p27 Deficiency Cooperates with Bcl-2 but Not Bax to Promote T-Cell Lymphoma

The effect of Bcl-2 on oncogenesis is complex and expression may either delay or accelerate oncogenesis. The pro-oncogenic activity is attributed to its well characterized anti-apoptotic function while the anti-oncogenic function has been attributed to its inhibition of cellular proliferation. Recent studies demonstrate that p27 may mediate the effects of Bcl-2 on cellular proliferation. We hypothesized that p27 may suppress tumor formation by Bcl-2 family members. To test this hypothesis, cell cycle inhibition and lymphoma development were examined in Lck-Bcl-2 and Lck-Bax38/1 transgenic mice deficient in p27. Strikingly, p27 deficiency synergistically cooperates with Bcl-2 to increase T cell hyperplasia and development of spontaneous T cell lymphomas. Within 1 year, >90% of these mice had developed thymic T cell lymphomas. This high penetrance contrasts with a one year incidence of <5% of thymic lymphoma in Lck-Bcl-2 or p27 −/− mice alone. In contrast, p27 deficiency had no effect on tumor formation in Lck-Bax38/1 transgenic mice, another model of T cell lymphoma. Histologically the lymphomas in p27 −/− Lck-Bcl-2 mice are lymphoblastic and frequently involve multiple organs suggesting an aggressive phenotype. Interestingly, in mature splenic T cells, Bcl-2 largely retains its anti-proliferative function even in the absence of p27. T cells from p27 −/− Lck-Bcl-2 mice show delayed kinetics of CDK2 Thr-160 phosphorylation. This delay is associated with a delay in the up regulation of both Cyclin D2 and D3. These data demonstrate a complex relationship between the Bcl-2 family, cellular proliferation, and oncogenesis and demonstrate that p27 up-regulation is not singularly important in the proliferative delay observed in T cells expressing Bcl-2 family members. Nonetheless, the results indicate that p27 is a critical tumor suppressor in the context of Bcl-2 expression

Cluster Analysis of Symptoms Among Patients with Upper Extremity Musculoskeletal Disorders

Introduction Some musculoskeletal disorders of the upper extremity are not readily classified. The study objective was to determine if there were symptom patterns in self-identified repetitive strain injury (RSI) patients. Methods Members (n = 700) of the Dutch RSI Patients Association filled out a detailed symptom questionnaire. Factor analysis followed by cluster analysis grouped correlated symptoms. Results Eight clusters, based largely on symptom severity and quality were formulated. All but one cluster showed diffuse symptoms; the exception was characterized by bilateral symptoms of stiffness and aching pain in the shoulder/neck. Conclusions Case definitions which localize upper extremity musculoskeletal disorders to a specific anatomical area may be incomplete. Future clustering studies should rely on both signs and symptoms. Data could be collected from health care providers prospectively to determine the possible prognostic value of the identified clusters with respect to natural history, chronicity, and return to work

"I think my body has become addicted to those tablets" Chronic heart failure patients' understanding of and beliefs about their illness and its treatment: a qualitative longitudinal study from Uganda

Patients with heart failure in Uganda present for health care with advanced structural heart disease, have repeated hospitalizations and poorly controlled disease symptoms. The reasons for these are unclear. Literature from other settings shows that patients' understanding of their illness and their beliefs influence their health related behaviour. The study aimed to explore the beliefs of patients with heart failure, their understanding of their illness and its treatment, and how this influenced their health related behaviour to inform future health education programs, information and palliative care services.Serial qualitative in-depth interviews were conducted with Heart Failure patients who were purposively sampled and recruited in Mulago National Referral Hospital until thematic saturation was reached. In-depth interviews were conducted at three time points over the course of their illness with intervals of 3 months between interviews. A grounded theory approach was used in data analysis. The University of Edinburgh ethics committee, Mulago Hospital Research Ethics committee and the Uganda National Council of Science and Technology (Reference numbers D/GC/178; MREC 33, SS 3083 respectively) approved the research.A total of 40 face to face qualitative longitudinal interviews (36-patient alone, 4 paired-patient and family carer), were conducted with 21 patients. The findings revealed that heart failure patients were unaware of the symptoms of the illness and their definition of illness differed from that of health professionals. Patients understood their diagnosis, cause of illness, prognosis and the importance of the medicines differently from health professionals, and had insufficient information on self-care. Lay beliefs were used to explain many aspects of the illness and treatments. All these influenced where patients sought care and their adherence to treatment, self-care and follow up leading to uncontrolled disease.There is a high level of health illiteracy among heart failure patients in Uganda. Patients rely on lay beliefs to make health decisions and medical information is often miscomprehended. There is an urgent need for health education using culturally appropriate information

A neuroscientist's guide to lipidomics

Nerve cells mould the lipid fabric of their membranes to ease vesicle fusion, regulate ion fluxes and create specialized microenvironments that contribute to cellular communication. The chemical diversity of membrane lipids controls protein traffic, facilitates recognition between cells and leads to the production of hundreds of molecules that carry information both within and across cells. With so many roles, it is no wonder that lipids make up half of the human brain in dry weight. The objective of neural lipidomics is to understand how these molecules work together; this difficult task will greatly benefit from technical advances that might enable the testing of emerging hypotheses

Deficient inflammasome activation permits an exaggerated asthma phenotype in rhinovirus C-infected immature mice

Compared to other RV species, RV-C has been associated with more severe respiratory illness and is more likely to occur in children with a history of asthma or who develop asthma. We therefore inoculated 6-day-old mice with sham, RV-A1B, or RV-C15. Inflammasome priming and activation were assessed, and selected mice treated with recombinant IL-1β. Compared to RV-A1B infection, RV-C15 infection induced an exaggerated asthma phenotype, with increased mRNA expression of Il5, Il13, Il25, Il33, Muc5ac, Muc5b, and Clca1; increased lung lineage-negative CD25+CD127+ST2+ ILC2s; increased mucous metaplasia; and increased airway responsiveness. Lung vRNA, induction of pro-inflammatory type 1 cytokines, and inflammasome priming (pro-IL-1β and NLRP3) were not different between the two viruses. However, inflammasome activation (mature IL-1β and caspase-1 p12) was reduced in RV-C15-infected mice compared to RV-A1B-infected mice. A similar deficiency was found in cultured macrophages. Finally, IL-1β treatment decreased RV-C-induced type 2 cytokine and mucus-related gene expression, ILC2s, mucous metaplasia, and airway responsiveness but not lung vRNA level. We conclude that RV-C induces an enhanced asthma phenotype in immature mice. Compared to RV-A, RV-C-induced macrophage inflammasome activation and IL-1β are deficient, permitting exaggerated type 2 inflammation and mucous metaplasia.http://deepblue.lib.umich.edu/bitstream/2027.42/175724/2/Deficient inflammasome activation permits an exaggerated asthma phenotype in rhinovirus C-infected immature mice.pdfPublished versio

Rhinovirus-A1B Decreases Coronavirus NL63 Replication and Inflammation in Adult Mice

http://deepblue.lib.umich.edu/bitstream/2027.42/192073/2/Rhinovirus-A1B decreases coronavirus NL63 replication and inflammation in adult mice. .pdfPublished versionDescription of Rhinovirus-A1B decreases coronavirus NL63 replication and inflammation in adult mice. .pdf : Published versio

Mouse Model of Human Coronavirus (HCOV)-NLL63: Comparison With Rhinovirus-(RV)-A1B and Effects of Prior RV Infection

http://deepblue.lib.umich.edu/bitstream/2027.42/192074/2/Mouse model of human coronavirus (HCoV)-NL63 for ATS final v2.pdfPublished versio

Poor medication adherence in clinical trials: consequences and solutions

Poor adherence to medicines in clinical trials can undermine the value of the trials; for example, by compromising estimates of the benefits and risks of a medicine. In this article, we highlight such consequences and also discuss approaches to tackle this problem