RAD6 promotes DNA repair and stem cell signaling in ovarian cancer and is a promising therapeutic target to prevent and treat acquired chemoresistance.

Ovarian cancer (OC) is the most deadly gynecological cancer and unlike most other neoplasms, survival rates for OC have not significantly improved in recent decades. We show that RAD6, an ubiquitin-conjugating enzyme, is significantly overexpressed in ovarian tumors and its expression increases in response to carboplatin chemotherapy. RAD6 expression correlated strongly with acquired chemoresistance and malignant behavior of OC cells, expression of stem cell genes and poor prognosis of OC patients, suggesting an important role for RAD6 in ovarian tumor progression. Upregulated RAD6 enhances DNA damage tolerance and repair efficiency of OC cells and promotes their survival. Increased RAD6 levels cause histone 2B ubiquitination-mediated epigenetic changes that stimulate transcription of stem cell genes, including ALDH1A1 and SOX2, leading to a cancer stem cell phenotype, which is implicated in disease recurrence and metastasis. Downregulation of RAD6 or its inhibition using a small molecule inhibitor attenuated DNA repair signaling and expression of cancer stem cells markers and sensitized chemoresistant OC cells to carboplatin. Together, these results suggest that RAD6 could be a therapeutic target to prevent and treat acquired chemoresistance and disease recurrence in OC and enhance the efficacy of standard chemotherapy.

An atraumatic femoral fracture in a patient with rheumatoid arthritis and osteoporosis treated with denosumab.

Osteoporosis is responsible for a significant burden both individually and socially, but is readily treated with antiresorptive agents and mineral supplementation. However, long-term usage of these agents, notably bisphosphonates, is rarely associated with atypical fractures. Denosumab is a monoclonal antibody that reduces osteoclast activity and thus increases bone mineral density. In this case report, we present a 78-year-old woman with a background of rheumatoid arthritis and osteoporosis who presented with an atypical diaphyseal femoral fracture.

Osteopontin: an effector and an effect of tumor metastasis.

Osteopontin (OPN) is a matricellular protein that is produced by multiple tissues in our body and is most abundant in bone. It is also produced by cancer cells and plays a determinative role in the growth, progression and metastasis of cancer. Clinically, OPN has been reported to be upregulated in tumor cells per se; this is also reflected by increased levels of OPN in the circulation. Thus, increased OPN levels the plasma are an effect of tumor growth and progression. Functionally, high OPN levels are determinative of higher incidence of bone metastases in mouse models and are clinically correlated with metastatic bone disease and bone resorption in advanced breast cancer patients. Several research efforts have been made to therapeutically target and inhibit the activities of OPN. In this article we have reviewed OPN in its role as an effector of critical steps in tumor progression and metastasis, with a particular emphasis on its role in facilitating bone metastasis of breast cancer. We have also addressed the role of the host-derived OPN in influencing the malignant behavior of the tumor cells.

Hydroxyapatite-ceramic-coated femoral components in young patients followed-up for 16 to 19 years: an update of a previous report.

In 2004 we described the ten-year prospective results of 38 total hip replacements using the Furlong hydroxyapatite-ceramic-coated femoral component in 35 patients < 50 years old. We have now reviewed the surviving 35 arthroplasties in 33 patients at a mean of 16 years (10.3 to 19.9). The mean age of the surviving patients at the time of operation was 41.3 years (26.0 to 49.0). Of these, eight have undergone revision of their acetabular component for aseptic loosening. None of the femoral components has had revision for aseptic loosening giving a survival rate of 100% at 16 years (95% confidence interval 89% to 100%). The Furlong hydroxyapatite-ceramic-coated femoral component gives excellent long-term survival in young and active patients.

Focal femoral osteolysis after revision hip replacement with a cannulated, hydroxyapatite-coated long-stemmed femoral component: a new route for particulate wear debris.

We describe a case of symptomatic focal femoral osteolysis around a screw hole distal to the hydroxyapatite-coated portion of a cannulated femoral component in a revision hip replacement. No locking screw had been inserted into this, the most proximal of the three distal holes for locking screws. The presence of polyethylene wear debris in the tissue excised from the lesion suggested that it had passed through the cannulated portion of the stem and out of the proximal unfilled distal locking hole, initiating an osteolytic reaction in an otherwise well-fixed stem. This case highlights an important design characteristic of such cannulated, uncemented femoral components. We recommend that the proximal aperture of these cannulated stems be occluded at implantation.

The utility of the general practice research database to examine selected congenital heart defects: a validation study.

OBJECTIVE: The purpose of this research was (1) to validate that ventricular septal defect (VSD), tetralogy of Fallot (TOF), and coarctation of the aorta (COA) can be studied in the UK General practice research database (GPRD) and (2) to understand which of the available GPRD components (computerized medical records, questionnaires, and maternal/infant free text) provide maximal information about these heart defects. METHODS: Using a practitioner questionnaire, the positive predictive value (PPV) of the computerized medical record for VSD, TOF, and COA were determined. Both infant and maternal free text was examined. Concordance between the infant free text information and questionnaires was calculated. The proportion of infant information captured in the maternal free text was determined. RESULTS: A 93% response rate was achieved. Based on questionnaire responses, an overall PPV of 93.5% was achieved (VSD = 95%, TOF = 90%, COA = 100%). Approximately half of the records contained infant free text information including information on the type and size of VSD, echocardiogram findings, and surgery. Concordance between the infant's free text and questionnaire information occurred in most of the cases (92-100%). The proportion of infant information in the maternal free text was low (4-19%). CONCLUSION: The GPRD computerized medical records are sufficient to assess VSD, TOF, and COA. This study confirms that maternal free text provides a low yield of limited information pertaining to the infants' defect, while the infant free text may provide an additional information usually obtainable from practitioner questionnaires. The information provided by an infant free text may limit the need for practitioner questionnaire validation.

Bruising associated with sibutramine: results from postmarketing surveillance in New Zealand.

OBJECTIVE: To determine whether postmarketing data provide evidence of an association of sibutramine with bruising. DESIGN AND PATIENTS: During a postmarketing surveillance study of sibutramine in New Zealand by the Intensive Medicines Monitoring Programme (IMMP), a series of reports of bruising was identified. Further case reports were also obtained from the World Health Organisation (WHO) adverse drug reactions database. OUTCOME MEASURES: All platelet, bleeding and clotting events associated with sibutramine were identified and causality assessments were performed. RESULTS: From the IMMP and WHO databases a total of 16 cases of bruising that improved on withdrawal of sibutramine were identified. Of these, two had a recurrence of bruising on reintroduction of sibutramine. CONCLUSIONS: Evidence from postmarketing surveillance suggests that there is a causal association between sibutramine and bruising/ecchymosis. This represents a newly recognized adverse reaction for this medicine.

Domestic violence screening, policies, and procedures in Indian health service facilities.

BACKGROUND: Research shows that domestic violence against women in the United States is common, and the prevalence of domestic violence is high among Native American women. Victims of domestic violence can benefit from appropriate office intervention and referral. This study examined the effect of administrative and legal requirements on screening for domestic violence in Indian Health Service (IHS) hospitals and clinics. METHODS: A questionnaire was mailed using the total design method to all IHS hospitals and clinics regarding activities related to domestic violence: screening; policies and procedures; presence of committees; staff training; and state and tribal mandatory reporting requirements. RESULTS: The response rate was 65%. Eighty-eight (62%) of 142 facilities screen for domestic violence. A facility was more likely to screen if it had policies and procedures for domestic violence. Ninety-one (64%) of sites had policies and procedures for domestic violence. Less than one half these sites evaluated the use of these policies and procedures. Hospitals were more likely to have policies and procedures than clinics, as were sites administered by the IHS, rather than those administered by tribal contract. Fifty-eight (40.8%) facilities indicated 18 states have mandatory domestic violence reporting requirements. Thirty-three (23.2%) facilities indicated 31 different tribes mandate reporting of domestic violence. Forty-two (29.6%) facilities reported mandatory staff training in at least one topic related to domestic violence in the past year. CONCLUSIONS: Domestic violence policies and procedures promote screening for this important health care problem.

Is there an association between selective serotonin reuptake inhibitors and risk of abnormal bleeding? Results from a cohort study based on prescription event monitoring in England.

OBJECTIVE: To investigate whether an association between the use of selective serotonin reuptake inhibitor (SSRI) antidepressants and abnormal bleeding is demonstrated in a large population study. METHODS: An observational cohort study using cohorts from the Drug Safety Research Unit's prescription event monitoring database was performed. RESULTS: Analysis of combined haemorrhagic event rates calculated for the first 6 months of treatment for four SSRIs showed no significant difference between the rate for abnormal bleeding in the first month after starting treatment compared with months 2-6 [difference in rates 0.63 per 1000 patient months of treatment, 99% confidence interval (CI) -0.4, 1.67]. Comparison of the rates for the exposed combined SSRI cohort with the unexposed non-psychiatric drug cohort for the first month [relative risk (RR) 1.38, 95% CI 0.82, 2.34] and months 2-6 (RR 1.17, 95% CI 0.81, 1.68) showed no significant differences after adjustment for age and gender. However, there was a tendency towards highest risk with the combined SSRI cohort and lowest with the baseline cohort. CONCLUSION: This study provides weak evidence to support the hypothesis of a link between SSRIs and precipitation of bleeding events at a population level. The 95% CI is consistent with a possible risk of bleeding associated with SSRI users versus non-psychiatric drug users in the first month. Fuller consideration of confounding would be possible using follow-up of identified cases in a nested case-control study.

Profiles of hepatic and dysrhythmic cardiovascular events following use of fluoroquinolone antibacterials: experience from large cohorts from the Drug Safety Research Unit Prescription-Event Monitoring database.

OBJECTIVE: To investigate how frequently serious dysrhythmic cardiovascular, and hepatotoxic events are reported during routine clinical use of fluoroquinolones (quinolones) in general practice. DESIGN: Cohorts prescribed quinolones (cohort sizes: ciprofloxacin 11 477; enoxacin 2790; ofloxacin 11 033 and norfloxacin 11 110; mean age in each cohort of 48.6 to 57.0 years) were selected from the Drug Safety Research Unit's Prescription-Event Monitoring (PEM) database. The monitoring periods were November 1988 to January 1989 for ciprofloxacin; April 1989 to January 1991 for enoxacin; May 1991 to December 1991 for ofloxacin and October 1990 to October 1991 for norfloxacin. Data collected over the total PEM surveillance period on selected gastrointestinal events were extracted and reviewed to identify possible hepatic events, together with selected cardiovascular events associated with dysrhythmias. For each quinolone, times to onset of the event and patient-months of observation (denominator values) were calculated. The analysis was based on two observation periods: rate of event during the first 7 days following dispensing of a prescription for each drug (W(1)), and rate of event during the second to sixth week inclusive (W(2)). RESULTS: Scrutiny of original green forms revealed no evidence of drug-induced hepatic dysfunction within 42 days of drug administration for any of the quinolones monitored. No evidence was found of drug-induced dysrhythmic events associated with enoxacin within 42 days of drug administration. Of the other quinolones, 'atrial fibrillation' was reported most often within 42 days following ciprofloxacin administration, with no change in event rate over that time, crude relative risk (CRR)[W(1)/W(2)] 1.0 [95% confidence interval (CI) 0.02 to 8.92]. Other less serious events associated with dysrhythmia were reported with varying incidence within 42 days of quinolone administration. The crude rate of palpitation did not change significantly over that time for ciprofloxacin, ofloxacin and norfloxacin: CRR 0.83 (95% CI 0.02 to 6.86), 2.00 (95% CI 0.19 to 12.20) and 4.99 (95% CI 0.06 to 391.94), respectively. Syncope and tachycardia were also reported for ofloxacin [CRR 9.99 (95% CI 0.52 to 589.49 for both events)] and ciprofloxacin [1.0 (95% CI 0.02, 8.92)] and 2.50 (95% CI 0.04, 47.96) for syncope and tachycardia, respectively]. CONCLUSION: It cannot be ruled out that some rare hepatic and dysrhythmic events associated with quinolones may be drug related. The primary purpose of PEM is signal generation. Compared with the other quinolones, ciprofloxacin was associated with the highest number of reports of dysrhythmic cardiovascular events occurring within 42 days of administration. This requires further investigation by other types of epidemiological study.

A comparison of the use, effectiveness and safety of bezafibrate, gemfibrozil and simvastatin in normal clinical practice using the New Zealand Intensive Medicines Monitoring Programme (IMMP).

AIMS: Because of the importance of treating dyslipidaemia in the prevention of ischaemic heart disease and because patient selection criteria and outcomes in clinical trials do not necessarily reflect what happens in normal clinical practice, we compared outcomes from bezafibrate, gemfibrozil and simvastatin therapy under conditions of normal use. METHODS: A random sample of 200 patients was selected from the New Zealand Intensive Medicines Monitoring Programme's (IMMP) patient cohorts for each drug. Questionnaires sent to prescribers requested information on indications, risk factors for ischaemic heart disease, lipid profiles with changes during treatment and reasons for stopping therapy. RESULTS: 80% of prescribers replied and 83% of these contained useful information. The three groups were similar for age, sex and geographical region, but significantly more patients on bezafibrate had diabetes and/or hypertension than those on gemfibrozil or simvastatin. After treatment and taking the initial measure into account, the changes in serum lipid values were consistent with those generally observed, but with gemfibrozil being significantly less effective than expected. More patients (15.8%S) stopped gemfibrozil because of an inadequate response compared with bezafibrate (5.4%) and simvastatin (1.6%). Gemfibrozil treatment was also withdrawn significantly more frequently due to a possible adverse reaction compared with the other two drugs. CONCLUSIONS: In normal clinical practice in New Zealand gemfibrozil appears less effective and more frequently causes adverse effects leading to withdrawal of treatment than either bezafibrate or simvastatin.

Colonoscopic miss rates of adenomas determined by back-to-back colonoscopies.

BACKGROUND & AIMS: The miss rate of colonoscopy for neoplasms is poorly understood. The aim of this study was to determine the miss rate of colonoscopy by same day back-to-back colonoscopy. METHODS: Two consecutive same day colonoscopies were performed in 183 patients. The patients were randomized to undergo the second colonoscopy by the same or a different endoscopist and in the same or different position. RESULTS: The overall miss rate for adenomas was 24%, 27% for adenomas < or = 5 mm, 13% for adenomas 6-9 mm, and 6% for adenomas > or = 1 cm. Patients with two or more adenomas at the first examination were more likely than patients with no or one adenoma detected at the first examination to have one or more adenomas at the second examination (odds ratio, 3.3; 95% confidence interval, 1.69-6.46). Right colon adenomas were missed more often (27%) than left colon adenomas (21%), but the difference was not significant. There was evidence of variation in sensitivity between endoscopists, but significant miss rates for small adenomas were found among essentially all endoscopists. CONCLUSIONS: Using current colonoscopic technology, there are significant miss rates for adenomas < 1 cm even with meticulous colonoscopy. Miss rates are low for adenomas > or = 1 cm. The results suggest the need for improvements in colonoscopic technology.

Motivational orientations of urban- and rural-based RNs: implications for staff development educators.

Part of professional development is influencing RNs to return for an undergraduate degree, a challenge for the staff development educator. Expanding on earlier research using Boshier's Educational Participation Scale to reveal motivational orientations, the authors queried 5 groups of RNs who were enrolled in BSN education between 1990 and 1992 (N = 235) and living in rural and urban areas of Texas. There were no significant differences of overall motivational orientations, yet RN students living in rural areas scored higher in professional knowledge (P = 0.03) whereas urban-based RN students scored higher in compliance with authority (P = 0.02). Specific marketing and educational strategies are discussed.

The prescribing and adverse reactions of nonsteroidal antiinflammatory drugs in general practice: a Dunedin study.

AIMS: The aims of this study were to describe the prescribing of nonsteroidal antiinflammatory drugs (NSAIDs) by some general practitioners and to assess the information recorded on computer records on their use in individual patients so that techniques could be developed for a broader investigation of the topic in general practice. METHODS: All prescribing and consulting data from five Dunedin practices was reviewed for a 6 month period. From all consultations generating a prescription for NSAIDs, data was collected relating to the name of the drug, dosage, strength and length of treatment and patient demographic and morbidity details. Recorded adverse drug reactions were classified into six groups and four age groups were used for the analysis. RESULTS: Prescriptions for NSAIDs accounted for 2.6% of all items prescribed. Diclofenac was the most commonly prescribed NSAID, for most conditions, but menstrual problems were more likely to be treated with mefenamic acid. Coprescription of possibly contraindicated medications (usually antihypertensive medicines) occurred for 20.8% of patients. Gastric adverse reactions were reported in 3% of cases while 0.9% of prescriptions resulted in no change in condition, leading to a change in therapy. Aspirin, fenbufen, ketoprofen, sulindac and flurbiprofen were never prescribed for patients under 20 years old. CONCLUSION: Routinely recorded patient and prescribing information from general practice permits an assessment of the use of NSAIDs which includes the conditions for which they are prescribed, the total numbers prescribed, concurrent medications prescribed and their recorded adverse effects. This is not possible from any other source. Data from clinical trials provides an incomplete assessment of the use of these medications in general practice.

Diabetic gastroparesis. What to do when gastric emptying is delayed.

Diagnostic evidence or symptoms of gastroparesis develop in about 20% to 30% of patients with long-standing diabetes. Diabetic gastroparesis is likely caused by autonomic neuropathy involving the nerves that regulate gastric motor function. The following are necessary for diagnosis: thorough history taking and physical examination to eliminate factors that might further delay gastric emptying; esophagogastroduodenoscopy or barium contrast studies to exclude structural abnormalities; and a radionuclide gastric emptying study. The three main agents available for therapy in the United States are metoclopramide (Maxolon, Octamide, Reglan), erythromycin, and cisapride (Propulsid). All have been shown to offer benefit in improving gastric emptying and symptoms, although use of metoclopramide is limited by a significant incidence of side effects. Surgical intervention should be avoided if possible.

Neuropsychiatric reactions to nonsteroidal anti-inflammatory drugs (NSAIDs). The New Zealand experience.

The New Zealand Medicines Adverse Reactions Committee has been monitoring reports of adverse drug reactions (ADRs) since 1965. We wished to determine the numbers of voluntary reports of different types of ADR to all nonsteroidal anti-inflammatory drugs (NSAIDs) over a long time period and relate these to age. As the elderly are known to suffer from neuropsychiatric adverse effects of many drugs, we investigated neuropsychiatric reactions to NSAIDs to determine whether these were more commonly reported in the elderly. We counted all reported ADRs suspected to be associated with NSAIDs as well as selected types of ADRs reported from 1970 to 1989. These were divided into 5-year periods and 10-year age groupings. In each consecutive 5-year period there was a progressive increase in the numbers of all ADRs reported for all NSAIDs. This was particularly marked above 50 years of age, but the numbers were reduced above 80 years. Reports for females accounted for about two-thirds of all reactions. Not unexpectedly, alimentary and dermatological ADRs accounted for most reactions and were more common in the group above 50 years. Overall, neuropsychiatric reactions were the third most common ADR type reported. Their numbers increased with age and peaked in the 50 to 59 age group, with a sharp decline after 69 years. This age distribution paralleled that for all ADRs to NSAIDs. Although neuropsychiatric reactions to NSAIDs were reported in all age groups, they were not reported more commonly in the elderly. This study suggests that neuropsychiatric reactions to NSAIDs may be more frequent than is commonly believed.

General practitioners' views on the role of the community pharmacist.

AIM: to determine the views of general practitioners on the roles and activities of community pharmacists. METHOD: the views of 137 general practitioners in Otago and Southland were canvassed by postal questionnaire. RESULTS: one hundred and three completed questionnaires were returned. All of the general practitioners reported that their professional contact with pharmacists was useful. Seventy-five percent expressed a desire for greater cooperation. Nearly all respondents (99%) accepted that pharmacists have a role in screening prescriptions for possible problems and preparing and dispensing medicines. They also accepted that pharmacists were capable of treating and advising in the management of minor illnesses. Providing drug information to general practitioners, information about previously diagnosed conditions to patients, and advice on personal and home hygiene were less widely accepted activities. The majority indicated that they considered it inappropriate for pharmacists to undertake screening programmes (blood pressure (70.6%), cholesterol (70.6%), glucose (60.8%), haemoglobin (72.5%)). Younger general practitioners objected more often than older general practitioners to reclassification of Acetopt eye drops from prescription only to availability through pharmacies (p < 0.05). Female general practitioners were more often in favour of reclassification of Gyno-Daktarin than their male colleagues (p < 0.05). CONCLUSION: this study shows that general practitioners accept several aspects of the current role of pharmacists in providing primary health care. However, there is room for improved communication between general practitioners and pharmacists to ensure optimum patient care.

Knowledgeable non-compliance with prescribed drugs in elderly subjects--a study with particular reference to non-steroidal anti-inflammatory and antidepressant drugs.

Knowledgeable non-compliance with non-steroidal anti-inflammatory drugs (NSAIDs) and antidepressant drugs was investigated in a community-based sample of elderly people. Everyone 70 years and over living in a defined area and taking one of the above drugs, and at least one other prophylactic or symptomatic drug, was studied. Non-steroidal anti-inflammatory drugs and antidepressant drugs are commonly regarded as symptomatic only and knowledgeable non-compliance is consequently high. They are also regarded as less important than drugs which produce no immediate relief of symptoms but which the patient recognizes as needing to be taken regularly to maintain health. In our study, compliance with non-steroidal anti-inflammatory drugs and antidepressant drugs was highest in those who were compliant with a prophylactic drug and were also taking a symptomatic drug. The greater the number of tablets the patient was taking the more likely he or she was to be compliant with the NSAID. Compliance with NSAIDs and antidepressant drugs requires clear label instructions and the patient knowing the purpose of the medication.

Technical aspects of the use of the Russell-Taylor reconstruction nail.

The introduction of the reconstruction nail has broadened the indications for the intramedullary fixation of difficult femoral fractures. The operative technique is, however, complicated. Some technical difficulties encountered during its use are presented, together with guidance to allow these problems to be avoided.