Ankylosing Spondylitis Response to TNF Inhibition Is Gender Specific: A 6-Year Cohort Study

Aim Recent studies have suggested gender-specific differences with respect to both baseline disease activity and severity in ankylosing spondylitis (AS). Tumour necrosis factor inhibitors (TNFi) have shown significant benefit in AS but there may be gender-specific differences regarding responses to TNFi therapy. Methods AS patients with active disease despite adequate trials of NSAIDs were commenced on TNFi and followed in a biologic clinic between 2004 and 2011. Response to treatment was measured based on clinical and serological outcomes. Baseline radiographic data were also collected where available. Results 147 AS patients commenced TNFi therapy and were followed in a biologic clinic between 2004 and 2011. One-hundred and six (72%) of the patients were male and 90 (61%) were current or ex-smokers. The specific TNFi prescribed included etanercept (74 patients, 50.3%), adalimumab (51 patients, 34.7%), infliximab (21 patients, 14.2%) and golimumab (1 patient, 0.7%). The median mSASSS score was 11 (interquartile range 5-35). At baseline, the metrology indices (BASMI) were significantly lower in women (2.6 v 4; p=0.01) but all other clinical indices were similar. At 3 months, female patients had significantly worse median disease activity and functional indices (BASDAI: 4 v 2; p<0.01; BASFI: 3 v 2; p=0.03) than male patients. In addition, females had higher median ESR (19 v 6; p<0.01) which correlated with their disease activity indices (r=0.42, p=0.02). Discussion Despite similar disease activity at baseline, post-TNFi therapy women had significantly higher disease activity. Furthermore, ESR levels in women during therapy correlated with their clinical disease activity scores. Further exploration of these gender-specific differences is crucial for a greater understanding of the pathogenesis of AS as well as development of targeted therapies.

Guideline Promotion Increases Prescription of Bone Protection with Steroids in Hospitalised Patients.

Guidelines for the prevention of glucocorticoid (GC) induced osteoporosis (GIOP) were implemented in a level 5 Irish Hospital with cross sectional audit of inpatient prescribing undertaken before and after. Prior to guideline implementation, elemental calcium (Ca) with Vitamin D (VitD) was prescribed for 11/66 (17%) of patients on GCs with 2/66 (3%) also receiving bisphosphonate (BP) therapy. Subsequent to guideline implementation, Ca with VitD was prescribed for 19/55 (35%) of patients on GCs with 11/55 (20%) also receiving BP therapy, representing a 2 and 6 fold respective increase. Internal promotion of guidelines is an effective strategy for healthcare improvement but needs refinement with or without repetition to achieve better patient outcomes.

Joint tenderness and swelling in biologic-treated inflammatory arthritis patients - a tricky trade off?

OBJECTIVE: To compare the pattern of joint responses in patients with rheumatoid arthritis and psoriatic arthritis treated with TNF inhibitor (TNFi) therapy. METHODS: A total of 182 PsA/Rheumatoid arthritis (RA) patients attending the rheumatology unit of a tertiary referral centre in Ireland were recruited and prospectively followed up by the attendant rheumatologists. Clinical progress of the patients was noted at baseline and 6 months after starting TNFi therapy. RESULTS: A total of 114 RA and 68 PsA patients were assessed; 20% of the patients had one of either tender joints or swollen joints after 6 months of therapy. Rheumatoid arthritis patients had a significantly higher proportion of non-tender swollen joints compared with PsA patients, whereas PsA patients had a higher proportion of tender non-swollen joints (p < 0.05). CONCLUSION: Residual joint swelling was found more commonly in RA patients than in PsA patients following TNFi therapy, whereas residual tender joints occurred more frequently in PsA; this may reflect enthesiopathy or periostitis.

Panton Valentine leukocidin MSSA leading to multi-organ failure.

We report a case of a 15-year-old boy who developed multiple organ failure secondary to a sport injury leading to infection with a Panton Valentine Leukocidin (PVL) secreting Community-Acquired Methicillin Sensitive Staphylococcus Aureus (CA MSSA). Aggressive antibiotic therapy eventually led to recovery.

Alcohol dehydrogenase 3 genotype and risk of oral cavity and pharyngeal cancers.

BACKGROUND: The consumption of alcoholic beverages is a strong risk factor for cancers of the oral cavity and pharynx (oral cancers). Alcohol dehydrogenase type 3 (ADH3) metabolizes ethanol to acetaldehyde, a carcinogen. We evaluated whether individuals homozygous for the fast-metabolizing ADH3(1) allele (ADH3[1-1]) have a greater risk of developing oral cancer in the presence of alcoholic beverage consumption than those with the slow-metabolizing ADH3(2) allele (ADH3[1-2] and ADH3[2-2]). METHODS: As part of a population-based study of oral cancer conducted in Puerto Rico, the ADH3 genotypes of 137 patients with histologically confirmed oral cancer and of 146 control subjects (i.e., individuals with no history of oral cancer) were determined by molecular genetic analysis of oral epithelial cell samples. Risks were estimated by use of multiple logistic regression analyses. RESULTS: Compared with nondrinkers with the ADH3(1-1) genotype, consumers of at least 57 alcoholic drinks per week with the ADH3(1-1), ADH3(1-2), and ADH3(2-2) genotypes had 40.1-fold (95% confidence interval [CI] = 5.4-296.0), 7.0-fold (95% CI = 1.4-35.0), and 4.4-fold (95% CI = 0.6-33.0) increased risks of oral cancer, respectively; the risk associated with the ADH3(1-1) genotype, compared with the ADH3(1-2) and ADH3(2-2) genotypes combined, was 5.3 (95% CI = 1.0-28.8) among such drinkers. Considering all levels of alcohol consumption, the risk of oral cancer per additional alcoholic drink per week increased 3.6% (95% CI = 1.9%-5.4%) for subjects with the ADH3(1-1) genotype and 2.0% (95% CI = 0.9%-3.0%) for subjects with the ADH3(1-2) or ADH3(2-2) genotype (two-sided P = .04). CONCLUSIONS: The ADH3(1-1) genotype appears to substantially increase the risk of ethanol-related oral cancer, thus providing further evidence for the carcinogenicity of acetaldehyde.

Collection of buccal cell DNA using treated cards.

We devised a simple, noninvasive, cost-efficient technique for collecting buccal cell DNA for molecular epidemiology studies. Subjects (n = 52) brushed their oral mucosa and expectorated the fluid in their mouths, which was applied to "Guthrie" cards pretreated to retard bacterial growth and inhibit nuclease activity (IsoCode, Schleicher and Schuell, Keene, NH). The cards are well-suited for transport and storage because they dry quickly, need no processing, and are compact and lightweight. We stored the samples at room temperature for 5 days to mimic a field situation and then divided them into portions from which DNA was extracted either immediately or after storage for 9 months at room temperature, -20 degrees C, or -70 degrees C. The fresh samples had a median yield of 2.3 microg of human DNA (range, 0.2-53.8 microg), which was adequate for at least 550 PCR reactions. More than 90% of the samples were amplified in all three beta-globin gene fragment assays attempted. DNA extract frozen for 1 week at -20 degrees C also performed well. Stored samples had reduced DNA yields, which achieved statistical significance for room temperature and -70 degrees C, but not -20 degrees C, storage. However, because all of the stored samples tested were successfully amplified, the observed reduction may represent tighter DNA fixation to the card over time rather than loss of genetic material. We conclude that treated cards are an alternative to brushes/swabs and mouth rinses for the collection of buccal cell DNA and offer some advantages over these methods, particularly for large-scale or large-scale or long-term studies involving stored samples and studies in which samples are collected off-site and transported. Future studies that enable direct comparisons of the various buccal cell collection methods are needed.

p53 mutations and occupational exposures in a surgical series of lung cancers.

p53 mutations are frequent in malignant lung tumors. Of 88 surgically treated lung cancers from cigarette smokers previously evaluated for p53 mutations, 45 tumors (51.1%) had mutations in exons 5-8 (D. G. Guinee, Jr. et al., Carcinogenesis (Lond.), 16: 993-1002, 1995). We report here the examination of 13 occupational exposures and 13 high-risk occupations in relation to these p53 mutations. Two molecular abnormalities were associated with occupational exposures: (a) G:C-->T:A transversions on the coding (nontranscribed) strand (n = 13) were associated with chromate exposure and employment in the metal industry (P < 0.05) and marginally associated with nickel exposure (P = 0.056); and (b) G:C-->A:T transitions at non-CpG sites (n = 9) were associated with work in the petrochemical industry (P = 0.05). No association was found between p53 mutations and gender, cigarette pack-years, tumor histology, age at diagnosis, or family history of lung cancer. Because all three chromate-exposed subjects had large cell carcinomas exhibiting G: C-->T:A coding-strand transversions, follow-up of a cohort with this exposure should clarify the association with the p53 gene.

Postmortem distribution of mexiletine in a fatal overdose.

A case involving a fatal overdose of mexiletine is presented. Quantitation of the drug was accomplished by gas chromatography with a flame-ionization detector. The presence of mexiletine was confirmed by gas chromatography-mass spectrometry. Toxicological analysis revealed the following tissue distribution of mexiletine: heart blood, 44.8 micrograms/mL; femoral blood, 10.0 micrograms/mL; vitreous, 8.6 micrograms/mL; liver, 171.6 micrograms/g; brain, 84.0 micrograms/g; and gastric contents, 1464 mg.

Dual energy X-ray absorptiometry analysis of peri-prosthetic stress shielding in the Birmingham resurfacing hip replacement.

INTRODUCTION: Numerous reports in the literature refer to the femoral neck fracture rate in hip resurfacing. The aim of this study was to determine the bone mineral density and evidence of stress shielding around the femoral component of the Birmingham resurfacing prosthesis. MATERIAL AND METHODS: Twenty-eight patients with primary unilateral osteoarthritis had a Birmingham resurfacing prosthesis. DEXA analysis of the proximal femur and femoral neck was performed and compared with the opposite unaffected side. RESULTS: Total periprosthetic bone mineral density was 0.49% greater than the control, but this did not achieve statistical significance. Although the BMD of the femoral neck was slightly increased on the prosthetic side (1.002 g/cm2) as opposed to the control side, this difference did not reach statistical significance. CONCLUSION: The Birmingham resurfacing prosthesis does not appear to reduce femoral neck bone mineral density in comparison to the normal femoral neck bone density. We conclude that femoral neck fractures are unlikely to be due to stress shielding related to the prosthesis.

Implementing a strategic recruitment and retention plan.

Nurse administrators were faced with how to staff for a rapid expansion in number of beds in the face of a 15% nurse vacancy rate. The authors discuss how they addressed this issue through their multifaceted strategic plan.

Sudden unexpected death in a male homosexual cohort.

There has been considerable debate as to the risk of suicide, accidents, and homicide in populations at high risk for HIV infection. The purpose of the present investigation was to determine the incidence of sudden and unexpected deaths in a well-defined cohort of homosexual and bisexual men prospectively studied since 1984. All subjects were enrolled in the Pitt Men's Study, the Pittsburgh, Pennsylvania, component of the Multicenter AIDS Cohort Study. Of this group, 861 were between the ages of 20 and 44, and 35% were seropositive for HIV. There were 70 deaths attributed to AIDS. Five additional deaths were classified as sudden and unexpected, an annual rate of 0.08% (80/100,000). Only one of these was classified by the coroner's office as a suicide; three were due to accidents, and one was a drug overdose of undetermined cause. Only two of the five unexpected deaths were HIV seropositive, and none had the diagnosis of AIDS. The sudden and unexpected death rate in this cohort did not significantly differ from the 0.07% (70/100,000) yearly incidence in the age- and race-matched male population. Thus, in this well-defined male gay cohort, there does not appear to be an increased risk of violent and drug-related deaths in persons at risk for, or with a diagnosis of, AIDS.

Self-collection of oral epithelial cell DNA under instruction from epidemiologic interviewers.

Oral epithelial cells provide an easily accessible source of germline DNA. Two methods for collection were compared in a 1992-1995 case-control study of oral cancer in Puerto Rico. One group of subjects (55 controls without oral cancer) collected oral rinse samples at home or work under the direction of a nonmedically trained interviewer ("self-collection"); the other group (94 controls) participated in a clinic-based collection, which also included blood and urine samples, conducted by a medical technician ("clinic collection"). Participation was higher for self-collection (98.2%) than for clinic collection (70.7%) (p < 0.001). DNA yields ranged from 2.0 to 204.5 microg (median, 25.9 microg) and did not differ by collection method, although yields varied by interviewer among self-collected samples (p = 0.02). Success rates for polymerase chain reaction amplification of the ADH3, NAT1, and multiplex CYP1A1/GSTT1/GSTM1 genotyping assays ranged from 76.4% (NAT1) to 98.2% (ADH3) for self-collected samples and were similar to those for clinic-collected samples (87.2-97.9%). Failure to amplify was associated with low DNA content (p = 0.015). Similar results were observed among cases (91 self-collected, 66 clinic collected), except that DNA yields did not vary by interviewer and a larger fraction (10.2%) of samples contained less than 5 microg of DNA, perhaps because of disease-related oral impairment. Self-collection of oral epithelial DNA samples appears satisfactory and efficient for many epidemiologic studies.

A clinical comparison of the anterolateral and posterolateral approaches to the hip.

Patients who had anterolateral and posterolateral approaches in total hip replacement surgery were compared clinically for limp, dislocation, hospital stay, and discharge disposition. The only statistical difference was that the posterior approach had a statistically higher dislocation rate. Although the number of patients with limp was higher in the anterolateral group, the difference was not statistically different.

Tobacco and alcohol use and oral cancer in Puerto Rico.

OBJECTIVES: To determine risk for oral cancer in Puerto Rico associated with use of alcohol and tobacco. METHODS: In Puerto Rico, alcohol and tobacco use were compared among nonsalivary gland cancers of the mouth and pharynx (n = 342), cancers of major and minor salivary glands (n = 25) and 521 population-based controls. RESULTS: Alcohol (usual use, Ptrend < 0.0001 for men and Ptrend = 0.02 for women) and tobacco (usual use, Ptrend < 0.0001, for both men and women) were strong independent risk factors for oral cancer in Puerto Rico, with a multiplicative effect from combined exposures. Risks did not vary systematically by use of filter vs. nonfilter cigarettes. Risks with use of other forms of smoked tobacco were about sevenfold among both men and women. Risks decreased only gradually after cessation of tobacco and alcohol use. Tobacco use, but not alcohol, was linked to cancers of the salivary glands. The burden of oral cancer due to alcohol and tobacco use in Puerto Rico (76% for men, 52% for women) agreed closely with earlier estimates for the mainland US population, while about 72% of salivary gland cancer (men and women, combined) was due to tobacco use. CONCLUSIONS: Excess risks for oral cancer in Puerto Rico are largely explained by patterns of alcohol and tobacco use. Smoking filter vs. nonfilter cigarettes does not alter risk, while cessation of alcohol and tobacco use appears to reduce risk only gradually.

Mouthwash in the etiology of oral cancer in Puerto Rico.

OBJECTIVES: To determine if the risk of cancers of the mouth and pharynx is associated with mouthwash use in Puerto Rico, an area of relatively high risk. METHODS: Interviews were conducted with 342 cases of oral and pharyngeal cancer registered in Puerto Rico and diagnosed between 1992 and 1995 and with 521 population-based controls regarding mouthwash use and other factors. Mouthwash-related risks were estimated using unconditional logistic regression controlling for potential confounders. RESULTS: The adjusted odds ratio associated with using mouthwash with an alcohol content of 25% or greater was 1.0. Risks were not higher with greater frequency, years of use, or lifetime mouthwash exposure. Among tobacco and alcohol abstainers the odds ratio associated with mouthwash use was 2.8 (CI = 0.8-9.9), in contrast to 0.8 (CI = 0.4-1.7) and 0.9 (CI = 0.6-1.3) among those with light and heavy cigarette smoking/alcohol drinking behaviors, respectively. CONCLUSIONS: There was no overall increased risk of oral cancer associated with mouthwash use. An elevated, but not statistically significant, risk was observed among the small number of subjects who neither smoked cigarettes nor drank alcohol, among whom an effect of alcohol-containing mouthwash would be most likely evident. Our findings indicate the need to clarify the mechanisms of oral carcinogenesis, including the possible role of alcohol-containing mouthwash.

Family cancer history and susceptibility to oral carcinoma in Puerto Rico.

BACKGROUND: Use of alcohol and tobacco are the major risk factors for cancers of the oral cavity and pharynx in most of the world. A heritable component to oral carcinoma risk also has been suggested, although only limited data are available on familial aggregation of this disease. METHODS: A population-based case-control study of 342 subjects with carcinomas of the oral cavity and pharynx (oral carcinoma) and 521 controls was conducted in Puerto Rico. The relation between family history of carcinomas of the oral cavity, the upper aerodigestive tract (UADT), and other selected sites with risk of oral carcinoma was explored using logistic regression modeling techniques. RESULTS: Risk of oral carcinoma was elevated for subjects reporting a first-degree relative with carcinoma of the oral cavity (odds ratio [OR], 2.5; 95% confidence interval [CI], 0.8-8.0) or any UADT carcinoma (OR, 2.6; 95% CI, 1.4-4.8). The increased risk associated with family history of UADT carcinoma tended to be greatest for subjects with known risk factors (i.e., heavy consumption of alcohol and/or tobacco and infrequent intake of raw fruits and vegetables) and with oral carcinoma diagnoses at ages younger than 65 years. CONCLUSIONS: These findings are consistent with a heritable component to oral carcinoma, although shared lifestyle risk factors may be partially involved.

Alcohol dehydrogenase 3 genotype modification of the association of alcohol consumption with breast cancer risk.

OBJECTIVES: Because alcohol dehydrogenase 3 (ADH3) is rate-limiting in alcohol oxidation and is polymorphic, we examined ADH3 genotype in relation to alcohol intake and breast cancer risk. METHODS: We conducted a case-control study among Caucasian women aged 40-85 with incident, pathologically confirmed breast cancer and controls, frequency-matched on age and county. Queries included alcohol intake in the past 20 years. Genomic DNA was genotyped for the exon VIII ADH polymorphism by PCR followed by restriction enzyme digestion. Computation of odds ratios (OR) and 95% confidence intervals (CI) was by unconditional logistic regression. RESULTS: We found increased risk among pre- (OR 2.3, 95%, CI 1.2-4.3) but not postmenopausal women (OR 1.1, 95% CI 0.7-1.7) associated with ADH3(1-1) compared to ADH3(1-2) and ADH3(2-2) genotypes. Risk was increased for premenopausal women with the ADH3(1-1) genotype and alcohol intake above the median (OR 3.6, 95% CI 1.5-8.8) compared to lighter drinkers with the ADH3(2-2) or ADH3(1-2) genotypes. ORs were close to null for premenopausal women in other drinking and genotype groups and for postmenopausal women categorized by genotype and alcohol consumption. CONCLUSION: Among premenopausal women there may be a group more genetically susceptible to an alcohol consumption effect on breast cancer risk.