We performed immunofluorescence examination using the antibody against the immediately early lytic gene BRLF1, and found that 2% of the AGS–EBV cells were positive for BRLF1, which are entering the lytic phase of EBV replication ( Supplementary Figure 1C). The 10 EBV genes verified in AGS–EBV, SNU719, and YCCEL1 were

verified further in primary EBV(+) gastric cancer tissues with a positive detection rate between 7.7% and 46.2% by RT-PCR ( Figure 1C). Expression of EBV genes may contribute to EBV-associated gastric carcinogenesis. We compared the whole genome sequences of AGS–EBV and AGS to identify EBV-caused host genomic alterations, including single-nucleotide variants (SNVs)/point mutations, small insertions and deletions (indels), and structural variations (SVs) (Supplementary Tables 3–8). Verteporfin mw A total of 139 EBV-associated SNVs covering 131 genes were identified to be of interest, including 45 nonsynonymous SNVs (affecting 44 genes), and 94 SNVs located at important regulatory regions

(splice sites, 5- or 3-untranslated regions, and promoter regions; affecting Selleck Fluorouracil 87 genes). We also found 56 indels covering 54 genes in AGS–EBV and 48 AGS–EBV–specific SV events affecting 24 genes and other nongene regions. Seven randomly selected SNVs in 6 genes (AKT2, CCNA1, TGFBR1, ACVR1C, MAP3K4, and NRXN1) were well validated in AGS–EBV, but not in AGS or AGS-hygro by PCR followed by Sanger sequencing ( Supplementary Figure 2A). Among them, AKT2, the putative oncogene documented with important functions in the cancer pathway of mitogen-activated protein kinase (MAPK) signaling, harbors 2 EBV-associated nonsynonymous SNVs. Two randomly selected indels (FAM35A and ADAMTS12) and 4 randomly selected SVs (GGT7-IRS1, KMD3A-KMD3A, SMAD5-STXBP5, and NA-KDM3B) also were well validated in AGS–EBV by PCR followed by Sanger sequencing, but were not detected in AGS or AGS-hygro cells ( Supplementary Figure 2B and C). By comparing the 45

EBV-associated nonsynonymous host SNVs/point mutations (covering 44 genes) (Figure 2A) identified in AGS–EBV with the selleck chemical Catalogue of Somatic Mutations in Cancer database, which collects somatic mutations in human cancers, we found that all 44 genes had been recorded, but none of the 45 mutation sites had been documented ( Supplementary Table 4), inferring the novelty and potential importance of these mutations caused by EBV infection. To clarify if the EBV-associated mutations in AGS–EBV also occurred in primary EBV(+) gastric cancers, we performed Sanger sequencing to compare the prevalence of mutations in AKT2, CCNA1, TGFBR1, ACVR1C, and MAP3K4 between EBV(+) and EBV(-) gastric cancer samples.

We are all human, we are not always right, and as scientists we should be constantly questioning and encouraging questioning. The most solid foundations of science are those built upon work that is questioned and proven. Work that has not been questioned and proven is of uncertain value to the foundations

of science and may weaken them. The above are my definitions of ‘crossing the scientific line’. I would be interested to hear whether readers agree, disagree or can suggest other sins. Letters to the Editor on this subject would be most welcome. So how and why was I accused of ‘crossing the line’ in an e-mail by my old colleague? Because I and my co-authors (Landrum et al., 2012, Page et al., in press and Page et al., 2012) are questioning work done by government scientists who my accuser considers “good” and who thus should not be “harassed” by questioning their findings – to quote from his e-mail “…the US Government Selleckchem RAD001 and its scientists are working for the people of the United States”. Because my research was funded by Exxon Mobil (related to the Exxon

Valdez oil spill), and as he stated, Exxon has a history of “some really dirty tricks”. Because I was working with what he called, “…the oil industry-hired scientists who are incompetent and/or out to prove something decided a priori, and who cheat and play dirty”. Because in questioning the government scientists’ work, I and my co-authors accessed laboratory notebooks; this was, my accuser believed, neither “necessary or ethical scientifically”. Selleckchem SAHA HDAC Because I am a consultant and, as he put it, “…a private consultant…has to earn a living and has to pursue issues which his clients want pursued”. In his opinion “…I think the best way of doing things is to have taxpayer-supported scientists seeking the

truth on behalf of the public interest”. Scientists do not have to like each other, but they do have to act like scientists – with good manners and forming their opinions based on facts not unsubstantiated beliefs, no matter how personally attractive those beliefs may be (Chapman (-)-p-Bromotetramisole Oxalate and Giddings, 1997). As scientists we have a responsibility to seek out the truth no matter what. All scientists, regardless of whom we work for, or what we choose to believe, need to be true to this responsibility. I sincerely thank the old colleague who accused me of ‘crossing the line’ for making me think hard about the work I am doing and have done, and which led to my writing this Editorial. As I told him, I still like him and I respect him for questioning (what scientists do) my work. “
“The publisher regrets that a typographic error appeared in the above article. On page 48, second column in the section Fine-scale spatial genetic structure, the formula for the Sp statistic should read as follows: Sp = −bLd/(1 − F1).

, 2000). Using rodent model of neuropathy, it has been demonstrated that systemic inhibition of AK295 reduces the behavioral and electrophysiological function associated with neuropathy without interfering with the primary Enzalutamide nmr antineoplastic effects of taxol on microtubules and cell death ( Wang et al., 2004). Oxaliplatin leads to an increase in the TUNEL-positive cells in rat DRG neurons

that is completely reversed by z-VAD-fmk, a caspase inhibitor ( Ta et al., 2006) indicating the involvement of caspase mediated apoptosis in oxaliplatin neurotoxicity. The studies have shown the involvement of the MAPKs family in platinum derivative (ciaplatin and oxaliplatin)-induced peripheral neuropathy (Scuteri et al., 2009). The prolonged exposure to oxaliplatin induces early activation of p38 and ERK1/2 in DRG neurons, which in-turn mediate neuronal apoptosis. On the other hand, oxaliplatin down regulates JNK/Sapk which in-turn is responsible for neurotoxic effects (Rutkove, 2001). Recently, buy GSI-IX it has been demonstrated that nerve growth factor protects DRG neurons from oxaliplatin-induced toxicity by restoring the MAPK activation. Furthermore, administration of retinoic acid, a pro-differentiative agent able to activate both JNK/Sapk and ERK1/2, is shown to prevent the toxicity

suggesting the dual role of ERK1/2 depending on the cellular stimulation (Scuteri et al., 2010). Excitotoxic glutamate release leading to excessive glutamatergic neurotransmission and activation of N-methyl-d-aspartate Erythromycin (NMDA) receptors, is associated

with neuronal damage and death in several nervous system disorders. An earlier study had shown that even with a maximally tolerated dose of the potent NMDA receptor antagonist, MK-801, no significant reversal of the mechanical allodynia/hyperalgesia takes place in paclitaxel-induced neuropathic pain (Flatters and Bennett, 2004). However in later studies, the role of glutamate and its NMDA in development of anti-cancer agents-induced neuropathic pain has been described. A recent study has shown that administration of ketamine, NMDA receptor antagonist, attenuates paclitaxel-induced mechanical and thermal hyperalgesia (Pascual et al., 2010). The pharmacological inhibition of enzyme glutamate carboxypeptidase (hydrolyses N-acetyl-aspartyl-glutamate to produce glutamate) leading to decreased glutamate is associated with neuroprotective effects in animal models of cisplatin, paclitaxel and bortezomib-induced peripheral neuropathy (Carozzi et al., 2010). In oxaliplatin-induced neuropathy, an increased expression of NMDA receptors subtype, NR2B (subtypes of NMDA receptors) protein and mRNA in the rat spinal cord is reported during late phase, but not in early phase. Administration of selective NR2B antagonists Ro25-6981 and ifenprodil significantly attenuates the oxaliplatin-induced pain behavior.

S1 and S2). This difference Doramapimod purchase might be explained by the presence of post-translational modification, such as N-glycosylation, as observed for the LAAO from C. rhodostoma, which is responsible for a mass increment of 3.7 kDa ( Geyer et al., 2001), and the presence of cofactor FAD (0.785 kDa).

LmLAAO has a molar mass (60.8 kDa) which is very similar to the values determined for the LAAO from Agkistrodon halys pallas (60.7 kDa) ( Zhang et al., 2004) and LAAO from Vipera libetina (60.9 kDa) ( Tonismagi et al., 2006). The isoeletric point of LmLAAO (pI 6.28) predicted by the software Protparam also showed a difference when compared with the experimentally determined pI (5.1) by isoelectric focusing (results not shown). This discrepancy can be explained by the outward orientation of charged amino acids in its click here three-dimensional structure or possibly by charges introduced by glycosylations. The acidic characteristic of LmLAAO is also observed in LAAOs from other snake venoms such as LAAO from B. pirajai (pI 4.9) ( Izidoro et al., 2006) and LAAO from Bothrops atrox (pI 4.4) ( Alves et al., 2008). It has been described that LAAOs substrate binding sites comprise three hydrophobic subsites, presenting one or two methyl/methylene carbons, and an amino binding subsite (Tan, 1998; Zhong et al., 2009). This explains

the catalytic preference of LmLAAO by hydrophobic amino acids (l-Met, l-Leu, l-Phe, l-Trp, l-Tyr and l-Ile). For other amino acids, the catalytic activity was very low or even absent (Fig. 4A). These results are in accordance with other previously characterized svLAAOs (Alves et al., 2008; Ciscotto et al., 2009; Izidoro et al., 2006; Rodrigues et al., 2009; Samel et al., 2008; Tonismagi et al., 2006; Zhong et al., 2009), showing that the catalytic site has a conserved structure among snake species. When the relative enzymatic activity of LmLAAO was measured between pH 7.0 and 9.0, it exhibited optimal hydrolysis of l-Leu at pH 8.0 (Fig. 4B), which is similar to results found for other svLAAOs (Dineshkumar and Muthuvelan, 2011; Zhong et al., 2009). Buffers with pH values above 9.0 and below 7.0 can cause structural changes in both LmLAAO

and horseradish peroxidase, interfering with the assay. The catalytic Florfenicol activity of LmLAAO was also evaluated at different temperatures. LmLAAO showed only 5.9% of its activity after freezing-thawing at −70 °C for 1 h. After 30 min at 100 °C, the enzyme had lost 100% of its enzymatic activity. The best temperature for storing LmLAAO was 4 °C (Fig. 4C). The determination of Km and Vmax for the substrate l-leucine was performed by derivation of the Michaelis–Menten elliptic curve by GraphPad Prism 5.0 program ( Fig. 4D). This software was used for setting the reliability of data in nonlinear regression. LmLAAO presented a Km value of 0.97 ± 0.07 mmol/L and Vmax de 0.063 ± 0.002 μmol min−1 for l-Leucine. The 95% confidence interval was 0.81–1.14 for Km and from 0.059 to 0.068 for Vmax (8 degrees of freedom).

The same takes place in the case of onshore winds except for the southward shift of radiance maxima ( Figure 3, (d)–(f)). The radiances of moderate intensity extend tens of kilometres further westwards in the case of the offshore wind as compared to the onshore one. This difference peaks at latitudes corresponding to Y ∼ 150–200 km ( Figure 3). The differences dLoff–onwnav (λ) = Loffwnav (λ) − Lonwnav (λ), where Loffwnav (λ) and Lonwnav (λ) are binned radiances at offshore and onshore winds, are mapped in Figure 4. The maximum dLoff–onwnav (λ) are comparable to the Loffwnav (λ) in magnitude, are located between the 10 and 15 m isobaths and extend from 90 to 180

km in the y-axis and from 140 to 200 km in the x-axis. In Figure 5, the zonal profiles of the Nutlin-3a in vitro bottom relief are compared to the profiles of radiance differences dLwnav at 443, 555 and 670 nm. It is evident that (1)dLwnav distributions west of the shallow are flat and exhibit minor between-profile distinctions; find more (2) profile segments at depths Z < 30 m indicate substantial enhancement of Loffav (λ) against Lonav (λ) at sites with moderate steepness of the sea floor (profiles (d)–(g)) and a virtually zero radiance difference at greater bottom steepness (profiles (a) and (b)); (3) profiles of dLav (443) and dLav (555) have the highest magnitude

and resemble each other in position and shape, but a number of dLav (670) profiles appear to be shifted eastwards and differ in shape from the corresponding radiance profiles at shorter wavelengths (d)–(f). The profiles of Loffav and Lonav in Figure 6 demonstrate the following trend: the onshore radiance slightly exceeds the offshore radiance

in the deep-water part of the middle and northern testing area; an inverse relation between them occurs at the western boundary of the shallow; further east, Loffav grows faster than oxyclozanide Lonav but the latter overtakes the former in the vicinity of the coastline. As a result, the summary radiance progression in the presence of easterly and westerly winds looks like a closed loop, whose lower and upper branches correspond to the onshore and offshore events. The eastern intersections of the branches occur at sites of less than a few metres of water, where the insufficient accuracy of the bottom topography model prevents a stricter association of intersections with bottom features. The higher-sensitivity profiles in Figure 6 (dashed) indicate that western intersections occurred at Z > 30 m if r < = 160 km but occurred at sites with 14–30 m of water in profiles at r > 160 km distinguished by roughness of bottom relief in the west of the shallow. In some cases the depth and radiance profiles show conformity in their shape: the two-step structures of the offshore branch of the radiance loop and of the bottom profile in Figure 6f appear to be a manifestation of such conformity. However, the more intricate relationships of these profiles outnumber the situations of straightforward interpretability.

Binarisation of the images was undertaken using a modified auto-threshold (where the overflow value was set as 48%), since the default settings did not satisfactorily separate the soil solids from the pore space. No binary filters were applied to these images since no improvement to the previously acquired images were observed. From processed

binary images measurements of the overall image porosity, the individual pore size (area) and the distribution of pores (nearest neighbour statistics) were determined and expressed as an average of the 6 slices. All analyses were conducted using GenStat Release 13.1 (Lawes Agricultural Trust). Analysis of variance (ANOVA) was performed on data using soil dilution (10−1 and 10−6), planting regime (defined as either bare soil, planted non-mycorrhizal or planted mycorrhizal) Enzalutamide buy CYC202 and harvest time (month) as factors. Data for pore size and nearest neighbour distance were analysed by

repeated measures ANOVA. Data were transformed where appropriate. TRF richness was determined from the number of peaks. Principal Components Analysis (PCA) was carried out on T-RFLP data that had been transformed into relative abundance data. Here, the peak height for each individual TRF was divided by the cumulative value for each sample. The covariance matrix was used on these normalised data as recommended by Culman et al. (2008) with principal component (PC) scores analysed by ANOVA. General Calpain linear regressions were performed on biological measurements to determine which factors contributed to the soil physical parameters. In GenStat ‘all possible models’ were fitted and evaluated using Akaike and adjusted R2 values. This enabled more than one explanatory model to be selected if

appropriate. In the planted macrocosms, root biomass significantly increased each month (month as a single factor in ANOVA, F3,37 = 70.50, P < 0.001) whilst shoot growth only increased up to the third month and thereafter remained constant apart from a slight decrease in month seven (month as a single factor, F3,37 = 27.07, P < 0.001, Fig. 1). Root to shoot ratio remained constant in months 1 and 3 (mean ratios 0.4 and 0.3 respectively) but increased in months 5 and 7 (1.98 and 2.58 respectively; month as a single factor, F3,37 = 51.49, P < 0.001, LSD = 0.45) reflecting the difference in root and shoot biomass at these harvest points. Arbuscular mycorrhizal colonisation significantly reduced both root (AM colonisation as a single factor, F1,37 = 12.51, P = 0.001) and shoot (F1,37 = 13.93, P < 0.001) biomass but did not affect root/shoot ratio. Whole plant dry weight was 7.34 g in the absence of AMF and 5.00 g in the presence of inoculum (F1,37 = 14.

SR140333B ((S)1-3-(3,4-dichloro-phenyl)-3-[2(4-phenyl-1-aza-bicyclo[2.2.2]oct-1-yl]-ethyl]-piperidin-1-yl-2-(3-isopropoxy-phenyl)-ethanone benzenesulfonate) was a kind gift from Sanofi-Aventis, France. The results are presented as the mean ± S.E.M. The statistical significance among the groups was assessed using one-way analysis of variance followed by Bonferroni’s post-hoc test. P values lower than 0.05 were considered an indication of significance. This work was supported by grants from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Fundação Araucária do Estado do Paraná. H.O.B.

is a recipient of a CNPq scholarship. We thank Sanofi-Aventis for the donation of SR140333B. “
“Biased information processing is an important marker Mitomycin C mouse of negative mood, and contributes to the development

of depression and anxiety disorders (Mathews & check details Macleod, 2005). A negative interpretation bias refers to the attribution of a negative compared to a benign or positive meaning to an ambiguous situation (Butler & Mathews, 1983); it is relative, and considering a lack of positive interpretation bias is also of interest. Negative interpretation bias has been associated with clinical depression and depressed mood (dysphoria) (Butler and Mathews, 1983, Lawson et al., 2002 and Rude et al., 2003). Cognitive models of depression suggest that negative interpretation bias – seeing one’s glass as perpetually half empty rather than half full – is critical to the maintenance of depressed mood (Beck,

1976). Promoting a less Interleukin-3 receptor negative interpretation bias is an important component of successful cognitive behavioral therapy (CBT) for depression (Hollon et al. 2005). CBM2 techniques have recently been developed to target such negative biases directly via computer-based training rather than face-to-face therapy (MacLeod, Koster, & Fox, 2009). For positive CBM interpretation bias (CBM-I), participants are trained to resolve situations that initially appear ambiguous in a benign/positive rather than negative way. CBM-I was initially developed in the context of anxiety disorders (e.g. Grey and Mathews, 2000 and Mathews and Mackintosh, 2000). A CBM-I procedure emphasising the use of mental imagery to simulate scenarios, has been developed to reduce vulnerability to depressed mood (Blackwell and Holmes, 2010 and Holmes et al., 2009). Experiments and treatments designed to modify interpretation bias would clearly benefit from tools to measure it. Perhaps surprisingly, the choice is currently limited; the measures include a physiological test – measuring the magnitude of blink reflex (from a puff of air to the eye) in response to ambiguous stimuli (Lawson et al. 2002) – and a behavioral test such as the Scrambled Sentences Task (Wenzlaff, Wegner, & Pennebaker, 1993). In the latter, participants are asked to make a sentence from a mixed sequence of words (under a cognitive load and constrained time).

Compared with that in the control cells, the initial rapid uptake of ascorbate in cobalt(II)-exposed cells has stopped 2–4 h after the addition of the cobalt to the cell culture medium. Then, within the next 16–18 h, the cellular [14C] ascorbate decreased gradually to barely detectable levels. This time course could be the result of a relatively slow interaction of the metals (or metal complexes) with critical target molecules (ligands) in the medium and/or cells, including ascorbic acid. Exposure

of cells to cobalt(II) causes activation of the HIF-1 transcription factor and up-regulates many of the hypoxia-inducible genes (Yuan et al., 2003). However, the exact mechanism of HIF-1 activation by cobalt (and also other metals) is not known. Very selleck chemical recently it has been shown that HIF-1alpha stabilization in human lung

epithelial cells occurred following exposure to various metal ions, including those that cannot substitute for iron in the hydroxylases. In each case addition of the reducing agent (ascorbic acid) abolished HIF-1alpha protein stabilization. To better understand JNK signaling inhibitors the role of iron oxidation in hydroxylase inhibition and to define the role of ascorbic acid in the enzyme recovery, applied molecular modeling techniques were adopted. The results indicate that the energy required for iron substitution by divalent metal ions in the enzyme is high and unlikely to be achieved in a biological system (Kaczmarek et al., 2009). As described above, cobalt is a

potent inducer of oxidative stress causing free radical generation, which in turn induce DNA damage, inhibit DNA repair mechanisms and the exchange of DNA between sister-chromatids and aneuploidy (Galanis et al., 2009). The toxicity of cobalt is relatively low compared to many other metals (Gal et al., 2008). Its toxic effect in higher concentrations affects mainly the lungs, leading to asthma, pneumonia and MRIP wheezing. Overdosing of cobalt (>5 mg/day) may lead to abnormal thyroid functions, polycythemia and overproduction of red blood cells (erythropoiesis), with increased production of the hormone erythropoietin. There is also a risk of pulmonary edema, peripheral vascular thrombosis, optic nerve atrophy. Intranasal use of vitamin B12 includes symptoms such as headache, sore throat and rhinitis. Inhalation of Co alone can cause asthma (Barceloux, 1999a and Barceloux, 1999b) and simultaneous inhalation of cobalt and tungsten carbide (WC) particles induce the development of hard metal lung disease via ROS mechanisms. The International Agency for Research on Cancer (IARC) recently classified the mixture Co/WC as “probably carcinogenic to humans”. Cobalt alone was only classified as “possibly carcinogenic to humans”. Several studies reported that metallic cobalt acquires a higher genotoxicity when associated to WC or to other carbides.

After washing, 100 μL of o-phenylenediamine (0.33 mg/mL in citrate buffer, pH 5.2, in the presence of 0.04% hydrogen peroxide) was added to the wells. The reaction was stopped after 20 min by the addition of 20 μL of a 1:20 sulfuric acid solution. Absorbance values were determined at 490 nm using an ELISA plate reader (BIO-RAD, 680 models). Duplicate readings were taken for all samples and the means were calculated. For the immunoblotting, an SDS-PAGE gel using H. lunatus venom was run according to the method of Laemmli (1970) using 12.5% gels and transferred onto Nivolumab in vivo nitrocellulose membrane (

Towbin et al., 1979). The membrane was blocked with PBS-Tween 0.3% for 1 h. After washing three times for 5 min with PBS-Tween 0.05%, the membrane was incubated with anti-H. lunatus rabbit serum (1:1500) for 1 h and 30 min. The membrane was washed (PBS-Tween 0.05%) more three times and immunoreactive proteins were detected using anti-rabbit IgG conjugated to peroxidase (1:8000) for 1 h at room temperature. After washing three times for 5 min with PBS-Tween 0.05%, blots were developed using DAB/chloronaphthol according to manufacturer’s instructions. The lethality of the H. lunatus soluble venom to mammals was examined using mice. After intracranial

(i.c.) and intraperitoneal injection (i.p.) toxic and lethal effects were observed. The LD50 value was determined as 0.1 mg/kg and 21.55 mg/kg (respectively). Injected mice displayed typical symptoms of intoxication such as excitability, agitation, salivation, eye secretions, sweating, convulsions and paralysis of legs. The symptoms lasted for 30–120 min before death. The observed Selleckchem AP24534 symptoms closely resemble those produced by the venom of Buthidae scorpions of the genera Centruroides or Tityus ( Possani et al.,

1977). The venoms from some species of Brazilian scorpions were analyzed regarding their lethality in mice by Nishikawa and co-workers, in 1994 via intraperitoneal injection, the same used by us. In this study, the venoms were grouped Farnesyltransferase as highly toxic Tityus stigmurus (LD50 = 0.773 mg/kg), Tityus bahiensis (LD50 = 1.062 mg/kg) and T. serrulatus (LD50 = 1.160 mg/kg); moderately toxic Tityus cambridgei (LD50 = 12.136 mg/kg) and practically non-toxic Rhopalurus agamemnon (LD50 = 36.363 mg/kg) and Brotheas amazonicus (LD50 = 90.909 mg/kg). In view of the results observed in our experiments and compared to the previous data, H. lunatus venom can be classified as moderately toxic. The value found for LD50 of the venom of H. lunatus (i.p. route) was more than three times lower than that found by Zavaleta et al. (1981). This divergence can be explained by the fact that in our experiments the venom collected was immediately diluted in ultrapure water (milli Q), pooled and stored at −20 °C until use and never lyophilized. The proteolytic activity (caseinase) of H. lunatus venom was detected, for the first time, by the dimethylcasein method ( Lin et al.

The treatment algorithm and clinical guidance, which this panel wishes to support, aim to treat men at a similar 10-year fracture risk as in women, because the morbidity and mortality associated with major osteoporotic fractures in men are substantial. Available evidence suggests that treatment algorithms in women are also applicable to men. In practice, this is likely to involve the use of FRAX and clinical risk factors (Table 1). The use of fixed intervention thresholds is viewed as counter-intuitive to current practice, because the risk is to exclude too many younger patients and, conversely, to include too many older patients above a threshold

value. The available level of evidence that Selleck RG7204 treatment decreases the risk of fracture in men is lower than for women. As such, the US Endocrine Society is of the opinion that there is currently not enough information in men to make a recommendation, because too few fractures have been recorded in men to link BMD changes Enzalutamide supplier with anti-fracture efficacy. Additional fracture data are needed to endorse the clinical care of osteoporosis in men. However, this panel believes that this view can be countered, based on available epidemiological and clinical efficacy data in male subjects, which display similarities with data acquired in women, in terms of treatment effects on BMD, biochemical markers

of bone turnover, and fracture endpoint, despite the recorded differences in pathophysiology of bone loss and bone microarchitecture. Overall, empirical data from men and women are so similar that differences in morphology may not be clinically relevant. Despite the wealth of available data from numerous studies in women, the current strategy of drug development for the treatment of osteoporosis in men is such that there is a delay of several years before clinical trial data in men become available. Perhaps the lag between comparable treatments becoming available for female and for male osteoporosis can be reduced. The situation is not unlike coronary artery disease, which was initially thought to be principally a male disease, Orotidine 5′-phosphate decarboxylase but for which female treatment was made

more rapidly available. A logical conclusion would eventually be to design mixed studies, as recommended by the WHO [111]. From a pragmatic point of view, it is unlikely that drugs for the specific treatment of osteoporosis in men will be developed. One area of research that deserves more attention is the hormonal and non-hormonal factors influencing bone loss in men. There appears to be potential in measuring serum oestradiol levels, in addition to testosterone levels in men with low BMD. We wish to encourage the development of standardised mass spectroscopy assays for the assessment of sex steroid contribution in male osteoporosis. Awareness of osteoporosis in men is improving, although it remains under-diagnosed and under-treated.