying the regulation of nuclear membrane biogenesis is not known. Here we show that Smp2, the yeast homologue of mammalian lipin, is a key regulator of nuclear membrane growth during the cell cycle. Smp2 is phosphorylated by Cdc28/Cdk1 and dephosphorylated by a nuclear/endoplasmic reticulum (ER) membrane-localized CPD phosphatase complex consisting of Nem1 and Spo7. Loss of either SMP2 or its dephosphorylated form causes transcriptional upregulation of key enzymes involved in lipid biosynthesis concurrent with a massive expansion of the nucleus. Conversely, constitutive dephosphorylation of Smp2 inhibits cell division. We show that Smp2 associates with the promoters of phospholipid biosynthetic enzymes in a Nem1-Spo7-dependent manner. Our data suggest that Smp2 is a critical factor in coordinating phospholipid biosynthesis at the nuclear/ER membrane with nuclear growth during the cell cycle.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/sj.emboj.7600672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1142606PMC
June 2005

Refined linkage to the RDP/DYT12 locus on 19q13.2 and evaluation of GRIK5 as a candidate gene.

Mov Disord 2004 Jul;19(7):845-847

Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, New York, USA.

By examining two previously described families with rapid-onset dystonia parkinsonism, we have identified a key recombination event that places the disease locus (DYT12) into a 5.9 cM interval flanked by markers D19S224 and D19S900. Evaluation of a positional candidate gene, the glutamate receptor subunit GRIK5, revealed no mutations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mds.20095DOI Listing
July 2004

An evaluation of a supplementary road safety package.

Accid Anal Prev 2004 Sep;36(5):893-904

Land Transport Safety Authority, P.O. Box 2840, Wellington, New Zealand.

A Supplementary Road Safety Package (SRSP) was developed in New Zealand in 1995/1996 to supplement the compulsory breath test (CBT) and speed camera programmes introduced in 1993. A major feature of the package was the use of emotion and shock advertising campaigns not only to affect high risk driving attitudes and behaviours towards speeding and drink-driving but also to encourage the use of safety belts. Furthermore, the SRSP also emphasised targeting enforcement to these three areas. This package continued for 5 years. This paper estimates the effect of the package on road trauma. The analysis shows that the Package made substantial impact on road safety and saved over 285 lives over the 5-year period.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.aap.2003.09.005DOI Listing
September 2004

Alcohol in New Zealand road trauma.

Appl Health Econ Health Policy 2003 ;2(4):183-90

Land Transport Safety Authority, Wellington, New Zealand.

Alcohol-impaired driving is one of the major contributing factors to fatal and serious crashes in New Zealand. To curb the high level of road trauma resulting from drink-driving, a compulsory breath test (CBT) programme was introduced in 1993 and a supplementary road safety package (SRSP) in 1995/1996. The SRSP aimed to enhance road safety enforcement and advertising activities, and focused primarily on drink-driving and speeding. These interventions have resulted in a substantial reduction in alcohol-related road trauma. Subsequently, in 1999, the drinking age was lowered from 20 to 18 years. This paper examines the impacts of these drink-driving interventions. The analysis shows that the CBT programme and the SRSP have contributed to the reduction in alcohol-related crashes in recent years. There is also some evidence that, following the lowering of the drinking age, there has been an increase in drink-driving and subsequent alcohol-related crash involvement for drivers under 18 years.
View Article and Find Full Text PDF

Download full-text PDF

Source
July 2004

Dopamine transmission in DYT1 dystonia.

Adv Neurol 2004 ;94:53-60

Center for Aging, Genetics, and Neurodegeneration, Massachusetts General Hospital, Charlestown, Massachusetts, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
October 2003

TorsinA protein and neuropathology in early onset generalized dystonia with GAG deletion.

Neurobiol Dis 2003 Feb;12(1):11-24

Pediatric Neurology Floating Hospital, Boston, MA, USA.

Familial, early onset, generalized torsion dystonia is the most common and severe primary dystonia. Most cases are caused by a 3-bp deletion (GAG) in the coding region of the TOR1A (DYT1) gene, which is widely expressed in human brain and encodes the protein torsinA. This study compares neuropathology and torsinA expression in the normal human brain with that in dystonia cases with and without the GAG deletion. TorsinA-like protein was expressed in neuronal cytoplasm throughout the human brain, including cerebellum, substantia nigra, hippocampus, and neostriatum, with higher levels in specific neurons. This immunostaining pattern was not discernibly different in dystonia and normal brains in midbrain and neostriatal regions. However, nigral dopaminergic neurons appeared to be larger in both GAG-deletion and non-GAG-deletion dystonia brains compared to normal, and may be more closely spaced in GAG-deletion brains. Beyond these apparent changes in neuronal size and spacing in dystonia brains, there was no indication of neuron loss, inflammation, DNA strand breaks, or altered distribution of torsin-like immunoreactivity, supporting a functional rather than degenerative etiology of early onset torsion dystonia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/s0969-9961(02)00010-4DOI Listing
February 2003

Epsilon-sarcoglycan mutations found in combination with other dystonia gene mutations.

Ann Neurol 2002 Nov;52(5):675-9

Department of Neurology, Medical University of Lübeck, Lübeck, Germany.

Myoclonus-dystonia is a movement disorder associated with mutations in the epsilon-sarcoglycan gene (SGCE) in most families and in the DRD2 and DYT1 genes in two single families. In both of the latter families, we also found a mutation of SGCE. The molecular mechanisms through which the detected mutations may contribute to myoclonus-dystonia remain to be determined.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.10358DOI Listing
November 2002

[18F]-Dopa positron emission tomography imaging in early-stage, non-parkin juvenile parkinsonism.

Mov Disord 2002 Jul;17(4):789-94

Neurodegenerative Disorders Centre, Vancouver Hospital & Health Sciences Centre, University of British Columbia, Vancouver, British Columbia, Canada.

There are few reports of positron emission tomography (PET) in juvenile parkinsonism (JP). We report on the results of (18)F-6-fluoro-L-dopa (FD) PET in a 14-year-old patient with JP of 5 years duration associated with atypical features. This is the youngest subject to be investigated to date. There was a severe asymmetric reduction in striatal FD uptake, with a rostrocaudal gradient in the putamen similar to that seen in adult-onset idiopathic parkinsonism. Extensive DNA analysis in this patient did not show mutations in the parkin gene.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mds.10133DOI Listing
July 2002

Molecular cloning and expression of rat torsinA in the normal and genetically dystonic (dt) rat.

Brain Res Mol Brain Res 2002 May;101(1-2):132-5

Molecular Neurogenetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

Deletions within the TOR1A gene cause early-onset (DYT1) torsion dystonia. We have cloned and sequenced the rat cDNA homologue of TOR1A and found a 91% identity with the human sequence. Northern blot analysis detects a single transcript of approximately 1.5 kb. In situ hybridization reveals a widespread distribution of torsinA mRNA within brain. No mutations were identified in the coding region of the gene in the genetically dystonic (dt) rat.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/s0169-328x(02)00176-6DOI Listing
May 2002

Intrafamilial phenotypic variability of the DYT1 dystonia: from asymptomatic TOR1A gene carrier status to dystonic storm.

Mov Disord 2002 Mar;17(2):339-45

Department of Neurology, Baylor College of Medicine, Houston, Texas 77030, USA.

When primary torsion dystonia is caused by a GAG deletion in the TOR1A gene (DYT1 dystonia), it typically presents with an early-onset dystonia involving distal limbs, subsequently spreading to a generalized dystonia. We describe a large family with an unusually broad variability in the clinical features of their dystonia both with regard to severity and age of onset. The proband of this family succumbed in his second decade to malignant generalized dystonia, whereas other family members carrying the same mutation are either asymptomatic or display dystonia that may be focal, segmental, multifocal, or generalized in distribution. One family member had onset of her dystonia at age 64 years, probably the oldest reported in genetically confirmed DYT1 dystonia. We conclude that marked phenotypic heterogeneity characterizes some families with DYT1 dystonia, suggesting a role for genetic, environmental, or other modifiers. These findings have implications for genetic testing and counseling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mds.10096DOI Listing
March 2002