PlantSimLab - a modeling and simulation web tool for plant biologists.

BACKGROUND: At the molecular level, nonlinear networks of heterogeneous molecules control many biological processes, so that systems biology provides a valuable approach in this field, building on the integration of experimental biology with mathematical modeling. One of the biggest challenges to making this integration a reality is that many life scientists do not possess the mathematical expertise needed to build and manipulate mathematical models well enough to use them as tools for hypothesis generation. Available modeling software packages often assume some modeling expertise. There is a need for software tools that are easy to use and intuitive for experimentalists. RESULTS: This paper introduces PlantSimLab, a web-based application developed to allow plant biologists to construct dynamic mathematical models of molecular networks, interrogate them in a manner similar to what is done in the laboratory, and use them as a tool for biological hypothesis generation. It is designed to be used by experimentalists, without direct assistance from mathematical modelers. CONCLUSIONS: Mathematical modeling techniques are a useful tool for analyzing complex biological systems, and there is a need for accessible, efficient analysis tools within the biological community. PlantSimLab enables users to build, validate, and use intuitive qualitative dynamic computer models, with a graphical user interface that does not require mathematical modeling expertise. It makes analysis of complex models accessible to a larger community, as it is platform-independent and does not require extensive mathematical expertise.

Identification of pigment epithelium-derived factor protein forms with distinct activities on tumor cell lines.

PURPOSE: Pigment epithelium-derived factor (PEDF) is a multifunctional serpin. The purpose of this study is to identify PEDF protein forms and investigate their biological activities on tumor cell lines. METHODS: Recombinant human PEDF proteins were purified by cation- and anion-exchange column chromatography. They were subjected to SDS-PAGE, IEF, deglycosylation, heparin affinity chromatography, and limited proteolysis. Cell viability, real-time electrical impedance of cells, and wound healing assays were performed using bladder and breast cancer cell lines, rat retinal R28, and human ARPE-19 cells. RESULTS: Two PEDF protein peaks were identified after anion-exchange column chromatography: PEDF-1 eluting with lower ionic strength than PEDF-2. PEDF-1 had higher pI value and lower apparent molecular weight than PEDF-2. Both PEDF forms were glycosylated, bound to heparin, and had identical patterns by limited proteolysis. However, PEDF-2 emerged as being highly potent in lowering cell viability in all tumor cell lines tested, and in inhibiting tumor and ARPE-19 cell migration. In contrast, PEDF-1 minimally affected tumor cell viability and cell migration but protected R28 cells against death caused by serum starvation. CONCLUSION: Two distinct biochemical forms of PEDF varying in overall charge have distinct biological effects on tumor cell viability and migration. The existence of PEDF forms may explain the multifunctional modality of PEDF.

E-selectin ligands recognised by HECA452 induce drug resistance in myeloma, which is overcome by the E-selectin antagonist, GMI-1271.

Multiple myeloma (MM) is characterized by the clonal expansion and metastatic spread of malignant plasma cells to multiple sites in the bone marrow (BM). Recently, we implicated the sialyltransferase ST3Gal-6, an enzyme critical to the generation of E-selectin ligands, in MM BM homing and resistance to therapy. Since E-selectin is constitutively expressed in the BM microvasculature, we wished to establish the contribution of E-selectin ligands to MM biology. We report that functional E-selectin ligands are restricted to a minor subpopulation of MM cell lines which, upon expansion, demonstrate specific and robust interaction with recombinant E-selectin in vitro. Moreover, an increase in the mRNA levels of genes involved in the generation of E-selectin ligands was associated with inferior progression-free survival in the CoMMpass study. In vivo, E-selectin ligand-enriched cells induced a more aggressive disease and were completely insensitive to Bortezomib. Importantly, this resistance could be reverted by co-administration of GMI-1271, a specific glycomimetic antagonist of E-selectin. Finally, we report that E-selectin ligand-bearing cells are present in primary MM samples from BM and peripheral blood with a higher proportion seen in relapsed patients. This study provides a rationale for targeting E-selectin receptor/ligand interactions to overcome MM metastasis and chemoresistance.

High-normal blood pressure and early diabetic nephropathy.

The relationship between high-normal blood pressure (BP) levels and early diabetic nephropathy is currently unknown. Blood pressure levels were checked longitudinally for a mean of 6.6 years in 230 subjects to determine their relationship to early diabetic nephropathy as monitored by microalbuminuria. High-normal BP level correlated with the presence of microalbuminuria. Microalbuminuria was 2.8 times as common in subjects with high-normal BP levels compared with those subjects with BP levels below the 90th percentile for their age. The elevated microalbumin excretion was primarily associated with high-normal diastolic BP levels. Our data suggest that either microalbuminuria or high-normal BP levels can precede the other. In a logistics model, diastolic BP and mean HbA1 (over 6.6 years) entered the model at similar levels, followed by duration of diabetes. When the influence of mean HbA1 was removed using logistic regression, the diastolic BP level remained a significant associated factor for the presence of microalbuminuria.

Vitreous fluorophotometry in insulin-dependent diabetes mellitus. Correlation with microalbuminuria and diastolic blood pressure.

Vitreous fluorophotometry was performed on 240 eyes of 120 young subjects who had insulin-dependent diabetes mellitus (type I) and various grades of retinopathy. The concentration of fluorescein was measured in the anterior chamber and posterior vitreous 1 hour after intravenous injection of fluorescein. There was a significant association (P less than .001) between the grade of retinopathy and the level of posterior vitreous leakage. The amount of posterior vitreous leakage in each eye also had a significant association with borderline elevation of diastolic blood pressure. Subjects with excessive posterior vitreous leakage had significantly higher levels of urinary microalbumin excretion. In a multiple linear regression analysis for posterior vitreous leakage, retinal grade consistently entered the model at a significant level (P less than or equal to .00001 to .003). Blood pressure also entered the model for posterior vitreous leakage at a significant level for retinal grades of the right and left eyes and of the worst eye. These results demonstrate an association between leakage of retinal and renal vessels, possibly linked at least in part to elevation in diastolic blood pressure.

Retinal changes and alterations in blood pressure and albumin excretion rate (AER) during exercise in type 1 diabetes.

The association of retinal changes with exercise microalbuminuria and with changes in systolic and diastolic blood pressure (BP) were evaluated in 162 young subjects with insulin-dependent (type 1) diabetes mellitus. Higher systolic and diastolic BPs at rest or after 10 or 20 min of exercise were significantly associated with more severe retinal changes in the subjects with diabetes compared to controls (P less than 0.02; global ANOVA). The mean (+/- SEM) exercise albumin excretion rate (AER) was 17.6 +/- 3.1 if there was no evidence of retinopathy compared to 81.5 +/- 23.5 when only microaneurysms were detected and 467.1 +/- 133.3 when more severe retinopathy was present. The percentage of subjects with abnormal AERs for these three retinal groups was 13, 30 and 60, respectively. (P less than 0.0001, chi-square test). It is clear that retinal changes relate to early renal changes, as monitored by exercise AERs and changes in resting and exercise BPs. It is concluded that the renal and retinal microvascular changes occur concurrently in young subjects with type 1 diabetes.

Elevation of resting and exercise blood pressures in subjects with type I diabetes and relation to albuminuria.

The etiology of diabetic nephropathy is currently unknown, but blood pressure is believed an important risk factor. A total of 173 subjects with type I diabetes who participated in two or more exercise tests with simultaneous measurements of blood pressure (BP) and heart rate were studied. Subjects with diabetes had significantly elevated resting and exercise diastolic and systolic BPs when compared with controls. This was not related to the presence of albuminuria. During exercise, elevation of diastolic BP was present in 65 (38%) of the 173 test subjects. Elevated exercise diastolic BPs among the subjects with diabetes (excluding controls) was present only for subjects with elevated exercise and overnight albuminuria. It is concluded that factors other than early diabetic nephropathy are likely related to elevated resting and exercise BPs in subjects with diabetes compared with controls. Early renal damage, however, is related to further elevations in resting and exercise diastolic BPs within the group of subjects with diabetes.

Use of the pen delivery system for intensive insulin therapy in college-age students with type I diabetes.

The present report describes our experience with 16 adolescents and young adults with insulin-dependent diabetes mellitus (IDDM; Type I) who switched from two injections of insulin per day to the NovolinPen and four insulin injections a day. Their mean age at the initiation of therapy was 19.2 years with a duration of diabetes of 8.9 years. Sixteen random computer-matched (for age, sex, and duration of diabetes) controls who remained on two insulin injections a day were evaluated for comparison. Most subjects were preparing to leave home for college. After a minimum of 1 year of using the pen, the mean weight gain of the test subjects was significantly greater (P less than .05) than for the computer-matched controls. Glycemic control, as monitored by mean HbA1c values, were similar for the NovolinPen and the control groups (10.8 versus 10.9, respectively) after almost 2 years. The main advantage to the pen expressed by the users was a sense of freedom of lifestyle.

Renal and retinal complications in insulin-dependent diabetes mellitus: the art of changing the outcome.

Over the past decade much has been learned about the relationship between good glycemic control and the alteration or prevention of long-term renal and retinal complications of insulin-dependent diabetes mellitus. The challenge for diabetes health professionals is to translate knowledge into improved patient care. A model program, using a multidisciplinary team approach, is presented to show how the art of changing the outcome can be incorporated into each patient encounter through screening, education, and counseling.

Pulmonary edema associated with the treatment of preterm labor: what critical care nurses need to know.

Knowledge of the physiologic changes, conditions, and therapies of pregnancy that increase the risk of pulmonary edema enables nurses to influence the outcome of their patients who develop medical complications while undergoing tocolytic therapy. Cooperation between perinatal and critical care nurses ensures optimal care of both the mother and the fetus.

Validity of the MoCA and MMSE in the detection of MCI and dementia in Parkinson disease.

BACKGROUND: Due to the high prevalence of mild cognitive impairment (MCI) and dementia in Parkinson disease (PD), routine cognitive screening is important for the optimal management of patients with PD. The Montreal Cognitive Assessment (MoCA) is more sensitive than the commonly used Mini-Mental State Examination (MMSE) in detecting MCI and dementia in patients without PD, but its validity in PD has not been established. METHODS: A representative sample of 132 patients with PD at 2 movement disorders centers was administered the MoCA, MMSE, and a neuropsychological battery with operationalized criteria for deficits. MCI and PD dementia (PDD) criteria were applied by an investigator blinded to the MoCA and MMSE results. The discriminant validity of the MoCA and MMSE as screening and diagnostic instruments was ascertained. RESULTS: Approximately one third of the sample met diagnostic criteria for a cognitive disorder (12.9% PDD and 17.4% MCI). Mean (SD) MoCA and MMSE scores were 25.0 (3.8) and 28.1 (2.0). The overall discriminant validity for detection of any cognitive disorder was similar for the MoCA and the MMSE (receiver operating characteristic area under the curve [95% confidence interval]): MoCA (0.79 [0.72, 0.87]) and MMSE (0.76 [0.67, 0.85]), but as a screening instrument the MoCA (optimal cutoff point = 26/27, 64% correctly diagnosed, lack of ceiling effect) was superior to the MMSE (optimal cutoff point = 29/30, 54% correctly diagnosed, presence of ceiling effect). CONCLUSIONS: The Montreal Cognitive Assessment, but not the Mini-Mental State Examination, has adequate psychometric properties as a screening instrument for the detection of mild cognitive impairment or dementia in Parkinson disease. However, a positive screen using either instrument requires additional assessment due to suboptimal specificity at the recommended screening cutoff point.

Techniques for improving glucose control in type I diabetes.

Intervention for poor glucose control was attempted in 38 children and adolescents with a mean follow-up time of 3 years. Changing the quantity of insulin or changing the number of injections per day resulted in improvement in 10 of the 21 patients who responded to intervention. Six others responded to a family conference and four responded to a parent temporarily taking over the diabetes management. The presence of a supportive family member living in the home was a major factor in the likelihood of intervention being successful.

Glycemic control and longitudinal testing for exercise microalbuminuria in subjects with type I diabetes.

There is a need for better and earlier markers of clinical renal damage in subjects with Type I diabetes. In this prospective study, exercise albumin excretion rates (AERs) were studied longitudinally for a 4-year period in 187 young subjects with Type I diabetes. For this time period, 54% of subjects continued to have normal overnight and exercise AERs, 11% had continuously elevated exercise and overnight AERs, 11% developed an elevated exercise AER with the overnight AER remaining normal, and 12% had a normal overnight AER throughout the study, with initially elevated exercise levels later decreasing to normal. This improvement in exercise AER was associated with improved glycosylated hemoglobin (HbA1) values for 64% of the subjects (p = 0.0004, paired t test). Five percent of subjects, who initially had only an elevated exercise AER, developed a consistently elevated overnight AER. Seven of these nine subjects showed either worsening (greater than 10%) or no improvement in their HbA1 values from the initial to the final study periods. Five percent of subjects continued to have an elevated exercise and normal overnight AER throughout the study. These results show that the elevated exercise AER represents a definite transitional stage between a normal and an abnormal (greater than 30 micrograms/min) overnight AER. In addition, a "window" exists during which an elevated exercise AER may be reversed by improved glucose control, but if this improvement does not occur, progression to an increased overnight AER is likely to result.

Angiotensin-converting enzyme inhibitor treatment for young normotensive diabetic subjects: a two-year trial.

Microangiopathy characterizes both diabetic retinopathy and nephropathy. It is currently unclear which diabetic subjects should be treated with angiotensin-converting enzyme (ACE) inhibitors. A double-blind, placebo-controlled protocol was implemented using captopril to treat subjects with Type I diabetes, early diabetic nephropathy (albumin excretion rates, 20-200 micrograms/min), and normal blood pressures. After two years, the final eye grades were improved in two treated subjects but not in any of the controls. Three control and one treated subject showed worsening of their eye grade after two years (P < .001, by chi-square test). Significant differences in renal albumin excretion were not seen between the two groups. The distribution of changes in retinal grades in the treatment group compared with the placebo group was improved after two years. Studies of larger numbers of patients will be necessary to determine if ACE inhibitors should be used routinely in subjects with diabetic retinopathy and to determine which subjects are most likely to respond.

The effect of sugar cereal with and without a mixed meal on glycemic response in children with diabetes.

The effect of sucrose consumption on glycemic control in children with insulin-dependent diabetes mellitus is unclear. Eight young subjects, 7-16 years of age, with a duration of diabetes of 2-8 years participated in this study. All subjects consumed four different breakfasts--oatmeal (OM) alone, oatmeal-sucrose (OMS), oatmeal-protein (OMP), and oatmeal with protein and sucrose (OMPS)--on four different days. Addition of sucrose resulted in a slightly greater area under the tolerance curve in 50% of the subjects; however, in 38% of subjects, the area decreased. The peak glucose level was lowest for OM, but there was no statistical difference in the peak levels of the four test meals. The most significant effect on glucose response was a delay in the peak time when protein was added to the meals. Peak times for OM and OMS (mean of 38 min) when fed alone were significantly (p less than 0.05, ANOVA) shorter when compared to the peak time for OMP and OMPS (mean of 54 min). The average recovery time for OMP was longest. Other indices (tolerance index and change of rise in blood glucose) measured were not significantly different among the test meals. This study demonstrates that adding limited sucrose to OM cereal has little effect on the blood glucose response in children with diabetes. Addition of protein and fat clearly delays the glycemic response.

Limited joint mobility in subjects with insulin dependent diabetes mellitus: relationship with eye and kidney complications.

Three hundred and fifty seven subjects (178 males and 179 females) with insulin dependent diabetes mellitus were evaluated for the presence of limited joint mobility of the interphalangeal joints. Sixty six subjects (19%) had stage 1 and 26 subjects (7%) had stage 2 involvement of their interphalangeal joints. The presence of contractures was significantly related to mean longitudinal glycated haemoglobin (HbA1) concentrations, duration of diabetes, age of onset, mean longitudinal cholesterol concentrations and blood pressure. Limited joint mobility was also significantly associated with early diabetic retinopathy and raised albumin excretion rates. Limited joint mobility remained a significant factor in the logistic regression model for albuminuria and grade of retinopathy when controlled for smoking, cholesterol concentrations, duration of diabetes, age, gender, and blood pressure. However, limited joint mobility was only significantly associated with diabetic retinopathy when the effect of HbA1 concentrations was included in the multivariate model.

Diagnosis of pre-type I diabetes.

Islet cell antibodies were found in 71 of 1169 first-degree relatives (6.1%) from 448 families who had a proband with type I diabetes. Seven children have since become insulin dependent. All had islet cell antibodies and were followed up prospectively with measurement of first-phase insulin production during intravenous glucose tolerance testing. In this group the statistical probability of developing type I diabetes within 12 months with 95% confidence was found to be 59% to 100% when the first-phase insulin secretion was less than 25 microU/mL. The identification of the prediabetes time period should allow an opportunity for intervention in the underlying disease process to determine if the onset of type I diabetes can be altered.

A trial of nicotinamide in newly diagnosed patients with type 1 (insulin-dependent) diabetes mellitus.

Various agents have been tried in subjects with newly diagnosed Type 1 (insulin-dependent) diabetes mellitus in an attempt to preserve Beta-cell function. In this double-blind study, nicotinamide or placebo were given for one year to 35 children and adolescents with newly-diagnosed Type 1 diabetes. All subjects were within six weeks of diagnosis and were between the ages of 6 and 18 years. Nicotinamide, a poly-(ADP-ribose) synthetase inhibitor, was given in a dose of 100 mg/year of age up to a maximum of 1.5 g/day. There were no initial differences between the 17 control and the 18 test subjects in relation to mean age, sex distribution, or severity at onset. Mean insulin dosages and HbA1 values were similar for the two groups during the year of study. Fasting and glucagon-stimulated C-peptide levels were similar for the control and nicotinamide treated groups at the beginning and after 4 and 12 months. There were no differences in remission rates between the two groups. Nicotinamide, at this dosage, does not preserve residual insulin secretion in subjects with newly diagnosed Type 1 diabetes.

Glucose control and the renal and retinal complications of insulin-dependent diabetes.

Two hundred thirty subjects with insulin-dependent diabetes were followed up longitudinally by measuring glycohemoglobin values to relate glucose control with renal and retinal complications. Subjects with long-term poor control (glycohemoglobin values greater than 1.5 times the upper limit of normal) had 3.6 times the prevalence of microalbuminuria and 2.5 times the prevalence of level 3 to 6 retinopathy than that found in subjects with long-term good control (glycohemoglobin values within 1.33 times the upper limit of normal). Variables related to kidney damage were glucose control and, to a lesser degree, duration of diabetes. Variables related to eye disease were, in descending order of significance, duration of diabetes, glucose control, and age. No subject whose mean glycohemoglobin value was consistently within 1.1 times the upper limit of normal had retinopathy or microalbuminuria. In contrast, when the mean glycohemoglobin value was more than 1.5 times the upper limit of normal, 24 (29%) of 82 subjects had microalbuminuria and 30 (37%) of 82 had level 3 to 6 retinopathy.

Oral contraceptives and renal and retinal complications in young women with insulin-dependent diabetes mellitus.

OBJECTIVE: To evaluate the effects of oral contraceptives (OCs) as a possible risk factor for early diabetic renal and/or retinal complications. DESIGN: A retrospective case-control study. SETTING: A university hospital diabetes clinic. PARTICIPANTS: Forty-three diabetic women who used OCs for 1 year or longer (mean, 3.4 years; range, 1.0 to 7.0 years) were compared with a computer-matched control group of 43 diabetic women who never used OCs. MAIN OUTCOME MEASURES: Hemoglobin A1c levels, albumin excretion rates, and mean retinopathy scores. RESULTS: The mean +/- SEM age and duration of diabetes were 22.7 +/- 0.5 years (range, 17.1 to 30.5 years) and 13.8 +/- 0.8 years, respectively, for the study group. The mean longitudinal hemoglobin A1c values were similar for study subjects and control subjects. The final mean albumin excretion rates, reflecting diabetic renal damage, and the mean eye grades were not significantly different between the groups. CONCLUSIONS: The use of OCs among young women with insulin-dependent diabetes mellitus does not pose an additional risk for the development of early diabetic retinopathy and/or nephropathy.