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Biomedical subjects

J A Shapiro

Publications and source records attributed to J A Shapiro.

At least 37 records · Page 2Linked to original sources
PubMed1996

Diet and rheumatoid arthritis in women: a possible protective effect of fish consumption.

Some researchers have hypothesized that omega-3 fatty acids, found primarily in fish oils, may protect against the development of rheumatoid arthritis. We conducted a population-based case-control study in women, comparing 324 incident rheumatoid arthritis cases with 1,245 controls. We used a food frequency questionnaire to ascertain diet during a 1-year period 5 years before a reference date (first physician visit for joint-symptoms). Consumption of broiled or baked fish, but not of other types of fish, was associated with a decreased risk of rheumatoid arthritis. The adjusted odds ratios (OR) for 1- < 2 servings and > or = 2 servings of broiled or baked fish per week, compared with < 1 serving, were 0.78 [95% confidence interval (CI) = 0.53-1.14] and 0.57 (95% CI = 0.35-0.93). Other analyses showed associations with protein as a percentage of calories (adjusted OR for the top quartile as compared with the bottom quartile = 0.65; 95% CI = 0.46-0.94) and total calories (adjusted OR for the top quartile = 1.62; 95% CI = 1.15-2.28). The associations with broiled or baked fish, protein, and calories became stronger when we restricted our analysis to cases positive for rheumatoid factor. These results support the hypothesis that omega-3 fatty acids may help prevent rheumatoid arthritis.

Adolescent↗
PubMed1996

Periodic phenomena in Proteus mirabilis swarm colony development.

Proteus mirabilis colonies exhibit striking geometric regularity. Basic microbiological methods and imaging techniques were used to measure periodic macroscopic events in swarm colony morphogenesis. We distinguished three initial phases (lag phase, first swarming phase, and first consolidation phase) followed by repeating cycles of subsequent swarming plus consolidation phases. Each Proteus swarm colony terrace corresponds to one swarming-plus-consolidation cycle. The duration of the lag phase was dependent upon inoculation density in a way that indicated the operation of both cooperative and inhibitory multicellular effects. On our standard medium, the second and subsequent swarm phases displayed structure in the form of internal waves visible with reflected and dark-field illumination. These internal waves resulted from organization of the migrating bacteria into successively thicker cohorts of swarmer cells. Bacterial growth and motility were independently modified by altering the composition of the growth medium. By varying the glucose concentration in the substrate, it was possible to alter biomass production without greatly affecting the kinetics of colony surface area expansion. By varying the agar concentration in the substrate, initial bacterial biomass production was unaffected but colony expansion dynamics were significantly altered. Higher agar concentrations led to slower, shorter swarm phases and longer consolidation phases. Thus, colony growth was restricted by higher agar concentrations but the overall timing of the swarming-plus-consolidation cycles remained constant. None of a variety of factors which had significant effects on colony expansion altered terracing frequencies at 32 degrees C, but the length of the swarming-plus-consolidation cycle was affected by temperature and medium enrichment. Some clinical isolates displayed significant differences in terracing frequencies at 32 degrees C. Our results defined a number of readily quantifiable parameters in swarm colony development. The data showed no connection between nutrient (glucose) depletion and the onset of different phases in swarm colony morphogenesis. Several observations point to the operation of density-dependent thresholds in controlling the transitions between distinct phases.

Agar↗
PubMed1996

Nasopharyngeal cancer in a low-risk population: defining risk factors by histological type.

Nasopharyngeal cancer (NPC) is a major public health problem in parts of Southeast Asia and North Africa, but is rare among whites and blacks. Although infection with the EBV and genetic susceptibility appear to play large roles in high-incidence populations, migrant studies suggest that environmental factors may also be important. Aside from the high risks associated with ingestion of salted fish, surprisingly few other risk factors have been established from studies in endemic areas. We studied a low-incidence population to determine whether tobacco use, alcohol consumption, and certain medical conditions and treatments are related to NPC and to examine variations in risk by histology. We reasoned that new relationships might be best identified in the absence of strong causal pathways, such as intake of preserved foods and genetic susceptibility. A population-based case-control study was conducted from 1987 to 1993 at five cancer registries in the United States: western Washington, metropolitan Detroit, Connecticut, Iowa, and Utah. Controls were identified by random digit dialing and frequency matched to the gender and age distribution of cases at each registry. Telephone interviews were completed by 231 cases and 246 controls. We observed a strong dose-response relationship between cigarette smoking and risk of differentiated squamous cell carcinoma (test for trend, P < .001). The highest risk [odds ratio (OR), 6.5; 95% confidence interval (CI), 2.0-21.3] occurred among current smokers with a history of more than 60 pack-years. In contrast, there was no evidence that undifferentiated or nonkeratinizing carcinomas were associated with cigarette smoking. Similarly, a significant increase in risk was observed for the heaviest alcohol consumers (21 or more drinks/week) only for differentiated squamous cell carcinomas (OR, 2.9; 95% CI, 1.2-6.9). The associations with cigarettes and alcohol appeared to be stronger among persons 50 years or older. There was a suggestion that diagnosis with infectious mononucleosis (a marker of late infection with EBV) is linked with decreased NPC risk (OR, 0.4; 95% CI, 0.1-1.1). This report indicates that over two-thirds of differentiated squamous cell NPC cases arising in older persons in the United States can be accounted for by cigarettes and alcohol, but leaves unexplained cases arising in the young and carcinomas of undifferentiated or nonkeratinizing histology. Future studies of NPC need to take into account histology and age in evaluating these and other environmental and genetic risk factors.

Adult↗
PubMed1995

The significances of bacterial colony patterns.

Bacteria do many things as organized populations. We have recently learned much about the molecular basis of intercellular communication among prokaryotes. Colonies display bacterial capacities for multicellular coordination which can be useful in nature where bacteria predominantly grow as films, chains, mats and colonies. E. coli colonies are organized into differentiated non-clonal populations and undergo complex morphogenesis. Multicellularity regulates many aspects of bacterial physiology, including DNA rearrangement systems. In some bacterial species, colony development involves swarming (active migration of cell groups). Swarm colony development displays precise geometrical controls and periodic phenomena. Motile E. coli cells in semi-solid media form organized patterns due to chemotactic autoaggregation. On poor media, B. subtilis forms branched colonies using group motility and long-range chemical signalling. The significances of bacterial colony patterns thus reside in a deeper understanding of prokaryotic biology and evolution and in experimental systems for studying self-organization and morphogenesis.

Bacteria↗
PubMed1995

Multicenter, placebo-controlled trial comparing acarbose (BAY g 5421) with placebo, tolbutamide, and tolbutamide-plus-acarbose in non-insulin-dependent diabetes mellitus.

BACKGROUND: Acarbose delays release of glucose from complex carbohydrates and disaccharides by inhibiting intestinal alpha-glucosidases, thereby attenuating postprandial increments in blood glucose and insulin. This multicenter, double-blind, placebo-controlled study compared the efficacy and safety of diet alone, acarbose, tolbutamide, and acarbose-plus-tolbutamide in non-insulin-dependent diabetes mellitus (NIDDM) patients. PATIENTS AND METHODS: A total of 290 patients with NIDDM and fasting plasma glucose levels of at least 140 mg/dL were randomized to receive treatment TID with acarbose 200 mg, tolbutamide 250 to 1,000 mg, a combination of both drugs, or placebo. A 6-week run-in period was followed by double-blind treatment for 24 weeks, then a 6-week follow-up period. RESULTS: All active treatments were superior (P < 0.05) to placebo in reducing postprandial hyperglycemia and HbA1c levels. The ranking in order of efficacy was: acarbose-plus-tolbutamide, tolbutamide, acarbose, and placebo. The postprandial reductions in glucose were approximately 85 mg/dL for acarbose-plus-tolbutamide, 71 mg/dL for tolbutamide, 56 mg/dL for acarbose, and 13 mg/dL for placebo. Tolbutamide was associated with increases in body weight and postprandial insulin levels when taken alone, but these were ameliorated when tolbutamide was taken in combination with acarbose. Acarbose alone or in combination with tolbutamide caused significantly more gastrointestinal adverse events (mainly flatulence and soft stools or diarrhea) than tolbutamide or placebo, but these were generally well tolerated. Clinically significant elevations in hepatic transaminase levels occurred in 3 patients in the acarbose group and 2 in the acarbose-plus-tolbutamide group. Transaminase levels returned to normal when therapy was discontinued. CONCLUSIONS: Acarbose was effective and well tolerated in the treatment of NIDDM. Control of glycemia was significantly better with acarbose compared with diet alone. Acarbose-plus-tolbutamide was superior to tolbutamide alone.

Acarbose↗
PubMed1995

Reduction of glycosylated hemoglobin and postprandial hyperglycemia by acarbose in patients with NIDDM. A placebo-controlled dose-comparison study.

OBJECTIVE: To compare the safety and efficacy of three doses of acarbose (100, 200, and 300 mg three times daily) with placebo for the treatment of non-insulin-dependent diabetes mellitus (NIDDM) in patients maintained on dietary therapy alone. RESEARCH DESIGN AND METHODS: This multicenter double-blind placebo-controlled trial was 22 weeks in duration. The trial consisted of a 2-week screening period, a 4-week placebo run-in period, and a 16-week double-blind treatment period. The primary measure of drug efficacy was the mean change from baseline in HbA1c levels. Additional efficacy variables included the mean change from baseline in fasting and postprandial plasma glucose and serum insulin levels. RESULTS: After 16 weeks of treatment, acarbose-treated patients had statistically significant reductions in mean HbA1c levels of 0.78, 0.73, and 1.10% (relative to placebo) in the 100-, 200-, and 300-mg t.i.d. groups, respectively. Significant reductions in fasting and postprandial plasma glucose levels, glucose area under the time-concentration curve, and maximum glucose concentration were also observed in acarbose-treated patients. Although there were no statistically significant differences among the 100-, 200-, and 300-mg treatment groups, there was a trend toward a dose-response relationship for most plasma glucose variables that were measured. Gastrointestinal side effects (e.g., abdominal pain, flatulence, and diarrhea) and serum transaminase elevations (e.g., aspartate aminotransferase [AST] and alanine aminotransferase [ALT] were more frequently reported in the acarbose-treated patients than in the placebo-treated control patients. Transaminase elevations occurred only at the 200-, and 300-mg dosages and were readily reversible on discontinuation of treatment. CONCLUSIONS: Acarbose at doses of 100, 200, and 300 mg administered three times daily for 16 weeks significantly reduced HbA1c levels and postprandial hyperglycemia. Treatment with acarbose is a safe and effective adjunct to dietary therapy for the treatment of NIDDM.

Acarbose↗
PubMed1995

A double-blind placebo-controlled trial evaluating the safety and efficacy of acarbose for the treatment of patients with insulin-requiring type II diabetes.

OBJECTIVE: To determine whether a forced titration of acarbose (from 50 to 300 mg three times daily) administered over a 24-week period, in conjunction with diet and insulin therapy, improves glycemic control and reduces daily insulin requirements in insulin-requiring type II diabetes. RESEARCH DESIGN AND METHODS: This multicenter, randomized, double-blind, placebo-controlled trial was 36 weeks in duration. The trial consisted of a 6-week pretreatment period, a 24-week double-blind treatment period, and a 6-week post-treatment follow-up period. The primary efficacy variables were the mean change from baseline in HbA1c levels and the mean percentage change from baseline in total daily insulin dose. RESULTS: Treatment with acarbose was associated with significant reductions in HbA1c levels of 0.40% (P = 0.0001) and in total daily insulin dose of 8.3% (P = 0.0015). There were also significant reductions in all plasma glucose variables measured, including a 0.9 mmol/l reduction in fasting glucose (P = 0.0440), a 2.6 mmol/l reduction in glucose Cmax (P = 0.0001) and a 270 mmol.min-1.l-1 reduction in glucose area under the curve (P = 0.0002). Although acarbose treatment was associated with a greater incidence of adverse events than was placebo treatment, primarily flatulence and diarrhea, these events did not generally prevent patients from completing the study. CONCLUSIONS: The results of this study suggest that acarbose is a safe and effective adjunct to diet and insulin therapy for the management of insulin-requiring type II diabetes.

Acarbose↗
PubMed1994

Long-term efficacy and safety of acarbose in the treatment of obese subjects with non-insulin-dependent diabetes mellitus.

BACKGROUND: Acarbose delays the release of glucose from complex carbohydrates and disaccharides by inhibiting intestinal alpha-glucosidases, attenuating postprandial increments in blood glucose and insulin. This multicenter double-blind study compared the efficacy and safety of acarbose with placebo in the treatment of obese subjects with non-insulin-dependent diabetes mellitus (NIDDM) managed by diet. METHODS: Two hundred twelve obese subjects with NIDDM who had not received any diabetic medication for at least 12 weeks were randomized to receive acarbose or placebo. The subjects were stratified by fasting glucose level above or below 11.1 mmol/L (200 mg/dL). Based on the subject's therapeutic response and tolerance, the acarbose dosage was titrated from 50 to 300 mg three times per day. This 36-week study consisted of a 6-week pretreatment period, a 24-week double-blind treatment period, and a 6-week posttreatment period. RESULTS: Ninety-one subjects given acarbose and 98 subjects who received placebo were evaluable for efficacy. During a standard meal tolerance test at the double-blind end point, the differences between treatment groups in mean change from baseline were as follows: 0.9 mmol/L (16 mg/dL) for fasting plasma glucose level, approximately 2.8 mmol/L (50 mg/dL) for postprandial plasma glucose level, and 0.59% (P < .0001) for hemoglobin A1c concentration (for all three measurements, values decreased in the acarbose group and increased in the placebo group). CONCLUSIONS: Acarbose improved both fasting and postprandial hyperglycemia and improved overall glycemic control as measured by the hemoglobin A1c level. These findings suggest a beneficial role for acarbose in combination with diet in the treatment of obese subjects with NIDDM.

Acarbose↗
PubMed1994

The roles of starvation and selective substrates in the emergence of araB-lacZ fusion clones.

The araB-lacZ fusion system has been a key case in the 'directed mutation' controversy. Fusions did not occur detectably during normal growth but formed readily after prolonged incubation on selective Ara-Lac medium. To distinguish the roles of starvation stress and selective substrates in coding sequence fusions, we applied sib selection and PCR technologies. Sib selection of the prefusion strain, MCS2, starved under aerobic conditions permitted us to isolate active fusion clones which had never been in contact with arabinose or lactose. Hence, a directive role for selective substrates is not essential. Aerobiosis was necessary for fusions to appear in glucose-starved cultures. The difference in fusion formation between normal and starved conditions is best explained by the response of a signal transduction network to physiological stimuli to activate Mu prophage joining of araB and lacZ sequences. PCR analysis revealed that direct plating on selective Ara-Lac agar yielded mostly a single class of 'standard' fusions, while sib selection yielded a broader spectrum of fusion structures. Standard fusions were found to occur within a narrow 9 bp window in lacZ. The high frequency of standard fusions in glucose-starved cultures suggested efficient and/or specific Mu action.

Base Sequence↗
PubMed1994

Adaptive mutation.

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Adaptation, Physiological↗
PubMed1994

Islet cell antigen 512 is a diabetes-specific islet autoantigen related to protein tyrosine phosphatases.

Islet cell Ag 512 (ICA512) is a recombinant human Ag that was isolated from an islet cDNA expression library by screening with human insulin-dependent diabetes mellitus sera. Specificity of reaction with diabetic sera was demonstrated initially by immunoprecipitation with a small number of diabetic and normal serum samples. To permit quantitative and rapid serum testing, ICA512 was purified and adapted to an ELISA format. In this way, a sensitivity of 48% with newly diagnosed diabetic sera has been measured with a panel of 80 sera. DNA sequencing of ICA512-3, a cDNA that contains a 1644 bp open reading frame, suggests that it codes for a transmembrane protein having a single membrane-spanning segment and a cytoplasmic domain that is closely related to the first intracellular (catalytic) domain of the T cell protein tyrosine phosphatase, CD45. Northern blot analysis of poly(A)+ RNAs from several human tissues indicates that ICA512 mRNA is expressed in brain and pancreas.

Amino Acid Sequence↗
PubMed1993

Natural genetic engineering of the bacterial genome.

The term 'natural genetic engineering' means viewing genetic change as a coordinated cell biological process, the reorganization of discrete genomic modules, resulting in the formation of new DNA structures. Examples of natural genetic engineering continue to accumulate, and the concept can be used to integrate observations which demonstrate the similarity between in vitro genetic engineering and the action of in vivo agents of genetic change.

DNA, Bacterial↗
PubMed1993

A role for the Clp protease in activating Mu-mediated DNA rearrangements.

Bacteriophage Mu, one of the best-characterized mobile genetic elements, can be used effectively to answer fundamental questions about the regulation of biochemical machinery for DNA rearrangement. Previous studies of Mu virulence have implicated the Clp protease in repressor inactivation (V. Geuskens, A. Mhammedi-Alaoui, L. Desmet, and A. Toussaint, EMBO J. 13:5121-5127, 1992). These studies were extended by analyzing the phenotypic consequences of clp alleles in two Escherichia coli systems: (i) the periodic replication of Mudlac transposons in colonies and (ii) the action of a Mu prophage in forming araB-lacZ coding sequence fusions. The clpP::CM mutation, which removes the proteolytic subunit of Clp protease, caused a drastic reduction in Mu activity in both systems. The clpA::Tn10 mutation, which removes a regulatory subunit of Clp protease, altered the timing of Mu activity in both systems. A clpA deletion reduced the extent of Mudlac replication in colonies. These results point to temporal changes in Clp proteolysis of the Mucts62 repressor as a key molecular event in the regulation of one class of genomic change in E. coli.

ATP-Dependent Proteases↗
PubMed1992

Natural genetic engineering in evolution.

The results of molecular genetics have frequently been difficult to explain by conventional evolutionary theory. New findings about the genetic conservation of protein structure and function across very broad taxonomic boundaries, the mosaic structure of genomes and genetic loci, and the molecular mechanisms of genetic change all point to a view of evolution as involving the rearrangement of basic genetic motifs. A more detailed examination of how living cells restructure their genomes reveals a wide variety of sophisticated biochemical systems responsive to elaborate regulatory networks. In some cases, we know that cells are able to accomplish extensive genome reorganization within one or a few cell generations. The emergence of bacterial antibiotic resistance is a contemporary example of evolutionary change; molecular analysis of this phenomenon has shown that it occurs by the addition rearrangement of resistance determinants and genetic mobility systems rather than by gradual modification of pre-existing cellular genomes. In addition, bacteria and other organisms have intricate repair systems to prevent genetic change by sporadic physicochemical damage or errors of the replication machinery. In their ensemble, these results show that living cells have (and use) the biochemical apparatus to evolve by a genetic engineering process. Future research will reveal how well the regulatory systems integrate genomic change into basic life processes during evolution.

Animals↗
PubMed1992

Differential action and differential expression of DNA polymerase I during Escherichia coli colony development.

A mini-Tn10 insertion in the polA cistron (polA2099) was isolated in a search for mutations that affect patterned Mudlac replication in colonies. The polA2099 mutation had a dramatic effect on cell morphogenesis during the first few hours of microcolony development. Abnormal microcolonies containing filamentous cells were produced as a result of SOS induction. Despite gross abnormalities in early microcolonies, mature polA2099 colonies after 2 to 4 days were morphologically indistinguishable from Pol+ colonies, and 44-h polA2099 colonies displayed a cell size distribution very similar to that of Pol+ colonies. These results suggested the involvement of a protective factor produced during colony growth that compensated for the polA deficiency. The action of a diffusible substance that stimulates growth of polA2099 microcolonies was shown by spotting dilute polA2099 cultures next to established colonies. Differential transcription of polA during colony development was visualized by growing colonies containing polA-lacZ fusions on beta-galactosidase indicator agar. When polA-lacZ colonies were inoculated next to established colonies, a diffusible factor was seen to inhibit polA transcription during the earliest stages of colony development. These results show that a basic housekeeping function, DNA polymerase I, is subject to multicellular control by the changing conditions which the bacteria create as they proliferate on agar.

Bacteriophage lambda↗
PubMed1992

Cloning and expression of IDDM-specific human autoantigens.

A DNA cloning approach was taken to identify islet cell protein antigens that are recognized specifically by insulin-dependent diabetes mellitus (IDDM) sera. A human islet cDNA library was generated and screened with diabetic sera. In this article, identification of two clones is described. Proteins expressed by these lambda phages appeared to react specifically with newly diagnosed diabetic sera. Islet cell antibody 12 (ICA12) was tested by Western blotting. ICA512 was not reactive with sera in the Western format but was specifically immunoprecipitated by diabetic sera from an Escherichia coli extract.

Autoantigens↗