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Reactive oxygen species (ROS), formed by the partial reduction of oxygen, were for a long time considered to be a byproduct of cellular metabolism. Since, increase in cellular levels of ROS results in oxidative stress leading to damage of nucleic acids, proteins, and lipids resulting in numerous pathological conditions; ROS was considered a bane for aerobic species. Hence, the discovery of NADPH oxidases (NOX), an enzyme family that specifically generates ROS as its prime product came as a surprise to redox biologists. NOX family proteins participate in various cellular functions including cell proliferation and differentiation, regulation of genes and protein expression, apoptosis, and host defence immunological response. Balanced expression and activation of NOX with subsequent production of ROS are critically important to regulate various genes and proteins to maintain homeostasis of the cell. However, dysregulation of NOX activation leading to enhanced ROS levels is associated with various pathophysiologies including diabetes, cardiovascular diseases, neurodegenerative diseases, ageing, atherosclerosis, and cancer. Although our current knowledge on NOX signifies its importance in the normal functioning of various cellular pathways; yet the choice of ROS producing enzymes which can tip the scale from homeostasis toward damage, as mediators of biological functions remain an oddity. Though the role of NOX in maintaining normal cellular functions is now deemed essential, yet its dysregulation leading to catastrophic events cannot be denied. Hence, this review focuses on the involvement of NOX enzymes in various pathological conditions imploring them as possible targets for therapies. SIGNIFICANCE OF THE STUDY: The NOXs are multi-subunit enzymes that generate ROS as a prime product. NOX generated ROS are usually regulated by various molecular factors and play a vital role in different physiological processes. The dysregulation of NOX activity is associated with pathological consequences. Recently, the dynamic proximity of NOX enzymes with different molecular signatures of pathologies has been studied extensively. It is essential to identify the precise role of NOX machinery in its niche during the progression of pathology. Although inhibition of NOX could be a promising approach for therapeutic interventions, it is critical to expand the current understanding of NOX's dynamicity and shed light on their molecular partners and regulators.

The assay in serum of non-caeruloplasmin copper, as exchangeable copper after complexation with EDTA (ExCu) and total copper has been evaluated and compared in patients with varying c-reactive protein(CRP). Measurement of ExCu and total copper, range 0.2-47.2 µmol/L, was developed using ICP-MS. The chelating agents EDTA and TEPA were compared over 0.0-10 g/L after incubation with serum for 60 mins followed by ultrafiltration with Amicon 10 kDa filter. The assay for ExCu was optimised with EDTA 3 g/L (8.1 mmol/L) maintained at pH 7.0-8.0 before ultrafiltration. TEPA was not as selective in chelation of copper. Patients

Purpose This study aims to explore the antecedents that may lead to turnover intentions among police personnel in the United Arab Emirates. Design/methodology/approach The data were collected from police personnel (n = 176) through a questionnaire survey, and structural equation modeling was used to test the relationships. Findings The findings revealed that the work-family conflict and job autonomy significantly correlate with turnover intentions. Alternatively, perceived organizational support does not predict turnover intentions. Research limitations/implications This research is limited by the study’s subjective assessment of police personnel turnover intentions through self-reported questionnaires. It provides implications for policymakers, organizational behavioral experts and those interested in formulating effective strategies to reduce turnover among police personnel. Originality/value This study offers a novel context as it assesses police personnel in an emerging Middle Eastern country. It provides insights to policymakers and academia concerning the factors strongly linked with police personnel turnover intentions and will help them formulate strategies for improving personnel satisfaction and advancing relationships between police and the community.

Osteoporosis is a disease with a significant disease burden worldwide, affecting more than 75 million people in the US, Europe and Japan. With an ageing population the incidence of osteoporosis is growing. Osteoporotic fractures have significant individual morbidity but also strain Healthcare services. There is no screening service for osteoporotic fractures in the UK and physicians must actively identify patients who are at risk of osteoporotic fractures as well as managing appropriately patients who have sustained osteoporotic fractures. Diagnosis of osteoporosis is done with Dual energy X-ray Absorptiometry (DXA) scans to measure Bone Mineral Density (BMD). The World Health Organisation Fracture Risk Assessment (FRAX) score is used to identify patients who are at risk of fractures. Pharmacological treatment is recommended for those who obtain a risk score sufficient enough to warrant treatment. The treatment of osteoporosis includes calcium and vitamin D replacement, bisphosphonates , denosumab , teriparatide and hormone replacement therapy in women. Potential therapies that are currently undergoing clinical trials include Abaloparatide and Romosozumab .

Background The acquisition of resistance to chemotherapy is a major hurdle in the successful application of cancer therapy. Several anticancer approaches, including chemotherapies, radiotherapy, surgery and targeted therapies are being employed for the treatment of cancer. However, cancer cells reprogram themselves in multiple ways to evade the effect of these therapies, and over a period of time, the drug becomes inactive due to the development of multi-drug resistance (MDR). MDR is a complex phenomenon where malignant cells become insensitive to anticancer drugs and attain the ability to survive even after several exposures of anticancer drugs. In this review, we have discussed the molecular and cellular paradigms of multidrug resistance in cancer. Recent findings An Extensive research in cancer biology revealed that drug resistance in cancer is the result of perpetuated intracellular and extracellular mechanisms such as drug efflux, drug inactivation, drug target alteration, oncogenic mutations, altered DNA damage repair mechanism, inhibition of programmed cell death signaling, metabolic reprogramming, epithelial mesenchymal transition (EMT), inherent cell heterogeneity, epigenetic changes, redox imbalance, or any combination of these mechanisms. An inevitable cross-link between inflammation and drug resistance has been discussed. This review provided insight molecular mechanism to understand the vulnerabilities of cancer cells to develop drug resistance. Conclusion MDR is an outcome of interplays between multiple intricate pathways responsible for the inactivation of drug and development of resistance. MDR is a major obstacle in regimens of successful application of anti-cancer therapy. An improved understanding of the molecular mechanism of multi drug resistance and cellular reprogramming can provide a promising opportunity to combat drug resistance in cancer and intensify anti-cancer therapy for the upcoming future.

When the Cause Is Not Crystal Clear A 55-year-old woman with a history of chronic renal insufficiency presented to the emergency department with recurrent falls, dizziness, and lethargy over a peri...

Toll-Like Receptors (TLRs) recognize a wide variety of pathogen-associated molecular patterns and are centrally involved in the initiation of the innate and adaptive immune responses. Extensive analysis of TLRs has shown specificity in terms of ligand recognition, expression and cellular localization in different cell types and tissues, and most importantly, its role in the pathogenesis of multiple chronic inflammatory diseases. In recent past extensive investigations showed that many TLRs are profoundly expressed in various types of cancers. This review is emphasized on human TLR4 structural and functional dynamics in cancer. The review was intended to explore the present understanding of the involvement of hTLR4 in different types of cancer and different danger signals that can affect the expression and function of TLR4 in both normal and cancer cells. Dual role of TLR4 in cancer has also been discussed along with therapeutic targeting, cellular response via signaling and the possible conformational changes that occur in response to agonist and antagonist. This review provides a comprehensive resource for designing and discovery of novel TLR4 ligands for therapeutic intervention.

Lithium toxicity can manifest as a variety of biochemical ­abnormalities. This case report describes a patient ­presenting to the emergency department with neuropsychiatric ­symptoms on a background of bipolar disorder, for which she was prescribed lithium for 26 years previously. Cases of lithium toxicity are rare but can be severe and this case report ­demonstrates to clinicians that they must be thorough in investigating patients with lithium toxicity, as there are many potential abnormalities that can manifest concurrently.

Toll-like receptor 4 (TLR4) is a member of Toll-Like Receptors (TLRs) family that serves as a receptor for bacterial lipopolysaccharide (LPS). TLR4 alone cannot recognize LPS without aid of co-receptor myeloid differentiation factor-2 (MD-2). Binding of LPS with TLR4 forms a LPS−TLR4−MD-2 complex and directs downstream signaling for activation of immune response, inflammation and NF-κB activation. Activation of TLR4 signaling is associated with various pathophysiological consequences. Therefore, targeting protein–protein interaction (PPI) in TLR4−MD-2 complex formation could be an attractive therapeutic approach for targeting inflammatory disorders. The aim of present study was directed to identify small molecule PPI inhibitors (SMPPIIs) using pharmacophore mapping-based approach of computational drug discovery. Here, we had retrieved the information about the hot spot residues and their pharmacophoric features at both primary (TLR4−MD-2) and dimerization (MD-2−TLR4*) protein–protein interaction interfaces in TLR4−MD-2 homo-dimer complex using in silico methods. Promising candidates were identified after virtual screening, which may restrict TLR4−MD-2 protein–protein interaction. In silico off-target profiling over the virtually screened compounds revealed other possible molecular targets. Two of the virtually screened compounds (C11 and C15) were predicted to have an inhibitory concentration in μM range after HYDE assessment. Molecular dynamics simulation study performed for these two compounds in complex with target protein confirms the stability of the complex. After virtual high throughput screening we found selective hTLR4−MD-2 inhibitors, which may have therapeutic potential to target chronic inflammatory diseases.

Various inhibitors have been developed for neuraminidase but resistance against these drugs in many viral strains makes it an advantageous and interesting task to discover compounds which can be more promising in preventing viral infection through neuraminidase. Virtual screening methods have been proved as an efficient in silico approach for drug discovery processes. In the present study, we used ligand based virtual screening process for identifying potent inhibitors against viral neuraminidase enzyme. The approach utilized in this study has been successful in identifying 15 compounds which may be potential inhibitors of neuraminidase. These compounds were screened via three screening platforms (MVD, PyRx, and FRED) by setting oseltamivir as reference compound, which is an FDA approved drug against influenza virus. These compounds were then filtered by their in silico ADME/T (Absorption, Distribution, Metabolism, Excretion, and Toxicity) values and only 12 of them were found to have comparatively better results. The results of the present study are reported herein so that researchers, who are having required laboratory facilities for synthesizing drugs, can utilize findings of this study for developing new drugs against influenza with better efficacy.

Context: Cardiovascular disease is a very common and serious problem in the western world. Statin drug therapy is used in primary, secondary prevention and familial hypercholesterolemia. However, these are frequently associated with adverse effects, causing poor adherence and thus putting patients at risk for future cardiovascular events. Aim: The objective of this study was to review the statin intolerance in lipid patients and to assess the impact of alternative lipid lowering therapy on lipid parameters and cardiovascular outcome in statin intolerant patients. Methodology: 50 patients attending the out-patient lipid clinic of our hospital with statin intolerance were identified. Clinical data on the study patients were gathered retrospectively relating to statin intolerance and the clinical effectiveness of alternative lipid lowering therapy on lipid parameters and cardiovascular outcome. Results: Rosuvastatin was the most intolerable whereas pravastatin or fluvastatin was the most tolerable statin in our study patients. Myalgia was the commonly reported adverse effect of statin. The low dose statin monotherapy or combination of low dose statin and ezetemibe was the most tolerable alternative lipid lowering therapy in statin intolerant patients. After an average period of 10 months of initiation of alternative lipid lowering therapy; combination of low dose statin plus ezetimibe showed the largest reduction in serum total cholesterol and low-density lipoprotein (LDL) cholesterol levels. Conclusions: Pravastatin should be preferred in statin intolerant patients. A combination of low dose statin plus ezetimibe appeared to be the most tolerable and clinically effective therapy in statin intolerant patients.

Context: Primary hyperparathyroidism (PHPT) is commonly associated with reduced bone mineral density (BMD) presenting with osteoporosis, increasing the risk of bone fragility fractures in these patients. Bisphosphonates, due to their anti-resorptive action, are known to improve the BMD and reduce the risk of bone fragility fractures. Therefore, bisphosphonates are considered as an alternative to surgical treatment in managing osteoporosis in PHPT patients. Aim: The aim of this observational study was to assess the effect of long term bisphosphonate therapy on BMD, bone fragility fracture and biochemical markers of bone metabolism in patients with PHPT. Methodology: Fifty patients (mean age 74 years) with PHPT who were treated with long term bisphosphonate therapy were studied retrospectively. The mean baseline (before commencing bisphosphonate therapy) BMD T-scores for lumbar spine (L2-L4) and left femoral neck were -2.5 and -2.1, respectively. Fourteen patients had bone fragility fractures before initiation of bisphosphonate therapy. Results: After an average of 5 years of bisphosphonate treatment, there was a significant increase in lumbar BMD T-score (-2.5 to -2.1, p = 0.013) and a non-significant change in left femoral neck BMD T-score (-2.1 to -2.2, p = 0.497). There was no increase in bone fragility fracture rate (p = 0.167). Serum corrected calcium reduced from 2.74 mmol/L to 2.60 mmol/L (p 0.001) and urine calcium to creatinine ratio from 0.70 to 0.55 (p 0.0001), both within the reference range. Conclusions: Our study suggests that long term bisphosphonate therapy improves lumbar BMD and prevents increase in bone fragility fracture rate. Additionally it improves hypercalcaemia in PHPT.

Ricin is known as a potent toxin against animals. It consists of two chains, Ricin Toxin A (RTA) and Ricin Toxin B (RTB). The toxic effect is known to be caused by RTA. Inhibitors for RTA with less efficiency have been reported. Hence, it is of interest to identify new inhibitors. Virtual screening methods (computer aided drug designing) to find similar molecules in drug database were used for screening new inhibitors against RTA. We used the structure of RTA in complex with Pteroic acid (PDB code: 1BR6) as target molecule. Ligand based virtual screening approach was used in which the known inhibitory molecule Pteroic acid (PTA) served as a template to identify similar ligands from the ZINC database. These ligands were docked inside the binding pocket of RTA by using the MVD (Molegro Virtual Docker). This approach successfully identified six novel compounds. These docked ligands interacted with Asn78, Ala79, Val81, Gly121 and Ser176 amino acids, which are key residues of the RTA active site. Three compounds in particular, ZINC05156321 (6, 7 diphenylpteridin-4-ol), ZINC05156324 (6, 7-bis (3-fluorophenyl) pteridin-4-ol) and ZINC08555900 (6, 7-bis (4-fluorophenyl)-1H-pteridin-4-one), showed higher binding affinity in comparison to PTA, with high interaction energy, better space fitting and electrostatic interactions. These molecules should be tested for in vitro and in vivo activities in future for consideration as effective inhibitors.

Introduction Intravenous fluids are one of the most commonly prescribed drugs in the hospital setting and yet the practice continues to fall short of National Institute for Health and Care Excellence (NICE) guidelines, with significant gaps in staff knowledge exposing patients to heightened morbidity and mortality. Aim Following the 2013 publishing of updated NICE guidelines on intravenous fluid prescribing, an intravenous fluid team was formed within the Royal Liverpool University Hospital (RLUH). Their role has been (and continues to be) to overhaul the culture of suboptimal intravenous fluid prescribing within the hospital and, ultimately, to improve patient outcomes. A framework to engender this change has been developed and is offered as an example to other Trusts within which improvement of guideline-compliant intravenous fluid prescribing remains stagnant. Method There have been three principal stages of the project to this point which are best demonstrated in a chronological manner. The period of 2010–2014 allowed for assessment of the issue of intravenous fluid prescribing and analysis of its causes through serial audits and a staff-wide survey. From 2015, there has been implementation of several measures (educative, managerial, administrative and technological) within the hospital to foster reproducible and positive change with regards to intravenous fluid prescribing. Finally, between 2016 and 2017, three cycles of a rolling audit based on NICE guidelines have been completed to allow measurement of improvement in intravenous fluid prescribing practice. Conclusion Results have demonstrated a significant improvement in the appropriateness of the intravenous maintenance and replacement fluids prescribed in the hospital since the March 2016 audit. Moreover, a 29-fold increase has been observed in the use of 4% dextrose/0.18% sodium chloride as maintenance fluid (gold standard as per NICE guidelines) since the staff-wide survey of 2015. Despite progress however, adherence to NICE guidelines remains below the recommended 100% and therefore further work remains to be done.

Summary Background & Aims This study aimed to assess the effect of high dose selenium (Se) supplementation on Se status in blood, oxidative stress, thyroid function and possible effects on requirement for renal replacement therapy (RRT) in severely septic patients admitted to the intensive care unit (ICU). Methods This prospective single-centre study was carried out in 40 septic ICU patients who were randomized to high dose Se (Se+ group, N =18 (474, 316,158 μg/day), each for 3 consecutive days followed by a standard dose of 31.6 μg/day of Se given as sodium selenite whereas the control group (Se−, N =22) received only the standard dose of Se. Plasma Se, glutathione peroxidase (GSH-Px), F2 isoprostanes, thyroid function tests (total T4 and total T3), C-reactive protein (CRP) and red blood cell (RBC) GSH-Px were estimated on day 0, 3, 7, 14. Results In the Se+ group, plasma Se increased by day 3 and 7 ( P P =0.02), plasma GSH-Px increased by day 3 and 7 ( P =0.01) as compared to Se− group. There was a significant negative correlation between plasma Se and SOFA (sepsis related organ failure assessment) ( r =−0.36, P =0.03) along with low plasma Se and high CRP at the time of admission. Requirement for renal replacement therapy was not significantly different between the groups. Conclusion Although high dose Se supplementation increased plasma Se and GSH-Px activity, it did not reduce oxidative damage or the requirement for RRT. Se levels in blood are influenced by redistribution and severity of illness and therefore should be interpreted with caution.

GFR category GFR (ml/min/1.73 m 2 ) Terms G1 >90 Normal or high G2 60–89 Mildly decreased* G3a 45–59 Mildly to moderately decreased G3b 30–44 Moderately to severely decreased G4 15–29 Severely decreased G5

Background: Over recent years, interest in total antioxidant capacity measurement in biological fluids has increased. A number of assays are now available, and we wished to compare an enhanced chemiluminescence (ECL) method to a spectrophotometric method, the total antioxidant status (TAS) assay. Methods: Serum urate concentration, ECL and TAS were measured in 34 healthy subjects. Additionally, 10 subjects participated in a two-way, randomised crossover study, and received urate 1000 mg or vitamin C 1000 mg intravenously over 1 h. Serum ECL and TAS were measured at 0, 15, 30, 45, 60, 90 and 120 min after commencing infusion. Results: Baseline measurements were poorly correlated between ECL and TAS assays, and between serum urate concentration and each antioxidant assay. There was good correlation between the change in antioxidant capacity detected by both assays during urate infusion (R=0.79, p

Gitelman syndrome is an autosomal recessive distal renal tubular disorder caused by defective sodium chloride transporters. Biochemically, it presents with hypokalaemic metabolic alkalosis, hypomagnesaemia and hypocalciuria. It is usually managed with oral potassium supplements and potassium-sparing diuretics. We report a case of a 28-year-old woman whose condition worsened during pregnancy; she became resistant to standard management after delivery of her second child. She was managed in a specialist metabolic clinic through a comprehensive approach including perseverance with oral potassium supplement, weekly intravenous potassium and magnesium infusion, correction of vitamin D level and the offering of appropriate dietary advice; this controlled the patient's symptoms and prevented repeated hospital admissions. In this case report, we illustrate a patient's presentation and diagnosis with Gitelman syndrome, discuss triggers of exacerbation, review the relevant literature in terms of differential diagnoses and provide practical advice on the management of difficult cases in a specialist clinic.

Sepsis or systemic inflammatory response (SIRS) to infection or to non-infectious stimuli such as trauma, surgery, pancreatitis or ischemia, is an increasingly common cause of morbidity and mortality in patients on intensive therapy unit (ITU). In critically ill patients, this accounts for 10% to 50% of all deaths. Oxidative stress has an important role in the development and manifestations of SIRS. Oxidative stress is an imbalance between the free radical production and the antioxidant defense. In critical illness, overwhelming inflammatory mediator response to infective or non-infective stimuli results in excessive production of free radicals (FR). The action of FR is normally limited by the antioxidant defense system of the body, but in critically ill patients the antioxidant capacity is likely to be compromised. Hence, provision of antioxidants to critically ill patients may help in removing the FR and therefore improving the clinical outcome. However, no study has yet provided conclusive evidence of the beneficial effect of antioxidant supplementation in critically ill patients. The clinical evidence provided so far shows that there are several factors which might determine the efficacy of antioxidant supplementation in critically ill patients. There is a need for large multicentre prospective randomized control trials to assess the effects of different types and doses of antioxidant supplementation in selected groups of patients with different types of critical illness.

Background: Oxidative stress is a consequence of critical illness, and may have an impact on survival. We studied markers of oxidative damage and antioxidant (AO) protection and compared them with clinical scores and outcome. Methods: Blood sampling and clinical scoring was carried out on 60 consecutively admitted intensive therapy unit (ITU) patients within 24 h of admission and then every three days of ITU stay. The patients included 30 surgical and 30 medical patients, of whom 46 survived their stay in ITU. Clinical scoring was by Acute Physiology and Chronic Health Evaluation (APACHE) II score, multiple organ dysfunction (MOD) score and sepsis rating. Oxidative damage was assessed by measurement of plasma malondialdehyde (MDA) and F2 isoprostanes (F2 IsoPs). AO protection was assessed by measurement of plasma total AO status, AO gap, ascorbic acid and the enzymes glutathione peroxidase and superoxide dismutase. Results: Both clinical markers, APACHE II and MOD, and oxidative damage markers MDA and F2 IsoPs were significantly higher in non-survivors (NS) than in survivors (S) at the time of admission. Median (interquartile ranges) were (APACHE II), 14[12-17] (S), 20.5[16.7-22.2] (NS), P Conclusion: Increased oxidative stress is associated with poor outcome in critically ill patients, and may be a prognostic indicator. Oxidative damage markers are more useful than AO protection markers in predicting outcome.

Bisphosphonates are increasingly used to treat metabolic bone disease and as prophylaxis against metastatic bone cancer.1 2 Zoledronic acid is a new intravenous bisphosphonate licensed to treat hypercalcaemia of malignancy, but it has been used off licence as prophylaxis for metastatic cancer, bone pain, treatment of osteoporosis, and Paget's disease of the bone. Zoledronic acid is 100 to 1000 times more potent than disodium pamidronate or oral alendronic acid, risedronate sodium, sodium clodronate, or disodium etidronate. A randomised controlled trial found that zoledronic acid is more effective than disodium pamidronate in treating hypercalcaemia of malignancy.3 Zoledronic acid does not cause the gastrointestinal side effects associated with oral bisphosphonates, but increased potency carries a higher risk of hypocalcaemia. We have recent experience of patients becoming hypocalcaemic after doctors gave intravenous bisphosphonates. ### Case 1 A 49 year old man with transitional cell carcinoma of the bladder received chemotherapy with cisplatin, methotrexate, and vinblastine after resection of a tumour. His prechemotherapy adjusted calcium was normal. Despite four cycles of chemotherapy every two weeks he had bone pain due to metastases. Doctors gave him 4 mg of zoledronic acid and intravenous diamorphine after diclofenac sodium and co-proxamol failed to relieve his symptoms. His adjusted calcium six days before being given zoledronic acid was low (table). View this table: Serum analyte concentrations in patents given bisphosphonates Three days after being given intravenous zoledronic acid, he had tetanic spasms and paraesthesia. Trousseau's sign was positive and an electrocardiogram showed a long QT interval—474 ms (RR < 440 ms). His adjusted calcium …

Editor—The word limit for lessons of the week can result in removal of discussion points during editing. We considered several of Breay's and Fergus's comments in early versions of our article. Their points are valid, and doctors prescribing bisphosphonates must read the product information and understand what can happen if the prescribing guidelines are not followed. Our cases highlighted severe hypocalcaemia after bisphosphonate treatment, and, although mild hypocalcaemia is a well documented side effect, we are sure that Breay would agree that such dangerously low serum calcium values are not seen in 1-10% of patients treated with bisphosphonates. Experienced doctors treating hypercalcaemia of malignancy commonly use doses of 60-90 mg pamidronate for a calcium concentration around 3.0 mmol/l, and the Novartis sponsored study comparing zoledronic acid and pamidronate in patients with values ≥ 3.0 mmol/l used 90 mg pamidronate.1 Although failure to comply with prescribing recommendations may have contributed to the effects seen in our cases, the inability to mount a normal physiological response as described played a large part in the severe hypocalcaemia. Palmieri et al misquote and wrongly interpret us. At no point did we advocate that “bisphosphonates can be used as prophylaxis against metastatic bone cancer.” We wrote: “Bisphosphonates are increasingly used to treat metabolic bone disease and as prophylaxis against metastatic cancer.” Reviews and meta-analyses of bisphosphonates in cancer have shown clear advantages in terms of reduced skeletal morbidity.2 Guidelines outline the accepted use of these drugs.3 Recent studies have further defined the value of bisphosphonates such as zoledronic acid in several clinical settings and show treatment advantage in reducing skeletal related events in some cancers.4 The study by Saarto et al seems to contradict these findings, but the methodological problems, including a randomisation schedule that resulted in a significant imbalance of hormone receptor positive breast cancers in the two treatment groups,5 are greatly discussed at international meetings. The adverse effect of clodronate on overall survival lost significance in multivariate analysis. Further trials should clarify the position of adjuvant bisphosphonates in treating and preventing cancer related bone disease.