Fine-needle aspiration in suspected inflammatory breast cancer: case series with emphasis on approach to specimen adequacy.
To highlight the utility of a tangential approach in the fine-needle aspiration (FNA) technique for obtaining cellular material adequate for a conclusive diagnosis in diffusely enlarged breast without a discrete lump. FNA was performed on 5 women clinically suspected to have inflammatory breast cancer (IBC). All had unilateral diffusely enlarged breasts with peau d'orange changes of the skin. No distinct lump was palpable. The procedure was performed using a 10 cm(3) syringe with a tangential approach of a 23-gauge needle in all 4 quadrants with extra passes in the antigravity areas. Rapid on-site evaluation for adequacy was done. All women were of African descent within the age range of 34-57 years. One case had a recent history of lactation. FNA smears showed low-to-moderate cellularity. One case was suspicious and 4 were positive for ductal carcinoma. Core biopsy confirmed IBC in 3 cases. Two cases had a mastectomy; 1 of these cases had preoperative neoadjuvant chemotherapy. The approach of FNA used in these cases helped to establish the diagnosis of IBC in 4 women presenting with a diffusely enlarged and tender breast, resulting in the timely initiation of appropriate management. The technique needs to be assessed in a larger cohort of women with diffusely enlarged breast to evaluate its diagnostic utility.


Motor neuron position and topographic order imposed by β- and γ-catenin activities.
Neurons typically settle at positions that match the location of their synaptic targets, creating topographic maps. In the spinal cord, the organization of motor neurons into discrete clusters is linked to the location of their muscle targets, establishing a topographic map of punctate design. To define the significance of motor pool organization for neuromuscular map formation, we assessed the role of cadherin-catenin signaling in motor neuron positioning and limb muscle innervation. We find that joint inactivation of β- and γ-catenin scrambles motor neuron settling position in the spinal cord but fails to erode the predictive link between motor neuron transcriptional identity and muscle target. Inactivation of N-cadherin perturbs pool positioning in similar ways, albeit with reduced penetrance. These findings reveal that cadherin-catenin signaling directs motor pool patterning and imposes topographic order on an underlying identity-based neural map.


Point source concentration of GDNF may explain failure of phase II clinical trial.
Significant differences have been reported in results from three clinical trials evaluating intraputamenal infusion of glial cell line-derived neurotrophic factor (GDNF) for the treatment of Parkinson's disease. To determine if problems in drug bioavailability could have contributed to the discrepancies between studies, we have analyzed the distribution of intraputamenally infused GDNF in the rhesus monkey brain using the delivery system and infusion protocol followed in a phase 2 clinical trial that failed to achieve its primary endpoint. I125-GDNF was unilaterally infused into the putamen of three adult rhesus monkeys for 7 days. Three age- and sex-matched animals received vehicle infusions following identical procedures. GDNF levels in the brain, peripheral organs, blood and CSF were quantified and mapped by GDNF immunocytochemistry, GDNF ELISAs and I125 measurements. Infused GDNF was found to be unevenly concentrated around the catheter, with tissue levels dropping exponentially with increasing distance from the point source of the single opening in the catheter tip. The volume of distribution of GDNF around the catheter, as determined by immunocytochemistry, varied over four-fold between animals ranging from 87 to 369 mm3. The concentration of GDNF around the catheter tip and limited diffusion into surrounding brain parenchyma support the hypothesis that drug bioavailability was limited to a small portion (2-9%) of the human putamen in the clinical trial using this catheter and infusion protocol.


Genetic and environmental factors that affect gestation length in dairy cattle.
Genetic and environmental factors that might affect gestation length (GL) were investigated. Data included information from >11 million parturitions from 1999 through 2006 for 7 US dairy breeds. Effects examined were year, herd-year, month, and age within parity of conception; parturition code (sex and multiple-birth status); lactation length and standardized milk yield of cow; service sire; cow sire; and cow. All effects were fixed except for service sire, cow sire, and cow. Mean GL for heifers and cows, respectively, were 277.8 and 279.4 d for Holsteins, 278.4 and 280.0 d for Jerseys, 279.3 and 281.1 d for Milking Shorthorns, 281.6 and 281.7 d for Ayrshires, 284.8 and 285.7 d for Guernseys, and 287.2 and 287.5 d for Brown Swiss. Estimated standard deviations of GL were greatly affected by data restrictions but generally were approximately 5 to 6 d. Year effects on GL were extremely small, but month effects were moderate. For Holstein cows, GL was 2.0 d shorter for October conceptions than for January and February conceptions; 4.7 and 5.6 d shorter for multiple births of the same sex than for single-birth females and males, respectively; 0.8 d longer for lactations of < or =250 d than for lactations of > or =501 d; and 0.6 d shorter for standardized yield of < or =8,000 kg than for yield of > or =14,001 kg. Estimates for GL heritability from parities 2 to 5 were 33 to 36% for service sire and 7 to 12% for cow sire; corresponding estimates from parity 1 were 46 to 47% and 10 to 12%. Estimates of genetic correlations between effects of service sire and cow sire on GL were 0.70 to 0.85 for Brown Swiss, Holsteins, and Jerseys, which indicates that those traits likely are controlled by many of the same genes and can be used to evaluate each other. More accurate prediction of calving dates can help dairy producers to meet management requirements of pregnant animals and to administer better health care during high-risk phases of animals' lives. However, intentional selection for either shorter or longer GL is not recommended without consideration of its possible effect on other dependent traits (e.g., calving ease and stillbirth).


Predicting anisotropic thermal displacements for hydrogens from solid-state NMR: a study on hydrogen bonding in polymorphs of palmitic acid.
The hydrogen-bonding environments at the COOH moiety in eight polycrystalline polymorphs of palmitic acid are explored using solid-state NMR. Although most phases have no previously reported crystal structure, measured 13C chemical shift tensors for COOH moieties, combined with DFT modeling establish that all phases crystallize with a cyclic dimer (R22(8)) hydrogen bonding arrangement. Phases A2, Bm and Em have localized OH hydrogens while phase C has a dynamically disordered OH hydrogen. The phase designated As is a mix of five forms, including 27.4% of Bm and four novel phases not fully characterized here due to insufficient sample mass. For phases A2, Bm, Em, and C the anisotropic uncertainties in the COOH hydrogen atom positions are established using a Monte Carlo sampling scheme. Sampled points are retained or rejected at the ±1σ level based upon agreement of DFT computed 13COOH tensors with experimental values. The collection of retained hydrogen positions bear a remarkable resemblance to the anisotropic displacement parameters (i.e. thermal ellipsoids) from diffraction studies. We posit that this similarity is no mere coincidence and that the two are fundamentally related. The volumes of NMR-derived anisotropic displacement ellipsoids for phases with localized OH hydrogens are 4.1 times smaller than those derived from single crystal X-ray diffraction and 1.8 times smaller than the volume of benchmark single crystal neutron diffraction values.


Electrosurgical loop excision of the cervical transformation zone: the experience of family physicians.
Electrosurgical loop excision of the cervical transformation zone (ELECTZ) is an excisional surgical procedure for treatment of premalignant cervical disease and the abnormal transformation zone by wire loop electrodes. The purpose of this study was to describe and assess the clinical experiences and complications of family-physician-performed ELECTZ and ELECTZ conization. Women who were scheduled for the ELECTZ or ELECTZ conization procedures were enrolled in the study between March 1992 and March 1993, inclusive. Subjects were recruited from the practices of six family physician colposcopists located at five sites. The ELECTZ and ELECTZ conization procedures were performed on patients with abnormal Papanicolaou (Pap) smears or abnormal histologic results and abnormal colposcopic findings. Procedural complications were documented. Subjects were serially assessed during the first postoperative year by Pap smears, colposcopy, and, when necessary, by biopsy to determine therapeutic cure. Of 198 subjects enrolled in the study, 148 women were assessed at least once in follow-up by Pap smear and colposcopy. Only 7.6% of women were defined as treatment failures by subsequent histologic assessment. Women treated by ELECTZ conization were older (32.2 vs 25.1 years, P = .02), were more likely to develop posttreatment cervical stenosis (25.9% vs 3.8%, P = .001), and were more likely to have the postoperative squamocolumnar junction positioned in the endocervical canal (32.4% vs 8.7%, P = .002) than were women treated by ELECTZ: Loop excision specimen margins demonstrated dysplasia for 27 (13.6%) subjects. Significant operative bleeding (> 25 mL) was noted in 6.8% of subjects. Histologic thermal artifact was reported for 9.6% of specimens. One case of microinvasive cancer and one case of invasive cancer were identified unexpectedly by ELECTZ conization. Electrosurgical loop excision of the cervical transformation zone and ELECTZ conization may be safely and effectively performed in office settings by family physicians. Complications and treatment failure rates for the ELECTZ and ELECTZ conization procedures were similar to those experienced by other clinicians.


Nuttalliella namaqua: a living fossil and closest relative to the ancestral tick lineage: implications for the evolution of blood-feeding in ticks.
Ticks are monophyletic and composed of the hard (Ixodidae) and soft (Argasidae) tick families, as well as the Nuttalliellidae, a family with a single species, Nuttalliella namaqua. Significant biological differences in lifestyle strategies for hard and soft ticks suggest that various blood-feeding adaptations occurred after their divergence. The phylogenetic relationships between the tick families have not yet been resolved due to the lack of molecular data for N. namaqua. This tick possesses a pseudo-scutum and apical gnathostoma as observed for ixodids, has a leathery cuticle similar to argasids and has been considered the evolutionary missing link between the two families. Little knowledge exists with regard to its feeding biology or host preferences. Data on its biology and systematic relationship to the other tick families could therefore be crucial in understanding the evolution of blood-feeding behaviour in ticks. Live specimens were collected and blood meal analysis showed the presence of DNA for girdled lizards from the Cordylid family. Feeding of ticks on lizards showed that engorgement occurred rapidly, similar to argasids, but that blood meal concentration occurs via malpighian excretion of water. Phylogenetic analysis of the 18S nuclear and 16S mitochondrial genes indicate that N. namaqua grouped basal to the main tick families. The data supports the monophyly of all tick families and suggests the evolution of argasid-like blood-feeding behaviour in the ancestral tick lineage. Based on the data and considerations from literature we propose an origin for ticks in the Karoo basin of Gondwanaland during the late Permian. The nuttalliellid family almost became extinct during the End Permian event, leaving N. namaqua as the closest living relative to the ancestral tick lineage and the evolutionary missing link between the tick families.


Separating Stimulus-Induced and Background Components of Dynamic Functional Connectivity in Naturalistic fMRI.
We consider the challenges in extracting stimulus-related neural dynamics from other intrinsic processes and noise in naturalistic functional magnetic resonance imaging (fMRI). Most studies rely on inter-subject correlations (ISC) of low-level regional activity and neglect varying responses in individuals. We propose a novel, data-driven approach based on low-rank plus sparse ( [Formula: see text]) decomposition to isolate stimulus-driven dynamic changes in brain functional connectivity (FC) from the background noise, by exploiting shared network structure among subjects receiving the same naturalistic stimuli. The time-resolved multi-subject FC matrices are modeled as a sum of a low-rank component of correlated FC patterns across subjects, and a sparse component of subject-specific, idiosyncratic background activities. To recover the shared low-rank subspace, we introduce a fused version of principal component pursuit (PCP) by adding a fusion-type penalty on the differences between the columns of the low-rank matrix. The method improves the detection of stimulus-induced group-level homogeneity in the FC profile while capturing inter-subject variability. We develop an efficient algorithm via a linearized alternating direction method of multipliers to solve the fused-PCP. Simulations show accurate recovery by the fused-PCP even when a large fraction of FC edges are severely corrupted. When applied to natural fMRI data, our method reveals FC changes that were time-locked to auditory processing during movie watching, with dynamic engagement of sensorimotor systems for speech-in-noise. It also provides a better mapping to auditory content in the movie than ISC.


Predominance of a single genotype of Mycobacterium tuberculosis in regions of Southern Africa.
Zimbabwe and Zambia. To determine the genetic diversity of Mycobacterium tuberculosis strains isolated from tuberculosis (TB) patients in Zimbabwe and Zambia. M. tuberculosis isolates cultured from TB patients presenting at referral hospitals in Zimbabwe and health care clinics in Zambia were characterised by IS6110 genotyping and/or spoligotyping using internationally standardised methods. Genotypic data were compared to those from Cape Town and the SpolDB3.0 database. A predominant group of strains could be identified among 116/246 (47.2%) Zimbabwean isolates by their characteristic IS6110-banding pattern and unique spoligotype signature, where spacers 21-24, 27-30 and 33-36 were deleted. Comparison with strains from Cape Town showed that they were closely related to a family of strains present in 2.3% of Cape Town patients. Comparison of the spoligotypes with those obtained from 114 isolates from Zambia showed that 74 (65%) of these isolates had the same spoligotype signature. Spoligotypes in the SpolDB3.0 database showed that this group of strains was rarely isolated in other parts of the world, but was commonly isolated in Southern Africa. A predominant group of strains infecting approximately half of the patients in the study are major contributors to the TB epidemic in this region. We have designated this group of strains the Southern Africa 1 (SAF1) family.


Focal cortical atrophy in multiple sclerosis: relation to lesion load and disability.
Multiple sclerosis (MS) is thought to predominantly affect white matter (WM). Recently, however, loss of cortical gray matter has also been described. Little is known about the cause of cortical atrophy in MS, whether it occurs early in the disease course, and whether it affects all cortical regions equally or if there is a preferential pattern of focal cortical atrophy. An automated method was used to compute the thickness at every vertex of the cortical surface of the brains of 425 early relapsing-remitting MS patients. We correlated cortical thickness with the WM lesion load and the Expanded Disability Status Scale score. Mean cortical thickness correlated with WM lesion load and disability. The correlations of cortical thickness with total lesion load and disability were most significant in cingulate gyrus, insula, and associative cortical regions. Conversely, primary sensory, visual, and motor areas showed a less significant relationship. The highest amount of atrophy per lesion volume or disability scale unit was in the anterior cingulate cortex. This study confirms the relation between cortical atrophy, WM lesion load, and disability in MS, and suggests that cortical atrophy occurs even in MS patients with only mild disability. Most interestingly, we show a specific regional pattern of focal atrophy in MS that is distinctively different from the one in normal aging. The predilection of the atrophic process for areas that are heavily inter-connected with other brain regions suggests that interruption of WM tracts by MS plaques contributes, at least in part, to the development of cortical atrophy.


Protective Effects of Activated Myofibroblasts in the Pressure-Overloaded Myocardium Are Mediated Through Smad-Dependent Activation of a Matrix-Preserving Program.
The heart contains abundant interstitial and perivascular fibroblasts. Traditional views suggest that, under conditions of mechanical stress, cytokines, growth factors, and neurohumoral mediators stimulate fibroblast activation, inducing ECM (extracellular matrix) protein synthesis and promoting fibrosis and diastolic dysfunction. Members of the TGF (transforming growth factor)-β family are upregulated and activated in the remodeling myocardium and modulate phenotype and function of all myocardial cell types through activation of intracellular effector molecules, the Smads (small mothers against decapentaplegic), and through Smad-independent pathways. To examine the role of fibroblast-specific TGF-β/Smad3 signaling in the remodeling pressure-overloaded myocardium. We examined the effects of cell-specific Smad3 loss in activated periostin-expressing myofibroblasts using a mouse model of cardiac pressure overload, induced through transverse aortic constriction. Surprisingly, FS3KO (myofibroblast-specific Smad3 knockout) mice exhibited accelerated systolic dysfunction after pressure overload, evidenced by an early 40% reduction in ejection fraction after 7 days of transverse aortic constriction. Accelerated systolic dysfunction in pressure-overloaded FS3KO mice was associated with accentuated matrix degradation and generation of collagen-derived matrikines, accompanied by cardiomyocyte myofibrillar loss and apoptosis, and by enhanced macrophage-driven inflammation. In vitro, TGF-β1, TGF-β2, and TGF-β3 stimulated a Smad3-dependent matrix-preserving phenotype in cardiac fibroblasts, suppressing MMP (matrix metalloproteinase)-3 and MMP-8 synthesis and inducing TIMP (tissue inhibitor of metalloproteinases)-1. In vivo, administration of an MMP-8 inhibitor attenuated early systolic dysfunction in pressure-overloaded FS3KO mice, suggesting that the protective effects of activated cardiac myofibroblasts in the pressure-overloaded myocardium are, at least in part, because of suppression of MMPs and activation of a matrix-preserving program. MMP-8 stimulation induces a proinflammatory phenotype in isolated macrophages. In the pressure-overloaded myocardium, TGF-β/Smad3-activated cardiac fibroblasts play an important protective role, preserving the ECM network, suppressing macrophage-driven inflammation, and attenuating cardiomyocyte injury. The protective actions of the myofibroblasts are mediated, at least in part, through Smad-dependent suppression of matrix-degrading proteases.


Receptor tyrosine phosphatases guide vertebrate motor axons during development.
Receptor-type protein tyrosine phosphatases (RPTPs) are required for appropriate growth of axons during nervous system development in Drosophila. In the vertebrate, type IIa RPTPs [protein tyrosine phosphatase (PTP)-delta, PTP-sigma, and LAR (leukocyte common-antigen-related)] and the type III RPTP, PTP receptor type O (PTPRO), have been implicated in the regulation of axon growth, but their roles in developmental axon guidance are unclear. PTPRO, PTP-delta, and PTP-sigma are each expressed in chick motor neurons during the period of axonogenesis. To examine potential roles of RPTPs in axon growth and guidance in vivo, we used double-stranded RNA (dsRNA) interference combined with in ovo electroporation to knock down RPTP expression levels in the embryonic chick lumbar spinal cord. Although most branches of the developing limb nerves appeared grossly normal, a dorsal nerve identified as the anterior iliotibialis was clearly affected by dsRNA knock-down of RPTPs. In experimental embryos treated with dsRNA targeting PTP-delta, PTP-sigma, or PTPRO, this nerve showed abnormal fasciculation, was reduced in size, or was missing entirely; interference with PTPRO produced the most severe phenotypes. Control embryos electroporated with vehicle, or with dsRNA targeting choline acetyltransferase or axonin-1, did not exhibit this phenotype. Surprisingly, embryos electroporated with dsRNA targeting PTP-delta together with PTPRO, or all three RPTPs combined, had less severe phenotypes than embryos treated with PTPRO alone. This result suggests that competition between type IIa and type III RPTPs can regulate motor axon outgrowth, consistent with findings in Drosophila. Our results indicate that RPTPs, and especially PTPRO, are required for axon growth and guidance in the developing vertebrate limb.


Effects of epidermal growth factor on the synthesis of the cholesterol side-chain cleavage enzyme complex in rat ovarian granulosa cells in primary culture.
The effect of epidermal growth factor (EGF) on the synthesis of the components of the cholesterol side-chain cleavage enzyme complex (SCC) was studied in rat ovarian granulosa cells. The cells were cultured for 48 h in the presence or absence of EGF (15 ng/ml) and/or FSH (50 ng/ml) after which proteins were radiolabeled by incubation with [35S]methionine followed by immunoprecipitation of newly synthesized P-450scc or adrenodoxin (ISP) with polyclonal antibodies directed against the corresponding proteins from bovine adrenal cortex. In addition the action of EGF on the level of translatable RNA for P-450scc was evaluated using a cell-free translation system programmed with RNA isolated from treated and untreated cells, followed by immunoisolation of newly synthesized proteins. Immunoisolated proteins were separated by polyacrylamide-gel electrophoresis, visualized by fluorography and quantified by densitometry. EGF stimulated progesterone formation by the cells 3-fold and potentiated the FSH-induced stimulation of progesterone formation, but had no effect on cAMP accumulation. EGF also stimulated the synthesis of P-450scc and ISP, and enhanced the FSH-induced synthesis of P-450scc and ISP in a concentration-dependent fashion with a maximal stimulation attained at concentrations ranging from 1.0 to 100 ng/ml. No appreciable changes in the induction pattern were observed when EGF and dibutyryl cyclic AMP (Bt2cAMP) were added together, as compared to when Bt2cAMP was added alone. Neither treatment affected the synthesis of the constitutive mitochondrial enzyme, F1-ATPase. Immunoisolation of P-450scc from the proteins synthesized in a rabbit reticulocyte in vitro translation system programmed with RNA isolated from EGF- and/or FSH-treated cells, revealed that EGF enhanced the FSH-stimulated synthesis of the precursor form of P-450scc.(ABSTRACT TRUNCATED AT 250 WORDS)


One-pot synthesis of imidazolinium salts via the ring opening of tetrahydrofuran.
A new one-pot synthesis of C2-hydroxypropyl-substituted imidazolinium salts via the ring opening of tetrahydrofuran (THF) with N,N'-disubstituted diamines has been developed. Preliminary studies of the reaction mechanism suggest the CO2-promoted oxidative ring opening of THF followed by Hg(ii)-mediated oxidation of an imidazolidine intermediate. These novel C2-substituted imidazolinium salts have shown to be active catalysts for the aza-Diels-Alder reactions.


Association Between Visit-to-Visit Blood Pressure Variability in Early Adulthood and Myocardial Structure and Function in Later Life.
Long-term blood pressure (BP) variability has emerged as a reproducible measure that is associated with heart failure independent of systemic BP. Visit-to-visit BP variability may be associated with the risk of heart failure early in the life course and thus may be reflected in subclinical alterations in cardiac structure and function. To evaluate the association between visit-to-visit BP variability in early adulthood and myocardial structure and function in middle age. This cohort study used data from the Coronary Artery Risk Development in Young Adults (CARDIA) study, a community-based cohort study of 5115 participants aged 18 to 30 years at baseline (year 0; March 25, 1985, to June 7, 1986) and followed up over a 30-year interval. A total of 2400 CARDIA study participants underwent evaluation at 4 field sites (Birmingham, Alabama; Oakland, California; Chicago, Illinois; and Minneapolis, Minnesota). Blood pressure was measured at 8 visits over a 25-year interval and participants received echocardiograms at year 25 (June 1, 2010, to August 31, 2011). Data analysis was conducted from June 7, 1986, to August 31, 2011. Visit-to-visit systolic and diastolic BP variability measures included SD, average real variability, and variability independent of the mean. Echocardiographic indices of myocardial structure, systolic function, and diastolic function at the year 25 examination. Of the 2400 participants, 1024 were men (42.7%) and 976 were African American (40.7%); mean (SD) age at the year 25 examination was 50.4 (3.6) years. Per 1-SD increment, greater visit-to-visit systolic BP variability independent of the mean was associated with higher left-ventricular (LV) mass index (β [SE], 2.66 [0.4] g/m2, P < .001), worse diastolic function (early peak diastolic mitral annular velocity [é]) (β [SE], -0.40 [0.1] cm/s, P < .001), higher LV filling pressures (mitral inflow velocity to early diastolic mitral annular velocity [E/é]) β [SE], 0.37 [0.1] cm/s, P < .001), and worse global longitudinal strain (β [SE], 0.17 [0.1], P = .002). Similarly, greater visit-to-visit diastolic BP variability was associated with higher LV mass index (β [SE], 3.21 [0.5] g/m2, P < .001), worse diastolic function (é: β [SE], -0.24 [0.1] cm/s [P < .001]; E/é: β [SE], 0.23 [0.1] cm/s [P < .001]), and worse global longitudinal strain (β [SE], 0.13 [0.1], P = .02). The findings remained consistent when other BP variability measures were used (SD and average real variability). In this cohort study using data from the CARDIA study, greater visit-to-visit systolic and diastolic BP variability have been associated with adverse alterations in cardiac structure as well as systolic and diastolic function independent of mean BP levels.


Large-scale screening of nasal swabs for Bacillus anthracis: descriptive summary and discussion of the National Institutes of Health's experience.
In October 2001, a letter containing a large number of anthrax spores was sent through the Brentwood post office in Washington, D.C., to a United States Senate office on Capitol Hill, resulting in contamination in both places. Several thousand people who worked at these sites were screened for spore exposure by collecting nasal swab samples. We describe here a screening protocol which we, as a level A laboratory, used on very short notice to process a large number of specimens (3,936 swabs) in order to report preliminary results as quickly as possible. Six isolates from our screening met preliminary criteria for Bacillus anthracis identification and were referred for definitive testing. Although none of the isolates was later confirmed to be B. anthracis, we studied these isolates further to define their biochemical characteristics and 16S rRNA sequences. Four of the six isolates were identified as Bacillus megaterium, one was identified as Bacillus cereus, and one was an unidentifiable Bacillus sp. Our results suggest that large-scale nasal-swab screening for potential exposure to anthrax spores, particularly if not done immediately postexposure, may not be very effective for detecting B. anthracis but may detect a number of Bacillus spp. that are phenotypically very similar to B. anthracis.


Sex Differences in Cancer Incidence and Survival: A Pan-Cancer Analysis.
Sex plays an important role in the incidence, prognosis, and mortality of cancers, but often is not considered in disease treatment. We quantified sex differences in cancer incidence using the United States Cancer Statistics (USCS) public use database and sex differences in cancer survival using Surveillance, Epidemiology, and End Results (SEER) public use data from 2001 to 2016. Age-adjusted male-to-female incidence rate ratios (IRR) with 95% confidence intervals (CI) were generated by primary cancer site, race, and age groups. In addition, age-adjusted hazard ratios with 95% CI by sex within site were generated. In general, cancer incidence and overall survival were lower in males than females, with Kaposi sarcoma (IRR: 9.751; 95% CI, 9.287-10.242; P < 0.001) having highest male-to-female incidence, and thyroid cancers (HR, 1.774; 95% CI, 1.707-1.845) having largest male-to-female survival difference. Asian or Pacific Islanders had particularly high male-to-female incidence in larynx cancers (IRR: 8.199; 95% CI, 7.203-9.363; P < 0.001), relative to other races. Among primary brain tumors, germ cell tumors had the largest male-to-female incidence (IRR: 3.03; 95% CI, 2.798-3.284, P < 0.001). Overall, incidence and survival of cancer vary significantly by sex, with males generally having lower incidence and survival compared with females. Male-to-female incidence differences were also noted across race and age groups. These results provide strong evidence that the fundamental biology of sex differences affects cancers of all types. This study represents the most recent and comprehensive reporting of sex differences in cancer incidence and survival in the United States. Identifying disadvantaged groups is critical as it can provide useful information to improve cancer survival, as well as to better understand the etiology and pathogenesis of specific cancers.


Analytical variables influencing the performance of a miRNA based laboratory assay for prediction of relapse in stage I non-small cell lung cancer (NSCLC).
Laboratory assays are needed for early stage non-small lung cancer (NSCLC) that can link molecular and clinical heterogeneity to predict relapse after surgical resection. We technically validated two miRNA assays for prediction of relapse in NSCLC. Total RNA from seventy-five formalin-fixed and paraffin-embedded (FFPE) specimens was extracted, labeled and hybridized to Affymetrix miRNA arrays using different RNA input amounts, ATP-mix dilutions, array lots and RNA extraction- and labeling methods in a total of 166 hybridizations. Two combinations of RNA extraction- and labeling methods (assays I and II) were applied to a cohort of 68 early stage NSCLC patients. RNA input amount and RNA extraction- and labeling methods affected signal intensity and the number of detected probes and probe sets, and caused large variation, whereas different ATP-mix dilutions and array lots did not. Leave-one-out accuracies for prediction of relapse were 63% and 73% for the two assays. Prognosticator calls ("no recurrence" or "recurrence") were consistent, independent on RNA amount, ATP-mix dilution, array lots and RNA extraction method. The calls were not robust to changes in labeling method. In this study, we demonstrate that some analytical conditions such as RNA extraction- and labeling methods are important for the variation in assay performance whereas others are not. Thus, careful optimization that address all analytical steps and variables can improve the accuracy of prediction and facilitate the introduction of microRNA arrays in the clinic for prediction of relapse in stage I non-small cell lung cancer (NSCLC).


Cilostazol blocks pregnancy in naturally cycling mice.
Administration of a phosphodiesterase three enzyme inhibitor (PDE3-I) in rodents and primates results in ovulation of immature oocytes. Concerns regarding inhibition of PDE3 enzymes that are expressed in heart and blood vessels discouraged further development of PDE3-Is as nonsteroidal contraceptives. Cilostazol (CLZ) is a PDE3A-I that is approved for medical indications in humans and has an additional effect of adenosine uptake inhibition that is believed to counterbalance the undesirable outcomes resulting from PDE inhibition. Cycling mature female mice were treated with 7.5 or 15 mg CLZ, dimethyl sulfoxide or water beginning on the day of proestrus. Animals were placed with fertility-proven males after 3 days of treatment. Treatments were continued until 1 day after detection of a vaginal plug, and then females were monitored up to 30 days postbreeding to assess the effects of the compounds on pregnancy. Each of the treated female with CLZ was then remated with the same male and again monitored up to 30 days. None of the CLZ-treated mice produced offspring, whereas all of the control animals maintained pregnancy and delivered normal pups (p<.0001). Remating of the previously CLZ-treated females exhibited normal pregnancies and gave birth to live offspring that were not different from the controls. CLZ is a potential nonsteroidal contraceptive agent that merits further evaluation in other mammals.


Detecting Anatomical Landmarks From Limited Medical Imaging Data Using Two-Stage Task-Oriented Deep Neural Networks.
One of the major challenges in anatomical landmark detection, based on deep neural networks, is the limited availability of medical imaging data for network learning. To address this problem, we present a two-stage task-oriented deep learning method to detect large-scale anatomical landmarks simultaneously in real time, using limited training data. Specifically, our method consists of two deep convolutional neural networks (CNN), with each focusing on one specific task. Specifically, to alleviate the problem of limited training data, in the first stage, we propose a CNN based regression model using millions of image patches as input, aiming to learn inherent associations between local image patches and target anatomical landmarks. To further model the correlations among image patches, in the second stage, we develop another CNN model, which includes a) a fully convolutional network that shares the same architecture and network weights as the CNN used in the first stage and also b) several extra layers to jointly predict coordinates of multiple anatomical landmarks. Importantly, our method can jointly detect large-scale (e.g., thousands of) landmarks in real time. We have conducted various experiments for detecting 1200 brain landmarks from the 3D T1-weighted magnetic resonance images of 700 subjects, and also 7 prostate landmarks from the 3D computed tomography images of 73 subjects. The experimental results show the effectiveness of our method regarding both accuracy and efficiency in the anatomical landmark detection.


Fractionation of trace elements in total atmospheric deposition by filtrating-bulk passive sampling.
We have developed and validated a new simple and effective methodology for fractionation of soluble and insoluble forms of trace elements in total atmospheric deposition. The proposed methodology is based on the modification of a standard total deposition passive sampler by integrating a quartz fiber filter that retains the insoluble material, allowing the soluble fraction to pass through and flow to a receiving bottle. The quartz filter containing the insoluble fraction and the liquid containing the soluble fraction are then separately assayed by standardized ICP-MS protocols. The proposed atmospheric elemental fractionation sampler (AEFS) was validated by analyzing a Coal Fly Ash reference material with proper recoveries, and tested for field fractionation of a set of 10 key trace elements in total atmospheric deposition at the industrial area of Puchuncaví-Ventanas, Chile. The AEFS was proven useful for pollution assessment and also to identify variability of the soluble and insoluble fractions of the selected elements within the study area, improving the analytical information attainable by standard passive samplers for total deposition without the need of using sophisticated and high cost wet-only/dry only collectors.


Esthetic management of mucogingival defects after total excision in a case of pyogenic granuloma.
Pyogenic granuloma is a relatively rare hyperplastic lesion of the oral tissues. Clinically it is heterogeneous and can be similar to malignant epithelial and mesenchymal neoplasms. The treatment of choice is the surgical excision of the lesion. This approach often results in unpleasant gingival defects, especially when the pyogenic granuloma is located in the esthetic zone. This report describes the clinical and histological findings of pyogenic granuloma diagnosed in the maxilla of a 24-year-old female, as well as the successful treatment of the mucogingival defect that occurred following excision of the lesion, by placement of a subepithelial free connective tissue graft with the envelope-technique concurrently with the biopsy procedure. One-year postoperative complete root coverage of tooth 11 was achieved with a harmonious gingival contour, and no further recurrence was noted. Early diagnosis of pyogenic granuloma, and consequent therapy with adequate excision in a safe distance of at least 1 mm, is essential for prevention of neighboring structures and minimizing the risk of a relapse. Histopathological evaluation is obligatory to confirm the tentative clinical diagnosis and to exclude malignant neoplasms. The immediate esthetic rehabilitation with free connective tissue grafts presents a complementary procedure in the treatment of mucogingival defects after total excision of oralmucosal diseases.


Supporting and Incentivizing Peer Leaders for an Internet-Based Private Peer Community for Youths With Type 1 Diabetes: Social Network and Directed Content Analysis.
Youths with type 1 diabetes (T1D) frequently experience stigma. Internet-based peer communities can mitigate this through social support but require leaders to catalyze exchange. Whether nurturing potential leaders translates into a central role has not been well studied. Another issue understudied in such communities is lurking, the viewing of exchanges without commenting or posting. We aimed to assess the centrality of the peer leaders we selected, trained, and incentivized within the Canadian Virtual Peer Network (VPN)-T1D. This is a private Facebook (Meta Platforms, Inc) group that we created for persons aged 14 to 24 years with T1D. We specifically sought to (1) compare a quantitative estimate of network centrality between peer leaders and regular members, (2) assess the proportions of network exchanges that were social support oriented, and (3) assess proportions of high engagement (posts, comments, reactions, and votes) and low engagement (lurking) exchanges. We recruited peer leaders and members with T1D from prior study cohorts and clinics. We trained 10 leaders, provided them with a monthly stipend, and encouraged them to post on the private Facebook group we launched on June 21, 2017. We extracted all communications (posts, messages, reactions, polls, votes, and views) that occurred until March 20, 2020. We calculated each member's centrality (80% of higher engagement communications comprising posts, comments, and reactions plus 20% of members with whom they connected). We divided each member's centrality by the highest centrality to compute the relative centrality, and compared the mean values between leaders and members (linear regression). We calculated the proportions of communications that were posts, comments, reactions, and views without reaction. We performed content analysis with a social support framework (informational, emotional, esteem-related, network, and tangible support), applying a maximum of 3 codes per communication. VPN-T1D gained 212 regular members and 10 peer leaders over 33 months; of these 222 members, 26 (11.7%) exited. Peer leaders had 10-fold higher relative centrality than regular members (mean 0.53, SD 0.26 vs mean 0.04, SD 0.05; 0.49 difference; 95% CI 0.44-0.53). Overall, 91.4% (203/222) of the members connected at least once through posts, comments, or reactions. Among the 75,051 communications, there were 5109 (6.81%) posts, comments, and polls, 6233 (8.31%) reactions, and 63,709 (84.9%) views (lurking). Moreover, 54.9% (3430/6253) of codes applied were social support related, 66.4% (2277/3430) of which were informational (eg, insurance and travel preparation), and 20.4% (699/3430) of which were esteem related (eg, relieving blame). Designating, training, and incentivizing peer leaders may stimulate content exchange and creation. Social support was a key VPN-T1D deliverable. Although lurking accounted for a high proportion of the overall activity, even those demonstrating this type of passive participation likely derived benefits, given that the network exit rate was low. RR2-10.2196/18714.


Informed Consent in Health Research: Challenges and Barriers in Low-and Middle-Income Countries with Specific Reference to Nepal.
Obtaining 'informed consent' from every individual participant involved in health research is a mandatory ethical practice. Informed consent is a process whereby potential participants are genuinely informed about their role, risk and rights before they are enrolled in the study. Thus, ethics committees in most countries require 'informed consent form' as part of an ethics application which is reviewed before granting research ethics approval. Despite a significant increase in health research activity in low-and middle-income countries (LMICs) in recent years, only limited work has been done to address ethical concerns. Most ethics committees in LMICs lack the authority and/or the capacity to monitor research in the field. This is important since not all research, particularly in LMICs region, complies with ethical principles, sometimes this is inadvertently or due to a lack of awareness of their importance in assuring proper research governance. With several examples from Nepal, this paper reflects on the steps required to obtain informed consents and highlights some of the major challenges and barriers to seeking informed consent from research participants. At the end of this paper, we also offer some recommendations around how can we can promote and implement optimal informed consent taking process. We believe that paper is useful for researchers and members of ethical review boards in highlighting key issues around informed consent.


Impact of hypertension on the diagnostic accuracy of coronary angiography with computed tomography.
Hypertension induces coronary artery disease (CAD) and progression of arterial wall calcification. As coronary calcifications may cause artefacts in 64-slice computed tomography coronary angiography (CTCA), we sought to determine the diagnostic accuracy of CTCA in patients with and without arterial hypertension. Eighty-five consecutive patients with suspected CAD underwent CTCA, calcium-scoring and conventional coronary angiography, and were grouped as hypertensive (28 women, 31 men, mean age 65 +/- 9 years, age range 49-82 years) or normotensive patients (10 women, 16 men, mean age 62 +/- 11 years, age range 39-77 years). On an intention-to-diagnose-basis, no coronary segment was excluded and non-evaluative segments were rated as false positive. Per-patient sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) in the hypertensive group were 91.4, 83.3, 88.9, and 86.9%, while the respective values in the normotensive group were 100, 78.9, 63.6, and 100% (P = 0.42, 0.71, 0.05, and 0.15). In the hypertensive group the prevalence of CAD was 59% and the mean calcium-score was 256; respective values in the normotensive group were 27% and 69, (P < 0.01, and < 0.05 vs. hypertensives). Although hypertensives have significantly higher coronary calcifications, sensitivity and specificity are comparably high as in normotensives. The prevalence of CAD is higher in hypertensives and brings about a trend towards a lower NPV and a higher PPV.


Song-induced ZENK gene expression in auditory pathways of songbird brain and its relation to the song control system.
The ZENK gene encodes a zinc-finger-containing transcriptional regulator and can be rapidly activated in songbird brain by presentation of birdsong (Mello et al., 1992). Here we map the areas of the songbird forebrain that show this genomic response to birdsong, using in situ hybridization. After 30 min of song presentation ZENK mRNA levels reach a peak in the caudomedial telencephalon, in areas adjacent to or closely related with primary auditory structures. These areas include subfields of field L (L1 and L3), the caudomedial neostriatum (NCM), the caudomedial hyperstriatum ventrale (CMHV) anterior to field L, the caudal paleostriatum, and two field L targets, HVC shelf and RA cup. In contrast, ZENK induction is absent in some areas that show a response to song by other measures and where ZENK induction might have been expected. These include the direct thalamo-recipient field L subfield L2, and the nuclei of the circuit involved in the acquisition and production of learned song. These results demonstrate that ZENK induction following song presentation occurs only in a subset of areas physiologically activated by song, and draw attention to areas previously unsuspected as related to processing of complex auditory stimuli. Based on what is known about ZENK function in mammalian systems (Christy et al., 1989; Cole et al., 1989; Wisden et al., 1990), we speculate that areas revealed by ZENK induction might correspond to sites where critical neuronal modifications occur in response to birdsong presentation, possibly leading to the formation of song-related memories.


Nodular lymphocyte predominant Hodgkin lymphoma. An immunophenotypic reappraisal based on a single-institution experience.
In our experience, certain commonly cited immunophenotypic features of nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) are not encountered in day-to-day practice. We reviewed 60 cases of NLPHL (18 women, 42 men; median age, 34 years) to discern immunophenotypic features from a large, single-institution cohort. All cases contained lymphocytic and histiocytic (L&H) cells. These cells expressed CD20 in 98% (59/60), CD79a (usually faint) in 87% (27/31), CD30 in 7% (4/59), epithelial membrane antigen in 21% (12/56), bcl-2 in 5% (2/41), and bcl-6 in 83% (30/36) of cases. CD10 was negative in all 36 cases studied; 100% of cases (55/55) demonstrated CD3+ rosettes. Although CD57+ T cells were common within the background infiltrate, CD57+ rosettes were seen in only 48% of cases (15/31) and were rare when encountered. Based on these patterns, we conclude that bcl-2 and bcl-6 may be useful additions to the immunophenotypic analysis of NLPHL, but that the diagnostic usefulness of epithelial membrane antigen and CD57 rosettes may have been overemphasized in previous reports.


Coagulation abnormalities in patients with Gaucher's disease: effect of therapy.
Various coagulation defects have been associated with Gaucher's disease, including factor IX deficiency and acquired von Willebrand's disease (VWD). We performed repeated coagulation assays in 9 patients with Gaucher's disease over a period of 2 years. The prothrombin time (PT) and fibrinogen levels were normal in 8 of 9 patients, while the partial thromboplastin time (PTT) was abnormal in 5 of 9; all mixing PTT tests showed correction. Factor IX was normal repeatedly in the 7 of 7 patients tested. In contrast, factor XI was decreased in 3 of 9 patients assayed. Anticardiolipin (ACL) IgM was normal in all patients. ACL IgG was highly variable; levels were abnormal at least once in 6 of 8 patients, but were also normal at least once in 7 of 8 patients. Factor VIII was also quite variable: levels were decreased at least once in 4 of 9 patients, and normal at least once in 8 of 9 patients. Von Willebrand factor antigen (VWF Ag) studies were normal in 7 of 8 patients, but VWF activity was decreased at least once in 4 of 8 patients. In some patients, these problems could be overcome by specimen dilution. In ony 1 patient was VWF Ag decreased; this patient had a factor VIIIC level of 13% , and VWF activity of 18.7%. Coagulation assays performed before and after alglucerase administration failed to demonstrate any significant improvement in these assays, and neither was there a consistent improvement over the duration of therapy. We suggest that previously reported decreases in factor IX and VWF may be secondary to the interfering presence of increased cerebroside levels. Caution must be used in the interpretation of clotting assays in the patient with Gaucher's disease.


A critical pathway for management of patients with acute chest pain who are at low risk for myocardial ischemia: recommendations and potential impact.
Use of resources for patients with acute chest pain may be improved with clinical strategies that integrate research, Bayesian analysis, and expert opinion. To 1) develop a critical pathway for management of patients with acute chest pain who are at low risk for complications of ischemic heart disease and 2) assess the potential effects of implementation of the pathway on patient safety and resource use. Evidence-based consensus and prospective cohort study. Urban teaching hospital. Patients at least 30 years of age who were seen in the emergency department for chest pain and who did not have a history of trauma or abnormalities on radiologic study. Physician-opinion leaders defined criteria for patient inclusion in the pathway and for remaining on the pathway after 6 or 12 hours of observation. Criteria were defined for appropriateness of direct admission, direct discharge, or 6 hours of observation followed by exercise treadmill testing. Number of patients admitted to the hospital, number of days that patients were hospitalized, and clinical outcome. 2898 of 4585 patients (63%) were admitted to the hospital; of the 2898, 1152 (40%) were classified as potentially eligible for the pathway and 1068 (93%) had a benign clinical course during the initial observation period. The 1068 patients had a mean length of stay of 2.8 +/- 4.8 days. If 47% of these patients had been discharged after observation and exercise testing, implementation of the pathway would have reduced the number of admissions by 505 (17%) and days of hospitalization by 1407 (11%). Retrospective analysis suggests that a critical pathway for patients with acute chest pain may substantially reduce resource use. Prospective study is needed to ensure increased efficiency without increased adverse outcomes.


[Generalized cost-effectiveness of preventive interventions against cervical cancer in Mexican women: results of a Markov model from the public sector perspective].
To develop a generalized cost-effectiveness analysis (GCEA) of the HPV vaccine, hybrid capture screening (HC) and Papanicolaou screening (Pap) in the Mexican context. From April to August 2007, in Mexico, a GCEA of the interventions was developed for 10 possible scenarios using a Markov model from the public sector perspective as payer. Scenarios considering 80% coverage show an ACER per DALY averted of $16678 pesos for Pap of women between ages 25 and 64, $17277 pesos for HC of women between ages 30 and 64, and $84008 pesos for vaccination of 12-year-old girls. Annual financing of $621, $741 and $2255 million pesos, respectively, is needed for these scenarios. A selective, combined introduction of Pap-HC screening that considers the comparative advantages of application in different populations and geographical areas is suggested. Additionally, it is suggested to introduce the vaccine once a threshold price of $181 pesos per dose -when the vaccine becomes equal in terms of cost-effectiveness to HC- has been achieved.


Early effects of mirtazapine on emotional processing.
Acute administration of selective serotonin and noradrenaline re-uptake blockers to healthy volunteers affects the processing of emotional information but it is not known if similar effects occur with antidepressants acting through other pharmacological mechanisms. Mirtazapine is a clinically established antidepressant with complex actions involving blockade of noradrenaline alpha(2)-adrenoceptors as well as a number of 5-HT receptor subtypes. The aim of the present study was to test whether, like monoamine re-uptake inhibitors, mirtazapine would also produce positive biases in emotional processing. We studied 30 healthy volunteers who received either a single dose of mirtazapine (15 mg) or placebo in a parallel group, double-blind study. Two hours following medication administration, participants completed a battery of tasks testing various aspects of emotional processing including facial expression recognition, emotion potentiated startle, and emotional categorization and memory. Compared to placebo, mirtazapine significantly impaired the recognition of fearful facial expressions and reduced eye-blink responses in the emotion potentiated startle task. Participants receiving mirtazapine were also significantly quicker to respond to emotional self-relevant information in the categorization task and showed a positive bias in memory recall compared to those receiving placebo. Our findings indicate that mirtazapine reduces fear processing in healthy volunteers, an effect similar to that produced by repeated administration of selective serotonin re-uptake inhibitors. In addition, mirtazapine increased memory for likeable versus dislikeable self-relevant information suggesting an induction of positive bias in emotional memory. Such effects may be important for our understanding of the neuropsychological mechanisms of antidepressant action in both anxiety and depressive disorders.


Multi-organ distribution of phosphorylated alpha-synuclein histopathology in subjects with Lewy body disorders.
A sensitive immunohistochemical method for phosphorylated alpha-synuclein was used to stain sets of sections of spinal cord and tissue from 41 different sites in the bodies of 92 subjects, including 23 normal elderly, 7 with incidental Lewy body disease (ILBD), 17 with Parkinson's disease (PD), 9 with dementia with Lewy bodies (DLB), 19 with Alzheimer's disease with Lewy bodies (ADLB) and 17 with Alzheimer's disease with no Lewy bodies (ADNLB). The relative densities and frequencies of occurrence of phosphorylated alpha-synuclein histopathology (PASH) were tabulated and correlated with diagnostic category. The greatest densities and frequencies of PASH occurred in the spinal cord, followed by the paraspinal sympathetic ganglia, the vagus nerve, the gastrointestinal tract and endocrine organs. The frequency of PASH within other organs and tissue types was much lower. Spinal cord and peripheral PASH was most common in subjects with PD and DLB, where it appears likely that it is universally widespread. Subjects with ILBD had lesser densities of PASH within all regions, but had frequent involvement of the spinal cord and paraspinal sympathetic ganglia, with less-frequent involvement of end-organs. Subjects with ADLB had infrequent involvement of the spinal cord and paraspinal sympathetic ganglia with rare involvement of end-organs. Within the gastrointestinal tract, there was a rostrocaudal gradient of decreasing PASH frequency and density, with the lower esophagus and submandibular gland having the greatest involvement and the colon and rectum the lowest.


A silica supported tricarbocyanine based pH nanosensor with a large Stokes shift and a near infrared fluorescence response: performance in vitro and in live cells.
We report the synthesis of a near-infrared (NIR) fluorescent pH probe with a remarkable Stokes shift (∼135 nm) based on a tricarbocyanine (Cy-PIP). The fluorescent molecule was anchored to SiO2 nanoparticles (Cy-PIP@SiO2) and is capable of monitoring pH changes within the physiological range (pH 6-8). The Cy-PIP@SiO2 nanoparticles were successfully internalized by HeLa cells as shown by fluorescence confocal microscopy, while flow cytometry revealed pH fluctuations during the endocytic pathway.


Effect of urinary total arsenic level and estimated glomerular filtration rate on the risk of renal cell carcinoma in a low arsenic exposure area.
We explored the relationship between urinary total arsenic and risk of renal cell carcinoma, and investigated whether having hypertension or a low estimated glomerular filtration rate would modify the risk of renal cell carcinoma. The case-control study was conducted between November 2006 and May 2009 with 132 patients with renal cell carcinoma, and 260 sex and age matched controls from a hospital based pool. Pathological verification of renal cell carcinoma was completed by image guided biopsy or surgical resection of renal tumors. Urinary arsenic species, including inorganic arsenic, monomethylarsonic acid and dimethylarsinic acid, were determined with a high performance liquid chromatography linked hydride generator and atomic absorption spectrometry. Estimated glomerular filtration rate was calculated using the Modification of Diet in Renal Disease Study equation. Urinary total arsenic was significantly associated with renal cell carcinoma risk in a dose-response relationship after multivariate adjustment. Low estimated glomerular filtration rate or hypertension was significantly related to renal cell carcinoma risk. Estimated glomerular filtration rate was significantly negatively related with urinary total arsenic. A significant interaction was seen between the urinary total arsenic and hypertension on renal cell carcinoma risk. The greatest odds ratio (6.01) was seen in the subjects with hypertension, low estimated glomerular filtration rate and high urinary total arsenic. A trend test indicated that the risk of renal cell carcinoma increased along with the accumulating number of these 3 risk factors (p <0.0001). Higher urinary total arsenic level was a strong predictor of renal cell carcinoma, and estimated glomerular filtration rate or hypertension interacts with urinary total arsenic in modifying the risk of renal cell carcinoma.


Cabozantinib-induced thyroid dysfunction: a review of two ongoing trials for metastatic bladder cancer and sarcoma.
Thyroid dysfunction is a common adverse event associated with tyrosine kinase inhibitors (TKI), but its underlying pathophysiology is unclear. Cabozantinib is a novel TKI currently Food and Drug Administration approved for advanced medullary thyroid cancer and tested in clinical trials on solid tumors including prostate, liver, bladder, breast, and ovarian cancer. We analyzed the thyroid function of patients enrolled in two phase 2 clinical trials using cabozantinib at the National Institutes of Health Clinical Center. Two cases of thyroiditis associated with cabozantinib therapy are presented in detail, and a systematic review of the literature on TKI-associated thyroid dysfunction is also discussed. Between September 2012 and September 2013, 33 patients were treated with cabozantinib, and follow-up thyroid function tests were available for 31 (20 males, 11 females; age 59±1 years). Thyroid dysfunction was recorded in the majority of patients (93.1%), with a predominance of subclinical hypothyroidism. Two cases showed a biphasic pattern of thyroid dysfunction characterized by a transient thyrotoxicosis followed by hypothyroidism. Color Doppler demonstrated an increase in vascularization during the thyrotoxic phase, but no uptake was visualized on nuclear medicine imaging. A systematic review of the literature resulted in the identification of 40 original manuscripts, of which 13 were case series and 6 were case reports describing TKI-associated thyroid dysfunction. TKI therapy often results in clinically significant thyroid dysfunction. Cabozantinib treatment commonly results in thyroid dysfunction varying from subclinical hypothyroidism to symptomatic thyrotoxicosis. Early detection and characterization of cabozantinib-associated thyroid dysfunction and close follow-up are essential to provide adequate management of this common adverse event.


Predicting Perceptual Decisions Using Visual Cortical Population Responses and Choice History.
Our understanding of the neural basis of perceptual decision making has been built in part on relating co-fluctuations of single neuron responses to perceptual decisions on a trial-by-trial basis. The strength of this relationship is often compared across neurons or brain areas, recorded in different sessions, animals, or variants of a task. We sought to extend our understanding of perceptual decision making in three ways. First, we measured neuronal activity simultaneously in early [primary visual cortex (V1)] and midlevel (V4) visual cortex while macaque monkeys performed a fine orientation discrimination perceptual task. This allowed a direct comparison of choice signals in these two areas, including their dynamics. Second, we asked how our ability to predict animals' decisions would be improved by considering small simultaneously-recorded neuronal populations rather than individual units. Finally, we asked whether predictions would be improved by taking into account the animals' choice and reward histories, which can strongly influence decision making. We found that responses of individual V4 neurons were weakly predictive of decisions, but only in a brief epoch between stimulus offset and the indication of choice. In V1, few neurons showed significant decision-related activity. Analysis of neuronal population responses revealed robust choice-related information in V4 and substantially weaker signals in V1. Including choice- and reward-history information improved performance further, particularly when the recorded populations contained little decision-related information. Our work shows the power of using neuronal populations and decision history when relating neuronal responses to the perceptual decisions they are thought to underlie.SIGNIFICANCE STATEMENT Decades of research has provided a rich description of how visual information is represented in the visual cortex. Yet how cortical responses relate to visual perception remains poorly understood. Here we relate fluctuations in small neuronal population responses, recorded simultaneously in primary visual cortex (V1) and area V4 of monkeys, to perceptual reports in an orientation discrimination task. Choice-related signals were robust in V4, particularly late in the behavioral trial, but not in V1. Models that include both neuronal responses and choice-history information were able to predict a substantial portion of decisions. Our work shows the power of integrating information across neurons and including decision history in relating neuronal responses to perceptual decisions.


Estrogen receptor beta protects against in vivo injury in RPE cells.
Epidemiological data suggest that estrogen deficiency in postmenopausal women may contribute to the severity of AMD. We discovered that 17beta-estradiol (E2) was a crucial regulator of the severity of extracellular matrix turnover (ECM) dysregulation both in vivo and in vitro. We also found in vitro that the presence of estrogen receptor (ER)beta regulates MMP-2 activity. Therefore in an attempt to delineate the role of the ER subtypes, female estrogen receptor knockout (ERKO) mice were fed a high-fat diet, and the eyes were exposed to seven 5-second doses of nonphototoxic levels of blue-green light over 2 weeks. Three months after cessation of blue light treatment, transmission electron microscopy was performed to assess severity of deposits, Bruchs membrane changes, and choriocapillaris endothelial morphology. We found that changes in the trimolecular complex of pro-MMP-2, MMP-14 and TIMP-2 correlated with increased Bruch's membrane thickening or sub-retinal deposit formation (basal laminar deposits) in ERKObeta mice. In addition RPE isolated from ERKObeta mice had an increase in expression of total collagen and a decrease in MMP-2 activity. Finally we found that ERK an intermediate signaling molecule in the MMP pathway was activated in RPE isolated from ERKObeta mice. These data suggest that mice which lack ERbeta are more susceptible to in vivo injury associated with environmental light and high fat diet.


The cost-effectiveness of HIV testing of physicians and dentists in the United States.
To evaluate the cost-effectiveness of alternative policies for human immunodeficiency testing (HIV) testing of physicians and dentists. Decision analysis and cost-effectiveness analysis from a societal perspective were used. Data were derived from extensive literature review and consultation with experts. We conducted sensitivity analyses and also performed a cost-benefit analysis. We analyzed policies for mandatory or voluntary testing of all physicians, surgeons, and dentists; for those testing positive, we analyzed mandatory or voluntary exclusion from practice, restriction from performance of invasive procedures, or requirements to inform patients of serostatus. Cost per patient infection averted. Although one-time mandatory testing of surgeons and dentists with mandatory restriction of those found to be HIV-positive is more cost-effective than other policies, the cost-effectiveness varies tremendously under different scenarios. Results were highly sensitive to several data inputs, especially HIV seroprevalence of surgeons and dentists and transmission risk. For example, under a medium seroprevalence and transmission risk scenario, mandatory testing of all surgeons might avert 25 infections at a total cost of $27.9 million or $1,115,000 per infection averted and an incremental cost of $291,000 compared with current testing; however, the incremental cost-effectiveness per patient infection averted ranges from $29,807,000 under a low-risk scenario to a savings of $81,000 under a high-risk scenario. Our analysis neither justifies nor precludes a mandatory testing policy. Further research on the key data inputs is needed. Given the ethical, social, and public health implications, mandatory testing policies should not be implemented without greater certainty as to their cost-effectiveness.


Recurrent laryngeal nerve injury in video-assisted thyroidectomy: lessons learned from neuromonitoring.
The objective of the study was to assess the mechanism of recurrent laryngeal nerve (RLN) injury during video-assisted thyroidectomy (VAT). The study examined 201 nerves at risk (NAR). VAT with laryngeal neuromonitoring (LNM) was outlined according to this scheme: (a) preparation of the operative space; (b) vagal nerve stimulation (V1); (c) ligature of the superior thyroid vessels; (d) visualization, stimulation (R1), and dissection of the RLN; (e) extraction of the lobe; (f) resection of the thyroid lobe; (g) final hemostasis; (h) verification of the electrical integrity of the RLN (V2, R2). The site, cause, and circumstance of nerve injury were elucidated with the application of LNM. Laryngeal nerve injuries were classified into type 1 injury (segmental) and 2 (diffuse). Fourteen nerves (6.9 %) experienced loss of R2 and V2 signals. 80 percent of lesions occurred in the distal 1 cm of the course of the RLN. The incidence of type 1 and 2 injuries was 71 and 29 % respectively. The mechanisms of injury were traction (70 %) and thermal (30 %). Traction lesions were created during the extraction of the lobe from the mini-incision [point (e)]. Thermal injury occurred during energy-based device use in (f) and (g) circumstances. RLN palsy still occurs with routine endoscopic identification of the nerve, even combined with LNM. LNM has the advantage of elucidating the mechanism of RLN injury. Traction and thermal RLN injuries are the most frequent lesions in VAT.


Lipid metabolism and signaling in cardiac lipotoxicity.
The heart balances uptake, metabolism and oxidation of fatty acids (FAs) to maintain ATP production, membrane biosynthesis and lipid signaling. Under conditions where FA uptake outpaces FA oxidation and FA sequestration as triacylglycerols in lipid droplets, toxic FA metabolites such as ceramides, diacylglycerols, long-chain acyl-CoAs, and acylcarnitines can accumulate in cardiomyocytes and cause cardiomyopathy. Moreover, studies using mutant mice have shown that dysregulation of enzymes involved in triacylglycerol, phospholipid, and sphingolipid metabolism in the heart can lead to the excess deposition of toxic lipid species that adversely affect cardiomyocyte function. This review summarizes our current understanding of lipid uptake, metabolism and signaling pathways that have been implicated in the development of lipotoxic cardiomyopathy under conditions including obesity, diabetes, aging, and myocardial ischemia-reperfusion. This article is part of a Special Issue entitled: Heart Lipid Metabolism edited by G.D. Lopaschuk.


Enhancement of thyrocyte HLA class II expression by thyroid stimulating hormone.
HLA Class II molecules are expressed by human thyroid epithelial cells (thyrocytes) in thyroid autoimmunity, although these cells are normally Class II-. gamma-Interferon (gamma-IFN) is probably involved in this expression, as suggested by its ability to induce Class II in cultured normal thyrocytes. We have now found that thyroid stimulating hormone (TSH) enhances Class II expression induced in cultured thyrocytes by gamma-IFN, and effects similar to those of TSH were obtained with dibutyryl cyclic AMP. A proportion of thyrocytes also expressed Class II following treatment with TSH or dibutyryl cyclic AMP in the absence of gamma-IFN, but the optimal activity of these mediators then appeared to be dependent upon the occurrence of some pre-existing Class II expression. These findings give insights into how a variety of mediators may influence Class II expression in thyroid autoimmunity.


Omega-3 polyunsaturated fatty acids and immune-mediated diseases: inflammatory bowel disease and rheumatoid arthritis.
Inflammation is part of the normal host response to infection and injury. However, inappropriate inflammation contributes to several diseases, including inflammatory bowel disease (IBD) and rheumatoid arthritis (RA). Both conditions are characterized by the excessive production of inflammatory cytokines, arachidonic acid (AA)-derived eicosanoids, and other inflammatory agents (e.g., reactive oxygen species, adhesion molecules). By virtue of their anti-inflammatory action, omega-3 polyunsaturated fatty acids (PUFA) may be beneficial in inflammatory diseases. A large body of evidence supports a protective effect of omega-3 PUFA in experimental animal and ex-vivo models of Crohn's disease (CD), Ulcerative colitis (UC) and Rheumatoid arthritis (RA). Although fish oil supplementation in patients with IBD results in omega-3 PUFA incorporation into gut mucosal tissue and modification of inflammatory mediator profiles, the evidence of clinical benefits of omega-3 PUFA is weak. On the other hand, more convincing data support the efficacy of omega-3 PUFA in reducing pain, number of tender joints, duration of morning stiffness, use of non-steroidal anti-inflammatory drugs and improving physical performance in RA patients. In both IBD and RA further clinical trials with large sample size are needed to clarify the efficacy of omega-3 PUFA as a treatment.


A novel cell-scale bio-nanogenerator based on electron-ion interaction for fast light power conversion.
Natural energy haversting devices serve as an alternative candidate for power supply in many micro-/nano-systems. However, traditional nanogenerators based on piezoelectricity or triboelectric power generation face challenges in terms of biocompatibility and stability in various biological systems. The bacteriorhodopsin (bR) protein in Halobacterium halobium is an ideal biocompatible material for photoelectric conversion. Conventional bR systems based on ion transport or enhanced light absorption layers have a limited light power conversion speed. On the other hand, bR-based biohybrid devices have a great potential for sensitive light power conversion as compared to conventional nanogenerators. Herein, we present a biohybrid nanogenerator made of bR and horizontally aligned-long carbon nanotubes (CNTs) with electron-ion interaction for the first time for sensitive light power conversion. The bR layer serves as the proton pump, whereas CNTs are utilized to enhance the photocurrent; thus, the photocurrent frequency response improves significantly because of the effect of the electron-ion interaction. The photocurrent shows a linear relationship with the intensity of light and can still obtain a stable signal at a light intensity of 0.03 mW cm-2. With regard to the influence of the light on-off period, the photocurrent initially increases and then decreases with an increase in flickering frequency up to 360 Hz; this can be ascribed to the combinational influence of light switch speed and photocycle decay time. The photocurrent shows highest value (99 nA cm-2) at a frequency of about 50 Hz at a light intensity of 0.43 mW cm-2, which matches well with the frequency standard of the electrical power supply system. Moreover, we found that a higher density of CNTs contributed to improve performance of the nanogenerators. Furthermore, a H+ ion releasing model was proposed to interpret the operating mechanism of the biohybrid nanogenerator. The biohybrid nanogenerator shows great potential for applications as a power source for bio-nanosystems.


Sexual precocity in a 2-year-old boy caused by indirect exposure to testosterone cream.
To report a rare case of sexual precocity caused by inadvertent exposure to testosterone cream. We report the clinical, laboratory, and radiologic findings of a boy presenting with sexual precocity; review short- and long-term consequences; and discuss preventative measures. A 2 and 7/12-year-old boy had onset of pubic hair without testicular enlargement and a period of rapid linear growth. History revealed possible topical testosterone exposure from close contact with the child's father. On physical examination, the boy had Tanner stage II pubic hair distribution. Laboratory evaluation findings were normal for age except for the testosterone concentration, which was comparable to late-pubertal and adult male levels at 371 ng/dL (reference range, <3-10 ng/dL for prepubertal male). Brain magnetic resonance imaging and testicular ultrasonography were normal. Skeletal age was advanced at age 4 and 6/12 years. Repeated laboratory evaluation, after the child's father ceased testosterone use, revealed a normal testosterone concentration of 10 ng/dL. Thus, this boy's sexual precocity was attributed to inadvertent exogenous androgen exposure. When examining a child with sexual precocity, asking about possible exposure to androgens and estrogens is important. Patients being treated with these products should be educated about the possible risks of testosterone exposure to others and ways to limit exposure.


Estimation of gestational age, using neonatal anthropometry: a cross-sectional study in India.
Prematurity is a significant contributor to neonatal mortality in India. Conventionally, assessment of gestational age of newborns is based on New Ballard Technique, for which a paediatric specialist is needed. Anthropometry of the newborn, especially birthweight, has been used in the past to predict the gestational age of the neonate in peripheral health facilities where a trained paediatrician is often not available. We aimed to determine if neonatal anthropometric parameters, viz. birthweight, crown heel-length, head-circumference, mid-upper arm-circumference, lower segment-length, foot-length, umbilical nipple distance, calf-circumference, intermammary distance, and hand-length, can reliably predict the gestational age. The study also aimed to derive an equation for the same. We also assessed if these neonatal anthropometric parameters had a better prediction of gestational age when used in combination compared to individual parameters. We evaluated 1,000 newborns in a cross-sectional study conducted in Guru Teg Bahadur Hospital in Delhi. Detailed anthropometric estimation of the neonates was done within 48 hours after birth, using standard techniques. Gestational age was estimated using New Ballard Scoring. Out of 1,250 consecutive neonates, 1,000 were included in the study. Of them, 800 randomly-selected newborns were used in devising the model, and the remaining 200 newborns were used in validating the final model. Quadratic regression analysis using stepwise selection was used in building the predictive model. Birthweight (R=0.72), head-circumference (R = 0.60), and mid-upper arm-circumference (R = 0.67) were found highly correlated with gestation. The final equation to assess gestational age was as follows: Gestational age (weeks) = 5.437 x W-0.781 x W(2) + 2.815 x HC-0.041 x HC(2) + 0.285 x MUAC-22.745 where W=Weight, HC=Head-circumference and MUAC=Mid-upper arm-circumference; Adjusted R = 0.76. On validation, the predictability of this equation is 46% (+/-1 week), 75.5% (+/- 2 weeks), and 91.5% (+/- 3 weeks). This mathematical model may be used in identifying preterm neonates.


Remodeling of engineered tissue anisotropy in response to altered loading conditions.
Structural and mechanical anisotropy are critical to the function of many engineered tissues. This study examined the ability of anisotropic tissue constructs to overcome contact guidance cues and remodel in response to altered mechanical loading conditions. Square tissues engineered from dermal fibroblasts and type-I collagen were uniaxially loaded to induce cell and matrix alignment. After an initial time, t*, of 5-72 h, loading was switched from the x-axis to the y-axis. Cell alignment was examined throughout the experiment until a steady state was reached. Before t*, cells spontaneously aligned in the x-direction. After t*, the strength of alignment transiently decreased then increased, and mean cell orientation transitioned from the x- to the y-direction following an exponential time course with a time constant that increased with t*. Collagen fiber orientation exhibited similar trends that could not be explained by passive kinematics alone. Structural realignment resulted in concomitant changes in biaxial tissue mechanical properties. The findings suggest that even highly aligned engineered tissue constructs retain the capacity to remodel in response to altered mechanical stimuli. This may have important functional consequences when an anisotropic engineered tissue designed in vitro is surgically implanted into a mechanically complex graft site.


HLA class I alleles tag HLA-DRB1*1501 haplotypes for differential risk in multiple sclerosis susceptibility.
The major locus for multiple sclerosis (MS) susceptibility is located within the class II region of the Major Histocompatibility Complex (MHC). HLA-DRB1 alleles, constituting the strongest MS susceptibility factors, have been widely exploited in research including construction of transgenic animal models of MS. Many studies have concluded that HLA-DRB1*15 allele itself determines MS-associated susceptibility. If this were true, haplotypes bearing this allele would confer equal risk. If HLA-DRB1*15 bearing haplotypes differed for risk, roles for other loci in this region would be implied and further study of the fine structure of this locus would be compelling. We have tested the hypothesis comparing haplotypes stratified by HLA class I tagging. We show here that HLA-DRB1*15-bearing-haplotypes in 1970 individuals from 494 MS families are indeed heterogeneous. Some HLA-DRB1*15 haplotypes determine susceptibility while others do not. Three groups of class I tagged HLA-DRB1*15 haplotypes were not over-transmitted: (i) HLA-DRB1*15-HLA-B*08 (TR = 25, NT = 23, Odds Ratio = 1.09), (ii) -HLA-B*27 (TR = 18, NT = 17, Odds Ratio = 1.06), and (iii) rare HLA-DRB1*15 haplotypes (frequency <0.02). Rare haplotypes were significantly different from common haplotypes, and transmissions were remarkably similar to those for class-I-matched non-HLA-DRB1*15 haplotypes. These results unambiguously indicate that HLA-DRB1*15 is part of a susceptibility haplotype but cannot be the susceptibility allele itself, requiring either epistatic interactions, epigenetic modifications on some haplotypes, or nearby structural variation. These findings strongly imply that differences among HLA-DRB1*15 haplotypes will furnish the basis for MHC-associated susceptibility in MS and raise the possibility that the MHC haplotype is the fundamental unit of genetic control of immune response.


Geriatric emergency medicine and the 2006 Institute of Medicine reports from the Committee on the Future of Emergency Care in the U.S. health system.
Three recently published Institute of Medicine reports, Hospital-Based Emergency Care: At the Breaking Point, Emergency Medical Services: At the Crossroads, and Emergency Care for Children: Growing Pains, examined the current state of emergency care in the United States. They concluded that the emergency medicine system as a whole is overburdened, underfunded, and highly fragmented. These reports did not specifically discuss the effect the aging population has on emergency care now and in the future and did not discuss special needs of older patients. This report focuses on the emergency care of older patients, with the intent to provide information that will help shape discussions on this issue.


Impact of ethics and economics on end-of-life decisions in an Indian neonatal unit.
The aim of this article was to describe how providers in an Indian NICU reach life-or-death treatment decisions. Qualitative in-depth interviews, field observations, and document analysis were conducted at an Indian nonprofit private tertiary institution that provided advanced neonatal care under conditions of resource scarcity. Compared with American and European units with similar technical capabilities, the unit studied maintained a much higher threshold for treatment initiation and continuation (range: 28-32 completed gestational weeks). We observed that complex, interrelated socioeconomic reasons influenced specific treatment decisions. Providers desired to protect families and avoid a broad range of perceived harms: they were reluctant to risk outcomes with chronic disability; they openly factored scarcity of institutional resources; they were sensitive to local, culturally entrenched intrafamilial dynamics; they placed higher regard for "precious" infants; and they felt relatively powerless to prevent gender discrimination. Formal or regulatory guidelines were either lacking or not controlling. In a tertiary-level academic Indian NICU, multiple factors external to predicted clinical survival of a preterm newborn influence treatment decisions. Providers adjust their decisions about withdrawing or withholding treatment on the basis of pragmatic considerations. Numerous issues related to resource scarcity are relevant, and providers prioritize outcomes that affect stakeholders other than the newborn. These findings may have implications for initiatives that seek to improve global neonatal health.


Antiviral activity of five Asian medicinal pant crude extracts against highly pathogenic H5N1 avian influenza virus.
To study the antiviral properties of the five Asian medicinal plants against in vitro infection by the highly pathogenic avian influenza virus (H5N1). Crude extracts of Andrographis paniculata, Curcuma longa (C. longa), Gynostemma pentaphyllum, Kaempferia parviflora (K. parviflora), and Psidium guajava obtained by both water and ethanol extractions were investigated for their cytotoxicity in the Madin-Darby canine kidney cells. Thereafter, they were investigated in vitro for antiviral activity and cytokine response upon H5N1 virus infection. The results revealed that both water and ethanol extracts of all the five studied plants showed significant antiviral activity against H5N1 virus. Among these plants, C. longa and K. parviflora showed strong anti-H5N1 activity. Thus, they were selected for further studies on their cytokine response upon virus infection. It was found that ethanol and water crude extracts of C. longa and K. parviflora induced significant upregulation of TNF-α and IFN-β mRNA expressions, suggesting their roles in the inhibition of H5N1 virus replication. To the best of the authors' knowledge, this study is among the earliest reports to illustrate the antiviral property of these Asian medicinal plants against the highly pathogenic avian H5N1 influenza virus. The results of this study shed light on alternative therapeutic sources for treatment of H5N1 influenza virus infection in the future.


Intradomain Allosteric Network Modulates Calcium Affinity of the C-Type Lectin Receptor Langerin.
Antigen uptake and processing by innate immune cells is crucial to initiate the immune response. Therein, the endocytic C-type lectin receptors serve as pattern recognition receptors, detecting pathogens by their glycan structures. Herein, we studied the carbohydrate recognition domain of Langerin, a C-type lectin receptor involved in the host defense against viruses such as HIV and influenza as well as bacteria and fungi. Using a combination of nuclear magnetic resonance and molecular dynamics simulations, we unraveled the molecular determinants underlying cargo capture and release encoded in the receptor architecture. Our findings revealed receptor dynamics over several time scales associated with binding and release of the essential cofactor Ca(2+) controlled by the coupled motions of two loops. Applying mutual information theory and site-directed mutagenesis, we identified an allosteric intradomain network that modulates the Ca(2+) affinity depending on the pH, thereby promoting fast ligand release.


The laminin-binding integrins regulate nuclear factor κB-dependent epithelial cell polarity and inflammation.
The main laminin-binding integrins α3β1, α6β1 and α6β4 are co-expressed in the developing kidney collecting duct system. We previously showed that deleting the integrin α3 or α6 subunit in the ureteric bud, which gives rise to the kidney collecting system, caused either a mild or no branching morphogenesis phenotype, respectively. To determine whether these two integrin subunits cooperate in kidney collecting duct development, we deleted α3 and α6 in the developing ureteric bud. The collecting system of the double knockout phenocopied the α3 integrin conditional knockout. However, with age, the mice developed severe inflammation and fibrosis around the collecting ducts, resulting in kidney failure. Integrin α3α6-null collecting duct epithelial cells showed increased secretion of pro-inflammatory cytokines and displayed mesenchymal characteristics, causing loss of barrier function. These features resulted from increased nuclear factor kappa-B (NF-κB) activity, which regulated the Snail and Slug (also known as Snai1 and Snai2, respectively) transcription factors and their downstream targets. These data suggest that laminin-binding integrins play a key role in the maintenance of kidney tubule epithelial cell polarity and decrease pro-inflammatory cytokine secretion by regulating NF-κB-dependent signaling.


Topical Administration of Ibuprofen for Injured Athletes: Considerations, Formulations, and Comparison to Oral Delivery.
Non-steroidal anti-inflammatory drugs (NSAIDs) are a class of drugs commonly used to treat both the acute and chronic injuries sustained by athletes during training and competition. In many parts of the world, NSAIDs can be purchased over-the-counter and used without any physician oversight. However, the chronic nature of overuse injuries requires NSAIDs to be taken orally for an extended period of time. As a result, they can have significant adverse effects on athletes, namely gastrointestinal (GI), renal, and cardiovascular damage. Dyspepsia and upper GI ulceration and bleeding are of great concern in chronic NSAID use, and as such oral NSAIDs are generally contraindicated in those with a history of peptic ulcers or irritable bowel disease. In the setting of chronic overuse soft tissue or joint disease, topically administered NSAIDs offer an alternate route of administration that has the potential to deliver a similar level of pain and anti-inflammatory relief while bypassing the harmful side effects associated with oral intake. Topically applied NSAIDs are able to achieve high concentrations within the targeted site of action while simultaneously keeping plasma concentrations low, offering several advantages over oral administration. One commonly used generic NSAID is ibuprofen (2-(4-isobutylphenyl)propanoic acid). First synthesized in the 1960s, ibuprofen has since become widely available as an over-the-counter pharmaceutical. In this review, we outline new and different techniques that have been used to deliver ibuprofen into diseased tissues, including supersaturations, microemulsions, gels, nanosystems, and microneedles. We also review relevant clinical trials comparing transdermally delivered ibuprofen to placebo and orally administered ibuprofen.


A genome-wide association study of anorexia nervosa suggests a risk locus implicated in dysregulated leptin signaling.
We conducted a genome-wide association study (GWAS) of anorexia nervosa (AN) using a stringently defined phenotype. Analysis of phenotypic variability led to the identification of a specific genetic risk factor that approached genome-wide significance (rs929626 in EBF1 (Early B-Cell Factor 1); P = 2.04 × 10-7; OR = 0.7; 95% confidence interval (CI) = 0.61-0.8) with independent replication (P = 0.04), suggesting a variant-mediated dysregulation of leptin signaling may play a role in AN. Multiple SNPs in LD with the variant support the nominal association. This demonstrates that although the clinical and etiologic heterogeneity of AN is universally recognized, further careful sub-typing of cases may provide more precise genomic signals. In this study, through a refinement of the phenotype spectrum of AN, we present a replicable GWAS signal that is nominally associated with AN, highlighting a potentially important candidate locus for further investigation.


Risk-based indicators of Canadians' exposures to environmental carcinogens.
Tools for estimating population exposures to environmental carcinogens are required to support evidence-based policies to reduce chronic exposures and associated cancers. Our objective was to develop indicators of population exposure to selected environmental carcinogens that can be easily updated over time, and allow comparisons and prioritization between different carcinogens and exposure pathways. We employed a risk assessment-based approach to produce screening-level estimates of lifetime excess cancer risk for selected substances listed as known carcinogens by the International Agency for Research on Cancer. Estimates of lifetime average daily intake were calculated using population characteristics combined with concentrations (circa 2006) in outdoor air, indoor air, dust, drinking water, and food and beverages from existing monitoring databases or comprehensive literature reviews. Intake estimates were then multiplied by cancer potency factors from Health Canada, the United States Environmental Protection Agency, and the California Office of Environmental Health Hazard Assessment to estimate lifetime excess cancer risks associated with each substance and exposure pathway. Lifetime excess cancer risks in excess of 1 per million people are identified as potential priorities for further attention. Based on data representing average conditions circa 2006, a total of 18 carcinogen-exposure pathways had potential lifetime excess cancer risks greater than 1 per million, based on varying data quality. Carcinogens with moderate to high data quality and lifetime excess cancer risk greater than 1 per million included benzene, 1,3-butadiene and radon in outdoor air; benzene and radon in indoor air; and arsenic and hexavalent chromium in drinking water. Important data gaps were identified for asbestos, hexavalent chromium and diesel exhaust in outdoor and indoor air, while little data were available to assess risk for substances in dust, food and beverages. The ability to track changes in potential population exposures to environmental carcinogens over time, as well as to compare between different substances and exposure pathways, is necessary to support comprehensive, evidence-based prevention policy. We used estimates of lifetime excess cancer risk as indicators that, although based on a number of simplifying assumptions, help to identify important data gaps and prioritize more detailed data collection and exposure assessment needs.


Randomized clinical trial on the survival of lithium disilicate posterior partial restorations bonded using immediate or delayed dentin sealing after 3 years of function.
The survival and success rate and the quality of survival of partial ceramic restorations bonded employing Immediate (IDS) or Delayed Dentin Sealing (DDS) in vital molar teeth were evaluated in a randomized clinical trial with within-subject comparison study. 30 patients received two lithium disilicate ceramic (IPS-e.max press, Ivoclar Vivadent) partial restorations on vital first or second molar teeth (N = 60). The two teeth randomly received either IDS (test group, n = 30) or DDS (control group, n = 30). Partial ceramic restorations were luted (Variolink Ultra, Ivoclar Vivadent) two weeks after preparation. Evaluations were performed at 1 week, 12 months and 36 months post-operatively, using qualitative (FDI) criteria. Representative failures were evaluated microscopically (SEM) and by means of simplified qualitative fractography analysis. One absolute failure occurred in the DDS group due to (secondary) caries. The overall survival rate according to Kaplan-Meier after 3 years was 98.3% (FDI criteria score 1-4, n = 59) and the overall success rate was 85% (FDI criteria score 1-3, n = 51), with no significant difference between restorations in the IDS and DDS group (p = 0.32; Kaplan-Meier, Log Rank (Mantel-Cox), CI = 95%). For the quality of the survival, no statistically significant differences were found between IDS and DDS (p = 0.7; Kaplan-Meier, Log Rank (Mantel-Cox), CI = 95%) restorations on any follow-up timepoints for any of the FDI criteria (Wilcoxon, McNemar, p > 0.05). Adhesively luted partial ceramic restorations in vital molar teeth have a good prognosis, however IDS did not show any differences in success and survival rates after 3 years of function.


The influence of positive and negative mood states on risk taking, verbal fluency, and salivary cortisol.
significant frontal cortex dysfunction. It is hypothesised that performance on frontal lobe tasks may be sensitive to induced fluctuations in mood state in non-clinical samples. Subjects performed one of two neuropsychological tasks immediately subsequent to a musical mood induction procedure designed to induce either elation or depression. Mood was assessed using self-report measures. Salivary cortisol levels were also measured in an attempt to objectively validate mood induction effects. The tasks used were verbal fluency and Damasio's Gambling Game. Two groups of subjects were recruited: a group with previous (subclinical) hypomanic experience (n=23) and a control group without previous hypomanic experience (n=23). The positive and negative mood inductions produced robust and contrasting effects on self-reported mood, but had no significant differential effects on salivary cortisol levels and neuropsychological performance. The findings are restricted by the absence of a neutral mood control condition. Salivary cortisol recording does not provide a simple and reliable method of validating psychological mood induction. Performance on frontal lobe tests appears to be insensitive to normal mood fluctuations, which supports the argument that the deficits in mood disorder patient groups may instead reflect core disturbances of neurobiological processes.


The public's health is too important to be left to public health workers. A commentary on Guide to Clinical Preventive Services.
Practicing physicians are the key to effective health promotion and disease prevention in their communities, according to the Guide to Clinical Preventive Services released in May by the United States Preventive Services Task Force. The Guide focuses on the clinical practitioner and strongly advocates integrating preventive activities into clinical practice. It also shows how required interventions can be done by the physician normally responsible for ongoing care. Case-finding is emphasized as a viable and desirable strategy in early detection of disease. The report also acknowledges behavioral and lifestyle components of risk factors for disease and the physician's opportunities to promote change in patients' risky behavior. We discuss the implications of including patient education and counseling in the physician's clinical armamentarium, highlighting changes in educational and health care delivery systems that can make such interventions work in preventive programs. The soundness of a best-evidence synthesis method to formulate recommendations and the use of a priori scientific rules to determine the effectiveness of many current and proposed preventive activities are hallmarks of the task force's approach to integrating science and clinical practice.


Performance of full-pupil line-scanning reflectance confocal microscopy in human skin and oral mucosa in vivo.
Point-scanning reflectance confocal microscopes continue to be successfully translated for detection of skin cancer. Line-scanning, with the use of a single scanner and a linear-array detector, offers a potentially smaller, simpler and lower cost alternative approach, to accelerate widespread dissemination into the clinic. However, translation will require an understanding of imaging performance deep within scattering and aberrating human tissues. We report the results of an investigation of the performance of a full-pupil line-scanning reflectance confocal microscope in human skin and oral mucosa, in terms of resolution, optical sectioning, contrast, signal-to-noise ratio, imaging and the effect of speckle noise.