Biomedical subjects
L Pearson
Publications and source records attributed to L Pearson.
Collaboration requires shared accountability.
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Calcium supplements and colorectal adenomas. Polyp Prevention Study Group.
Experimental and observational findings suggest that calcium intake may protect against colorectal neoplasia. To investigate this hypothesis, we conducted a randomized, double-blind trial of colorectal adenoma recurrence. Nine hundred thirty patients with a recent history of colorectal adenomas were randomly given calcium carbonate (3 gm daily; 1200 mg elemental calcium) or placebo, with follow-up colonoscopies one and four years after the qualifying examination. The main analysis focused on new adenomas found after the first follow-up endoscopy, up to (and including) the second follow-up examination. Risk ratios of at least one recurrent adenoma and ratios of the average numbers of adenomas were calculated as measures of calcium effect. There was a lower risk of recurrent adenomas in subjects assigned calcium. Eight hundred thirty-two patients had two follow-up examinations and were included in the main analysis; the adjusted risk ratio of one or more adenomas was 0.81 (95% CI 0.67 to 0.99); the adjusted ratio of the average numbers of adenomas was 0.76 (95% CI 0.60 to 0.96). Among subjects who had at least one follow-up colonoscopy, the adjusted risk ratio of one or more recurrent adenomas was 0.85 (95% CI 0.74 to 0.98). The effect of calcium seemed independent of initial dietary fat and calcium intake. No toxicity was associated with supplementation. These findings indicate that calcium supplementation has a modest protective effect against colorectal adenomas, precursors of most colorectal cancers.
Maintaining "alternative" standards.
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NP perspectives on an American tragedy.
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Stress-less: a modern fable.
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Pramlintide, a synthetic analog of human amylin, improves the metabolic profile of patients with type 2 diabetes using insulin. The Pramlintide in Type 2 Diabetes Group.
OBJECTIVE: To examine the effects of 4 weeks of subcutaneous administration of pramlintide, a synthetic analog of human amylin, on metabolic control in patients with type 2 diabetes using insulin. RESEARCH DESIGN AND METHODS: Serum fructosamine, HbA1c, and fasting plasma lipids were measured in 203 patients in a randomized double-blind placebo-controlled parallel-group multicenter trial using doses of 30 micrograms q.i.d., 60 micrograms t.i.d., and 60 micrograms q.i.d. RESULTS: Statistically significant reductions in serum fructosamine concentrations were observed in the pramlintide 30 micrograms q.i.d. group (17.5 +/- 4.9 mumol/l, P = 0.029), the pramlintide 60 micrograms t.i.d. group (24.1 +/- 4.9 mumol/l, P = 0.003), and the 60 micrograms q.i.d. group (22.6 +/- 4.1 mumol/l, P = 0.001) compared with the placebo group (3.5 +/- 3.8 mumol/l). There were also statistically significant shifts in the proportion of patients with an abnormal serum fructosamine concentration at baseline that normalized at week 4 within the pramlintide 60 micrograms t.i.d. group and the 60 micrograms q.i.d. group. Consistent with the fructosamine results, there were statistically significant reductions in HbA1c in the pramlintide 30 micrograms q.i.d. group (0.53 +/- 0.07%, P = 0.0447), the pramlintide 60 micrograms t.i.d. group (0.58 +/- 0.07%, P < 0.0217), and the pramlintide 60 micrograms q.i.d. group (0.51 +/- 0.08%, P = 0.0242) compared with the placebo group (0.27 +/- 0.08%). Total cholesterol concentrations were also statistically significantly reduced in both the pramlintide 60 micrograms t.i.d. group (8.4 mg/dl, P < 0.01) and 60 micrograms q.i.d. group (10.5 mg/dl, P < 0.01) compared with placebo (1.2 mg/dl). Body weight decreased in both of the pramlintide 60 micrograms groups, but the trend did not achieve statistical significance. The incidence of hypoglycemia was similar in all treatment groups. CONCLUSIONS: Reductions in serum fructosamine, plasma total and LDL cholesterol concentrations, and HbA1c support the hypothesis that pramlintide may improve metabolic control in patients with type 2 diabetes using insulin.
Alternative therapy: a cautionary tale.
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Effects of 4 weeks' administration of pramlintide, a human amylin analogue, on glycaemia control in patients with IDDM: effects on plasma glucose profiles and serum fructosamine concentrations.
The effects of 4 weeks' administration of pramlintide, an analogue of the human hormone amylin, on blood glucose control in 215 patients with insulin-dependent diabetes mellitus were examined in a 4-week, randomized, double-blind, placebo-controlled, parallel-group trial. Pramlintide was administered subcutaneously prior to meals in four dosing regimens: 30 microg four times per day (breakfast, lunch, dinner, and evening snack), 30 microg three times per day (breakfast, lunch and dinner [BLD]), 30 microg three times per day (breakfast, dinner and evening snack [BDS]), and 60 microg twice per day (breakfast and dinner). After 4 weeks of pramlintide 30 microg four times per day administration, there was a statistically significant reduction in the mean 24 h plasma glucose concentration when compared to placebo (-1.4 +/- 0.5 vs 0.3 +/- 0.5 micromol/l, p = 0.009). Serum fructosamine concentrations were reduced 62 +/- 10 micromol/l in the pramlintide 30 mg four times per day group, 43 +/- 7 micromol/l in the pramlintide 30 microg three times per day (BLD) group, 47 +/- 6 micromol/l in the pramlintide 30 microg three times per day (BDS) group, 46 +/- 7 micromol/l in the pramlintide 60 microg twice per day group, and 29 +/- 8 micromol/l by placebo. The incidence of hypoglycaemia was not different in any pramlintide group compared to the placebo group. Nausea, the most frequent adverse event, subsided after the first week of treatment in the majority of patients. In conclusion, pramlintide improved blood glucose control over a 4-week period without increased hypoglycaemia and was well tolerated. Future studies using a longer period of pramlintide administration with assessment of HbA1c as the measurement of glycaemic control are warranted.
Predictive assessment of vocal efficiency (PAVE). A method for voice therapy outcome measurement.
A prospective study was carried out to examine the degree to which a standard voice assessment could discriminate between the potential benefits of two different voice therapy programmes for individual patients. The study encompassed 200 dysphonia subjects who were referred for voice therapy and had completed treatment within a prescribed two-year period. A standard assessment procedure was carried out on first attendance for each patient and guidelines were used to assign patients to different treatment programmes on the basis of the assessment results. The assessment discriminated well between patients requiring voice therapy to change physiological parameters of voice usage and patients able to self adjust voice usage, and provided an objective means of measuring outcomes.
Validation of the heat treatment step used in the production of diaspirin crosslinked hemoglobin (DCLHb) for viral inactivation--effect of crosslinking.
Two experiments were performed to assess viral inactivation during the crosslinking and heat treatment steps of the DCLHb manufacturing process. Stroma free hemoglobin (SFHb) collected from a large scale manufacturing lot was tested in a 1:680 scaled down system in which the key parameters used in the manufacturing process were replicated. In the first study Porcine Parvovirus (PPV), a non-enveloped virus, was used to assess inactivation, while in the second study Bovine Viral Diarrhea Virus (BVDV), an enveloped virus, was utilized. In both experiments, the SFHb solution was deoxygenated and an aliquot of virus suspension was added. To initiate the crosslinking reaction, a solution of bis (3,5-dibromosalicyl) fumarate (DBBF) in HEPES buffer was added to the test solution. In both experiments the reaction times and the degree of crosslinking were normal. After crosslinking, the reaction mixtures were heated to 74 +/- 1 degrees C over 30 minutes, held at 74 +/- 1 degrees C for 90 minutes, and cooled to less than 10 degrees C over 30 minutes. In each experiment the degree of crosslinking of final product was 100% and yield of hemoglobin recovery was normal. Samples were removed prior to crosslinking, after crosslinking and before, during and after heat treatment for determination of virus titer and evaluation of key process parameters. The results from these experiments were consistent with those obtained from the full scale manufacturing process for the deoxygenation, crosslinking and the heat treatment step during the production of DCLHb. The results of virus assays showed that crosslinking has no effect on viruses and their subsequent inactivation by heat treatment.
Proximal promoter elements of the human zeta-globin gene confer embryonic-specific expression on a linked reporter gene in transgenic mice.
We have investigated the transcriptional regulation of the human embryonic zeta-globin gene promoter. First, we examined the effect that deletion of sequences 5' to zeta-globin's CCAAT box have on zeta-promoter activity in erythroid cell lines. Deletions of sequences between -116 and -556 (cap = 0) had little effect while further deletion to -84 reduced zeta-promoter activity by only 2-3-fold in both transiently and stably transfected erythroid cells. Constructs containing 67, 84 and 556 bp of zeta-globin 5' flanking region linked to a beta-galactosidase reporter gene (lacZ) and hypersensitive site -40 (HS-40) of the human alpha-globin gene cluster were then employed for the generation of transgenic mice. LacZ expression from all constructs, including a 67 bp zeta-globin promoter, was erythroid-specific and most active between 8.5 and 10.5 days post-fertilisation. By 16.5 days gestation, lacZ expression dropped 40-100-fold. These results suggest that embryonic-specific activation of the human zeta-globin promoter is conferred by a 67 bp zeta-promoter fragment containing only a CCAAT and TATA box.
Engineering of DNA binding proteins into site-specific cutters: reactivity of Trp repressor-1,10-phenanthroline chimeras.
Trp repressor (TrpR) can be converted into a site-specific nuclease by chemical modification of the cysteine mutants TrpR D46C or TrpR E49C with 5-iodoacetamido-1,10-phenanthroline (OP). In the presence of cupric ion and 3-mercaptopropionic acid, TrpR-regulated operators are cleaved. The properties of these semisynthetic scission reagents have been compared. The E49C construct cleaves efficiently at two sites within the operator and the D46C cleaves at multiple sites. Molecular modeling indicates that the reason for the focused reactivity of E49C is that the OP is rigidly oriented in the protein-DNA complexes whereas the OP can adopt several orientations in TrpR D46C. Mutations and reaction conditions that increase the affinity of the repressor enhance the scission efficiency which approaches 100% within the acrylamide matrix. TrpR E49C-OP smoothly cleaves the trpEDCBA operator in a plasmid in a reaction dependent on the corepressor L-tryptophan. In the absence of tryptophan, non-specific cleavage of the plasmid is observed under the same conditions. Therefore, tryptophan not only directs cleavage to a specific site but also blocks it at non-specific sites. The analysis of the cleavage pattern of the trpEDCBA operator provides strong evidence for the tandem binding model in which protein-protein interactions stabilize binding on the DNA. TrpR E49C-OP should serve as the basis for the engineering of a family of highly specific semisynthetic scission reagents.
Clustering of marine bacteria in seawater enrichments.
Seawater enrichments of marine bacteria clustered in 20- to 50-(mu)m-wide bands near air-water interfaces. The cells within the band travelled at up to 212 (mu)m s(sup-1) and at an average speed of 163 (mu)m s(sup-1). Mean cell speeds peaked mid-run at 187 (mu)m s(sup-1). At the end of the run, bacteria reversed direction rather than randomly reorienting. The duration of the stops during reversal was estimated at 18 ms, six to seven times shorter than that found in enteric bacteria. Cells hundreds of micrometers from the band travelled at half the speed of the bacteria in the band. The fastest isolate from the seawater enrichment was identified as Shewanella putrefaciens and had an average speed of 100 (mu)m s(sup-1) in culture. Air-water interfaces produced no clustering or speed changes in isolates derived from enrichments. Salinity and pH, however, both influenced speed. The speed and reversal times of the seawater enrichments indicate that the bacteria in them are better adapted for clustering around small point sources of nutrients than are either enteric or cultured marine bacteria.
Mode of action of a lysostaphin-like bacteriolytic agent produced by Streptococcus zooepidemicus 4881.
Electron microscopy of zoocin A-treated sensitive streptococcus cells revealed cytoplasmic disruption and ultimately complete rupture of the cell wall. Culture viability and optical density were shown to decrease rapidly and simultaneously in Streptococcus pyogenes FF22 but less quickly in the relatively more resistant Streptococcus mutans 10449. Zoocin A was shown to cleave hexaglycine in a colorimetric cell-free microtiter assay system, and it is concluded that the killing action of zoocin A, like that of lysostaphin, is most probably the result of direct cleavage of the peptidoglycan cross-links in the cell wall. The relationship between sensitivity to zoocin A and the peptidoglycan cross-linkage structure of Streptococcus zooepidemicus, Lactococcus spp., S. pyogenes, Streptococcus gordonii, Streptococcus oralis, S. mutans, and Streptococcus rattus has been evaluated.
Multidrug resistance-1 (MDR1) expression and functional dye/drug efflux is highly correlated with the t(8;21) chromosomal translocation in pediatric acute myeloid leukemia.
Resistance to chemotherapy is a major problem in acute myeloid leukemia (AML). An important resistance mechanism in adult AML is active drug efflux mediated by the multidrug resistance protein-1 (MDR1). To determine if MDR1 is important in childhood AML, we examined MDR1 expression and functional dye/drug efflux in 20 pediatric/adolescent AML patients; results were correlated with cytogenetics and clinical outcome. Using flow cytometry, MDR1 protein expression on the leukemic blasts was measured with the antibody MRK16, while efflux was measured by extrusion of the fluorescent dye DiO(C2)3 in the presence/absence of cyclosporin A (CsA). Six of 20 cases expressed MDR1. While all six MDR1+ cases were efflux+, three of 14 MDR1- cases also demonstrated efflux. Both MDR1 and efflux were strongly correlated with the t(8;21). All six MDR1 +/efflux+ cases and 2/3 MDR1 -/efflux+ cases had a t(8;21), while no MDR1-/efflux- cases had a t(8;21) (P < 0.0005). This correlation between MDR1, efflux, and the t(8;21) in pediatric AML was not found in 11 adult t(8;21) cases similarly studied. Although the clinical relevance of MDR1 in pediatric AML awaits larger studies, our results suggest a biologic subset of pediatric AML patients may benefit from regimens which include MDR1-reversing agents or non-MDR1 substrates.
Nucleic acid chemistry of the cuprous complexes of 1,10-phenanthroline and derivatives.
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