Childhood de novo CD5+ Diffuse Large B-cell Lymphoma: a Separate Entity?

De novo CD5-positive diffuse large B- cell lymphoma (CD5+ DLBCL) is a subtype of DLBCL found predominantly in older individuals. This particular subtype has been associated with a female pre- dominance and a more aggressive clinical course. Conversely, this entity has not been described in the pe- diatric population. We report a case of a 12 year-old boy who presented with an ileocecal intussusception. Radiologic, morphologic, and immunophenotypic analysis revealed an isolated extranodal mass consistent with a CD5+ DLBCL, germinal center cell phenotype. Fluorescent in situ hybridization analysis was nega- tive for cMYC, BCL6, BCL2, MLL, and IGH/CCND1 rearrangement and showed loss of one copy of MLL in 32% cells. The patient was treated with four cycles of cyclophosphamide, vincristine, prednisolone, methotrexate, and doxorubicin and achieved complete remission. To the best of our knowledge, this is the first detailed report of a de novo CD5+ DLBCL occurring in a child

Caveat medicus:Clinician experiences in publishing reports of serious oncology-associated adverse drug reactions

Oncology-associated adverse drug/device reactions can be fatal. Some clinicians who treat single patients with severe oncology-associated toxicities have researched case series and published this information. We investigated motivations and experiences of select individuals leading such efforts. Clinicians treating individual patients who developed oncology-associated serious adverse drug events were asked to participate. Inclusion criteria included having index patient information, reporting case series, and being collaborative with investigators from two National Institutes of Health funded pharmacovigilance networks. Thirty-minute interviews addressed investigational motivation, feedback from pharmaceutical manufacturers, FDA personnel, and academic leadership, and recommendations for improving pharmacovigilance. Responses were analyzed using constant comparative methods of qualitative analysis. Overall, 18 clinicians met inclusion criteria and 14 interviewees are included. Primary motivations were scientific curiosity, expressed by six clinicians. A less common theme was public health related (three clinicians). Six clinicians received feedback characterized as supportive from academic leaders, while four clinicians received feedback characterized as negative. Three clinicians reported that following the case series publication they were invited to speak at academic institutions worldwide. Responses from pharmaceutical manufacturers were characterized as negative by 12 clinicians. One clinician's wife called the post-reporting time the "Maalox month," while another clinician reported that the manufacturer collaboratively offered to identify additional cases of the toxicity. Responses from FDA employees were characterized as collaborative for two clinicians, neutral for five clinicians, unresponsive for negative by six clinicians. Three clinicians endorsed developing improved reporting mechanisms for individual physicians, while 11 clinicians endorsed safety activities that should be undertaken by persons other than a motivated clinician who personally treats a patient with a severe adverse drug/device reaction. Our study provides some of the first reports of clinician motivations and experiences with reporting serious or potentially fatal oncology-associated adverse drug or device reactions. Overall, it appears that negative feedback from pharmaceutical manufacturers and mixed feedback from the academic community and/or the FDA were reported. Big data, registries, Data Safety Monitoring Boards, and pharmacogenetic studies may facilitate improved pharmacovigilance efforts for oncology-associated adverse drug reactions. These initiatives overcome concerns related to complacency, indifference, ignorance, and system-level problems as barriers to documenting and reporting adverse drug events- barriers that have been previously reported for clinician reporting of serious adverse drug reactions

The Peculiar Motions of Early-Type Galaxies in Two Distant Regions. IV. The Photometric Fitting Procedure

The EFAR project is a study of 736 candidate early-type galaxies in 84 clusters lying in two regions towards Hercules-Corona Borealis and Perseus-Cetus at distances $cz \approx 6000-15000$ km/s. In this paper we describe a new method of galaxy photometry adopted to derive the photometric parameters of the EFAR galaxies. The algorithm fits the circularized surface brightness profiles as the sum of two seeing-convolved components, an $R^{1/4}$ and an exponential law. This approach allows us to fit the large variety of luminosity profiles displayed by the EFAR galaxies homogeneously and to derive (for at least a subset of these) bulge and disk parameters. Multiple exposures of the same objects are optimally combined and an optional sky-fitting procedure has been developed to correct for sky subtraction errors. Extensive Monte Carlo simulations are analyzed to test the performance of the algorithm and estimate the size of random and {\it systematic} errors. Random errors are small, provided that the global signal-to-noise ratio of the fitted profiles is larger than $\approx 300$. Systematic errors can result from 1) errors in the sky subtraction, 2) the limited radial extent of the fitted profiles, 3) the lack of resolution due to seeing convolution and pixel sampling, 4) the use of circularized profiles for very flattened objects seen edge-on and 5) a poor match of the fitting functions to the object profiles. Large systematic errors are generated by the widely used simple $R^{1/4}$ law to fit luminosity profiles when a disk component, as small as 20% of the total light, is present.Comment: 47 pages, Latex File, aaspp4.sty, flushrt.sty, 16 Postscript figures, to appear in ApJ

Impact of five years of peer-mediated interventions on sexual behavior and sexually transmitted infections among female sex workers in Mombasa, Kenya

<p>Abstract</p> <p>Background</p> <p>Since 2000, peer-mediated interventions among female sex workers (FSW) in Mombasa Kenya have promoted behavioural change through improving knowledge, attitudes and awareness of HIV serostatus, and aimed to prevent HIV and other sexually transmitted infection (STI) by facilitating early STI treatment. Impact of these interventions was evaluated among those who attended peer education and at the FSW population level.</p> <p>Methods</p> <p>A pre-intervention survey in 2000, recruited 503 FSW using snowball sampling. Thereafter, peer educators provided STI/HIV education, condoms, and facilitated HIV testing, treatment and care services. In 2005, data were collected using identical survey methods, allowing comparison with historical controls, and between FSW who had or had not received peer interventions.</p> <p>Results</p> <p>Over five years, sex work became predominately a full-time activity, with increased mean sexual partners (2.8 versus 4.9/week; <it>P </it>< 0.001). Consistent condom use with clients increased from 28.8% (145/503) to 70.4% (356/506; <it>P </it>< 0.001) as well as the likelihood of refusing clients who were unwilling to use condoms (OR = 4.9, 95%CI = 3.7–6.6). In 2005, FSW who received peer interventions (28.7%, 145/506), had more consistent condom use with clients compared with unexposed FSW (86.2% versus 64.0%; AOR = 3.6, 95%CI = 2.1–6.1). These differences were larger among FSW with greater peer-intervention exposure. HIV prevalence was 25% (17/69) in FSW attending ≥ 4 peer-education sessions, compared with 34% (25/73) in those attending 1–3 sessions (P = 0.21). Overall HIV prevalence was 30.6 (151/493) in 2000 and 33.3% (166/498) in 2005 (<it>P </it>= 0.36).</p> <p>Conclusion</p> <p>Peer-mediated interventions were associated with an increase in protected sex. Though peer-mediated interventions remain important, higher coverage is needed and more efficacious interventions to reduce overall vulnerability and risk.</p

Azithromycin plus chloroquine: combination therapy for protection against malaria and sexually transmitted infections in pregnancy

INTRODUCTION: The first-line therapy for the intermittent preventive treatment of malaria in pregnancy (IPTp) is sulphadoxine-pyrimethamine (SP). There is an urgent need to identify safe, well-tolerated and efficacious alternatives to SP due to widespread Plasmodium falciparum resistance. Combination therapy using azithromycin and chloroquine is one possibility that has demonstrated adequate parasitological response > 95% in clinical trials of non-pregnant adults in sub-Saharan Africa and where IPTp is a government policy in 33 countries. AREAS COVERED: Key safety, tolerability and efficacy data are presented for azithromycin and chloroquine, alone and/or in combination, when used to prevent and/or treat P. falciparum, P. vivax, and several curable sexually transmitted and reproductive tract infections (STI/RTI). Pharmacokinetic evidence from pregnant women is also summarized for both compounds. EXPERT OPINION: The azithromycin-chloroquine regimen that has demonstrated consistent efficacy in non-pregnant adults has been a 3-day course containing daily doses of 1 g of azithromycin and 600 mg base of chloroquine. The pharmacokinetic evidence of these compounds individually suggests that dose adjustments may not be necessary when used in combination for treatment efficacy against P. falciparum, P. vivax, as well as several curable STI/RTI among pregnant women, although clinical confirmation will be necessary. Mass trachoma-treatment campaigns have shown that azithromycin selects for macrolide resistance in the pneumococcus, which reverses following the completion of therapy. Most importantly, no evidence to date suggests that azithromycin induces pneumococcal resistance to penicillin

Chemically-synthesised, atomically-precise gold clusters deposited and activated on titania

Synchrotron XPS was used to investigate a series of chemically-synthesised, atomically-precise gold clusters Au(n)(PPh₃)(y) (n = 8, 9, 11 and 101, with y depending on cluster size) immobilized on titania nanoparticles. The gold clusters were washed with toluene at 100 °C or calcined at 200 °C to remove the organic ligand. From the position of the Au 4f₇/₂ peak it is concluded that cluster size is not altered through the deposition. From the analysis of the phosphorous spectra, it can be concluded that the applied heat treatment removes the organic ligands. Washing and calcination leads to partial oxidation and partial agglomeration of the clusters. Oxidation of the clusters is most likely due to the interaction of the cluster core with the oxygen of the titania surface after removal of ligands. The position of the Au 4f₇/₂ peak indicates that the size of the agglomerated clusters is still smaller than that of Au₁₀₁.David P. Anderson, Jason F. Alvino, Alexander Gentleman, Hassan Al Qahtani, Lars Thomsen, Matthew I. J. Polson, Gregory F. Metha, Vladimir B. Golovko and Gunther G. Andersso

Juvenile king scallop, Pecten maximus, is potentially tolerant to low levels of ocean acidification when food is unrestricted.

The decline in ocean water pH and changes in carbonate saturation states through anthropogenically mediated increases in atmospheric CO2 levels may pose a hazard to marine organisms. This may be particularly acute for those species reliant on calcareous structures like shells and exoskeletons. This is of particular concern in the case of valuable commercially exploited species such as the king scallop, Pecten maximus. In this study we investigated the effects on oxygen consumption, clearance rates and cellular turnover in juvenile P. maximus following 3 months laboratory exposure to four pCO2 treatments (290, 380, 750 and 1140 µatm). None of the exposure levels were found to have significant effect on the clearance rates, respiration rates, condition index or cellular turnover (RNA: DNA) of individuals. While it is clear that some life stages of marine bivalves appear susceptible to future levels of ocean acidification, particularly under food limiting conditions, the results from this study suggest that where food is in abundance, bivalves like juvenile P. maximus may display a tolerance to limited changes in seawater chemistry

Discovery of Diverse Small Molecule Chemotypes with Cell-Based PKD1 Inhibitory Activity

Protein kinase D (PKD) is a novel family of serine/threonine kinases regulated by diacylglycerol, which is involved in multiple cellular processes and various pathological conditions. The limited number of cell-active, selective inhibitors has historically restricted biochemical and pharmacological studies of PKD. We now markedly expand the PKD1 inhibitory chemotype inventory with eleven additional novel small molecule PKD1 inhibitors derived from our high throughput screening campaigns. The in vitro IC50s for these eleven compounds ranged in potency from 0.4 to 6.1 µM with all of the evaluated compounds being competitive with ATP. Three of the inhibitors (CID 1893668, (1Z)-1-(3-ethyl-5-methoxy-1,3-benzothiazol-2-ylidene)propan-2-one; CID 2011756, 5-(3-chlorophenyl)-N-[4-(morpholin-4-ylmethyl)phenyl]furan-2-carboxamide; CID 5389142, (6Z)-6-[4-(3-aminopropylamino)-6-methyl-1H-pyrimidin-2-ylidene]cyclohexa-2,4-dien-1-one) inhibited phorbol ester-induced endogenous PKD1 activation in LNCaP prostate cancer cells in a concentration-dependent manner. The specificity of these compounds for PKD1 inhibitory activity was supported by kinase assay counter screens as well as by bioinformatics searches. Moreover, computational analyses of these novel cell-active PKD1 inhibitors indicated that they were structurally distinct from the previously described cell-active PKD1 inhibitors while computational docking of the new cell-active compounds in a highly conserved ATP-binding cleft suggests opportunities for structural modification. In summary, we have discovered novel PKD1 inhibitors with in vitro and cell-based inhibitory activity, thus successfully expanding the structural diversity of small molecule inhibitors available for this important pharmacological target

Perfluoroalkyl substances and lipid concentrations in plasma during pregnancy among women in the Norwegian Mother and Child Cohort Study

Perfluoroalkyl substances (PFASs) are widespread and persistent environmental pollutants. Previous studies, primarily among non-pregnant individuals, suggest positive associations between PFAS levels and certain blood lipids. If there is a causal link between PFAS concentrations and elevated lipids during pregnancy, this may suggest a mechanism by which PFAS exposure leads to certain adverse pregnancy outcomes, including preeclampsia

Perfluoroalkyl Substances During Pregnancy and Validated Preeclampsia Among Nulliparous Women in the Norwegian Mother and Child Cohort Study

Perfluoroalkyl substances (PFAS) are persistent and ubiquitous environmental contaminants, and human exposure to these substances may be related to preeclampsia, a common pregnancy complication. Previous studies have found serum concentrations of PFAS to be positively associated with pregnancy-induced hypertension and preeclampsia in a population with high levels of exposure to perfluorooctanoate. Whether this association exists among pregnant women with background levels of PFAS exposure is unknown. Using data from the Norwegian Mother and Child Cohort Study conducted by the Norwegian Institute of Public Health, we carried out a study of nulliparous pregnant women enrolled in 2003–2007 (466 cases, 510 noncases) to estimate associations between PFAS concentrations and an independently validated diagnosis of preeclampsia. We measured levels of 9 PFAS in maternal plasma extracted midpregnancy; statistical analyses were restricted to 7 PFAS that were quantifiable in more than 50% of samples. In proportional hazards models adjusted for maternal age, prepregnancy body mass index (weight (kg)/height (m)2), educational level, and smoking status, we observed no strongly positive associations between PFAS levels and preeclampsia. We found an inverse association between preeclampsia and the highest quartile of perfluoroundecanoic acid concentration relative to the lowest quartile (hazard ratio = 0.55, 95% confidence interval: 0.38, 0.81). Overall, our findings do not support an increased risk of preeclampsia among nulliparous Norwegian women with background levels of PFAS exposure