Biomedical subjects

S Manley

Publications and source records attributed to S Manley.

At least 19 recordsLinked to original sources

PubMed2005

Glasslike arrest in spinodal decomposition as a route to colloidal gelation.

Colloid-polymer mixtures can undergo spinodal decomposition into colloid-rich and colloid-poor regions. Gelation results when interconnected colloid-rich regions solidify. We show that this occurs when these regions undergo a glass transition, leading to dynamic arrest of the spinodal decomposition. The characteristic length scale of the gel decreases with increasing quench depth, and the nonergodicity parameter exhibits a pronounced dependence on scattering vector. Mode coupling theory gives a good description of the dynamics, provided we use the full static structure as input.

Colloids↗

PubMed2005

Time-dependent strength of colloidal gels.

Colloidal silica gels are shown to stiffen with time, as demonstrated by both dynamic light scattering and bulk rheological measurements. Their elastic moduli increase as a power law with time, independent of particle volume fraction; however, static light scattering indicates that there are no large-scale structural changes. We propose that increases in local elasticity arising from bonding between neighboring colloidal particles can account for the strengthening of the network, while preserving network structure.

Journal Article↗

PubMed2005

Gravitational collapse of colloidal gels.

We present a unified framework for understanding the compaction of colloidal gels under their own weight. The dynamics of the collapse are determined by the value of the gravitational stress sigma(g), as compared to the yield stress sigma(Y) of the network. For sigma(g) sigma(Y), the network eventually yields, leading to rapid settling. In both cases, the rate of collapse is backflow limited, while its overall magnitude is determined by a balance between gravitational stress and network elastic stress.

Biophysics↗

PubMed2004

Limits to gelation in colloidal aggregation.

We show that the dynamics of large fractal colloid aggregates are well described by a combination of translational and rotational diffusion and internal elastic fluctuations, allowing both the aggregate size and internal elasticity to be determined by dynamic light scattering. The comparison of results obtained in microgravity and on Earth demonstrates that cluster growth is limited by gravity-induced restructuring. In the absence of gravity, thermal fluctuations ultimately inhibit fractal growth and set the fundamental limitation to the lowest volume fraction which will gel.

Colloids↗

PubMed2004

Introduction of IFCC reference method for calibration of HbA: implications for clinical care.

Abstract HbA(1c) is recommended for monitoring glycaemic control and quantifying the risk of complications in patients with diabetes. National guidelines for treatment of patients with diabetes in UK specify that HbA(1c) measurements should be Diabetes Control and Complications Trial (DCCT)-aligned i.e. comparable to the DCCT and UK Prospective Diabetes Study (UKPDS). The IFCC reference method for HbA(1c) will be introduced in Europe in December 2003 for calibration of all laboratory and POCT (point of care testing) methods for HbA(1c) following the recent EC "In Vitro Diagnostic" (IVD) directive. This reference method involves measurement of HbA(1c) and HbA(0) by electron-spray ionisation-mass spectrometry or capillary electrophoresis with the reference range approximately 2% HbA(1c) lower than the corresponding range from the DCCT. However, this EC IVD directive will not change reporting of DCCT-aligned HbA(1c) in the UK. Professionals involved in the care of patients with diabetes in the UK met with Dr Sue Roberts in London in July 2003. It was decided that in the UK DCCT-aligned HbA(1c) will continue to be reported from December 2003 for patient care and that laboratories currently reporting non-aligned DCCT HbA(1c) should change to reporting DCCT-aligned results as soon as possible. It was considered important for diabetes care in the UK that the reporting of HbA(1c) should not fragment. The UK HbA(1c) Standardization Committee was set up to hold "a watching brief " on HbA(1c) especially with relation to reporting of HbA(1c) in other countries.

Biomarkers↗

PubMed2003

Universal non-diffusive slow dynamics in aging soft matter.

We use conventional and multispeckle dynamic light scattering to investigate the dynamics of a wide variety of jammed soft materials, including colloidal gels, concentrated emulsions, and concentrated surfactant phases. For all systems, the dynamic structure factor f(q,t) exhibits a two-step decay. The initial decay is due to the thermally activated diffusive motion of the scatterers, as indicated by the q(-2) dependence of the characteristic relaxation time, where q is the scattering vector. However, due to the constrained motion of the scatterers in jammed systems. the dynamics are arrested and the initial decay terminates in a plateau. Surprisingly, we find that a final, ultraslow decay leads to the complete relaxation of f(q,t), indicative of rearrangements on length scales as large as several microns or tens of microns. Remarkably, for all systems the same very peculiar form is found for the final relaxation of the dynamic structure factor: f(q,t) approximately exp[-(t/tau s)p], with p approximately equal to 1.5 and tau s approximately q(-1), thus suggesting the generality of this behavior. Additionally, for all samples the final relaxation slows down with age. although the aging behavior is found to be sample dependent. We propose that the unusual ultraslow dynamics are due to the relaxation of internal stresses, built into the sample at the jamming transition, and present simple scaling arguments that support this hypothesis.

Algorithms↗

PubMed2002

Nonuniversal velocity fluctuations of sedimenting particles.

Velocity fluctuations in sedimentation are studied to investigate the origin of a hypothesized universal scale [P. N. Segre, E. Herbolzheimer, and P. M. Chaikin, Phys. Rev. Lett. 79, 2574 (1997)]. Our experiments show that fluctuations decay continuously in time for sufficiently thick cells, never reaching steady state. Simulations and scaling arguments suggest that the decay arises from increasing vertical stratification of particle concentration due to spreading of the sediment front. The results suggest that the velocity fluctuations in sedimentation depend sensitively on cell geometry.

Journal Article↗

PubMed2001

Relational database structure to manage high-density tissue microarray data and images for pathology studies focusing on clinical outcome: the prostate specialized program of research excellence model.

With the completion of the Human Genome Project and high-throughput screening methods using cDNA array and tissue microarray (TMA) technology, there is a pressing need to manage the voluminous data sets generated from these types of investigations. Herein is described a database model to handle 1) clinical and pathology data, 2) TMA location information, and 3) web-based histology results. The model is useful for managing clinical, pathology, and molecular data on >1300 prostate cancer patients dating back to 1995 from the University of Michigan Specialized Program of Research Excellence for prostate cancer. The key components in this multidatabase model are 1) the TMA database, 2) the TMA-image database (TMA-I DB), and 3) the prostate pathology and clinical information databases. All databases were created in Microsoft Access (Microsoft, Redmond, WA). Desired patient, tissue, block, diagnosis, array location, and respective clinical and pathology information is obtained by linking the unique identifier fields among database tables. The TMA database is comprised of interrelated data from 336 prostate cancer patients transferred into 19 TMA blocks with 5451 TMA biopsy cores. Tissue samples include 1695 normal prostate, 3171 prostate cancer, 464 prostatic intraepithelial neoplasia, and 121 atrophy. All 19 TMA blocks have been analyzed over the Internet for several immunohistochemical biomarkers including E-cadherin, prostate-specific antigen, p27(Kip1), and Ki-67 labeling index. This system facilitates the statistical analysis of high-density TMA data with clinical and pathology information in an efficient and cost-effective manner. Because the review is performed over the Internet, this system is ideal for collaborative multi-institutional studies.

Databases as Topic↗

PubMed2001

Analysis of three-dimensional ultrasound Doppler for the detection of prostate cancer.

OBJECTIVES: To investigate the relative effectiveness of Doppler ultrasound quantitative measures in discriminating prostate cancer from normal prostate tissue. The true locations of prostate cancer within these prostates were determined by histologic examination after radical prostatectomy. METHODS: Three-dimensional Doppler ultrasound data were acquired from 39 men before radical prostatectomy. The removed prostates were sectioned and all cancerous regions in each prostate were identified on whole-mount hematoxylin-eosin-stained slides. The ultrasound and histologic data were then spatially registered. Biopsy results were simulated on a grid of potential sites within each prostate. Along each simulated biopsy site, the amount of cancer was computed from the hematoxylin-eosin-identified cancerous regions and the peak speed-weighted pixel density (SWD) was compared. RESULTS: By selecting the biopsy sites with higher associated SWDs within each sextant, the probability of having at least one positive biopsy within a prostate increased from 75% if the SWD was ignored to 85% if only the top 15% of potential biopsy sites in each sextant were selected. This trend was seen within each sextant individually as well. CONCLUSIONS: Doppler ultrasound provides discriminatory information for prostate cancer using the SWD. Translating this into a practical strategy that might improve the yield of prostate biopsy remains under development. The results of our study indicate that biopsying regions of high Doppler color could potentially increase the cancer yield to a small degree and improve the accuracy of the biopsy results. These results also objectively verify previous visual studies suggesting a modest improvement with the use of color Doppler.

Aged↗

PubMed2001

Predictors of Gleason pattern 4/5 prostate cancer on prostatectomy specimens: can high grade tumor be predicted preoperatively?

PURPOSE: Radical prostatectomy provides excellent cancer control in men with clinically localized prostate carcinoma. However, to our knowledge preoperative parameters for distinguishing indolent from clinically significant cancer are not well characterized. In fact, recent evidence suggests that the percent of Gleason pattern 4/5 carcinoma in the complete radical prostatectomy specimen is one of the strongest predictors of prostate cancer progression and a valid measure of cancer severity. However, it is unclear whether preoperative parameters, including biopsy Gleason pattern 4/5 carcinoma, may predict radical prostatectomy Gleason pattern 4/5 disease and, thereby, distinguish indolent from clinically significant cancer. MATERIALS AND METHODS: We prospectively obtained 101 consecutive radical prostatectomy specimens and processed them in whole mount fashion. In addition to total tumor volume, we determined tumor volume for each Gleason pattern. Biopsy tumor area was measured in a similar fashion. Univariate and multivariate analyses were performed to identify preoperative clinical and pathology parameters for predicting Gleason pattern 4/5 carcinoma on prostatectomy specimens. RESULTS: Biopsy Gleason score 7 or greater, Gleason pattern 4/5 carcinoma, perineural invasion and biopsy tumor area had statistically significant associations for identifying Gleason pattern 4/5 carcinoma on prostatectomy specimens. Logistic regression models for predicting any or greater than 10% Gleason pattern 4/5 carcinoma on prostatectomy specimens revealed that an area of pattern 4/5 disease of greater than 0.01 cm.2 on biopsy was the best single predictor with odds ratios of 15.0 (95% confidence interval 3.3 to 69.0, p = 0.0005) and 3.9 (95% confidence interval 1. 4 to 10.9, p = 0.009), respectively. For predicting any pattern 4/5 carcinoma on prostatectomy specimens a biopsy area of pattern 4/5 disease of greater than 0.01 cm.2 had only 38% sensitivity but 96% specificity. Similarly for predicting significant pattern 4/5 disease on prostatectomy specimens, defined as 10% or greater pattern 4/5, sensitivity and specificity for a biopsy area of greater than 0.01 cm.2 were 34% and 88%, respectively. Therefore, due to high false-negative rates these models had limited predictive value on an individual basis. CONCLUSIONS: Biopsy parameters such as Gleason pattern 4/5 carcinoma may provide adequate specificity for predicting clinically significant cancer, as defined by high grade Gleason patterns in the corresponding radical prostatectomy specimen. However, the accuracy of these parameters for predicting indolent cancer is limited by a prohibitive rate of false-negative findings.

Adenocarcinoma↗

PubMed2001

Analysis of three-dimensional Doppler ultrasonographic quantitative measures for the discrimination of prostate cancer.

OBJECTIVE: The purpose of this study was to determine whether several quantitative ultrasonographic measures have potential to discriminate prostate cancer from normal prostate and to determine the best combination of these measures. The true spatial distributions of cancer within the prostates studied were obtained histologically after radical prostatectomy. The relationship between Doppler ultrasonography and microvessel count was also investigated. METHODS: Three-dimensional Doppler ultrasonographic data were acquired from 39 patients before radical prostatectomy. The removed prostate was sectioned, and whole-mount hematoxylineosin-stained slides were used to identify all regions of cancer within each prostate. These histologic and ultrasonographic data were spatially registered. Doppler ultrasonographic measures were calculated within uniformly sized three-dimensional regions that were either entirely cancerous or noncancerous, and receiver operating characteristic analysis was performed on the results. Microvessel counts were made within each contiguous cancerous region and correlated with ultrasonographic measures. RESULTS: Color pixel density was the best simple measure for discriminating prostate cancer (accuracy, 80%). The mean power mode value (normalized mean power in color pixels) was inversely related to cancer with an accuracy of 1--normalized mean power in color pixels = 65% (low mean power is more cancerous). When color pixel density was combined with the normalized mean power in color pixels, its accuracy improved slightly to 84%. The peak microvessel count had a negative correlation with color pixel density as well as with cancer stage. CONCLUSION: Doppler ultrasonography does provide discriminatory information for prostate cancer, with color pixel density being the most promising measure.

Humans↗

PubMed2001

Lack of association of prostate carcinoma nuclear grading with prostate specific antigen recurrence after radical prostatectomy.

PURPOSE: Grading prostate cancer using the Gleason system relies only on architectural tumor growth, in contrast to other systems, such as the WHO system, which grade prostate carcinoma based on nuclear features as well as architectural patterns. The prognostic significance of nuclear grading remains controversial since most studies were performed before prostate specific antigen (PSA) screening became widely available. We evaluated the significance of nuclear grade for predicting PSA recurrence in a contemporary cohort of patients treated with radical prostatectomy for clinically localized prostate carcinoma. MATERIALS AND METHODS: Nuclear grades 1 to 3 were determined in 141 consecutive radical prostatectomies in 1995. Predominant and worst nuclear grade was determined by a consensus of 3 pathologists. Statistical analysis compared nuclear grade with Gleason score using the chi-square test. The Cox proportional hazards analysis was performed to calculate the ability of nuclear grade, Gleason score and other variables to predict PSA recurrence. RESULTS: We identified a significant association of Gleason score with worst nuclear grade (p = 0.007). All 6 cases with a Gleason score of 8 or greater had a worst nuclear grade of 3, in contrast to 36 of 60 (60%) with a score 6 or less, in which the worst nuclear grade was 3. Of the 141 patients 31 (21.9%) had PSA recurrence at a median followup of 3.7 years. The univariate Cox model revealed significant associations of PSA recurrence with Gleason score 8 or greater (hazards ratio 5.5, p = 0.005), extraprostatic extension (hazards ratio 3.4, p = 0.001), positive surgical margin (hazards ratio 2.6, p = 0.009), seminal vesicle involvement (hazards ratio 7.3, p <0.001), preoperative serum PSA (hazards ratio 1.03, p = 0.007), tumor stage (hazards ratio 3.6, p = 0.001) and maximal tumor dimension (hazards ratio 2.4, p <0.001). However, overall and worst nuclear grade did not predict PSA recurrence (p = 0.89 and 0.13, respectively). Nuclear grade did not fit any multivariate model tested, which otherwise included Gleason score, log(PSA), surgical margin status, extraprostatic extension, seminal vesicle status, tumor size and pathological stage. By varying sample fixation time we also showed that benign prostate tissue in the same section as prostate carcinoma had grade 2 or 3 nuclear changes, that is moderate to marked anaplasia. CONCLUSIONS: High nuclear grade is associated with high Gleason score. However, prostate carcinoma with a Gleason score of 6 or less shows extreme variability. Nuclear grade determined by light microscopy failed to predict PSA recurrence in a contemporary series of men with clinically localized prostate cancer treated with radical prostatectomy. Nuclear morphology is subject to tissue fixation and processing artifact. Any nuclear morphometric study must consider this artifact.

Adult↗

PubMed2000

Universal aging features in the restructuring of fractal colloidal gels.

We use multispeckle dynamic light scattering to measure the dynamic structure factor, f(q,tau), of gels formed by aggregation of colloids. Although the gel is an elastic solid, f(q,tau) nearly completely decays on long time scales, with an unusual form, f(q, tau) approximately exp{-(tau/tau(f))(mu)}, with mu approximately 1.5 and with tau(f) proportional variant q(-1). A model for restructuring of the gel with aging correctly accounts for this behavior. Aging leads to a dramatic increase in tau(f); however, all data can be scaled on a single master curve, with tau(f) asymptotically growing linearly with age. This behavior is strikingly similar to that predicted for aging in disordered glassy systems, offering convincing proof of the universality of these concepts.

Journal Article↗

PubMed1999

Genetic heterogeneity of autoimmune diabetes: age of presentation in adults is influenced by HLA DRB1 and DQB1 genotypes (UKPDS 43). UK Prospective Diabetes Study (UKPDS) Group.

AIMS/HYPOTHESIS: Juvenile-onset, insulin-dependent diabetes is associated with islet cell antibodies and with specific "high-risk" HLA-DRB1 and HLA-DQB1 genotypes. Patients with Type II (non-insulin-dependent) diabetes mellitus can have islet-related antibodies, but the genotypic associations at different ages of onset have not been evaluated. Our aim was to determine (i) the prevalence of DRB1 and DQB1 genotypes in patients at diagnosis of Type II diabetes at different ages from 25 to 65 years compared with the general population, and (ii) whether the presence of islet cell antibodies (ICA) or glutamic acid decarboxylase antibodies (GADA) or both by age is associated with different DRB1 and DQB1 genotypes. METHODS: The antibodies to islet cells and those to glutamic acid decarboxylase were measured in 1712 white Caucasian diabetic subjects at diagnosis of diabetes and they were genotyped for HLA DRB1*03 and DRB1*04 and the high-risk DRB1*04-DQB1* 0302 haplotype. To assess over-representation of high-risk alleles for Type I (insulin-dependent) diabetes mellitus, the prevalence of high-risk alleles in diabetic patients was expressed relative to the prevalence of low-risk alleles, non-DR3/non-DR4, that provided a reference denominator in both the diabetic patients and in 200 non-diabetic control subjects. The prevalence of ICA or GADA or both in patients with different HLA genotypes was assessed in those diagnosed in four age groups, 25-34 years, 35-44 years, 45-54 years and 55-65 years. RESULTS: In Type II diabetic patients presenting at ages 25-34, 35-44 and 45-54 years, there was an increased prevalence of DR3/DR4 compared with the general population with approximately 6.5-fold, 2.9-fold, 2.1-fold over-representation, respectively (p < 0.0001, < 0.01, < 0.05) but this was not found in those aged 55-65 years old. In the group aged 25-34 years, 32 % of patients with ICA or GADA or both had DRB1*03/DRB1*04-DQB1*0302 compared with 10% in those aged 55-65 years and expected 3% prevalence. Conversely, only 14% of those aged 25-34 years with antibodies had non-DR3/non-DR4, compared with 35 % in those aged 55-65 years. There was thus pronounced age heterogeneity in DRB1 and DQB1 predisposition to Type II diabetes. The antibodies displaced DRB1 or DQB1 genotypes in the multivariate model for requiring insulin therapy by 6 years of follow-up. CONCLUSION/HYPOTHESIS: The age of presentation of Type I diabetes in adulthood was in part dependent on the DRB1/DQB1 genotype. Islet cell antibodies and glutamic acid decarboxylase antibodies were strongly associated with DRB1*03/DRB1*04-DQB1*0302 in early adulthood but showed little relation with specific HLA genotypes after the age of 55 years.

Adult↗

PubMed1999

UTP-preferring P2 receptor mediates inhibition of sodium transport in porcine thyroid epithelial cells.

1. The effects of adenosine 5'-triphosphate (ATP), uridine 5'-triphosphate (UTP) and analogues on forskolin-stimulated absorption of Na+ by porcine thyroid epithelial cells were analysed in cultures grown as confluent monolayers on permeable supports in Transwell Ussing chambers. 2. 85% of the forskolin (10 microM)-stimulated short-circuit current was inhibited by phenamil (1 microM), which is a selective antagonist for epithelial type Na+ channels. 3. Phenamil-sensitive current was inhibited in a dose dependent manner by nucleotides added to the apical compartment of Ussing chambers. In contrast, the phenamil-resistant current, previously shown to represent anion secretion, was unaffected by nucleotides. 4. The order of potency (with EC50 values given in microM) was UTP (0.08)>>ATP (6.3)=uridine 5'-diphosphate (UDP) (6. 6)>2methyl-thio-adenosine-5'-triphosphate (2MeSATP) (84.5)>adenosine 5'-diphosphate (ADP) (147.8)>alpha,beta-methylene ATP (>150)>>adenosine (>1000). 5. P2 receptors mediating inhibition of sodium absorption were present on the apical membrane of the cells since addition of UTP (1-1000 microM) to the basal compartment of the Ussing chambers had little effect while subsequent addition to the apical compartment produced a normal response. 6. Cibachron blue (Reactive blue 2) (1-100 microM), an antagonist at some P2 receptor subtypes, inhibited phenamil sensitive current in a dose dependent manner with half maximal inhibition occurring at 14.25 microM. 7. Suramin (100 microM), pyridoxalphosphate-6-azophenyl-2', 4'-disulphonic acid (PPADS) (100 microM) and pyridoxal 5'-phosphate (P5P) (100 microM) showed only slight competitive antagonism against the response to UTP. 8 These results indicate that a UTP-preferring P2 receptor located on the apical membrane of thyroid epithelial cells mediates inhibition of Na+ absorption.

Animals↗

PubMed1999

Safety and biological efficacy of an adeno-associated virus vector-cystic fibrosis transmembrane regulator (AAV-CFTR) in the cystic fibrosis maxillary sinus.

OBJECTIVE: The host immune response and low vector efficiency have been key impediments to effective cystic fibrosis transmembrane regulator (CFTR) gene transfer for cystic fibrosis (CF). An adeno-associated virus vector (AAV-CFTR) was used in a phase I dose-escalation study to transfer CFTR cDNA into respiratory epithelial cells of the maxillary sinus of 10 CF patients. STUDY DESIGN: A prospective, randomized, unblinded, dose-escalation, within-subjects, phase I clinical trial of AAV-CFTR was conducted. PATIENTS: Ten patients with previous bilateral maxillary antrostomies were treated. MAIN OUTCOME MEASURES: Safety, gene transfer as measured by semiquantitative polymerase chain reaction (PCR), and sinus transepithelial potential difference (TEPD) were measured. RESULTS: The highest level of gene transfer was observed in the range of 0.1-1 AAV-CFTR vector copy per cell in biopsy specimens obtained 2 weeks after treatment. When tested, persistence was observed in one patient for 41 days and in another for 10 weeks. Dose-dependent changes in TEPD responses to pharmacologic intervention were observed following treatments. Little or no inflammatory or immune responses were observed. CONCLUSION: AAV-CFTR administration to the maxillary sinus results in successful, dose-dependent gene transfer to the maxillary sinus and alterations in sinus TEPD suggestive of a functional effect, with little or no cytopathic or host immune response. Further study is warranted for AAV vectors as they may prove useful for CFTR gene transfer and other in vivo gene transfer therapies. A prospective, randomized, double-blind, placebo-controlled, within-subjects, phase II clinical trial of the effect AAV-CFTR on clinical recurrence of sinusitis will determine the clinical efficacy of AAV gene therapy for CF.

Adult↗

PubMed1997

UKPDS 25: autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes. UK Prospective Diabetes Study Group.

BACKGROUND: Autoantibodies to islet-cell cytoplasm (ICA) and glutamic acid decarboxylase (GADA) can occur in apparently typical, non-insulin dependent diabetes mellitus (type 2). We investigated whether the presence of either or both antibodies characterises a subtype of diabetes and provides better prediction of requirement for insulin therapy by 6 years' follow-up than clinical variables. METHODS: We measured ICA and GADA at diagnosis of diabetes in a representative population of 3672 white patients with type 2 diabetes, aged between 25 and 65 years. The phenotype was assessed by age of onset, body-mass index, percentage haemoglobin A1c (HbA1c), and islet beta-cell function. We investigated the need for insulin therapy among 1538 patients not assigned insulin and followed up for 6 years from diagnosis. FINDINGS: The proportion of patients with ICA and GADA decreased with increasing age at diagnosis (from 33 [21%] of 157 patients aged 25-34 [corrected] to 66 [4%] of 1769 aged 55-65 for ICA; from 53 [34%] to 122 [7%] for GADA). Among patients younger than 35 at diagnosis, those with ICA or GADA had lower body-mass index than those without (mean 24.9 [SD 6.0] vs 31.7 [7.3] kg/m2; p < 0.0001 and had higher percentage of HbA1c (9.7 vs 8.7%, p < 0.05). 94% of patients with ICA and 84% of those with GADA required insulin therapy by 6 years, compared with 14% of those without the antibodies (p < 0.0001). Among patients older than 55 at diagnosis, the difference between those with and without antibodies in body-mass index was smaller (27.2 [5.4] vs 28.6 [4.8] kg/m2, p < 0.001); 44% of those with ICA, 34% of those with GADA, and 5% with neither antibody required insulin therapy by 6 years (p < 0.0001). Among patients older than 45 years, body-mass index and HbA1c provided little predictive information for insulin requirement, whereas the positive predictive values of GADA (> or = 60 U/L) alone, or both GADA (> or = 20 U/L) and ICA (> 5 U/L), for insulin therapy were 52% and 68%. INTERPRETATION: Among young adults with type 2 diabetes, the phenotype of those with ICA or GADA antibodies was similar to that of classic juvenile-onset insulin-dependent diabetes, and either phenotype or antibodies predicted insulin requirement. In older adults, the phenotype was closer to that of patients without antibodies and only the presence of antibodies predicted an increased likelihood of insulin requirement.

Adult↗

PubMed1997

BRCA1 sequence analysis in women at high risk for susceptibility mutations. Risk factor analysis and implications for genetic testing.

CONTEXT: A mutation in the BRCA1 gene may confer substantial risk for breast and/or ovarian cancer. However, knowledge regarding all possible mutations and the relationship between risk factors and mutations is incomplete. OBJECTIVES: To identify BRCA1 mutations and to determine factors that best predict presence of a deleterious BRCA1 mutation in patients with breast and/or ovarian cancer. DESIGN: A complete sequence analysis of the BRCA1 coding sequence and flanking intronic regions was performed in 798 women in a collaborative effort involving institutions from the United States, Italy, Germany, Finland, and Switzerland. PARTICIPANTS: Institutions selected 798 persons representing families (1 person for each family) thought to be at elevated a priori risk of BRCA1 mutation due to potential risk factors, such as multiple cases of breast cancer, early age of breast cancer diagnosis, and cases of ovarian cancer. No participant was from a family in which genetic markers showed linkage to the BRCA1 locus. MAJOR OUTCOME MEASURES: Sequence variants detected in this sample are presented along with analyses designed to determine predictive characteristics of those testing positive for BRCA1 mutations. RESULTS: In 102 women (12.8%), clearly deleterious mutations were detected. Fifty new genetic alterations were found including 24 deleterious mutations, 24 variants of unknown significance, and 2 rare polymorphisms. In a subset of 71 Ashkenazi Jewish women, only 2 distinct deleterious mutations were found: 185delAG in 17 cases and 5382insC in 7 cases. A bias in prior reports for mutations in exon 11 was revealed. Characteristics of a patient's specific diagnosis (unilateral or bilateral breast cancer, with or without ovarian cancer), early age at diagnosis, Ashkenazi Jewish ethnicity, and family history of cancer were positively associated with the probability of her carrying a deleterious BRCA1 mutation. CONCLUSIONS: Using logistic regression analysis, we provide a method for evaluating the probability of a woman's carrying a deleterious BRCA1 mutation for a wide range of cases, which can be an important tool for clinicians as they incorporate genetic susceptibility testing into their medical practice.

Breast Neoplasms↗