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.

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.

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.

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.

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.

[Respiratory function in idiopathic scoliosis in adolescents treated by Harrington instrumentation with or without sublaminar segmental wiring]. / La fonction respiratoire dans les scolioses idiopathiques de l'adolescent, traitée par instrumentation de Harrington, associée ou non à un cerclage sous lamaire segmentaire.

The forced expiratory volume in one second (FEV1) and the forced vital capacity (FVC) of 40 adolescents with idiopathic scoliosis were studied before and after surgery. The values obtained are expressed as percentages of the predicted normal. Twenty-one patients underwent surgical correction of the curve with Harrington rods followed by cast and brace immobilisation for one and a half years (Group A). In the other 19 patients the Harrington rod was contoured in the sagittal plane and supplemented with segmented sublaminar wires to allow rapid post-operative mobilisation free of any orthosis (Group B). A negative correlation was found pre-operatively between the magnitude of the curve and the FEV1 and FVC. The post-operative pulmonary function showed no statistically significant improvement. Contouring the Harrington rod to improve kyphosis in Group B did not affect the outcome.

Orthopaedic problems in the elderly.

Orthopaedic problems affecting the elderly are discussed and related to basic bone and joint pathology. The treatment of these problems is outlined with a special call for the highest standards of medical and surgical care, by a multidisciplinary team. Early internal fixation of pathological fractures is recommended to allow early mobilisation. Total replacement arthroplasty similarly allows an early return to normal mobility in patients disabled by osteoarthrosis of a major weight bearing joint. Some aspects of the medical treatment of metabolic bone disease are also discussed.

Psychological preparation influences nitrous oxide analgesia: replication of laboratory findings in a clinical setting.

In an earlier laboratory study, administration of 33% nitrous oxide yielded lower, not higher, pain thresholds when combined with appropriately altered expectations of enhanced creativity and sensitivity. The present study was undertaken in an attempt to replicate this finding in a group of clinical dental patients. It was expected that anxiety would play a significant role in our findings. The present study experimentally confirms that controlled psychological preparation of the clinical subject prior to administration of conventional dental dosages of nitrous oxide can significantly modify the perception of tooth pulp pain, neutralizing and even reversing its analgesic efficacy without increasing anxiety.

Genetically determined variability in acetylation and oxidation. Therapeutic implications.

The clinical significance of two separate genetic polymorphisms which alter drug metabolism, acetylation and oxidation is discussed, and methods of phenotyping for both acetylator and polymorphic oxidation status are reviewed. Particular reference is made to the dapsone method, which provides a simple means of distinguishing fast and slow - and possibly intermediate - acetylators, and to the sparteine method which allows a clear separation of oxidation phenotypes. Although acetylation polymorphism has been known for some time, definite indications for phenotyping are few. It is doubtful whether acetylator phenotype makes a significant difference to the outcome in most isoniazid treatment regimens, and peripheral neuropathy from isoniazid in slow acetylators is easily overcome by pyridoxine administration. However, in comparison with rapid acetylators, slow acetylators receiving isoniazid have an increased susceptibility to phenytoin toxicity, and perhaps also to carbamazepine toxicity. It is also possible that rapid acetylators receiving isoniazid attain higher serum fluoride concentrations from enflurane and similar anaesthetics than do similarly treated slow acetylators. Thus, when drug interactions of these types are suspected, phenotyping for acetylator status may be advisable. If routine monitoring of serum procainamide and N-acetylprocainamide concentrations is practised, phenotyping of subjects prior to therapy with these agents should not be necessary. Although acetylator phenotype influences serum concentrations of hydralazine, when this drug is given in combination with other drugs acetylator phenotype has not been shown to influence the therapeutic response. Slow acetylator phenotype along with female gender and the presence of HLA-DR antigens appear to be risk factors in the development of hydralazine-induced systemic lupus erythematosus (SLE). Determination of acetylator phenotype may therefore help determine susceptibility to this adverse reaction. In the case of sulphasalazine, adult slow acetylators require a lower daily dose of the drug than fast acetylators in order to maintain ulcerative colitis in remission without significant side effects. It is therefore advisable to determine acetylator phenotype prior to sulphasalazine therapy. Work on the association of acetylation polymorphism with various disease states is also reviewed. It is possible that a higher incidence of bladder cancer is associated with slow acetylation phenotype - especially in individuals exposed to high levels of arylamines. The question as to whether idiopathic SLE is more common in slow acetylators remains unresolved. There appears to be no difference between fa

Effects of oestrogens and pregnancy on the distribution of sheep erythrocytes and the antibody response in mice.

Mice pre-treated with three oestrogenic preparations showed increased hepatic and reduced splenic uptake of 51Cr-labelled sheep erythrocytes (SRBC). The anitbody response to SRBC wahe number of antibody-forming cells in the spleen parallels the amount of SRBC localizing in this organ and that both can be depressed or enhanced by appropriate pre-treatments with oestrogens or colloidal carbon. The effects of these agents are mediated through stimulation or 'blockade' of the phagocytic activity of liver macrophages. Changes in localization of SRBC in pregnant mice were similar to those found after treatment with oestrogens. These changes were, however, rather small and the antibody response of pregnant animals was not affected.