International Osteoporosis Foundation and European Calcified Tissue Society Working Group. Recommendations for the screening of adherence to oral bisphosphonates.

Adherence to oral bisphosphonates is low. A screening strategy is proposed based on the response of biochemical markers of bone turnover after 3 months of therapy. If no change is observed, the clinician should reassess the adherence to the treatment and also other potential issues with the drug. INTRODUCTION: Low adherence to oral bisphosphonates is a common problem that jeopardizes the efficacy of treatment of osteoporosis. No clear screening strategy for the assessment of compliance is widely accepted in these patients. METHODS: The International Osteoporosis Foundation and the European Calcified Tissue Society have convened a working group to propose a screening strategy to detect a lack of adherence to these drugs. The question to answer was whether the bone turnover markers (BTMs) PINP and CTX can be used to identify low adherence in patients with postmenopausal osteoporosis initiating oral bisphosphonates for osteoporosis. The findings of the TRIO study specifically address this question and were used as the basis for testing the hypothesis. RESULTS: Based on the findings of the TRIO study, specifically addressing this question, the working group recommends measuring PINP and CTX at baseline and 3 months after starting therapy to check for a decrease above the least significant change (decrease of more than 38% for PINP and 56% for CTX). Detection rate for the measurement of PINP is 84%, for CTX 87% and, if variation in at least one is considered when measuring both, the level of detection is 94.5%. CONCLUSIONS: If a significant decrease is observed, the treatment can continue, but if no decrease occurs, the clinician should reassess to identify problems with the treatment, mainly low adherence.

Sensitivity and specificity of radiographic characteristics in atypical femoral fractures.

Using the American Society for Bone and Mineral Research Task Force case definition for atypical femoral fractures, sensitivity and specificity of radiographic fracture characteristics were calculated. Fracture pattern was the most sensitive and specific characteristic. This suggests that some characteristics should be weighted more heavily when identifying these fractures. INTRODUCTION: To estimate the sensitivity and specificity of each radiographic criterion in the 2013 ASBMR atypical femoral fracture (AFF) case definition for distinguishing AFF from other subtrochanteric/diaphyseal fractures (non-AFF) among women enrolled in a large integrated health care organization. METHODS: Radiographs from 55 physician-confirmed AFFs and a sample of 39 non-AFFs were reviewed by four independent expert reviewers representing four medical specialties. One image per fracture was selected for review. Using a standardized data collection tool, based on the 2013 AFF case definition, reviewers indicated the presence or absence of the following characteristics viewable on radiograph: fracture pattern, comminution, periosteal and/or endosteal thickening, and cortical thickening. Sensitivity and specificity for each characteristic was calculated for each reviewer and summarized across reviewers with the mean and range. Agreement across reviewers was quantified using Fleiss's kappa (FK) statistic. RESULTS: The most sensitive factors distinguishing AFF from non-AFF were lateral cortex transverse fracture pattern (mean 93.6 %, range 85.5-98.2 %), medial cortex transverse or oblique fracture pattern (mean 84.1 %, range 72.7-98.2 %), and minimal/non-comminution (mean 93.2 %, range 89.1-98.2 %). Specificity was the greatest for lateral cortex transverse fracture pattern (mean 95.5 %, range 92.3-97.4 %). Agreement across reviewers was the highest for lateral cortex transverse fracture pattern (FK 0.83) and incomplete fracture through the lateral cortex only (FK 0.80). CONCLUSION: Lateral cortex transverse fracture pattern was the most sensitive and specific characteristic and the most highly agreed upon across reviewers. Other characteristics were less readily agreed upon across reviewers. Measurement of discrete combinations of individual characteristics may enhance sensitivity and/or specificity.

Primary non-adherence to bisphosphonates in an integrated healthcare setting.

UNLABELLED: We estimated primary non-adherence to oral bisphosphonate medication and examined the factors associated with primary non-adherence. Nearly 30% of women did not pick up their new bisphosphonate within 60 days. Identifying barriers and developing interventions that address patients' needs and concerns at the time a new medication is prescribed are warranted. INTRODUCTION: To estimate primary non-adherence to oral bisphosphonate medications using electronic medical record data in a large, integrated healthcare delivery system and to describe patient and prescribing provider factors associated with primary non-adherence. METHODS: Women aged 55 years and older enrolled in Kaiser Permanente Southern California (KPSC) with a new prescription for oral bisphosphonates between December 1, 2009 and March 31, 2011 were identified. Primary non-adherence was defined as failure to pick up the new prescription within 60 days of the order date. Multivariable logistic regression models were used to investigate patient factors (demographics, healthcare utilization, and health conditions) and prescribing provider characteristics (demographics, years in practice, and specialty) associated with primary non-adherence. RESULTS: We identified 8,454 eligible women with a new bisphosphonate order. Among these women, 2,497 (29.5%) did not pick up their bisphosphonate prescription within 60 days of the order date. In multivariable analyses, older age and emergency department utilization were associated with increased odds of primary non-adherence while prescription medication use and hospitalizations were associated with lower odds of primary non-adherence. Prescribing providers practicing 10 or more years had lower odds of primary non-adherent patients compared with providers practicing less than 10 years. Internal medicine and rheumatology providers had lower odds of primary non-adherent patients than primary care providers. CONCLUSION: This study found that nearly one in three women failed to pick up their new bisphosphonate prescription within 60 days. Identifying barriers and developing interventions aimed at reducing the number of primary non-adherent patients to bisphosphonate prescriptions are warranted.

Use of curcuminoids in a cohort of patients with oral lichen planus, an autoimmune disease.

OBJECTIVES: To summarize long-term open-label use of curcuminoids and experience of side-effects in 53 patients with the autoimmune condition oral lichen planus (OLP) who had previously participated in randomized controlled trials (RCTs) of curcuminoids at UCSF. METHODS: This descriptive retrospective cohort study conducted in 2009 collected information from clinic charts and patient interview on the over-the-counter (OTC) use of curcuminoids during a 1-5 year follow-up period. Of the 53 eligible patients, 33 had previously participated in a RCT (2003-2004) that evaluated a dose of 2000mg/day of curcuminoids and which was ended early for futility and 20 had participated in a RCT (2007-2008) that evaluated a dose of 6000mg/day which demonstrated its efficacy. At the last study visit of each of the 2 RCTs all participants were given current published information about curcuminoids, and some went on to take OTC curcuminoids. RESULTS: Follow-up data was available on 43 participants [25/33 (75%) from the first and 19/20 (95%) from the second RCT]. 18/25 (72%) participants from the first trial took OTC curcuminoids after completion of the trial period. The mean total daily dose was 2137.5mg (SD=793, range 500-3000mg) and mean duration of curcuminoids use was 30 months (SD=27.5). The total follow-up time after completion of the RCT for the 18 participants was mean 68.2 months (SD 5.9). 10/18 (56%) reported that curcuminoids controlled OLP symptoms, and the mean duration of use among these patients was 35.8 months (SD 27.4). 8/18 (44%) were unsure whether curcuminoids helped and the mean duration of use was 21.0 months (SD 27.3). 2 of 18 patients (11%) reported a side-effect (SE) of diarrhea. 19/19 (100%) patients from the second trial took OTC curcuminoids after completion of the trial period. The mean total daily dose was 5058mg (SD=1445, range 1000-6000mg) and mean duration of curcuminoids use 9.6 months (SD=8.04). The total follow-up time after completion of the RCT for the 19 participants was mean 15.8 months (SD 4.8). 12/19 (63%) reported that curcuminoids controlled OLP symptoms, and the mean duration of use was 14.1 months (SD 6.7). 2/19 (11%) reported lack of improvement with a daily dose of 1500mg and 2500mg for 3 months each. 5/19 (26%) were unsure whether curcuminoids helped and the mean duration of use was 1.5 months (1.2 SD). Six of these 19 patients (32%) reported SEs, three had abdominal discomfort, two diarrhea and one slight urgency in defecation on the capsule but not the tablet formulation. The SEs resolved with dose reduction to 4500mg/day in one and 3000mg/day in two patients, while two patients [2/19 (11%)] discontinued curcuminoids due to the SE. CONCLUSIONS: A total of 22/37 (60%) of patients reported a reduction of symptoms with curcuminoids, 13/37 (35%) were unsure and 2/37 (5%) reported that it did not help in reduction of symptoms. Side-effects included abdominal discomfort and diarrhea, however occurrence was dose-related, and complaints were mild.

Medium-term results of ultrasound-guided foam sclerotherapy for small saphenous varicose veins.

BACKGROUND: The results of surgery for small saphenous varicose vein (SSV) varicosities may be suboptimal in terms of recurrence and complications. The role of minimally invasive alternatives remains incompletely defined. The aim was to review the medium-term outcomes of ultrasound-guided foam sclerotherapy (UGFS) for SSV. METHODS: Eighty-six patients (92 legs) undergoing UGFS for SSV were assessed before, and 1, 6 and 12 months after treatment. Outcome measures were occlusion of, and abolition of reflux in, the SSV (technical success), absence of visible varicose veins (clinical success) and improvement in disease-specific health-related quality of life (HRQL) following treatment (Aberdeen Varicose Vein Symptom Severity Score (AVSS)). RESULTS: The technical and clinical success rates at 12 months were 91 and 93 per cent respectively; only three patients required a second treatment. After treatment of isolated SSV varicosities there was a significant improvement in AVSS, from a median of 19.0 (interquartile range 13.4-26.8) before treatment to 10.2 (4.0-18.3) and 9.7 (3.5-19.1) at 6 and 12 months respectively. The only complication was a popliteal vein thrombosis that required anticoagulation. CONCLUSION: UGFS was an effective treatment for SSV, with abolition of reflux and visible varicose veins, and improvement in HRQL for at least 12 months.

A randomized, placebo-controlled, double-blind clinical trial of curcuminoids in oral lichen planus.

We studied the efficacy of curcuminoids in the treatment of oral lichen planus (OLP), a chronic, mucocutaneous, immunological disease. Curcuminoids are components of turmeric (Curcuma longa) that have anti-inflammatory activity. Turmeric has been used in Ayurveda (Indian traditional medicine) for centuries. A randomized, double-blind, placebo-controlled trial was conducted. In all, 100 consecutive, eligible patients with OLP presenting to the oral medicine clinic at the University of California, San Francisco, were to be selected. Two interim analyses were to be conducted during the trial. The trial was conducted between February 2003 and September 2004. The first interim analysis was conducted in October 2004 using data from the first 33 subjects. Study subjects were randomized to receive either placebo or curcuminoids at 2000 mg/day for 7 weeks. In addition, all subjects received prednisone at 60 mg/day for the first 1 week. The primary outcome was a change in symptoms from baseline. Secondary outcomes were changes in clinical signs and occurrence of side effects. The first interim analysis did not show a significant difference between the placebo and curcuminoids groups. Conditional power calculations suggested a less than 2% chance that the curcuminoids group would have a significantly better outcome as compared with the placebo group if the trial were continued to completion. Therefore, the study was ended early for futility. Reaching a conclusion regarding the efficacy of curcuminoids based on the results of this study is not possible as it was ended early for futility. Curcuminoids at this dose were well tolerated and the results suggest that for future studies a larger sample size, a higher dose and/or longer duration of curcuminoids administration should be considered; however, for the next step, an RCT of a shorter duration, using a higher dose of curcuminoids, and without an initial course of prednisone, should be considered.

The analgesic role of calcitonin following osteoporotic fracture.

Osteoporosis is a systemic skeletal condition characterized by decreased bone strength with consequent increased susceptibility to bone fracture. Fragility fractures in osteoporosis are often painful and result in loss of quality of life and disability. Salmon calcitonin (SCT) is a natural hormone that may assist in the management of osteoporotic patients following fracture by reducing fracture risk and decreasing pain. SCT is an antiresorptive agent which has been shown to reduce the risk of vertebral fractures (by 36%) in postmenopausal women with osteoporosis and previous fractures, with a safety profile comparable to placebo over long-term use. Clinical evidence suggests that SCT (with either subcutaneous and intranasal delivery) is an analgesic for the acute pain following osteoporotic fracture. Pain relief with SCT occurs after 1 week or less of treatment. Associated with this pain relief, vertebral fracture patients receiving SCT have been observed to have earlier mobilization compared with those receiving a placebo. Both preclinical and clinical data suggest a central analgesic effect for SCT. The mechanism(s) by which SCT induces pain relief has (have) not been conclusively shown. Neither a direct receptor-mediated action nor an indirect endorphin-mediated effect can be ruled out.

Is it premenstrual syndrome? Keys to focused diagnosis, therapies for multiple symptoms.

Premenstrual syndrome (PMS) is sometimes facetiously blamed when a woman behaves erratically, when in fact, the cyclic symptoms of true PMS do cause significant difficulties in everyday life and relationships. In this article, Drs Frye and Silverman outline the criteria for diagnosing PMS and premenstrual dysphoric disorder and describe medications, nutritional supplements, and behavior modifications that have proved effective for relief of PMS symptoms.

Interventional and intraoperative magnetic resonance imaging.

The goal of the Image Guided Therapy Program, as the name implies, is to develop the use of imaging to guide minimally invasive therapy. The program combines interventional and intraoperative magnetic resonance imaging (MRI) with high-performance computing and novel therapeutic devices. In clinical practice the multidisciplinary program provides for the investigation of a wide range of interventional and surgical procedures. The Signa SP 0.5 T superconducting MRI system (GE Medical Systems, Milwaukee, WI) has a 56-cm-wide vertical gap, allowing access to the patient and permitting the execution of interactive MRI-guided procedures. This system is integrated with an optical tracking system and utilizes flexible surface coils and MRI-compatible displays to facilitate procedures. Images are obtained with routine pulse sequences. Nearly real-time imaging, with fast gradient-recalled echo sequences, may be acquired at a rate of one image every 1.5 s with interactive image plane selection. Since 1994, more than 800 of these procedures, including various percutaneous procedures and open surgeries, have been successfully performed at Brigham and Women's Hospital (Boston, MA).

Evaluation of serum and tissue levels of alpha-tocopherol.

This study was designed to test the effect of supplementation of several antioxidants, including alpha-tocopherol, on the clinical reduction of premalignant oral lesions. Samples of oral mucosa and serum were taken from baseline to 9 months of supplementation from patients with premalignant oral lesions and analyzed for alpha-tocopherol by HPLC. Statistical increases in both serum and tissue alpha-tocopherol were found after supplementation. There was no statistical relationship between alpha-tocopherol and beta-carotene levels.

Use of antioxidant supplements in the treatment of human oral leukoplakia.

An increasing public awareness of antioxidants may prompt a patient's request to be treated without surgery if a leukoplakic lesion is discovered. However, surgical excision remains the treatment of choice for oral leukoplakia. The use of antioxidant supplements has shown some promise, but the predictability of success remains uncertain and long-term results are unavailable. Before the decision to use any antioxidant is made, it is critical to obtain a histopathologic diagnosis of the lesion. When dealing with a lesion diagnosed as hyperkeratosis, it may be appropriate to choose an antioxidant that may take some time for clinical improvement to occur. However, as the grade of epithelial dysplasia becomes more severe, consideration must be given to the possibility of malignant transformation during antioxidant treatment. We do not recommend the use of antioxidant supplements in the treatment of any carcinoma. The therapeutic use of antioxidant supplements outside of clinical trials conducted at academic medical centers should be done with considerable caution by practitioners in private practice. It should be emphasized that in these clinical trial patients were seen at frequent intervals to monitor their progress and to intervene if there was a noticeable deterioration in the clinical appearance of the lesion. In spite of the uncertainty with respect to antioxidant treatment, there are circumstances in which it should be considered. Recurrence after surgical excision when there is little reason to believe that a second surgical excision would be any more successful is an ideal candidate. Also, patients with widespread leukoplakia that involves a large area of the oral mucosa might be suitable for treatment with antioxidants, as well as patients who have extensive medical problems that make them surgical risks. The choice of which antioxidant(s) to use is complex because thus far there is no combination that is superior to the others. Beta-carotene with ascorbic acid or alpha-tocopherol is attractive because of a lack of side effects, but the range in reported values for lesion improvement has been broad and the clinical improvement typically takes several months. Clinical response with 13-cRA is faster but requires baseline and periodic serologic testing, as well as close monitoring for side effects. In those circumstances in which time is an important consideration, 13-cRA might be useful because clinical improvement can be evaluated within a matter of weeks as compared with beta-carotene. The group from M.D. Anderson Hospital has shown the value of an induction dose of 13-cRA that is followed by a lower maintenance dose. Unfortunately, the problem of recurrence after discontinuation of 13-cRA is quite common. One aspect that has not been evaluated is the combination of conventional surgical excision and the administration of postoperative antioxidants. This would have the obvious advantage of conventional treatment of surgery together with the possible protective effect of the antioxidants. Although this is an attractive hypothesis, we do not know of any studies that have proven this to be beneficial.

Use of hyperbaric oxygen in rheumatic diseases: case report and critical analysis.

Hyperbaric oxygen has been used in patients with rheumatic disease for many years without reports of untoward or unusual complications for a variety of non-rheumatic indications. Recent evidence that hyperbaric oxygen inhibits the actions of certain cytokines, acts as an immune modulator and may help cognitive dysfunction has resulted in a re-examination of its potential role in rheumatic diseases. A case report of a lupus/scleroderma crossover patient is presented whose cognitive dysfunction improved after hyperbaric oxygen therapy. The history of hyperbaric oxygen and its physiology are related, along with a focused review of its effects on the immune and central nervous systems. Areas which might warrant further consideration by rheumatologists are outlined, as well as areas of concern.

Clinical and lymphocyte responses to beta-carotene supplementation in 11 HIV-positive patients with chronic oral candidiasis.

Eleven HIV-positive patients with chronic oral candidiasis were supplemented with 60 to 120 mg of beta-carotene daily for 3 to 7 months. Lymphocyte profiles were evaluated at intervals to help assess immune competence. Although there was a modest increase in some lymphocyte values at 2 months, there was a significant decrease in numbers of CD4 and CD8 cells and CD4 percentage of lymphocytes after 6 months of beta-carotene supplementation. Serum triglyceride and liver enzyme levels were not affected by the beta-carotene supplementation. No improvement was observed in the control of the oral candidiasis. Under the conditions of the study, there was no indication that daily beta-carotene supplements enhanced immune competence or was of benefit in managing oral candidiasis.

A clinical trial of antioxidant supplements in the treatment of oral leukoplakia.

Seventy-nine patients with oral leukoplakia that was histologically verified as either hyperkeratosis or epithelial dysplasia with hyperkeratosis were enrolled in an antioxidant supplementation program for the treatment of the oral lesions. The patients received 30 mg of beta-carotene, 1000 mg of ascorbic acid, and 800 IU of alpha-tocopherol per day for 9 months. Clinical improvement of the oral lesion was noted in 55.7% of the patients and was more likely to occur in patients who reduced their use of alcohol or tobacco (p = 0.0056). Although risk-factor reduction was important, approximately half of the patients who did not alter their exposure to either alcohol or tobacco showed clinical improvement. The antioxidant supplementation significantly increased serum and tissue levels of beta-carotene, ascorbic acid, and alpha-tocopherol, but these changes did not correlate strongly with clinical improvement.

Evaluation of serum and tissue levels of beta-carotene.

Interest in beta-carotene (BC) has increased as studies show that low dietary or serum BC is associated with increased risk of cancer. Patients with oral epithelial dysplasia had serum and oral mucosa punch biopsy samples taken before supplementation of 30 mg/day of beta-carotene and after 6 and 9 months of supplementation. BC was analyzed for 28 patients by high-performance liquid chromatography. At baseline, serum BC and gender accounted for 48% of tissue BC variance: Tissue BC = -0.13 + 0.08(Serum BC) + 1.21(Sex) with sex as male = 0 or female = 1. Following supplementation, serum BC had an exponential relationship to tissue BC which accounted for 52% of tissue variance: Tissue BC = 1.15 + 5.7 x 10(-5)(Serum BC)2 + 3.91(Sex). Women had higher mean concentrations of serum and oral mucosal BC before and during supplementation. The need for oral mucosal sampling may be eliminated by the correlation between serum and tissue BC.

Identification of conserved amino acids in the human granulocyte-macrophage colony-stimulating factor receptor alpha subunit critical for function. Evidence for formation of a heterodimeric receptor complex prior to ligand binding.

A superfamily of growth factor and cytokine receptors has recently been identified, which is characterized by four spatially conserved cysteine residues, a tryptophan-serine motif (WSXWS) in the extracellular domain, and a proline-rich cytoplasmic domain. The high affinity human granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor (hGM-CSFR) consists of two subunits, alpha (hGM-CSFR alpha) and beta (hGM-CSFR beta), both of which are members of the receptor superfamily. In this study, we prepared mutations in conserved amino acids of the receptor subunit necessary for GM-CSF binding (hGM-CSFR alpha) and analyzed mutant receptors for low affinity binding, internalization, and high affinity binding when complexed with the beta subunit. Mutations in the cytoplasmic domain did not affect GM-CSF binding or receptor internalization. Mutation of a single conserved serine residue within the WSXWS motif diminishes cell surface receptor expression but not ligand binding. Mutation of either the second or third conserved cysteine residue of hGM-CSFR alpha resulted in complete loss of low affinity binding; however, co-expression of the cysteine 2 mutant with hGM-CSFR beta yielded a high affinity receptor complex. Since neither the cysteine 2 mutant nor the beta subunit can bind ligand alone, this result suggests that hGM-CSFR alpha and hGM-CSFR beta exist in a preformed heterodimeric protein complex on the plasma membrane.

The effect of vitamin E on lipid peroxidation in the copper-deficient rat.

The present study was designed to determine whether the supplementation of vitamin E in the copper-deficient diet would ameliorate the severity of copper deficiency in fructose-fed rats. Lipid peroxidation was measured in the livers and hearts of rats fed a copper-deficient diet (0.6 microg Cu/g) containing 62% fructose with adequate vitamin E (0.1 g/kg diet) or supplemented with vitamin E (1.0 g/kg diet). Hepatic lipid peroxidation was significantly reduced by vitamin E supplementation compared with the unsupplemented adequate rats. In contrast, myocardial lipid peroxidation was unaffected by the level of vitamin E. Regardless of vitamin E supplementation, all copper-deficient rats exhibited severe signs of copper deficiency, and some of the vitamin E-supplemented rats died of this deficiency. These findings suggest that although vitamin E provided protection against peroxidation in the liver, it did not protect the animals against the severity of copper deficiency induced by fructose consumption.

Single dose, oral antibiotic cover for transurethral prostatectomy.

A double-blind, randomised, placebo-controlled study was carried out to determine the incidence and significance of bacteriuria in 110 patients undergoing transurethral resection of the prostate (TURP) and to assess the effect of a single pre-operative dose of Ciprofloxacin, a 4-quinolone antibiotic. Fifteen (68%) of the 22 patients in the placebo group with a positive post-operative urine culture subsequently developed a clinically apparent urinary tract infection (UTI) or received antibiotics in view of a positive urine culture. Adequate prostatic concentrations of Ciprofloxacin were achieved in all who received the drug. A significant reduction in the number of positive post-operative urine cultures and urinary tract infections requiring antibiotic therapy was achieved in this group. Six patients (5.5%) developed clinical evidence of septicaemia, 5 of whom were in the placebo group. No organisms resistant to Ciprofloxacin were encountered. Prior to surgery, 19% of all patients were found to have previously unsuspected bacteriuria. Ciprofloxacin tended to reduce the chances of this group developing a UTI or requiring antibiotics. Further, there was a highly significant reduction in post-operative infective complications in those with sterile urine at the time of resection who had received the drug. This study suggests that antibiotic cover for TURP is of clinical benefit. Ciprofloxacin may prove suited to this purpose, although further experience with the drug is still required.