Roles of the Bötzinger complex in the formation of respiratory rhythm.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
M Lu
Publications and source records attributed to M Lu.
The appearance of retinopathy and progression to proliferative retinopathy: the WHO Multinational Study of Vascular Disease in Diabetes.
AIMS/HYPOTHESIS: We aimed to estimate incidences of any retinopathy and proliferative diabetic retinopathy (PDR) by direct ophthalmoscopy and relate them to baseline risk factors in re-examined diabetic survivors from 10 centres of the WHO Multinational Study of Vascular Disease in Diabetes. METHODS: After a mean follow-up of 8.4years (11.7 years in Oklahoma), 2877 (71.6%) survivors were resubmitted to standardised direct ophthalmoscopy as at baseline. The presence of any retinopathy and PDR were recorded at each centre and their incidence estimated in those without retinopathy and PDR at baseline. The independent associations of these incidences with baseline risk factors are expressed as odds ratios derived from multiple logistic regression analyses, within individual centres (which included fasting plasma glucose in 8 and triglyceride in 5) and in pooled data. RESULTS: Of the 4662 original patients, 465 (10.4%) of those without and 77 (43.0%) of those with baseline PDR had died (p < 0.001). Any retinopathy was newly reported at follow-up in 47.7 % and PDR in 9.7 % of those free of them at baseline, with reported incidences varying substantially among centres. Incident retinopathy appeared earlier in the known course of diabetes but incidence rates rose more slowly with duration in patients with Type II (non-insulin-dependent) diabetes mellitus than in those with Type I (insulin-dependent) diabetes mellitus. In pooled data and in some individual centres, any retinopathy incidence gave significantly positive odds ratios with age, diabetes duration, systolic pressure, plasma cholesterol, BMI, insulin treatment and proteinuria, and with fasting plasma glucose in the centres where it was measured. Positive odds ratios for PDR were similarly obtained for age, duration, insulin treatment, cholesterol, proteinuria and fasting glycaemia. Smoking status odds ratios were negative for both outcomes. CONCLUSION/INTERPRETATION: Incidence of ophthalmoscopically ascertained any retinopathy varied about twofold and of PDR about threefold among centres. Although, in part attributable to differences between observers, variation in incidence in all centres and in some cases within centres was associated with a number of baseline risk factors. Such associations are not likely due to observer variation or selection biases and emerged despite the imprecision of clinical ophthalmoscopy. Improved detection and control of these risk factors should reduce the impact of diabetic retinopathy and its consequences.
Age Factors↗
Follow-up of the WHO Multinational Study of Vascular Disease in Diabetes: general description and morbidity.
AIMS: The incidence of retinal, renal and cardiovascular complications and their relation to baseline risk factors was documented in this follow-up study of 10 of the 14 original centres of the WHO Multinational Study of Vascular Disease in Diabetes (WHO MSVDD). METHODS: The incidence of specified items of vascular disease and some associated risk factors was ascertained after 7 to 9 years (11-12 years in Oklahoma, USA) follow-up, re-using baseline examination methodology in 3165 patients (66.9 %) and, through secondary information in 717 (15.2%) of the 4729 original patients, of whom 540 (11.4%) had died and 307 (6.5 %) were untraceable. RESULTS: During follow-up, approximately one third of the patients developed hypertension and one third started insulin. Coronary heart disease incidence varied 10 to 20-fold among centres as did limb amputation rates. Inter-centre differences in incident retinopathy and severe visual impairment were smaller but incident clinical proteinuria and renal failure varied markedly. Vascular disease incidence of all categories was high in Native Americans though coronary heart disease incidence was relatively low in Pima Indians and absolutely low in Hong Kong and Tokyo patients. Specific vascular events and their relation with baseline risk factors are analysed in accompanying papers, summarised in the Epilogue. CONCLUSION/INTERPRETATION: These 10 centres reported very different incidence rates of vascular complications. Observer variation, selection biases and competing causes of mortality contributed to these differences but their validity is supported by the more objective outcome indicators. The following papers also suggest that baseline factors such as raised arterial pressure, cholesterol and fasting glucose (in the centres where it was measured) were important and potentially reversible predictors of risk.
Adult↗
The incidence of visual impairment and its determinants in the WHO Multinational Study of Vascular Disease in Diabetes.
AIMS/HYPOTHESIS: Incidence of severe visual impairment and the ultimate prevalence of all grades of impairment were estimated in the 10 centres of the WHO Multinational Study of Vascular Disease in Diabetes (WHO MSVDD) participating in the follow-up. METHODS: Visual function was ascertained at follow-up in 2994 (77.9 %) of the 3845 eligible participating survivors of the 4709 originally recruited for the WHO MSVDD using the same baseline enquiry method. The associations between incident severe visual impairment, follow-up prevalence of all grades of impairment and baseline risk factors were examined by univariate and stepwise multiple logistic regression analysis. RESULTS: Overall, 8.4 year incidence of severe visual impairment was 1.94 % and showed statistically significant univariate correlations with age at diagnosis, diabetes duration, systolic blood pressure, fasting blood glucose and cholesterol, insulin treatment and strongly with baseline retinopathy. Baseline retinopathy, systolic pressure and cholesterol were statistically significant in multivariable analysis. Differences between centres (0.3% to 3.45%) were not significant. Ultimate prevalence of all grades of impairment differed between centres and within almost all of them was correlated in multivariable analysis with baseline retinopathy and proteinuria. CONCLUSION/INTERPRETATION: Comparisons of incident severe visual impairment between centres are restricted by selective mortality, low incidence rates and relatively small numbers in each centre but before retinopathy, baseline systolic pressure and cholesterol predicted severe visual impairment. Follow-up prevalence of all degrees of impairment varied among centres and were associated with prior retinopathy and renal disease at baseline.
Adult↗
Increased urinary albumin excretion and its associations in the WHO Multinational Study of Vascular Disease in Diabetes.
AIM/HYPOTHESIS: We aimed to determine variations in the prevalence of increased urinary albumin excretion, associated risk factors and complications in patients with diabetes participating in the WHO Multinational Study of Vascular Disease in Diabetes follow-up. METHODS: Urinary albumin to urinary creatinine ratios were measured centrally in 2,033 of the 2,550 (79.7%) re-examined patients from eight centres in seven countries and the frequency of microalbuminuria and macroalbuminuria and their associations with risk factors and complications were examined. RESULTS: Macroalbuminuria prevalence (overall 15.6%) varied tenfold (3-37%) among centres, was higher in American Indian and Asian centres and not clearly related to type of diabetes. Microalbuminuria (overall 19.7 %) varied less (12-31%). Increased albumin excretion was related overall to baseline fasting plasma glucose in the pooled group in whom it was measured and to increased arterial pressure, insulin use, coronary heart disease, lower extremity amputation, retinopathy and stroke in most centres. CONCLUSION/INTERPRETATION: Centres varied widely in the prevalence of increased albumin excretion but associations with risk factors and vascular complications were generally similar in most centres and in both major types of diabetes with ethnic and genetic differences probably contributing.
Albuminuria↗
Risk factors for renal failure: the WHO Mulinational Study of Vascular Disease in Diabetes.
AIMS/HYPOTHESIS: We aimed to examine risk factors for, and differences in, renal failure in diabetic patients from 10 centres. METHODS: Risk factors for renal failure were examined in 3,558 diabetic patients who did not have renal disease at baseline in the WHO Multinational Study of Vascular Disease in Diabetes (WHO MSVDD). RESULTS: In 959 subjects with Type I (insulin-dependent) diabetes mellitus and 2,559 with Type II (non-insulin-dependent) diabetes mellitus, the average follow-up was 8.4 years (+/- 2.7). By the end of the follow-up period 53 patients in the Type I diabetic group and 134 patients in the Type II diabetic group had developed renal failure (incidence rate 6.3:1,000 person years). Increasing age and duration of diabetes were associated with renal failure in Type II and Type I diabetes. In Type II diabetes duration of diabetes was a more important risk factor than age. In both Type I and Type II diabetic retinopathy and proteinuria were strongly associated with renal failure. Systolic blood pressure was associated with renal failure in Type I but not in Type II diabetic patients. ECG abnormalities at baseline, self-reported smoking and cholesterol were not associated with renal failure. Triglycerides were measured in a subset of centres. Among those with Type II, but not Type I diabetes, triglycerides were associated with renal failure independently of systolic blood pressure, proteinuria or retinopathy. In Type II diabetes fasting plasma glucose was associated with renal failure independently of other risk factors. CONCLUSION/INTERPRETATION: We have confirmed the role of proteinuria and retinopathy as markers of renal failure and the importance of hyperglycaemia in renal failure in Type I and Type II diabetes. Plasma triglycerides seem to be an important predictor of renal failure in Type II diabetes. In Type I diabetes systolic blood pressure is an important predictor of renal failure.
Blood Glucose↗
Risk factors, ethnic differences and mortality associated with lower-extremity gangrene and amputation in diabetes. The WHO Multinational Study of Vascular Disease in Diabetes.
AIMS/HYPOTHESIS: We aimed to examine geographic differences, risk factors and mortality associated with amputation. METHODS: Data from 10 of the original 14 centres of the WHO Multinational Study of Vascular Disease in Diabetes were used. This included 3443 men and women aged 35 to 55 years at baseline. RESULTS: Incidences of amputation, adjusted for sex and duration in Type I (insulin-dependent) diabetes mellitus, were 31.0, 8.2, 3.5 and 1.0 per 1,000 person years in the American Indian, Cuban, European and East Asian centres respectively. In Type II (non-insulin-dependent) diabetes mellitus, incidences of amputation were 9.7, 2.0, 2.5 and 0.7 per 1000 person years in the American Indian, Cuban, European and East Asian centres respectively. Key risk factors for amputation included glucose, triglyceride, and retinopathy, and were similar for American Indians and Europeans. The age, duration and sex adjusted relative risk for amputation in American Indians compared with Europeans was 11.48 (95% CI 3.56, 36.98) in Type I diabetes and 3.86 (95 % CI 2.36, 6.32) in Type II diabetes. Adjusting for heart disease, retinopathy, proteinuria, glucose, blood pressure and triglyceride attenuated these relative risks to 10.83 (95 % CI 3.20, 36.65) and 3.15 (1.91, 5.20) in Type I and Type II diabetes respectively. Amputation doubled mortality rates in all groups. CONCLUSION/INTERPRETATION: Vascular complications and their risk factors are themselves risk factors for amputation in both Type I and Type II diabetes and are common to several geographical regions worldwide. However, reasons for differences between geographical regions and the degree to which different health care systems could be responsible is not clear.
Adult↗
Vascular disease in younger-onset diabetes: comparison of European, Asian and American Indian cohorts of the WHO Multinational Study of Vascular Disease in Diabetes.
AIMS/HYPOTHESIS: This study compared the incidence of vascular disease in subjects with younger-onset diabetes from different ethnic groups. METHODS: The incidence of vascular disease endpoints has been studied in a sub-group (n = 994) of participants of the World Health Organization Multinational Study of Vascular Disease in Diabetes (WHO MSVDD) who had younger-onset diabetes (diagnosed before the age of 30 years). The study participants have been divided into European (n = 631), Asian (n = 84) and American Indian (n = 91) cohorts. RESULTS: For Type I (insulin-dependent) and Type II (non-insulin-dependent) diabetes mellitus, American Indian men had a higher incidence of lower-extremity amputation and renal failure than the other cohorts, whereas European women had a higher incidence of angina than other cohorts. American Indians also had a higher incidence of any retinopathy, clinical proteinuria and albuminuria than the European and Asian cohorts. CONCLUSION/INTERPRETATION: This study confirms the high burden of large and small-vessel disease complications manifest in American Indian people with younger-onset diabetes.
Adult↗
Vascular disease prevalence in diabetic patients in China: standardised comparison with the 14 centres in the WHO Multinational Study of Vascular Disease in Diabetes.
AIMS/HYPOTHESIS: Rates of vascular complications of diabetes in a cohort of mainland Chinese patients with diabetes, ascertained and examined by similar methodology, are compared with those of the WHO Multinational Study of Vascular Disease in Diabetes (WHO MSVDD). METHODS: The standardised procedures carried out in the WHO MSVDD were followed in assembling and examining a Chinese cohort of 447 diabetic patients recruited in Beijing and Tianjin [2]. RESULTS: Compared with the WHO MSVDD centres, the Chinese cohort was slightly older, had a shorter duration of known diabetes and had fewer insulin-treated patients. Arterial pressure, total blood cholesterol and body mass index were substantially lower. Large vessel disease rate for age, sex and duration adjusted data (17.9 % ) was about half that of the combined WHO MSVDD centres (33.5 % p < 0.001). However, retinopathy (47.4% vs 35.8% p < 0.001) and proteinuria (57.1 vs 24.9 % p < 0.001) rates were significantly higher. CONCLUSION/INTERPRETATION: Relatively low arterial pressures and blood cholesterol are likely contributors to the notably low arterial disease rates in this Chinese diabetic cohort; they reflect low rates in the Chinese mainland general population and resemble the Tokyo and Hong Kong centres of the WHO MSVDD. The high rates of retinopathy and proteinuria could relate to later diagnosis, degree of hyperglycaemia and/or increased susceptibiltiy to microangiopathy.
Adult↗
Significance of plasma cytokine levels in melanoma patients with histologically negative sentinel lymph nodes.
INTRODUCTION: Although sentinel lymph node (SLN) status is the most powerful predictor of prognosis in patients with clinically localized melanoma, a proportion of melanoma patients with histologically negative SLNs will still recur. It is hypothesized that tumor response may be altered or mediated by specific cytokines. We therefore investigated whether levels of IL-4, IL-6, IL-10, TNF-alpha, or IFN-gamma would predict disease recurrence in melanoma patients with histologically negative SLNs. METHODS: This prospective cohort study involved 218 patients with clinically localized melanoma who underwent a histologically negative SLN biopsy. Preoperative plasma cytokine levels were determined by enzyme-linked immunosorbent assay on these patients, as well as on 90 healthy controls. Kaplan-Meier life tables were constructed, and Cox proportional hazards analyses were performed to assess predictors of disease-free survival (DFS). RESULTS: At a median follow-up of 43 months, 33 of 218 patients (15%) had suffered disease recurrence. Melanoma patients had significant elevations of IL-4, IL-6, and IL-10 compared to healthy controls; levels of IFN-gamma were less elevated in melanoma patients compared to controls. Despite this, melanoma patients with detectable IFN-gamma levels were at significantly higher risk for recurrence compared to patients with undetectable levels (5-year DFS 70% vs. 86%, P = .03). On multivariate analysis including standard melanoma prognostic factors, only tumor thickness (P = .004) and the presence of detectable IFN-gamma levels (P = .05) were significant independent prognostic factors for disease-free survival. CONCLUSIONS: Among melanoma patients with clinically localized disease who have undergone a histologically negative SLN biopsy, presence of a detectable plasma level of IFN-gamma is an independent predictor of disease recurrence. Elevated levels of IFN-gamma may identify a group of early-stage melanoma patients who are more likely to have recurrence of disease and who may benefit from adjuvant therapies, including immunotherapies.
Adolescent↗
Aberrant expression of fetal RNA-binding protein p62 in liver cancer and liver cirrhosis.
p62 is a RNA-binding protein that was isolated by immunoscreening a cDNA expression library with autoantibodies from patients with hepatocellular carcinoma (HCC). This autoantigen binds to mRNA encoding insulin-like growth factor II, which has been found to be overexpressed in HCC and is tumorigenic in transgenic animals. Immunohistochemical analysis of HCC liver showed that 33% (9 of 27) exhibited readily detectable staining of p62 protein in the cytoplasm of all malignant cells in cancer nodules, whereas it was undetectable in adjacent nonmalignant liver cells. In addition one of two patients with cholangiocarcinoma expressed p62 in malignant bile duct epithelial cells. p62 expression was also detected in scattered cells in cirrhotic nodules in contrast to uniform expression in all cells in HCC nodules. In HCC nodules, p62 mRNA was also detected by reverse transcriptase-polymerase chain reaction analysis. Nine normal adult livers did not contain detectable p62 mRNA or p62 protein whereas five fetal livers were all positive for mRNA and protein. The observations show that p62 is developmentally regulated, expressed in fetal, but not in adult liver, and aberrantly expressed in HCC and could be playing a role in abnormal cell proliferation in HCC and cirrhosis by modulating expression of growth factors such as insulin-like growth factor II.
Adult↗
Intracerebral transplantation of bone marrow stromal cells in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease.
Adult C57BL/6 mice were injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Intrastriatal transplantation of bone marrow stromal cells (MSCs) was performed 1 week after MPTP administration. MSCs were harvested from donor adult mice, and then cultured and prelabeled with bromodeoxyuridine (BrdU). MPTP-Parkinson's disease (PD) mice treated with intrastriatal injection of phosphate-buffered saline (PBS), and normal non-MPTP mice were used as controls. MPTP-PD mice with MSC intrastriatal transplantation exhibit significant improvement on the rotarod test (P<0.05) at day 35 compared with PBS controls. Immunohistochemistry shows that BrdU reactive cells survive in the transplanted areas in the MPTP-PD striatum at least 4 weeks after administration. Scattered BrdU reactive cells express tyrosine hydroxylase (TH) immunoreactivity. Our findings suggest that MSCs injected intrastriatally survive, express dopaminergic protein TH immunoreactivity, and promote functional recovery.
Animals↗
A method for efficient isotopic labeling of recombinant proteins.
A rapid and efficient approach for preparing isotopically labeled recombinant proteins is presented. The method is demonstrated for 13C labeling of the C-terminal domain of angiopoietin-2, 15N labeling of ubiquitin and for 2H/13C/15N labeling of the Escherichia coli outer-membrane lipoprotein Lpp-56. The production method generates cell mass using unlabeled rich media followed by exchange into a small volume of labeled media at high cell density. Following a short period for growth recovery and unlabeled metabolite clearance, the cells are induced. The expression yields obtained provide a fourfold to eightfold reduction in isotope costs using simple shake flask growths.
Angiopoietin-2↗
A DNA computing readout operation based on structure-specific cleavage.
We describe a structure-specific cleavage-based READOUT strategy for surface-based DNA computing. The strategy was demonstrated in the solution of a 4-variable/3-satisfiability (SAT) problem. The READOUT step identifies the DNA molecules present at the end of the computational process. The specificity of the sequence detection used here derives from the sequence specificity of DNA hybridization coupled with the structure specificity of the enzymatic cleavage. The process is linear, yielding a higher uniformity of detection of the DNA computing products compared to that obtained with PCR amplification. The structure-specific cleavage-based readout is simple, accurate, and compatible with multiple-word DNA computing.
Animals↗
Expression, purification, immunological characterization and application of Escherichia coli-derived hepatitis C virus E2 proteins.
The envelope glycoprotein E2 of hepatitis C virus (HCV) has been shown to bind human target cells. Anti-E2 antibodies have been associated with both recovery from natural infection in humans and protection from challenge with homologous HCV in chimpanzees. Therefore E2 has become a major target for the development of anti-HCV vaccines. Two E2 fragments [amino acids (aa) 450-565 and aa 385-565] derived from a subtype 1b HCV genome were expressed as N-terminally hexahistidine-tagged proteins in Escherichia coli and purified to over 85% purity. Both proteins were specifically recognized by homologous hepatitis-C-patient's serum on Western blotting, suggesting that these E. coli-derived E2 proteins displayed E2-specific antigenicity. E2-116 (aa 450-565) elicited strong antibody responses in BALB/c mice and rabbits. Rabbit antiserum raised against renatured E2-116 (R(E2-116R)) was able to recognize subtype 1b and 1a E2 glycoproteins expressed in mammalian cells on Western blotting. E2-181 (aa 385-565) reacted with 40% of anti-HCV(+) patients' sera in ELISA. R(E2-116R) and E2-181 were successfully used in preliminary modified vaccinia virus Ankara- and DNA-based E2 vaccine studies for detecting antigen expression in vitro and assessing induced humoral immune responses in mice. The E2 proteins and rabbit antiserum reported here could find wider applications in the development of effective diagnostic, prophylactic and therapeutic measures against HCV.
Animals↗
Competition for microtubule-binding with dual expression of tau missense and splice isoforms.
How tau mutations lead to neurodegeneration is unknown but may be related to altered microtubule binding properties of mutant tau protein. The tendency for the mutations to cluster around the microtubule-binding domain of tau or to alter the ratios of those splice isoforms that affect binding supports the view that the tau/microtubule interaction is critical and finely regulated. In cells transfected with both mutant and wild-type tau isoforms fused to either yellow fluorescent protein or cyan fluorescent protein we can observe tau fusion proteins that differ by a single amino acid or by the inclusion or exclusion of exon 10. With coexpression of mutant and wild-type tau, the mutant isoform appears diffuse throughout the cytoplasm; however, when mutant tau is expressed alone, it appears mostly bound to the microtubules. Dual imaging of the three- and four-repeat tau isoforms indicated that the expression of four-repeat tau displaced three-repeat tau from the microtubules. These results suggest that altered kinetic competition among the isoforms for microtubule binding could be a disease precipitant.
3T3 Cells↗
Induction of cancer cell apoptosis by alpha-tocopheryl succinate: molecular pathways and structural requirements.
The vitamin E analog alpha-tocopheryl succinate (alpha-TOS) can induce apoptosis. We show that the proapoptotic activity of alpha-TOS in hematopoietic and cancer cell lines involves inhibition of protein kinase C (PKC), since phorbol myristyl acetate prevented alpha-TOS-triggered apoptosis. More selective effectors indicated that alpha-TOS reduced PKCalpha isotype activity by increasing protein phosphatase 2A (PP2A) activity. The role of PKCalpha inhibition in alpha-TOS-induced apoptosis was confirmed using antisense oligonucleotides or PKCalpha overexpression. Gain- or loss-of-function bcl-2 mutants implied modulation of bcl-2 activity by PKC/PP2A as a mitochondrial target of alpha-TOS-induced proapoptotic signals. Structural analogs revealed that alpha-tocopheryl and succinyl moieties are both required for maximizing these effects. In mice with colon cancer xenografts, alpha-TOS suppressed tumor growth by 80%. This epitomizes cancer cell killing by a pharmacologically relevant compound without known side effects.
Animals↗
Arabidopsis NHO1 is required for general resistance against Pseudomonas bacteria.
Nonhost interactions are prevalent between plants and specialized phytopathogens. Although it has great potential for providing crop plants with durable resistance, nonhost resistance is poorly understood. Here, we show that nonhost resistance is controlled, at least in part, by general resistance. Arabidopsis plants are resistant to the nonhost pathogen Pseudomonas syringae pv phaseolicola NPS3121 and completely arrest bacterial multiplication in the plant. Ten Arabidopsis mutants were isolated that were compromised in nonhost (nho) resistance to P. s. phaseolicola. Among these, nho1 is caused by a single recessive mutation that defines a novel gene. nho1 is defective in nonspecific resistance to Pseudomonas bacteria, because it also supported the growth of P. s. tabaci and P. fluorescens bacteria, both of which are nonpathogenic on Arabidopsis. In addition, the nho1 mutation also compromised resistance mediated by RPS2, RPS4, RPS5, and RPM1. Interestingly, the nho1 mutation had no effect on the growth of the virulent bacteria P. s. maculicola ES4326 and P. s. tomato DC3000, but it partially restored the in planta growth of the DC3000 hrpS(-) mutant bacteria. Thus, the virulent bacteria appear to evade or suppress NHO1-mediated resistance by means of an Hrp-dependent virulence mechanism.
Arabidopsis↗