Are there differences between young- and older-onset early inflammatory arthritis and do these impact outcomes? An analysis from the CATCH cohort.

OBJECTIVE: The aim of this study was to determine the impact of age on disease and remission in suspected early RA (ERA). METHODS: Data from the Canadian Early Arthritis Cohort (CATCH) were examined at baseline, 6 and 12 months. Patients were divided into three groups based on age. Analysis of variance (ANOVA) and regression models were performed to determine the impact of age on the 28-joint DAS (DAS28) and remission at 12 months. RESULTS: A total of 1809 patients were initially assessed: 442 (24.4%) young (<42 years), 899 (49.7%) middleaged (542<64 years) and 468 (25.9%) old (564 years); 72.9% female; 63.8% met 2010 ACR/European League Against Rheumatism (EULAR) classification criteria for RA; symptom duration at first visit 186.0 days; DAS28 4.9; HAQ 1.0; 25.3% had baseline erosions. A significant correlation existed between older age and a lower percentage of females, less positive RF and CCP, fewer meeting RA criteria, shorter symptom duration, more erosions at first visit, higher DAS28 and HAQ at baseline and 12 months and fewer DAS28 remission at 12 months (all P<0.003). The age group did not affect the change in DAS28 and HAQ from 0 to 12 months. Co-morbidities increased with age; more DMARDs, including MTX and steroids, and fewer biologics were used in older age. Age and female had a lesser chance of remission in the regression model. CONCLUSION: In suspected ERA, older-onset patients start and end their first year worse in terms of DAS28 and HAQ, with fewer meeting RA criteria, less remission, more DMARDs and steroids use but less biologics use. However, there were no differences between age groups in the change in DAS28.

Physician global assessment at 3 months is strongly predictive of remission at 12 months in early rheumatoid arthritis: results from the CATCH cohort.

OBJECTIVE: The objective of this study was to determine predictors of 1-year remission in early RA (ERA) using baseline and 3-month data. METHODS: The Canadian Early Arthritis Cohort (CATCH) patients were included if baseline, 3- and 12-month data were available. Regression analyses for four different definitions of remission at 12 months were done to determine baseline and 3-month predictors of remission. RESULTS: Five hundred and sixty-two patients had complete data at 12 months (mean age 53.4 years, disease duration 6.2 years, 73% female). The factors at baseline associated with all four remission outcomes at 12 months were age, gender, income, education, tender joint count (TJC), patient global assessment (PtGA), HAQ and pain. Baseline ESR was associated with the 28-joint DAS (DAS28) remission only. At 3 months, all four remission definitions were associated with TJC, swollen joint count, physician global assessment (PGA), PtGA, HAQ, pain, ESR and CRP in univariate analyses. In the regression model, variables associated with Simple Disease Activity Index remission were PGA [odds ratio (OR) 0.77, P < 0.001), pain (OR 0.85, P = 0.004), age (OR 0.98, P = 0.006) and HAQ (OR 0.49, P = 0.011); Clinical Disease Activity Index remission was associated with PGA (OR 0.77, P < 0.001), pain (OR 0.85, P = 0.003), age (OR 0.98, P = 0.015) and CRP (OR 0.80, P = 0.031). DAS28 remission was predicted by ESR (OR 0.95, P < 0.001), PGA (OR 0.76, P < 0.001), age (OR 0.98, P = 0.001), HAQ (OR 0.57, P = 0.006) and male gender (OR 2.01, P = 0.005), whereas Boolean remission was associated with pain (OR 0.79, P = 0.009), age (OR 0.98, P = 0.016), PtGA (OR 0.83, P = 0.025) and PGA (OR 0.86, P = 0.038). CONCLUSION: A low PGA at 3 months was consistently associated with 1-year remission in ERA.

Safe ablation of the anal mucosa and perianal skin in rats using Photodynamic Therapy--a promising approach for treating Anal Intraepithelial Neoplasia.

BACKGROUND: Anal Intraepithelial Neoplasia (AIN), a pre-cursor of anal squamous carcinoma, is increasingly detected in individuals with impaired immune function. However, choices for effective, low morbidity treatment are limited. Photodynamic Therapy (PDT) is promising as it is known to ablate more proximal gastrointestinal mucosa with safe healing, without damage to underlying muscle. It can also ablate skin with safe healing and minimal scarring. METHODS: Pharmacokinetics: Normal rats were sensitised with 200mg/kg 5-aminolaevulinic acid (ALA) and killed 1-8h later. Anal tissues were examined by fluorescence microscopy to quantify the concentration of PPIX (protoporphyrin IX, the active derivative of ALA) in anal mucosa and in the underlying sphincter. PDT: Normal rats were sensitised similarly 3h later, laser light (635 nm) was delivered. Anal canal: 50-150 J/cm using 1cm diffuser fibre; for peri-anal skin, 50-200 J/cm(2), using microlens fibre. In each group, 2 rats were killed 3, 7, 14 and 28 days later and the anal region removed for histological examination. RESULTS: Pharmacokinetics: Peak concentration of PPIX in mucosa was at 3h, peak ratio mucosa: muscle, 6, seen at same time. PDT. Anal canal 50 J/cm: complete mucosal ablation by 3 days, complete regeneration by 28 days. Higher energies caused muscle damage with scarring. Peri-anal skin: 200 J/cm(2); complete ablation of skin, including appendages, complete healing by 28 days. Minimal effect with lower energy. CONCLUSION: ALA-PDT can ablate anal mucosa and peri-anal skin with safe healing and no underlying damage. However, over treatment can damage the sphincters. This technique is ready to undergo clinical trials.

Anticitrullinated protein antibodies and rheumatoid factor fluctuate in early inflammatory arthritis and do not predict clinical outcomes.

OBJECTIVE: In inflammatory arthritis, rheumatoid factor (RF) and anticitrullinated protein antibodies (ACPA) are believed to be associated with more severe clinical outcomes. Our objective was to determine whether ACPA and RF remain stable in early inflammatory arthritis and whether their trajectories over time or baseline levels predicted clinical outcomes. METHODS: The study population consisted of patients enrolled in the Canadian Early Arthritis Cohort Study with baseline and at least 12-month followup values of RF and ACPA. Primary outcomes were Disease Activity Score (DAS) remission and the presence of erosions at 12 and 24 months. Other objectives included swollen joint count, Health Assessment Questionnaire score, and DAS. RESULTS: At baseline, 225/342 (66%) patients were ACPA-positive and 334/520 (64%) were RF-positive. At 24 months, 15/181 (8%) ACPA-positive patients became negative. A larger number of patients changed from ACPA-negative to positive: 13/123 (11%). For RF, fluctuations were more common: 67/240 (28%) reverted from positive to negative and 21/136 (18%) converted from negative to positive. RF and ACPA fluctuations did not predict disease outcomes. Patients who remained ACPA-positive throughout followup were more likely to have erosive disease (OR 3.86, 95% CI 1.68, 8.92). CONCLUSION: RF and ACPA have the potential to revert and convert during the early course of disease. Fluctuations in RF and ACPA were not associated with clinical outcomes.

Quantitative MRI of colonic mural enhancement: segmental differences exist in endoscopically proven normal colon.

OBJECTIVES: Abnormal contrast enhancement on MRI is advocated as a biomarker for inflammation in colitis, although the enhancement kinetics of normal colon are poorly described. Our purpose was to quantitatively assess mural enhancement in normal colon and test for intersegmental differences. METHODS: Eight patients without prior history of inflammatory bowel disease underwent standard MRI colonography followed by normal same-day colonoscopy. Acquired sequences included a volumetric interpolated breath-hold examination (VIBE) to encompass the whole colonic volume, performed at 5°, 10° and 35° flip angles for T(1) quantitation and then at a fixed 35° flip angle three times prior to and every 30 s following intravenous gadoterate meglumine for 220 s. Ascending colon, descending colon and rectal R(1) (1/T(1)) was plotted against time. Mean pre-contrast R(1), initial change of R(1) (ΔR(1)), early and late "plateau phase" enhancement and the area under the R(1)-time (AUC-R(1)) curve were compared between segments using the Student's paired t-test. RESULTS: There was no significant difference of pre-contrast R(1) between segments (p=0.49 to 0.62). ΔR(1) was higher for ascending colon compared with descending colon (0.0023±0.0012 ms(-1) vs 0.0010±0.0011 ms(-1), p=0.03). There was no significant difference for early or late plateau phase R(1) between colonic segments (p=0.08 to 1.00). AUC-R(1) was greater for ascending than descending colon (0.54±0.19 vs 0.30±0.14, p=0.03). CONCLUSIONS: Intersegmental differences in colonic enhancement are present and should be considered when interpreting differential segmental enhancement.

Patient experiences of MR colonography and colonoscopy: a qualitative study.

OBJECTIVES: The aim of this study was to apply qualitative techniques to assimilate data on patient experience and attitudes during MR colonography (MRC) and colonoscopy (CC). METHODS: 18 patients (11 male, 8 female, median age 40.5 years), 10 of whom had known colonic inflammatory bowel disease (IBD) and 8 who were under investigation for suspected colonic neoplasia (non-IBD), underwent MRC and conventional CC. Semi-structured interviews were performed to assimilate test experiences and preferences, and themes were extracted using thematic analysis. RESULTS: Thematic analysis identified three main themes: (i) physical experience, (ii) information provision and (iii) overall preference. Patients expressed mixed views about the physical experience of MRC but specifically identified water filling, breath holding and lying still as problematic. Anxiety was expressed regarding potential incontinence. Scanner noise interfered with the understanding of instructions, particularly amongst non-IBD patients. Non-IBD patients expressed greater anxiety over the delay in receiving the MRC report than IBD patients. In general MRI was considered as the more informative and safer investigation. Patients reported more physical discomfort during CC (notably IBD patients) related to air insufflation and colonoscopic manipulation but were more satisfied with the feedback they received. 10 patients (56%) stated an overall preference for MRC and 5 (28%) preferred CC. Reasons for preferences stated by the patients included discomfort, speed of the test, safety, perceived diagnostic ability and the ability to take biopsies. CONCLUSION: Experiences of MRC and CC are complex and influenced by clinical indication. Individuals place different weightings on the relative importance of test attributes including discomfort, noise, immobility, feedback, safety and fear of incontinence and this defines overall preference.

Diagnostic and therapeutic impact of MR enterography in Crohn's disease.

AIM: To assess the impact of magnetic resonance enterography (MRE) on clinician diagnostic confidence and therapeutic strategy in patients under investigation for small bowel Crohn's disease. MATERIAL AND METHODS: Gastroenterologists completed a proforma before and following MRE in 51 patients (mean age 35 years, 26 female) under investigation for small bowel Crohn's disease, indicating percentage confidence for presence/absence of small bowel involvement. In suspected disease, diagnostic confidence (using a scoring system from 1=no to 6=yes) was scored for subcategories: extent >30 cm (DE), terminal ileum (lTI), jejunal (JD), colonic disease (CoD), strictures (ST), activity (AD), extraluminal complications (EL), and surgical need (NS). Therapeutic strategy was recorded. Patients were divided into three groups: 1=suspected disease, MRE normal (n=15); 2=suspected disease, MRE abnormal (n=30); 3=no suspected disease, MRE normal (n=6). Binomial exact and paired t-tests were use to compare confidence pre and post-MRE. RESULTS: Mean percentage confidence for the presence/absence of small bowel disease increased from 62 to 84% (p=0.003), 87 to 98% (p=0.0001), and 83 to 98% (p=0.005) after MRE for groups 1, 2, and 3, respectively. In suspected disease, confidence changed significantly for all of the subcategories (p<0.001) except EL in group 1. The percentage of patients with a confidence change ranged from 40% (CoD) to 87% (lTI; group 1) and from 7% (EL) to 93% (DE; group 2). Therapeutic strategy changed in 31/51 (61%, 95% CI 47-74%), 14 with a reduction in planned therapy and 17 with an increase. CONCLUSION: MRE had a positive diagnostic impact in patients under investigation for small bowel Crohn's disease and this influenced therapeutic strategy in 61% of the patients.

Effect of rectal distension on voluntary external anal sphincter function in healthy subjects.

AIM: Quantification of the anorectal reflex function is critical for explaining the physiological control of continence. Reflex external anal sphincter activity increases with rectal distension in a dynamic response. We hypothesized that rectal distension would similarly augment voluntary external anal sphincter function, quantified by measuring the anal maximum squeeze pressure. METHOD: Fifty-seven subjects (32 men, 25 women; median age 62 years), with normal anal canal manometry and endoanal ultrasound results, underwent a rectal barostat study with simultaneous anal manometry. Stepwise isovolumetric 50-ml distensions (n=35) or isobaric 4-mmHg distensions (n=22) above the minimum distending pressure were performed (up to 200 ml or 16 mmHg respectively), whilst anal resting pressure and maximum squeeze pressure were recorded and compared with the baseline pressure. RESULTS: The distension-induced squeeze increment was calculated as the maximum percentage increase in maximum squeeze pressure with progressive rectal distension. This was observed in 53 of the 57 subjects as a mean ± standard deviation (range) increase of 32.8 ± 24.1 (-5.5 to 97.7)%. The mean ± standard deviation (range) distension-induced squeeze increment in male subjects was 36.1 ± 25.7 (-5.5 to 97.7)% and in female subjects was 28.1 ± 20.1 (-3.8 to 70.2)%. There was no significant difference between the sexes (P=0.194). CONCLUSION: Rectal distension augments external anal sphincter function, confirming the existence of a dynamic rectoanal response. This may represent a quantifiable and important part of the continence mechanism.

The role of ¹8fluoro-deoxy glucose combined position emission and computed tomography in the clinical management of anal squamous cell carcinoma.

AIM: Anal squamous cell carcinoma (SCC) is uncommon in the western world but continues to increase in incidence. Optimal treatment and outcome are dependent upon pretreatment staging strategies. We evaluate the role of ¹8fluoro-deoxyglucose (¹8FDG) combined position emission and computed tomography (PETCT) in the management of anal SCC. METHOD: Patients with a histologically confirmed anal SCC underwent standard staging investigations, including computed tomography, Magnetic resonance imaging and examination under anaesthetic. A tumour, node, metastasis (TNM) system was used. All patients subsequently underwent additional whole-body ¹8FDG PETCT scanning. Management was planned accordingly, blinded to ¹8FDG PETCT findings, at a multidisciplinary meeting, and reviewed again following disclosure of PETCT results. RESULTS: Forty patients (24 men), with a median age of 57 years (range 38-87 years), were prospectively recruited. All primary tumours were ¹8FDG avid. PETCT did not alter the T stage but did result in disease upstaging (N and M stages). Management was altered in five (12.5%) patients: one patient was identified to have an isolated distant metastasis, and four patients had ¹8FDG-avid lymph nodes not otherwise detected, all of which were tumour-positive on fine needle aspiration cytology/biopsy. CONCLUSION: PETCT upstages anal SCC and influences subsequent management. PETCT should be considered in the staging of anal SCC, although the definitive benefit of such a strategy requires further evaluation.

A 'living' prosthetic iris.

AIM: To design and demonstrate dynamic pupils, which react to light for use with ocular prostheses. METHODS: The realism of ocular prostheses is limited by the immobility of the pupil. Our solution is to use a liquid crystal display (LCD) in the prosthesis to vary the pupil size as a function of the ambient light. Several liquid crystal cells were fabricated and tested for survivability through the ocular prosthesis manufacturing process. The dynamic pupil is controlled by a novel and entirely autonomous, self-powered passive electronic circuit using a solar cell, matching the minimum diameter of the pupil. RESULTS: The first LCD surviving the rugged conditions of the ocular prosthesis manufacturing steps and an entirely passive circuit controlling the pupil have been demonstrated for the first time to our knowledge. A design for a complete prosthesis with a dynamic pupil has been proposed. Finally, a standard device for the mass production of ocular prostheses is presented. CONCLUSION: We have shown that a practical solution for an autonomous self-powered dynamic pupil is possible, given the constraints of size, fabrication process, weight, cost and manufacturability on a mass scale. We envision that the LCD could be mass produced, and only the final steps for the integration of the iris matched to a patient would be necessary before assembly using standard processing steps for the production of the prosthesis. Using a clinical trial, we hope to demonstrate that the dynamic pupil will have a positive impact on the quality of life of patients.

Analysis of innervation of human mesenteric vessels in non-inflamed and inflamed bowel--a confocal and functional study.

We investigated the distribution and density of perivascular nerves in human mesenteric arteries and veins and their responses to noradrenaline (NA), ATP and neuropeptide Y (NPY) in control (non-inflamed) and inflamed bowel, using confocal microscopy and in vitro pharmacology. The density of innervation at the adventitial-medial border of arteries and within the medial muscle coat of veins was increased in inflammatory bowel disease (IBD). Expression of markers for both sympathetic nerves and sensory-motor nerves was significantly increased in IBD. Calcitonin gene-related peptide-containing sensory-motor nerves were present in control arteries and IBD, but not in control veins. The density of 5-hydroxytryptamine-containing nerves was variable in controls, but consistently increased (three to four times) in IBD. Vasoactive intestinal peptide (VIP) expression increased (doubled) in arteries and veins. Arteries and veins contracted to NA and ATP, but only veins constricted to NPY. ATP contractions were reduced in arteries and veins in IBD, while contractions to NA were only slightly reduced. Neuropeptide Y induced significantly greater (20%) contractions of IBD veins. In summary, the density of sympathetic and sensory-motor innervation of both mesenteric arteries and veins was increased in IBD. Both 5-hydroxytryptamine and VIP immunoreactivity were also increased. The responses of both arteries and veins to ATP, and to a lesser extent NA, were reduced in IBD while responses to NPY were greater in veins. Decreased responses to ATP indicate changes in purinergic-mediated transmission in the pathological state.

Could a policy of provision of hip protectors to elderly nursing home residents result in cost savings in acute hip fracture care? The case of Ontario, Canada.

UNLABELLED: Hip fractures are an important problem in nursing homes. Hip protectors are external devices that decrease the risk of hip fracture in elderly nursing home residents. We estimated the overall healthcare cost savings from a hypothetical strategy of provision of hip protectors to elderly nursing home residents in Ontario, Canada. In a recent meta-analysis, we determined that a strategy of provision of hip protectors decreases the risk of hip fracture in nursing home residents. INTRODUCTION: Our objective was to determine whether the provision of hip protectors to all Ontario nursing home residents aged > or =65 years could result in cost savings, stemming from reductions in initial hospitalizations for hip fracture. METHODS: We conducted a cost analysis from a Ministry of Health perspective (one year cycle length). The efficacy of the intervention was estimated from a meta-analysis of randomized controlled trials. RESULTS: A strategy of provision of hip protectors to all 60,775 elderly Ontario nursing home residents could result in an overall mean cost savings of 6.0 million Canadian dollars in one year (95% credibility interval, -26.4 million, 39.7 million), with a probability of cost savings of 0.63 (assuming no additional labor costs). In sensitivity analyses, decreasing hip protector price increased cost savings, whereas additional labor expenditures for application for hip protectors decreased cost savings. CONCLUSION: In conclusion, if hip protectors can be provided to elderly Ontario nursing home residents without additional labor expenditures, there is a reasonable probability that such a strategy may result in healthcare cost savings.

Accuracy and test-retest precision of quantitative cartilage morphology on a 1.0 T peripheral magnetic resonance imaging system.

OBJECTIVE: Quantitative magnetic resonance imaging (qMRI) of knee cartilage morphology is a powerful research tool but relies on expensive and often inaccessible 1.5 T whole-body equipment. Here we examine the reproducibility and accuracy of qMRI at 1.0 T by direct comparison with previously validated technology. METHODS: Coronal images of the knee were obtained in six healthy and six osteoarthritic participants. Two data sets were acquired with a 1.5T whole-body magnetic resonance imaging (MRI) system and two with a 1.0 T peripheral MRI system, with repositioning between scans. Proprietary software was used to analyze surface area, volume, and thickness of femoral and tibial cartilage. RESULTS: At 1.0 T, precision errors for surface areas (root-mean-square (RMS) coefficient of variation (CV%)=1.7-2.6%) were higher than those at 1.5 T (1.0-2.1%). For volume and thickness, precision errors were 2.9-5.5% at 1.0 T compared to 1.6-3.4% at 1.5 T. High levels of agreement were found between the two scanners over all plates. With the exception of lateral femoral cartilage (volume and thickness), no statistically significant systematic bias was found between 1.0 T and 1.5 T. CONCLUSIONS: This is the first reported study to show that knee cartilage morphology can be determined with a reasonable degree of accuracy and precision using a 1.0 T peripheral scanner. Peripheral MRI is less costly, can be performed in clinical offices, and is associated with higher patient comfort and tolerance than 1.5 T whole-body MRI. Implementation of qMRI with peripheral systems may thus permit its more widespread use in clinical research and patient care.

Improving the morbidity of anorectal injury from pelvic radiotherapy.

OBJECTIVE: Radiation anorectal injury due to pelvic radiotherapy for non intestinal cancer is a significant cause of morbidity which may limit the treatment dose required. Conservative treatment options are of limited value and surgery is reserved only for the most severe complications. This review addresses radioprotection of the anorectum and aims to increase awareness amongst surgeons of the strategies that have been in practice in order to minimize the side-effects of radiotherapy while preserving its therapeutic efficacy. METHODS: This review is based on a literature search (Medline and NLM PubMed) with manual cross-referencing of all articles related to anorectal radiation injury. RESULTS: Optimization of radiation dose, the use of radioprotective agents and improvement in radiation delivery are the main areas of development. There are few data on the potential of altered fractionation schedules in reducing anorectal injury. A few phase I and II studies suggest that the pharmacological agents amifostine and misoprostol could be beneficial in limiting radiation damage but larger phase III studies are awaited. CONCLUSION: The introduction of 3-dimensional conformal radiation therapy and intensity modulated radiation therapy has been the most significant advance in reducing radiation morbidity.

Changes in vasoconstrictor and vasodilator neurotransmitters in nerves supplying arterioles in developing colorectal polyps.

OBJECTIVE: To examine the changes that occur in the immunohistochemistry of vasoconstrictor and vasodilator transmitters in nerves supplying early and advanced colorectal polyps. SUBJECTS AND METHODS: We studied the perivascular innervation of submucosal arterioles of colorectal polyps (n = 18) and the innervation of the epithelial layer of polyps compared to normal controls (n=8), using immunohistochemical markers for the neurotransmitters; noradrenaline (NA) (marker used; tyrosine hydroxylase (TH)), neuropeptide Y (NPY), vasoactive intestinal polypeptide (VIP), substance P (SP), and calcitonin gene-related polypeptide (CGRP). (Advanced polyps; villous adenomas>1.5 cm, polyps with severe dysplasia or partial carcinoma). RESULTS: In submucosal arterioles there was a progressive decrease from controls through early polyps to advanced polyps in TH and NPY perivascular immunoreactivity (P<0.015 for both). VIP and SP immunoreactivity was higher in early polyps compared to controls, but markedly reduced in advanced polyps (P<0.05 for VIP). Sparse CGRP immunoreactivity was present in polyps only. Neural VIP and SP immunoreactivity in the lamina propria of polyp mucosa was more intense than in controls. CONCLUSION: There is a decrease in vasoconstrictor neurotransmitters NPY and NA (shown by TH) around submucosal arterioles of both early and advanced polyps, but an increase in the vasodilator neurotransmitters, particularly VIP, in early colorectal polyps. These results suggest a predominantly vasodilatory neural influence in early polyps, perhaps indicating a mechanism that maintains polyp growth.

Is MSI-H of value in predicting the development of metachronous colorectal cancer?

Nearly 10% of patients with colorectal cancer (CRC) develop a metachronous cancer after curative resection of their primary malignancy, however identifying these patients is problematic. Although microsatellite instability (MSI) is associated with the development of multiple CRC, this is predominantly seen in those with hereditary non-polyposis colon cancer (HNPCC). This study has examined the value of MSI analysis in identifying patients at risk of developing metachronous cancer from the general population. MSI analysis was performed at the Bat25, Bat26, Bat40, D2S123, D5S346 and D17S250 loci using polymerase chain reaction and single-stranded conformational polymorphism on DNA extracted from 62 specimens taken from 49 patients with metachronous CRC, and from 71 primary single CRCs. MSI status was classified into MSI-H, MSI-L and MSS. MSI-H was more prevalent in metachronous cancers, 34/62 compared to 8/71 single cancers (P < 0.0001). The incidence of MSI-H from proximal colon cancers in index metachronous group, 4/22 was similar to single cancer group, 7/71 (P = 0.28), however MSI-H was more commonly identified in index metachronous cancers located distal to the splenic flexure 9/22 than single cancers 1/71 (P < 0.0001). Patients presenting with MSI-H colorectal cancers distal to the splenic flexure are more likely to develop a metachronous cancer and will benefit from surveillance.

The relationships between bone mineral density in the spine, hip, distal femur and proximal tibia and medial minimum joint space width in the knees of healthy females.

OBJECTIVE: To investigate the relationships between bone mineral density (BMD) in the hip, spine, distal femur and proximal tibia and minimum joint space width (mJSW) in the knees of healthy women. METHODS: Women 22-68 years old without a history of knee pain, bone or joint disease or injury underwent a single, fixed-flexion knee X-ray. Radiographs were graded according to the Kellgren-Lawrence scale and analyzed for mJSW using a computer algorithm. Dual X-ray absorptiometry scans of the spine, hip, distal femur and proximal tibia were also acquired for each participant. Femur and tibia scans were acquired and analyzed using a modified version of the lumbar spine software. RESULTS: Forty-five females, mean [standard deviation (SD)] age and body mass index (BMI) of 40.1 (13.9) years and 24.6 (4.5)kg/m(2), respectively, participated. The mean (SD) mJSW was 4.64 (0.68)mm. Linear regression analyses controlling for age and BMI revealed that BMD in the femoral trochanter and the central two regions of the tibia (T2 and T3) was significantly related to mJSW in the knee. A backwards regression analysis performed to determine which region of interest is most significantly related to mJSW revealed that femoral trochanter BMD (beta-value=0.416) is the most significant. CONCLUSIONS: In contrast to the suggestion that BMD is negatively correlated with mJSW in the knees of osteoarthritic individuals, these results suggest that increasing BMD in the femoral trochanter and tibia is significantly associated with increasing mJSW in healthy females. Further investigation of this relationship is warranted.

The role of MLH1, MSH2 and MSH6 in the development of multiple colorectal cancers.

There is increased incidence of microsatellite instability (MSI) in patients who develop multiple primary colorectal cancers (CRC), although the association with hereditary nonpolyposis colon cancer (HNPCC) is unclear. This study aims to evaluate the underlying genetic cause of MSI in these patients. Microsatellite instability was investigated in 111 paraffin-embedded CRCs obtained from 78 patients with metachronous and synchronous cancers, and a control group consisting of 74 cancers from patients with a single CRC. Tumours were classified as high level (MSI-H), low level (MSI-L) or stable (MSS). MLH1, MSH2 and MSH6 gene expression was measured by immunohistochemistry. Methylation of the MLH1 promoter region was evaluated in MSI-H cancers that failed to express MLH1, and mutational analysis performed in MSI-H samples that expressed MLH1, MSH2 and MSH6 proteins. The frequency of MSI-H was significantly greater in the multiple, 58 out of 111 (52%), compared to the single cancers, 10 out of 74 (13.5%), P < 0.01. Of the 32 patients from whom two or more cancers were analysed, eight (25%) demonstrated MSI-H in both cancers, 13 (41%) demonstrated MSI-H in one cancer and 11 (34%) failed to demonstrate any MSI-H. MSI-H single cancers failed to express MLH1 or MSH2 in seven out of nine (78%) cases and MSI-L/MSS cancers failed to express MLH1 or MSH2 in one out of 45 (2.2%) cases, all cancers expressed MSH6. MSI-H multiple cancers failed to express MLH1 or MSH2 in 21 out of 43 (48%) cases and MSI-L/MSS cancers failed to express MLH1 or MSH2 in four out of 32 (12.5%) cases. MSH6 expression was lost in five MSI-H multiple cancers, four of which also failed to express MLH1 or MSH2. Loss of expression of the same mismatch repair (MMR) gene was identified in both cancers from six out of 19 (31%) patients. Methylation was identified in 11 out of 17 (65%) multiple and three out of six (50%) single MSI-H cancers that failed to express MLH1. Mutational analysis of 10 MSI-H multiple cancers that expressed MLH1, MSH2 and MSH6 failed to demonstrate mutations in the MLH1 or MSH2 genes. We suggest that, although MSI-H is more commonly identified in those with multiple colorectal cancers, this does not commonly arise from a classical HNPCC pathway.

Anal intraepithelial neoplasia.

BACKGROUND: Anal intraepithelial neoplasia (AIN) is believed to be a precursor of anal squamous cell cancer and its incidence is rising in high-risk groups, particularly those infected with the human immunodeficiency virus (HIV). The natural history of AIN is unclear and management strategies are lacking. METHODS: This review is based on a literature search (Medline and PubMed) with manual cross-referencing of all articles related to AIN. RESULTS AND CONCLUSIONS: The aetiology of AIN is intricately linked with human papilloma viruses. The pathological processes involved in the progression of AIN are becoming clearer but the natural history, particularly the rate of progression to invasive cancer, remains unknown. There is no standard management for AIN and this is mainly due to difficulties in both diagnosis and treatment. A variety of treatment options have been tried with varying success. Surgery is associated with significant recurrence, particularly in HIV-positive patients. Non surgical approaches with imiquimod, photodynamic therapy and vaccination are appealing, and further work is required. Long-term follow-up of these patients is essential until the natural history of AIN becomes clearer.