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Biomedical subjects

A Herbert

Publications and source records attributed to A Herbert.

At least 19 recordsLinked to original sources
PubMed2006

Endoscopic ultrasound-guided fine needle aspiration cytology of pancreatic neuroendocrine tumours: cytomorphological and immunocytochemical evaluation.

OBJECTIVES: Endoscopic ultrasound (EUS)-guided fine needle aspiration (FNA) is increasingly used in preoperative localization and diagnosis of pancreatic neoplasms including neuroendocrine tumours (NETs). The objective of the present study was to identify the cytological features of pancreatic NETs obtained by EUS-FNA. METHODS: The study group consisted of nine cases of pancreatic tumours correctly diagnosed or strongly suggestive of NETs based on EUS-FNA. Cytological smears were retrospectively reviewed. The clinical data and immunocytochemical stains applied to the cell block preparations were also reviewed and examined. RESULTS: All cases except one showed characteristic cytomorphological features sufficient for their recognition and separation from pancreatic adenocarcinoma and other lesions. The most helpful cytological features that facilitated the cytological diagnosis of NET were a richly cellular aspirate with a monotonous, poorly cohesive population of small cells with a speckled or dusty chromatin pattern and plasmacytoid morphology. The neuroendocrine differentiation of these tumours was further confirmed by immunocytochemistry. CONCLUSION: EUS-FNA is a valuable method in the recognition of pancreatic NETs. By adherence to the characteristic cytomorphological criteria of pancreatic NET together with collection of suitable material for ancillary immunocytochemical stains, cytopathologists could reach a correct diagnosis in most instances.

Adenocarcinoma↗
PubMed2006

Fine needle aspiration cytology: a survey of current European practice.

Fine needle aspiration cytology (FNAC) is practised widely throughout Europe. The majority of countries have dedicated cytopathologists as well as histopathologists practicing cytology. Despite this, FNAC is performed mostly by clinicians and radiologists except in the larger centres with dedicated staff with a special interest in cytopathology. The advent of One-Stop diagnostic services and image-guided procedures are prompting further development of FNAC clinics where cytopathologists take their own samples, issue reports in the same clinical session and take extra material for ancillary tests to complete the diagnosis. The volume of FNAC work varies accordingly; in dedicated centres FNAC represents up to 80% of the workload whilst, in the majority of countries, it represents one quarter or less. Hence, the rate of inadequate FNAC varies widely, depending on the local sampling policies and the organ, but does not exceed 25% in any of the countries. The most sampled organs are breast and thyroid, followed by lymph nodes. Most countries have dedicated training in cytopathology for pathology trainees, the duration varying between 6 months and 2 years of the total training time. This discussion, focusing on European practices, highlights the heterogeneity of FNAC activity but also its success in many centres where it is practiced to a high standard, particularly in breast, thyroid and lymph node pathology. The relatively high rate of inadequate material in some centres reflects local policies and calls for greater uniformity of FNAC practice, particularly specimen sampling. To achieve this, the future direction should concentrate on specialist training, to include performing as well as interpreting FNAC, as part of the curriculum. Current emphasis on web-based training may not provide first hand experience of the FNAC procedure and should be supplemented by attending FNAC clinics and developing the technique to its full potential.

Biopsy, Fine-Needle↗
PubMed2006

Insulin resistance, oxidative stress, hypertension, and leukocyte telomere length in men from the Framingham Heart Study.

Insulin resistance and oxidative stress are associated with accelerated telomere attrition in leukocytes. Both are also implicated in the biology of aging and in aging-related disorders, including hypertension. We explored the relations of leukocyte telomere length, expressed by terminal restriction fragment (TRF) length, with insulin resistance, oxidative stress and hypertension. We measured leukocyte TRF length in 327 Caucasian men with a mean age of 62.2 years (range 40-89 years) from the Offspring cohort of the Framingham Heart Study. TRF length was inversely correlated with age (r = -0.41, P < 0.0001) and age-adjusted TRF length was inversely correlated with the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) (r =-0.16, P = 0.007) and urinary 8-epi-PGF(2alpha) (r = -0.16, P = 0.005) - an index of systemic oxidative stress. Compared with their normotensive peers, hypertensive subjects exhibited shorter age-adjusted TRF length (hypertensives = 5.93 +/- 0.042 kb, normotensives = 6.07 +/- 0.040 kb, P = 0.025). Collectively, these observations suggest that hypertension, increased insulin resistance and oxidative stress are associated with shorter leukocyte telomere length and that shorter leukocyte telomere length in hypertensives is largely due to insulin resistance.

Adult↗
PubMed2005

The -174 IL-6 GG genotype is associated with a reduced risk of type 2 diabetes mellitus in a family sample from the National Heart, Lung and Blood Institute's Framingham Heart Study.

AIMS/HYPOTHESIS: We evaluated the -174 IL-6 gene polymorphism as a risk factor for type 2 diabetes mellitus in a family-based analysis. METHODS: We tested for associations between the -174 IL-6 G/C promoter polymorphism and fasting plasma glucose (FPG) and type 2 diabetes in a sample of 1,428 individuals from the largest 182 families in the National Heart, Lung and Blood Institute's Framingham Heart Study population. RESULTS: A significant association was found with FPG (p=0.01) and log (FPG) (p=0.005) using a modified family-based transmission disequilibrium test, the family-based association test (FBAT). The association between IL-6 genotype and FPG (p=0.035) and log (FPG) (p=0.03) was also found in the subset of families that were informative in FBAT using a mixed-effects regression model and strengthened after adjustment for potential confounders (p=0.008 for log [FPG]). The mean glucose level estimated from models with log (FPG) as the dependent variable for the GG genotype in the informative families was significantly lower (5.20+/-0.06 mmol/l) than for the GC (5.41+/-0.06 mmol/l) and CC (5.38+/-0.06 mmol/l) genotypes (p=0.03 for contrast between GG and GC genotypes). In the subset of informative families, the risk of type 2 diabetes associated with the GG genotype was lower relative to the GC and CC genotypes combined (potential confounder-adjusted, mixed-effects odds ratio 0.35, 95% CI 0.14-0.88, p=0.026, unaffected n=391, affected n=32). CONCLUSIONS/INTERPRETATION: These results are consistent with a protective role for the -174 IL-6 G allele against type 2 diabetes and warrant further analysis of this polymorphism.

Blood Glucose↗
PubMed2005

Absence of previously reported variants in the SCNA (G88C and G209A), NR4A2 (T291D and T245G) and the DJ-1 (T497C) genes in familial Parkinson's disease from the GenePD study.

Parkinson's disease (PD) is a neurodegenerative disorder in which relatives of the probands are affected approximately 4 times as frequently as relatives of control subjects. Several genes have been implicated as genetic risk factors for PD. We investigated the presence of six reported genetic variations in the SCNA, NR4A2, and DJ-1 genes in 292 cases of familial Parkinson's disease from the GenePD study. None of the variants were found in the GenePD families. Our results suggest that other variants or genes account for the familial risk of PD within the GenePD study.

Aged↗
PubMed2005

Self-reported bladder function five years post-hysterectomy.

We have examined the contribution of hysterectomy, compared with less invasive surgery, for dysfunctional uterine bleeding (DUB) on the prevalence of bladder problems five years after surgery. We report a prospective cohort study of over 25,000 women treated for benign cause menorrhagia by three types of surgery - transcervical endometrial resection/ablation and hysterectomy with or without bilateral oophorectomy. Postal questionnaires were sent five years after surgery investigating satisfaction with surgery and bladder function. When adjusted for confounders the odds of severe urinary incontinence (OR = 1.59, CI 95%, 1.35 - 1.87), urinary frequency (1.23 (1.04 - 1.45)), and nocturia (1.19, (1.03 - 1.38)) - were increased for women who had a hysterectomy compared with endometrial ablation. Hysterectomy with bilateral oophorectomy was not as strongly associated with severe bladder problems. Women who had the LAVH were most likely to report severe urinary incontinence (2.02, CI 95% 1.32 - 3.07), but not severe frequency or nocturia.

Adult↗
PubMed2005

BSCC, Bethesda or other? Terminology in cervical cytology European panel discussion.

The European panel agreed that reproducibility and translatability of terminology in cervical cytology were essential, arguing well for harmonization of reporting systems. The majority at this meeting use a modification of the Bethesda system (BS). Local modifications involved reporting subcategories within high grade and low grade lesions, which would not alter the overall translatability of their systems both with each other and BS. The majority agree that low grade lesions with and without koilocytosis should be managed similarly as should high grade lesions (moderate dysplasia/CIN2 or worse). Those systems linking moderate dysplasia with mild rather than severe dysplasia would need to define moderate dysplasia as such, if their results were to be translatable, which would be preferable to their using a different definition of low grade and high grade lesions. Translation between systems might anyway be facilitated by reporting moderate dysplasia as a subcategory within high grade, which was favoured by most of those present. Therefore, there is no need for exact agreement of terminology if broad principles are agreed. This useful discussion adds weight to the British Society for Clinical Cytology recommendation that the new classification should be adopted by the UK National Health Service Cervical Screening Programme. If the new classification is adopted, the UK would join the European consensus opinion on terminology.

Consensus↗
PubMed2005

Readmission to hospital 5 years after hysterectomy or endometrial resection in a national cohort study.

OBJECTIVES: To investigate the readmission experience of a large national prospective cohort of women up to 5 years after undergoing either transcervical resection of the endometrium (TCRE) or hysterectomy to assess reasons for readmission and whether TCRE can be viewed as a definitive substitute for hysterectomy. DESIGN AND PARTICIPANTS: Data are from the VALUE/MISTLETOE prospective national cohort studies of hysterectomy and TCRE respectively. 5294 women who underwent hysterectomy for dysfunctional uterine bleeding in 1994/5 and 4032 women who underwent TCRE in 1993/4 and who responded to postal questionnaires were included. Surgeons gathered operative details. Women completed postal follow up questionnaires at 3 and 5 years after surgery asking about readmission to hospital and reasons for readmission. Adjusted proportional hazard ratios were calculated for likelihood of readmission in each category comparing types of surgery. RESULTS: 41.7% of women undergoing hysterectomy and 44.6% of women undergoing TCRE experienced one or more readmissions to hospital overall within 5 years (adjusted hazard ratio for all readmissions (AHR) 0.87 (95% confidence interval (CI) 0.80 to 0.95)). 12.6% of hysterectomy patients and 30.3% of TCRE patients were readmitted for gynaecological reasons (AHR 0.40 (95% CI 0.33 to 0.48)). Rates of readmission for gynaecological reasons were similar up to 6 months but were markedly reduced for hysterectomy compared with TCRE patients towards the end of the follow up period (AHR for readmission at 3-5 years 0.28 (95% CI 0.20 to 0.39)). CONCLUSIONS: There are differences in the pattern of readmission to hospital after hysterectomy and TCRE for dysfunctional uterine bleeding. Women undergoing a hysterectomy are less likely to be readmitted to hospital up to 5 years after their operation overall, and are significantly less likely to be readmitted for reasons related to their operation, particularly for gynaecological reasons. Hysterectomy appears to be a more definitive operation. The different options for surgery for dysfunctional uterine bleeding are not interchangeable; they represent different patterns of care. Information should be available to women and practitioners to inform choices between these options.

Adult↗
PubMed2004

Severe complications of hysterectomy: the VALUE study.

OBJECTIVES: To model the determinants of serious operative and post-operative complications of hysterectomy and their potential risk factors. DESIGN: A prospective cohort of women undergoing hysterectomies for benign indications in 1994/1995, with a six-week postsurgery follow up. POPULATION AND SETTING: A total of 37,512 women from 276 NHS and 145 private hospitals in England, Wales and Northern Ireland, originally recruited to compare the outcomes of endometrial destruction with those of hysterectomy. METHODS: Gynaecologists reported hysterectomies for non-malignant indications carried out during a 12-month period beginning in October 1994 and follow up data were obtained at outpatient follow up six weeks postsurgery. Odds ratios of severe complications by indication and method, adjusting for measured intrinsic risk factors, were calculated. MAIN OUTCOME MEASURES: Severe operative and post-operative complications. RESULTS: Severe operative complications occurred in 3%. The risk decreased with age and increased with greater parity and history of serious illness. Women with symptomatic fibroids (4.4%, 95% CI 3.9-4.9) experienced more complications than women with dysfunctional uterine bleeding (3.6%, 3.2-3.8), adjusted odds ratio (OR) = 1.3 (95% CI 1.1-1.6). Laparoscopic procedures (6.1%) doubled the risk of operative complications of abdominal hysterectomy (3.6%) (adjusted OR = 1.9, 1.5-2.5). Post-operative complications occurred in around 1% of women, with a slight decrease with increasing age, and the strongest risk factor was a history of operative complications. Relative to dysfunctional uterine bleeding (1.0%), a higher risk for fibroids (1.2%) persisted after adjustments (RR = 1.5, 1.1-2.0). Both vaginal (1.2%) and laparoscopic (1.7%) techniques had significantly higher adjusted risks than abdominal operations (0.9%), RR = 1.4 (1.0-1.9) and RR = 1.6 (1.0-2.7). There were no operative deaths; 14 women died within the six-week postsurgery (a crude mortality rate of 3.8/1000, 2.5-6.4). CONCLUSIONS: Hysterectomy is a common, routine surgery with comparatively rare serious complications. However, younger women, women with more vascular pelvis, who undergo hysterectomy, especially laparoscopically assisted vaginal surgery for symptomatic fibroids, are at most risk of experiencing severe complications both operatively and post-operatively. Therefore, a less invasive alternative treatment for symptomatic fibroids could particularly benefit this group of women, while less invasive treatments for dysfunctional uterine bleeding, such as various methods of endometrial ablations or resections, would need to meet the current low levels of clinical complications in order to replace hysterectomy.

Adolescent↗
PubMed2003

A haplotype at the PARK3 locus influences onset age for Parkinson's disease: the GenePD study.

OBJECTIVE: To identify a haplotype influencing onset age for Parkinson's disease (PD) in the PARK3 region on chromosome 2p13. METHODS: Single nucleotide polymorphisms (SNP) spanning 2.2 Mb and located in or near potential candidate genes were used to fine map the PARK3 region in 527 patients with familial PD, from 264 families. RESULTS: TT homozygotes for rs1876487 (G/T) had a 7.4-year younger mean age at onset (p = 0.005) compared to patients with GT and GG genotypes. Furthermore, SNP flanking the sepiapterin reductase (7,8-dihydrobiopterin: NADP+ oxidoreductase) (SPR) gene, rs1876487 (p = 0.02) and rs1150500 (p = 0.04), were associated with younger onset age among persons who did not carry the 174 allele of D2S1394. The SPR gene is implicated in dopamine synthesis. Haplotype analysis of three SNP-rs2421095, rs1876487, rs1561244-revealed an association with onset age (p = 0.023) and a haplotype of A-T-G alleles was associated with younger onset for PD (p = 0.005). CONCLUSIONS: A haplotype at the PARK3 locus, harboring the SPR gene, is associated with onset age of PD. This may suggest a role for the SPR gene in modifying the age at onset of PD.

Adolescent↗
PubMed2002

Three-dimensional structure and flexibility of proteins of the RCA family - a progress report.

Members of the regulator of complement activation (RCA) protein family perform a vital role in health and disease. In this report we describe our efforts to solve the structures of human membrane cofactor protein (CD46), the vaccinia virus complement control protein, which mimics mammalian RCA proteins, and human complement receptor type 1 (CD35). These examples illustrate that, despite good progress over the last decade, the regulators of complement, as extracellular multiple domain glycoproteins, still pose formidable problems to structural biologists. Many important questions remain unanswered, in particular with regard to the flexibility of these proteins and the extent to which they undergo conformational rearrangements on engaging their binding partners.

Animals↗
PubMed2002

Genome screen for quantitative trait loci contributing to normal variation in bone mineral density: the Framingham Study.

A genome-wide scan was performed in a randomly ascertained set of 330 extended families from the population-based Framingham Study to identify chromosomal regions possibly linked to bone mineral density (BMD). A set of 401 microsatellite markers was typed at a 10-centimorgan (cM) average density throughout the genome. BMD was measured at the femoral neck, trochanter, Ward's area, and lumbar spine in 1557 participants of both Framingham cohorts. BMDs were adjusted for age, body mass index (BMI), height, alcohol, caffeine, calcium and vitamin D intakes, smoking, physical activity, and estrogen use in women within each sex and cohort. Strong heritabilities (values between 0.543 and 0.633) were found for the adjusted BMD at all sites. Two-point and multipoint quantitative linkage analyses were performed for each BMD site using the maximum likelihood variance components method. By two-point screening, loci of suggestive linkage were identified on chromosomes 6 and 21, with the maximum log10 of the odds ratio (LOD) scores of 2.34 for the trochanter at D21S1446 and 2.93 for the femoral neck at D6S2427. Lumbar spine BMD had maxima at D6S2427 (LOD = 1.88) and at D12S395 (LOD = 2.08). Multipoint linkage analysis revealed suggestive linkage of trochanteric BMD at a broad (approximately 20 cM) interval on chromosome 21q, with the peak linkage close to D21S1446 (LOD = 3.14). LOD scores were 2.13 at 8q24 with Ward's BMD and 1.92 at 14q21.3 with lumbar spine BMD. This largest genome screen to date for genes underlying normal variation in BMD, adjusted for a large number of covariates, will help to identify new positional candidate genes, otherwise unrecognized.

Aged↗
PubMed2001

The role of binding domains for dsRNA and Z-DNA in the in vivo editing of minimal substrates by ADAR1.

RNA editing changes the read-out of genetic information, increasing the number of different protein products that can be made from a single gene. One form involves the deamination of adenosine to form inosine, which is subsequently translated as guanosine. The reaction requires a double-stranded RNA (dsRNA) substrate and is catalyzed by the adenosine deaminase that act on dsRNA (ADAR) family of enzymes. These enzymes possess dsRNA-binding domains (DRBM) and a catalytic domain. ADAR1 so far has been found only in vertebrates and is characterized by two Z-DNA-binding motifs, the biological function of which remains unknown. Here the role of the various functional domains of ADAR1 in determining the editing efficiency and specificity of ADAR1 is examined in cell-based assays. A variety of dsRNA substrates was tested. It was found that a 15-bp dsRNA stem with a single base mismatch was sufficient for editing. The particular adenosine modified could be varied by changing the position of the mismatch. Editing efficiency could be increased by placing multiple pyrimidines 5' to the edited adenosine. With longer substrates, editing efficiency also increased and was partly due to the use of DRBMs. Additional editing sites were also observed that clustered on the complementary strand 11-15 bp from the first. An unexpected finding was that the DRBMs are not necessary for the editing of the shorter 15-bp substrates. However, mutation of the Z-DNA-binding domains of ADAR1 decreased the efficiency with which such a substrate was edited.

Adenosine Deaminase↗