Catalyzing stem cell research

In 2001, the Stem Cell Network was the first of its kind, a bold initiative to forge and nurture pan-Canadian collaborations involving researchers, engineers, clinicians and private and public sector partners. Canada's broad and deep pool of stem cell talent proved to be a fertile ground for such an initiative, giving rise to a strong, thriving network that, 7 years later, can list innovative cell expansion and screening technologies, early-phase clinical trials for stroke, pulmonary hypertension, muscular dystrophy and cornea replacement, and leading discourse on ethical, legal and social issues among its accomplishments. As it moves into its second and final phase of funding, the Stem Cell Network continues to push boundaries and has set its sights on overcoming the obstacles that impede the transfer of research findings to clinical applications, commercial products and public policy.     

The final illness in cancer: the widow''s perspective.

Widows of cancer patients were compared with other widows in general and with widows of men with chronic cardiovascular disease in particular, special attention being given to the vicissitudes of the final illness. Despite the recent emphasis on the need for open communication about the impending death between the dying patient and his family, interviews with 73 women whose husbands had died of cancer revealed that 40% of those who had been told their husband was dying refused to accept the warning. Only 29% of the couples openly discussed the possibility of the husband dying of his disease. More than half of those who did not talk with their husband about the impending death reported that this made no difference to their initial adjustment to bereavement. The stress for a woman of her husband's final illness leads to an especially difficult bereavement period; for example, significantly more widows of cancer patients than of patients with other illnesses perceived themselves to be in poor health during the initial bereavement period. Some of the problems specific to cancer patients and their families are described, along with recommendations for their alleviation.     

Serological response of paediatric oncology patients to human herpesvirus-6

The serological response of paediatric oncology patients to human herpesvirus-6 (HHV-6) was investigated at presentation and during treatment. Sera from 66 patients presenting with malignancy and 66 controls were examined for anti-HHV-6 IgG by indirect immunofluorescence test (IFA) and enzyme linked immunosorbent assay (ELISA), and for anti-HHV-6 IgM by IFA. Serial samples from 45 children on chemotherapy were examined for anti-HHV-6 IgG by ELISA and sera from selected patients on chemotherapy were examined for IgM by IFA. The response of these patients to four other herpesviruses was also investigated. Ninety percent of presenting patients and controls were IgG positive for HHV-6 by IFA and ELISA. Anti-HHV-6 IgG as measured by the HHV-6 ELISA index declined overtime in patients on chemotherapy. Two presenting controls and one leukaemic child with a primary cytomegalo-virus seroconversion were anti-HHV-6 IgM positive. In the patient group seropositivity to herpesviruses (types 1–6) increased with age, the mean age of those with IgG to HHV-6 alone was 3.7 years compared to 6.8 years for those with antibodies to all five viruses. At the time of presentation paediatric oncology patients have a similar serological response to HHV-6 as age-matched controls and this IgG response wanes with treatment. Whether this is significant in terms of viral pathogenicity is not known and will require investigation of viral activity in these patients. © 1994 Wiley-Liss, Inc.     

Thermal therapy: a viable adjunct in the treatment of heart failure?

The aim of this work was to review and provide a summary of published literature on the clinical impact of thermal therapy (ie, warm water immersion, traditional sauna bathing, and dry infrared sauna) in patients with heart failure. Medline and Embase database literature searches were conducted, and studies that included measurement of heart failure-related clinical parameters were reviewed. Thermal therapy was found to have a positive impact on key heart failure-related parameters across multiple studies. Significant improvements were noted across a wide scope of heart failure-related parameters in the areas of (1) endothelial function, (2) hemodynamics, (3) cardiac geometry, (4) neurohormonal markers, and (5) quality of life. Of special note, thermal therapy also conveyed a strong antiarrhythmic effect in heart failure patients. The clinical evidence highlights repeatable and compelling data showing that thermal therapy may provide an important and viable adjunct in the treatment of heart failure.     

Review of current research on breastmilk and mothe-to-infant transmission of HIV

This review summarises whatis known about breastfeeding and HIV and discusses interventions such as micronutrient supplements and antiretroviral treatment in the perinatal and possibly the breastfeeding period, to try to decrease the risk of HIV transmission through breastmilk. It shows that breastfeeding seems to double the risk of HIV infection in infants, with a constant and cumulative risk of infection throughout the breastfeedingperiod. Formula feeding is an option but increases the risk of infant morality and morbidity from other causes. Breastfeeding could be stopped after 4–6 months where early weaning foods are available and fewer infants would become infected, but women maybe stigmatised and milk remains an important part of the infant diet for 2–3 years. Not enough is known about the effectiveness of antibody responses to HIV in breastmilk; however, women whose milk does not contain detectable antibodies maybe more likely to transmit the virus. The effect ofmaternal HIV disease on the risk of transmission has not yet been confirmed, noris it clearhow the infection crosses the infant gut mucosa, although several routes are feasible. A better scientific understanding of the infectivity ofbreastmilk and the susceptibility of the infant would help to clarify the relative risk of infection, and would seem to be a priority. In the long term, the best way to prevent infant infection with HIV is to prevent infection of women.     

Profiling markers of prognosis in colorectal cancer.

PURPOSE: Colorectal cancer is one of the most common forms of cancer in developed nations and the incidence of this disease is increasing. There is a need to further stratify prognostically distinct groups of colorectal cancer, and the purpose of this study was to identify prognostically significant immunohistochemical marker profiles in colorectal cancer. EXPERIMENTAL DESIGN: In this study, a range (n = 23) of markers [pRb, p16, p21, p27, p53, proliferating cell nuclear antigen, cyclin D1, bcl-2, epidermal growth factor receptor, C-erb-B2, topoisomerase-I, liver fatty acid-binding protein, matrix metalloproteinases (MMP) 1-3, 7, 9, and 13, MT1-MMP, MT2-MMP, and tissue inhibitors of MMP 1-3] of putative prognostic significance have been investigated by immunohistochemistry on formalin-fixed, wax-embedded sections in a series (n = 90) of stage III (Dukes C) colorectal cancers. An immunohistochemical score based on the intensity of immunoreactivity and, where relevant, the proportion of immunoreactive cells was established for each marker. RESULTS: Unsupervised two-dimensional hierarchical cluster analysis identified three distinct cluster groups (designated groups 1-3) with different marker profiles. There were significant survival differences between groups 1 and 2 (log rank = 11.48; P = 0.0007) and between groups 1 and 3 (log rank = 8.32; P = 0.0039). Multivariate analysis showed that the complete marker profile was independently the most significant prognostic factor (hazard ratio, 2.27; 95% confidence interval, 1.15-4.48; P = 0.004). CONCLUSIONS: This study has identified an immunohistochemical marker profile of colorectal cancer and showed that it is an independent indicator of prognosis in this type of cancer.     

Rab14 Regulates Maturation of Macrophage Phagosomes Containing the Fungal Pathogen Candida albicans and Outcome of the Host-Pathogen Interaction

Avoidance of innate immune defense is an important mechanism contributing to the pathogenicity of microorganisms. The fungal pathogen Candida albicans undergoes morphogenetic switching from the yeast to the filamentous hyphal form following phagocytosis by macrophages, facilitating its escape from the phagosome, which can result in host cell lysis. We show that the intracellular host trafficking GTPase Rab14 plays an important role in protecting macrophages from lysis mediated by C. albicans hyphae. Live-cell imaging of macrophages expressing green fluorescent protein (GFP)-tagged Rab14 or dominant negative Rab14, or with small interfering RNA (siRNA)-mediated knockdown of Rab14, revealed the temporal dynamics of this protein and its influence on the maturation of macrophage phagosomes following the engulfment of C. albicans cells. Phagosomes containing live C. albicans cells became transiently Rab14 positive within 2 min following engulfment. The duration of Rab14 retention on phagosomes was prolonged for hyphal cargo and was directly proportional to hyphal length. Interference with endogenous Rab14 did not affect the migration of macrophages toward C. albicans cells, the rate of engulfment, the overall uptake of fungal cells, or early phagosome processing. However, Rab14 depletion delayed the acquisition of the late phagosome maturation markers LAMP1 and lysosomal cathepsin, indicating delayed formation of a fully bioactive lysosome. This was associated with a significant increase in the level of macrophage killing by C. albicans. Therefore, Rab14 activity promotes phagosome maturation during C. albicans infection but is dysregulated on the phagosome in the presence of the invasive hyphal form, which favors fungal survival and escape.     

HIV-1 drug resistance in HIV-1-infected children in the United Kingdom from 1998 to 2004

We reviewed HIV-1 genotypes from 200 of 979 (20%) HIV-infected children in the U.K. Collaborative HIV in Pediatric Study (CHIPS) cohort (343 resistance tests). Three of 44 samples had major primary resistance mutations before antiretroviral therapy. Three-class resistance was noted in 42 samples (14.1%). Our study also highlighted underutilization of testing and the need for prompt genotyping after drug discontinuation which may have lead to an underestimation of HIV-1 resistance.     

Blood pressure, left ventricular mass and intracellular calcium in primary hyperparathyroidism

1. Blood pressure, left ventricular mass and platelet cytosolic free calcium concentrations were measured in 23 patients with untreated primary hyperparathyroidism, 30 normotensive control subjects and 23 control subjects matched for age, sex and blood pressure. In 12 patients measurements were repeated after parathyroidectomy. 2. Patients with primary hyperparathyroidism had significantly elevated blood pressures (139 +/- 6/86 +/- 3 mmHg, mean +/- SEM) compared with control subjects (125 +/- 2/78 +/- 1 mmHg), but high values persisted after hypercalcaemia was corrected. 3. Despite chronic extracellular hypercalcaemia, intracellular free calcium levels were lower in patients with hyperparathyroidism than in controls matched for age, sex and blood pressure (median concentrations 81.5 nmol/l vs 93 nmol/l, 95% confidence interval 0.1 to 20.1; P less than 0.05) and values tended to increase after parathyroidectomy. 4. Left ventricular mass index was increased in the primary hyperparathyroid group as compared with control subjects matched for age, sex and blood pressure (123 g/m2 vs 100 g/m2, 95% confidence interval -36.1 to -3.1; P = 0.03). Parathyroidectomy resulted in a small reduction of the left ventricular mass index (123.5 g/m2 vs 104 g/m2, 95% confidence interval 46.5 to 2.5; P = 0.1) but no change in blood pressure. 5. Hypertension and left ventricular hypertrophy in primary hyperparathyroidism are associated with relatively low levels of free calcium in platelets.