The role of cytokines and transcription factors on the regulation of megakaryocy topoiesis and platelet production are reviewed in this article. Megakaryocytopoiesis involves the proliferation and differentiation of megakaryocytic pro genitor cells into immature megakaryocytes, and the differentiation of immature megakaryocytes to mature megakaryocytes which produce platelets. The former is regulated mainly by thrombopoietin (TPO) and to a lesser degree by other cytokines such as interleukin-1 (IL-1), IL-3 and platelet-derived growth factor (PDGF), the later by TPO and probably IL-6 and IL-11. A number of transcription factors have been implicated in the control of megakaryocyte differentiation. GATA-1, FOG-1 and Fli-1 are essential regulators in early- and mid-stages of megakaryocytopoiesis. NF-E2 regulates late-stage of megakaryocytopoiesis and platelet production. However, the platelet release mechanism is poorly understood. Nitric oxide (NO) may act in the stage of platelet release through induction of apoptosis in megakaryocytes.
Animals ; Cytokines ; physiology ; DNA-Binding Proteins ; physiology ; Erythroid-Specific DNA-Binding Factors ; GATA1 Transcription Factor ; Hematopoiesis ; Humans ; Interleukins ; physiology ; Megakaryocytes ; physiology ; NF-E2 Transcription Factor ; NF-E2 Transcription Factor, p45 Subunit ; Platelet-Derived Growth Factor ; physiology ; Thrombopoiesis ; physiology ; Thrombopoietin ; physiology ; Transcription Factors ; physiology

Severe acute respiratory syndrome (SARS) has recently recognized as a new human infectious disease. A novel coronavirus was identified as the causative agent of SARS. This report summarizes the hematological findings in SARS patients and proposes a hypothesis for the pathophysiology of SARS coronavirus related abnormal hematopoiesis. Hematological changes in patients with SARS were common and included lymphopenia (68% - 90% of adults; 100% of children, n = 10), thrombocytopenia (20% - 45% of adults, 50% of children), and leukopenia (20% - 34% of adults, 70% of children). The possible mechanisms of this coronavirus on blood system may include (1) directly infect blood cells and bone marrow stromal cells via CD13 or CD66a; and/or (2) induce auto-antibodies and immune complexes to damage these cells. In addition, lung damage in SARS patients may also play a role on inducing thrombocytopenia by (1) increasing the consumption of platelets/megakaryocytes; and/or (2) reducing the production of platelets in the lungs. Since the most common hematological changes in SARS patients were lymphopenia and immunodeficiency. We postulate that hematopoietic growth factors such as G-CSF, by mobilizing endogenous blood stem cells and endogenous cytokines, could become a hematological treatment for SARS patients, which may enhance the immune system against these virus.
Adult ; Antigens, CD ; immunology ; Antigens, Differentiation ; immunology ; CD13 Antigens ; immunology ; Cell Adhesion Molecules ; Child ; Hematologic Diseases ; immunology ; physiopathology ; Hematopoiesis ; physiology ; Humans ; SARS Virus ; Severe Acute Respiratory Syndrome ; immunology ; physiopathology ; virology

BACKGROUND/AIMS: Previous studies reported that integrated information in the brain ultimately determines the subjective experience of patients with chronic pain, but how the information is integrated in the brain connectome of functional dyspepsia (FD) patients remains largely unclear. The study aimed to quantify the topological changes of the brain network in FD patients. METHODS: Small-world properties, network efficiency and nodal centrality were utilized to measure the changes in topological architecture in 25 FD patients and 25 healthy controls based on functional magnetic resonance imaging. Pearson's correlation assessed the relationship of each topological property with clinical symptoms. RESULTS: FD patients showed an increase of clustering coefficients and local efficiency relative to controls from the perspective of a whole network as well as elevated nodal centrality in the right orbital part of the inferior frontal gyrus, left anterior cingulate gyrus and left hippocampus, and decreased nodal centrality in the right posterior cingulate gyrus, left cuneus, right putamen, left middle occipital gyrus and right inferior occipital gyrus. Moreover, the centrality in the anterior cingulate gyrus was significantly associated with symptom severity and duration in FD patients. Nevertheless, the inclusion of anxiety and depression scores as covariates erased the group differences in nodal centralities in the orbital part of the inferior frontal gyrus and hippocampus. CONCLUSIONS: The results suggest topological disruption of the functional brain networks in FD patients, presumably in response to disturbances of sensory information integrated with emotion, memory, pain modulation, and selective attention in patients.
Anxiety ; Brain* ; Chronic Pain ; Connectome ; Depression ; Dyspepsia* ; Gyrus Cinguli ; Hippocampus ; Humans ; Magnetic Resonance Imaging ; Memory ; Orbit ; Putamen

INTRODUCTIONMajor workplace related accidents pose a significant healthcare resource challenge in Singapore.

MATERIALS AND METHODSOur study looks at the epidemiology of patients who were admitted for workplace related accidents, in a single institution, with an Injury Severity Score of >9.

RESULTSThere were 196 cases of major workplace related accidents admitted between January 2006 and December 2007. The median age of patients admitted was 37 years with a large percentage being males (95.4%) and non-residents (57.1%). The most common ethnic group was Chinese (53.1%) followed by Indians (23.5%). The most common mechanism of injury was fall from height (66.3%) followed by injuries as a result of falling objects at work (21.9%). The percentage of patients who required surgical intervention was 69.9%. Patients admitted for major workplace related accidents had a median length of stay of 5 days in the hospital, a median length of 24 days of medical leave (ML), certifying them unfit for duty and the average cost of stay for each patient was S$11,000.

CONCLUSIONSWe have a better understanding of the epidemiology and socio-economic impact of workplace related accidents through this study. Workplace related accidents result in significant number of man-days lost from work and monetary cost to employers, medical insurance and the hospital. With an improved understanding, we propose methods to prevent and reduce such accidents in future. A direct consequence of which will be the possible reduction of hospitalisation costs and better allocation of healthcare resources in the future.

Accidents, Occupational ; trends ; Adult ; Female ; Humans ; Male ; Middle Aged ; Registries ; Singapore ; epidemiology ; Trauma Centers ; Trauma Severity Indices ; Wounds and Injuries ; epidemiology ; surgery ; Young Adult

Delivery of follistatin (FST) represents a promising strategy for both muscular dystrophies and diabetes, as FST is a robust antagonist of myostatin and activin, which are critical regulators of skeletal muscle and adipose tissues. FST is a multi-domain protein, and deciphering the function of different domains will facilitate novel designs for FST-based therapy. Our study aims to investigate the role of the N-terminal domain (ND) of FST in regulating muscle and fat mass in vivo. Different FST constructs were created and packaged into the adeno-associated viral vector (AAV). Overexpression of wild-type FST in normal mice greatly increased muscle mass while decreasing fat accumulation, whereas overexpression of an N terminus mutant or N terminus-deleted FST had no effect on muscle mass but moderately decreased fat mass. In contrast, FST-I-I containing the complete N terminus and double domain I without domain II and III had no effect on fat but increased skeletal muscle mass. The effects of different constructs on differentiated C2C12 myotubes were consistent with the in vivo finding. We hypothesized that ND was critical for myostatin blockade, mediating the increase in muscle mass, and was less pivotal for activin binding, which accounts for the decrease in the fat tissue. An in vitro TGF-beta1-responsive reporter assay revealed that FST-I-I and N terminus-mutated or -deleted FST showed differential responses to blockade of activin and myostatin. Our study provided direct in vivo evidence for a role of the ND of FST, shedding light on future potential molecular designs for FST-based gene therapy.
Activins ; Animals ; Follistatin* ; Genetic Therapy ; In Vitro Techniques ; Mice ; Muscle Fibers, Skeletal ; Muscle, Skeletal ; Muscular Dystrophies ; Myostatin ; Negotiating

The immunological role of megakaryocytes is not well known. This project studies the involvement of megakaryocytes on immuno-inflammatory processes and the possible mechanism via the adhesion molecule CD36 and the synthesis of relevant cytokines. The expression of adhesion protein CD36 on human platelets, megakaryocytes and megakaryocytic cell lines (Meg-01, Dami, CHRF-288-11 and M-07e) was analyzed by using flow cytometry, ELISA and immunocytochemical methods. The expression of interleukin-1 (IL-1) to interleukin-10 (IL-10), TNF-alpha, TNF-gamma and IFN-gamma on the four megakaryocytic cell lines was also determined by RT-PCR. The effect of IL-1beta, IL-3, IL-6 and TPO on murine megakaryocyte colony formation (CFU-MK) was studied by using a plasma clot culture system. The CFU-MK was confirmed by acetylcholine esterase staining. The results showed that: (1) CD36 was expressed on platelets, megakaryocytes and the four megakaryocytic cell lines, the relative expression level is as follows: platelets > megakaryocytes > Meg-01 > Dami > CHRF-288-11 > M-07e, suggesting that the level of CD36 expression correlates with the degree of maturity of megakaryocytic differentiation; (2) inflammatory cytokines TNF-alpha, IL-1beta, IL-3 and IL-6 were detected in all the four megakaryocytic cell lines, suggesting that different stages of megakaryocytes can be as a source of inflammatory cytokines; and (3) IL-1beta, IL-3 and IL-6, as well as TPO, play a stimulating effect on CFU-MK formation, suggesting that there is an "autocrine" effect on megakaryocytopoiesis. The data obtained suggest that megakaryocytes may involve in immuno-inflammatory processes via the synthesis of platelet adhesion molecules and inflammatory cytokines.

To identify the expression of thrombopoietin (TPO) receptors (c-mpl) on central nervous system (CNS) and to evaluate the role of TPO on neural cell proliferation and protection, immunohistochemical staining, RT-PCR, MTT, and annexin-V methods were used in this study. The results showed the expression of TPO receptor on human CNS and murine neural cells. C-mpl mRNA was identified in human cerebral hemispheres and cerebellum, and mouse neural cell line C17.2 by RT-PCR. C-mpl was also confirmed in human cerebral hemispheres by immunohistostaining with con-focal microscopy. Furthermore, TPO had a stimulating effect on the growth of in vitro neural cell C17.2 by MTT assay. The anti-apoptotic effect of TPO on C17.2 cells was also demonstrated by staining with annexin-V and PI. In conclusion, the first evidence showed the expression of TPO receptor c-mpl in central nervous system. Moreover, the effect of TPO on neural cell proliferation and anti-apoptosis was also demonstrated on in vitro neural cells.
Animals ; Apoptosis ; drug effects ; Brain Chemistry ; Cell Line ; Cell Proliferation ; drug effects ; Erythropoietin ; pharmacology ; Humans ; Mice ; Neoplasm Proteins ; analysis ; Neurons ; drug effects ; Oncogene Proteins ; analysis ; Proto-Oncogene Proteins ; analysis ; Receptors, Cytokine ; analysis ; Receptors, Thrombopoietin ; Thrombopoietin ; pharmacology

This study investigated the expression of interleukin-17 (IL-17) and T cell immunoglobulin mucin and domain-containing molecule-3 (Tim-3) in bronchoalveolar lavage fluid (BALF) of asthmatic mice and the effect of dexamethasone (DEX) on these factors. Thirty-six mice were randomly divided into three groups: normal group, asthmatic group and DEX group. The mouse model of asthma was established by sensitization with ovalbumin in both the asthmatic and DEX groups. The levels of IL-6, IL-10, IL-17 and TGF-β were measured in BALF by enzyme-linked immunesorbent assay (ELISA). The mRNA expression level of Tim-3 was detected by reverse transcription polymerase chain reaction (RT-PCR). The ratio of Tim-3+CD4+ cells to total CD4+ cells in BALF was determined by flow cytometry. Differential inflammatory cells in BALF were detected. The correlations among IL-17, IL-6, IL-10, Tim-3 and inflammatory cells were analyzed. The results showed that the levels of IL-17, IL-6 and Tim-3 were substantially increased and the IL-10 level decreased in BALF in the asthmatic mice, which was significantly reversed by DEX treatment. IL-17 expression was positively correlated with IL-6 and Tim-3 expression and the number of inflammatory cells but negatively with IL-10 expression. These results indicate that the increased expression of IL-17 and Tim-3 in BALF may be implicated in the occurrence and development of asthmatic inflammation; the mechanism by which DEX suppresses asthmatic airway inflammation involves down-regulation of IL-17 and Tim-3 levels.
Animals ; Asthma ; drug therapy ; genetics ; metabolism ; Bronchoalveolar Lavage Fluid ; chemistry ; Dexamethasone ; pharmacology ; Female ; Gene Expression ; drug effects ; genetics ; Hepatitis A Virus Cellular Receptor 2 ; Interleukin-17 ; genetics ; metabolism ; Mice ; Mice, Inbred BALB C ; Receptors, Virus ; genetics ; metabolism

INTRODUCTIONThis study aimed to characterise interpersonal violence victims admitted to a major trauma centre.

MATERIALS AND METHODSA retrospective cohort study of interpersonal violence victims who were admitted to our centre from 1 January 2001 to 31 December 2010 was conducted. Data were obtained from our trauma registry.

RESULTSInterpersonal violence victims constituted 444 (90.1% males and 9.9% females) out of a total of 8561 trauma admissions in the same time period. The average age was 36.6 years (range, 14 to 83 years). Majority were Chinese (53.4%) and Singaporeans (77.3%). The number of cases increased from 10 per year to 96 per year in the first 8 years, then decreased in the last 2 years (55 in year 2010). Time of injury was predominantly 0000 to 0559 hours (72.3%). Interpersonal violence mostly occurred in public spaces for both genders (88.7%). However, the number of females who were injured at home was significantly higher than males (P = 0.000). Blunt trauma (58.3%) was more common than penetrating trauma (41.7%). The average injury severity score (ISS) was 13.5 (range, 1 to 75); 34.9% of patients had major trauma (ISS >15). The average Glasgow coma scale (GCS) score was 13.5 (range, 3 to 15); 16.4% of patients had moderate-to-severe brain injury (GCS 3-8). Blunt trauma was significantly more likely to cause major trauma than penetrating trauma (P = 0.003). The sole case of firearm assault caused most morbi-mortality. Overall mortality was 4.5%. Major trauma (OR: 25.856; P = 0.002) and moderate-to-severe brain injury (OR: 7.495; P = 0.000) were independent risk factors of mortality.

CONCLUSIONThere has been no prior published data on interpersonal violence locally. This study is thus useful as preliminary data for future population-based studies. It also provides data for authorities to formulate preventive and intervention strategies.

Adolescent ; Adult ; Aged ; Aged, 80 and over ; Cohort Studies ; Female ; Humans ; Injury Severity Score ; Male ; Middle Aged ; Patient Admission ; statistics & numerical data ; Retrospective Studies ; Time Factors ; Trauma Centers ; Violence ; statistics & numerical data ; Young Adult