Medical and endovascular management of critical limb ischemia.
Critical limb ischemia (CLI) is the term used to designate the condition in which peripheral artery disease has resulted in resting leg or foot pain or in a breakdown of the skin of the leg or foot, causing ulcers or tissue loss. If not revascularized, CLI patients are at risk for limb loss and for potentially fatal complications from the progression of gangrene and the development of sepsis. The management of CLI requires a multidisciplinary team of experts in different areas of vascular disease, from atherosclerotic risk factor management to imaging, from intervention to wound care and physical therapy. In the past decade, the most significant change in the treatment of CLI has been the increasing tendency to shift from bypass surgery to less invasive endovascular procedures as first-choice revascularization techniques, with bypass surgery then reserved as backup if appropriate. The goals of intervention for CLI include the restoration of pulsatile, inline flow to the foot to assist wound healing, the relief of rest pain, the avoidance of major amputation, preservation of mobility, and improvement of patient function and quality of life. The evaluating physician should be fully aware of all revascularization options in order to select the most appropriate intervention or combination of interventions, while taking into consideration the goals of therapy, risk-benefit ratios, patient comorbidities, and life expectancy. We discuss the incidence, risk factors, and prognosis of CLI and the clinical presentation, diagnosis, available imaging modalities, and medical management (including pain and ulcer care, pharmaceutical options, and molecular therapies targeting angiogenesis). The endovascular approaches that we review include percutaneous transluminal angioplasty (with or without adjunctive stenting); subintimal angioplasty; primary femoropopliteal and infrapopliteal deployment of bare nitinol, covered, drug-eluting, or bioabsorbable stents; cryoplasty; excimer laser-assisted angioplasty; excisional atherectomy; and cutting balloon angioplasty.


Role of DECT in coronary artery disease: a comparative study with ICA and SPECT.
Earlier imaging techniques for coronary artery disease (CAD) focused primarily on either morphological or functional assessment of CAD. However, dual-energy computed tomography (DECT) can be used to assess myocardial blood supply both morphologically and functionally. We aimed to evaluate the diagnostic accuracy of DECT in detecting morphological and functional components of CAD, using invasive coronary angiography (ICA) and single photon emission computed tomography (SPECT) as reference standards. Twenty-five patients with known or suspicious CAD and scheduled for ICA were investigated by DECT and SPECT. DECT was performed during the resting state using retrospective electrocardiography (ECG) gating. CT coronary angiography and perfusion images were generated from the same raw data. All patients were evaluated for significant stenosis (≥50%) on both ICA and DECT coronary angiography, and for myocardial perfusion defects on SPECT and DECT perfusion. Comparison was done between ICA and DECT coronary angiography for detection of significant stenosis and between SPECT and DECT perfusion for detecting myocardial perfusion defects. Using ICA as reference standard, sensitivity, specificity, and accuracy of DECT coronary angiography in detecting ≥50% stenosis of coronary artery lumen were 81.6%, 97.8%, and 95.0%, respectively, by segment-based analysis and 92.1%, 96.1%, and 93.7%, respectively, by vessel-based analysis. Using SPECT as the reference standard, the sensitivity, specificity, and accuracy of DECT perfusion in detecting myocardial perfusion defects were 70.4%, 86.4%, and 80.6%, respectively, on per-segment analysis and 90.7%, 66.6%, and 84.7%, respectively, on per-territorial basis. DECT accurately detected coronary artery stenosis and myocardial ischemia using ICA and SPECT as reference standards. In the same scan, DECT can accurately provide integrative imaging of coronary artery morphology and myocardial perfusion.


Lamin proteins form an internal nucleoskeleton as well as a peripheral lamina in human cells.
The nuclear lamina forms a protein mesh that underlies the nuclear membrane. In most mammalian cells it contains the intermediate filament proteins, lamins A, B and C. As their name indicates, lamins are generally thought to be confined to the nuclear periphery. We now show that they also form part of a diffuse skeleton that ramifies throughout the interior of the nucleus. Unlike their peripheral counterparts, these internal lamins are buried in dense chromatin and so are inaccessible to antibodies, but accessibility can be increased by removing chromatin. Knobs and nodes on an internal skeleton can then be immunolabelled using fluorescein- or gold-conjugated anti-lamin A antibodies. These results suggest that the lamins are misnamed as they are also found internally.


Phylogeny-based comparative analysis of venom proteome variation in a clade of rattlesnakes (Sistrurus sp.).
A long-standing question in evolutionary studies of snake venoms is the extent to which phylogenetic divergence and diet can account for between-species differences in venom composition. Here we apply phylogeny-based comparative methods to address this question. We use data on venom variation generated using proteomic techniques for all members of a small clade of rattlesnakes (Sistrurus sp.) and two outgroups for which phylogenetic and diet information is available. We first complete the characterization of venom variation for all members of this clade with a "venomic" analysis of pooled venoms from two members of this genus, S. milarius streckeri and S. m. milarius. These venoms exhibit the same general classes of proteins as those found in other Sistrurus species but differ in their relative abundances of specific protein families. We then test whether there is significant phylogenetic signal in the relative abundances of major venom proteins across species and if diet (measured as percent mammals and lizards among all prey consumed) covaries with venom composition after phylogenetic divergence is accounted for. We found no evidence for significant phylogenetic signal in venom variation: K values for seven snake venom proteins and two composite venom variables [PC 1 and 2]) were all nonsignificant and lower (mean = 0.11+0.06 sd) than mean K values (>0.35) previously reported for a wide range of morphological, life history, physiological and behavioral traits from other species. Finally, analyses based on Phylogenetic Generalized Least Squares (PGLS) methods reveal that variation in abundance of some venom proteins, most strongly CRISP is significantly related to snake diet. Our results demonstrate that venom variation in these snakes is evolutionarily a highly labile trait even among very closely-related taxa and that natural selection acting through diet variation may play a role in molding the relative abundance of specific venom proteins.


Lung inflammation, injury, and proliferative response after repetitive particulate hexavalent chromium exposure.
Chronic inflammation is implicated in the development of several human cancers, including lung cancer. Certain particulate hexavalent chromium [Cr(VI)] compounds are well-documented human respiratory carcinogens that release genotoxic soluble chromate and are associated with fibrosis, fibrosarcomas, adenocarcinomas, and squamous cell carcinomas of the lung. Despite this, little is known about the pathologic injury and immune responses after repetitive exposure to particulate chromates. In this study we investigated the lung injury, inflammation, proliferation, and survival signaling responses after repetitive exposure to particulate chromate. BALB/c mice were repetitively treated with particulate basic zinc chromate or saline using an intranasal exposure regimen. We assessed lungs for Cr(VI)-induced changes by bronchoalveolar lavage, histologic examination, and immunohistochemistry. Single exposure to Cr(VI) resulted in inflammation of lung tissue that persists for up to 21 days. Repetitive Cr(VI) exposure induced a neutrophilic inflammatory airway response 24 hr after each treatment. Neutrophils were subsequently replaced by increasing numbers of macrophages by 5 days after treatment. Repetitive Cr(VI) exposure induced chronic peribronchial inflammation with alveolar and interstitial pneumonitis dominated by lymphocytes and macrophages. Moreover, chronic toxic mucosal injury was observed and accompanied by increased airway pro-matrix metalloprotease-9. Injury and inflammation correlated with airways becoming immunoreactive for phosphorylation of the survival signaling protein Akt and the proliferation marker Ki-67. We observed a reactive proliferative response in epithelial cells lining airways of chromate-exposed animals. These data illustrate that repetitive exposure to particulate chromate induces chronic injury and an inflammatory microenvironment that may promote Cr(VI) carcinogenesis.


MIF signal transduction initiated by binding to CD74.
Macrophage migration inhibitory factor (MIF) accounts for one of the first cytokine activities to have been described, and it has emerged recently to be an important regulator of innate and adaptive immunity. MIF is an upstream activator of monocytes/macrophages, and it is centrally involved in the pathogenesis of septic shock, arthritis, and other inflammatory conditions. The protein is encoded by a unique but highly conserved gene, and X-ray crystallography studies have shown MIF to define a new protein fold and structural superfamily. Although recent work has begun to illuminate the signal transduction pathways activated by MIF, the nature of its membrane receptor has not been known. Using expression cloning and functional analysis, we report herein that CD74, a Type II transmembrane protein, is a high-affinity binding protein for MIF. MIF binds to the extracellular domain of CD74, and CD74 is required for MIF-induced activation of the extracellular signal-regulated kinase-1/2 MAP kinase cascade, cell proliferation, and PGE2 production. A recombinant, soluble form of CD74 binds MIF with a dissociation constant of approximately 9 x 10-9 Kd, as defined by surface plasmon resonance (BIAcore analysis), and soluble CD74 inhibits MIF-mediated extracellular signal-regulated kinase activation in defined cell systems. These data provide a molecular basis for MIF's interaction with target cells and identify it as a natural ligand for CD74, which has been implicated previously in signaling and accessory functions for immune cell activation.


Structural requirements of steroidal agonists of transient receptor potential melastatin 3 (TRPM3) cation channels.
Transient receptor potential melastatin 3 (TRPM3) proteins form non-selective but calcium-permeable membrane channels, rapidly activated by extracellular application of the steroid pregnenolone sulphate and the dihydropyridine nifedipine. Our aim was to characterize the steroid binding site by analysing the structural chemical requirements for TRPM3 activation. Whole-cell patch-clamp recordings and measurements of intracellular calcium concentrations were performed on HEK293 cells transfected with TRPM3 (or untransfected controls) during superfusion with pharmacological substances. Pregnenolone sulphate and nifedipine activated TRPM3 channels supra-additively over a wide concentration range. Other dihydropyridines inhibited TRPM3 channels. The natural enantiomer of pregnenolone sulphate was more efficient in activating TRPM3 channels than its synthetic mirror image. However, both enantiomers exerted very similar inhibitory effects on proton-activated outwardly rectifying anion channels. Epiallopregnanolone sulphate activated TRPM3 almost equally as well as pregnenolone sulphate. Exchanging the sulphate for other chemical moieties showed that a negative charge at this position is required for activating TRPM3 channels. Our data demonstrate that nifedipine and pregnenolone sulphate act at different binding sites when activating TRPM3. The latter activates TRPM3 by binding to a chiral and thus proteinaceous binding site, as inferred from the differential effects of the enantiomers. The double bond between position C5 and C6 of pregnenolone sulphate is not strictly necessary for the activation of TRPM3 channels, but a negative charge at position C3 of the steroid is highly important. These results provide a solid basis for understanding mechanistically the rapid chemical activation of TRPM3 channels.


Postprandial zinc stable isotope response in human blood serum.
In recent years, considerable advances have been made in the field of medical isotope metallomics, but numerous fundamental physiological processes remain to be investigated. Past studies report that blood serum Zn concentrations decrease by between about 10 and 25%, depending on the size of meal, approximately three hours postprandially (i.e. after eating), before returning to baseline values if no meals are consumed over the following four to five hours. Nine participants were recruited for this study to investigate whether this postprandial Zn concentration decrease is accompanied by a stable isotope response. A baseline serum sample was collected from participants in the morning after overnight fasting. A 576 kcal meal was then provided and additional serum samples were taken 90 and 180 minutes post-meal to coincide with the postprandial response. Serum Zn concentrations decreased postprandially by an average of 21 ± 9% (1SD), but this was not accompanied by a change in stable Zn isotope composition (mean Δ66Zn180-minute-baseline = 0.01 ± 0.09‰, 2SD). We propose that hemodilution and the rapid, efficient postprandial transfer of albumin-bound Zn from serum to the liver and pancreas is responsible for the lack of postprandial serum Zn isotopic response. These results indicate that studies examining solely the distribution of Zn isotopes in serum may obtain samples without considering timing of the most recent meal. However, future studies seeking to compare serum Zn concentrations with δ66Zn values should draw blood samples in the morning after overnight fasting.


Bilateral periorbital necrotizing fasciitis: case report.
Necrotizing fasciitis is a severe infection of the subcutaneous tissue characterized by necrosis of the superficial fascia and overlying skin and is usually associated with previous trauma and comorbidities. Periorbital necrotizing fasciitis is rare and commonly causes visual loss and soft tissue defects. A better prognosis relies critically on early diagnosis, prompt medical treatment, and timely surgical intervention. We describe a rare case of periorbital necrotizing fasciitis in the absence of an inciting event. A 55-year-old female patient presented with acute painful swelling and redness of the right upper eyelid that spread to both eyelids bilaterally within 24 h. We swiftly started the patient on intravenous antibiotic therapy, and we surgically debrided the necrotic tissue the following day. We performed two further procedures to improve eyelid closure and appearance. Despite the severe presentation, timely antibiotic therapy and proper surgical interventions led to a successful outcome in this case.


Reverse altitudinal cline in cold hardiness among Erebia butterflies.
There is strong evidence for a shifting of range boundaries by many temperate butterfly species to higher altitudes and latitudes. Climate change represents a potential threat to mountain fauna. Nevertheless, information on ecophysiological limits of individual species is scarce. We studied the lower thermal limits of four species representing the prevailingly mountain Holarctic butterfly genus Erebia. We measured the cold tolerance of hibernating larvae, namely the supercooling point (SCP) and the lower lethal temperature (LLT). Three mountain species were freeze avoiding, with various levels of SCP (-8 to -22 degree C), and LLT close to SCP. The only exception was lowland E. medusa, whose caterpillars were freeze tolerant with LLT (-21 degree C) slightly below its SCP (-17 degree C). Surprisingly, LLT was highest in the alpine E. tyndarus and lowest in E. medusa inhabiting lower altitudes with higher mean winter temperatures. We explain the observed reversed altitudinal cline in cold hardiness by the buffering function of snow cover in the hibernacula of caterpillars that is strong at high mountains but irregular, unpredictable and thus unreliable in lowlands.


Accidental intravenous infusion of air: a concise review.
The unintended intravenous infusion of small volumes of air is common in clinical practice. International Electrotechnical Commission guidelines for infusion pumps permit infusion of up to 1 mL in 15 minutes and discount bubbles smaller than 50 μL. A review of the literature, however, suggests that these limits may be too generous. Neonates and patients with right-to-left cardiac shunts (eg, patent foramen ovale [PFO]) are at risk from lower volumes. Because PFO is prevalent in 20% to 27% of healthy adults and generally asymptomatic, all patients are at risk from small air bubbles, although clinically significant air embolism from intravenous infusion is rare. Attention to good clinical practice and use of an inline air filter should be considered to reduce any risk.


Current concept of neuromyelitis optica (NMO) and NMO spectrum disorders.
Neuromyelitis optica (NMO) has been described as a disease clinically characterised by severe optic neuritis (ON) and transverse myelitis (TM). Other features of NMO include female preponderance, longitudinally extensive spinal cord lesions (>3 vertebral segments), and absence of oligoclonal IgG bands . In spite of these differences from multiple sclerosis (MS), the relationship between NMO and MS has long been controversial. However, since the discovery of NMO-IgG or aquaporin-4 (AQP4) antibody (AQP4-antibody), an NMO-specific autoantibody to AQP4, the dominant water channel in the central nervous system densely expressed on end-feet of astrocytes, unique clinical features, MRI and other laboratory findings in NMO have been clarified further. AQP4-antibody is now the most important laboratory finding for the diagnosis of NMO. Apart from NMO, some patients with recurrent ON or recurrent longitudinally extensive myelitis alone are also often positive for AQP4-antibody. Moreover, studies of AQP4-antibody-positive patients have revealed that brain lesions are not uncommon in NMO, and some patterns appear to be unique to NMO. Thus, the spectrum of NMO is wider than mere ON and TM. Pathological analyses of autopsied cases strongly suggest that unlike MS, astrocytic damage is the primary pathology in NMO, and experimental studies confirm the pathogenicity of AQP4-antibody. Importantly, therapeutic outcomes of some immunological treatments are different between NMO and MS, making early differential diagnosis of these two disorders crucial. We provide an overview of the epidemiology, clinical and neuroimaging features, immunopathology and therapy of NMO and NMO spectrum disorders.


Enhancement of RNA polymerase II initiation complexes by a novel DNA control domain downstream from the cap site of the cytomegalovirus major immediate-early promoter.
The major immediate-early promoter (MIEP) of human cytomegalovirus is a remarkably strong RNA polymerase II transcription control unit. We have identified and characterized a novel regulatory domain associated with MIEP downstream from the initiation site of transcription. The downstream regulatory region was first identified by analyzing a series of mutations in the 5' untranslated leader exon. This regulatory domain was shown to enhance the number of functional initiation complexes without significantly altering the apparent elongation rate by RNA polymerase II transcription. In addition, run-off in vitro transcription and DNA-binding experiments identified two distinct downstream elements that specify the interaction of cellular transcription factors. One of these elements contains a reiterated sequence motif, present twice within the leader exon. The second element is an 18-bp sequence located at approximately nucleotide position +33 that is conserved between strains of cytomegalovirus from different species. On the basis of two criteria, an oligonucleotide competition assay and oligomerization upstream of the promoter, the binding of factors to the conserved box was shown to be critical for mediating the level of transcription from MIEP. Two discrete cellular nuclear proteins, designated LTF A and B (for leader transcription factor A and B binding factors), were found to specifically recognize the conserved element. This study of promoter-proximal elements within transcribed sequences demonstrates the recognition of the control domain at the DNA level that functions to increase the number of committed RNA polymerase II transcription complexes.


The effect of caffeine on retrobulbar hemodynamics.
To investigate the acute effect of caffeine on intraocular pressure and retrobulbar blood flow velocity. In this randomized, double-masked, placebo-controlled, prospective study, we examined the effects of single 300-mg oral administration of caffeine on retrobulbar arteries' hemodynamics by using color Doppler ultrasonography imaging in healthy human volunteers. The subjects were divided into two groups; group 1 received a 300-mg caffeine tablet and group 2 received placebo. Measurements were obtained in two eyes at baseline, and 1 hr after acute ingestion of caffeine. Blood pressure, pulse rate, and intraocular pressure were monitored. When compared with placebo, no significant change in mean blood pressure or intraocular pressure was observed after administration of caffeine. No significant differences were detected in the peak systolic and end diastolic velocities of retrobulbar arteries, compared with baseline values. Resistive index of ophthalmic, central retinal, and short posterior nasal ciliary artery were significantly increased after oral application of caffeine in group 1 (p<0.05). The vascular resistance of the retrobulbar vessels appears to be altered by caffeine consumption. Further studies are needed to investigate the effects of caffeine on hemodynamics in patients with glaucoma.


False-positive reaction between syphilis and hepatitis C infection.
There are limited data about false-positive reactions against hepatitis C virus (HCV) in syphilitic patients and false-positive reactions against syphilis in the patients with HCV infection. The aim of this study was to demonstrate the false-positivity of syphilis in patients with HCV infection, the false-positivity of anti-HCV in patients with syphilis and the validity of the serological tests in such patients. Fifty patients with positive anti-HCV, 21 patients with positive VDRL and 50 healthy subjects were studied. Syphilis serology was determined by the Venereal Disease Research Laboratory (VDRL) test and microhemagglutination for T. pallidum (MHA-TP) test. Hepatitis C serology was determined by a second generation ELISA (Ortho Diagnostics) test for HCV antibody, and anti-HCV positive patients were tested for HCV RNA by polymerase chain reaction (PCR). All assays were performed on all subjects. Not only the false-positive VDRL reaction in the patients with HCV infection but also false-positive anti-HCV tests in syphilitic patients have been observed. Four patients with syphilis had positive anti-HCV and negative HCV-RNA, whereas 10% (5 of 50) of patients with hepatitis C infection had positive VDRL and these patients were negative for MHA-TP test. The rates of false-positivity of VDRL and anti-HCV were higher than within the control group (p < 0.05). According to these data, positive anti-HCV in syphilitic patients and positive VDRL in chronic hepatitis C may be false-positive results with regard to the reaginic tests. Therefore, therapeutic measures should not be initiated without confirmation with a treponemal test or PCR. VDRL and HCV-ELISA tests may be interacted with IgM or IgG antibodies. This relationship should be investigated in further studies.


Genetic determinants of polycystic ovary syndrome: progress and future directions.
The field of the genetics of polycystic ovary syndrome (PCOS) has relatively recently moved into the era of genome-wide association studies. This has led to the discovery of 16 robust loci for PCOS. Some loci contain genes with clear roles in reproductive (LHCGR, FSHR, and FSHB) and metabolic (INSR and HMGA2) dysfunction in the syndrome. The next challenge facing the field is the identification of causal variants and genes and the role they play in PCOS pathophysiology. The potential for gene discovery to improve diagnosis and treatment of PCOS is promising, though there is much to be done in the field before the current findings can be translated to the clinic.


Network-based approach to prediction and population-based validation of in silico drug repurposing.
Here we identify hundreds of new drug-disease associations for over 900 FDA-approved drugs by quantifying the network proximity of disease genes and drug targets in the human (protein-protein) interactome. We select four network-predicted associations to test their causal relationship using large healthcare databases with over 220 million patients and state-of-the-art pharmacoepidemiologic analyses. Using propensity score matching, two of four network-based predictions are validated in patient-level data: carbamazepine is associated with an increased risk of coronary artery disease (CAD) [hazard ratio (HR) 1.56, 95% confidence interval (CI) 1.12-2.18], and hydroxychloroquine is associated with a decreased risk of CAD (HR 0.76, 95% CI 0.59-0.97). In vitro experiments show that hydroxychloroquine attenuates pro-inflammatory cytokine-mediated activation in human aortic endothelial cells, supporting mechanistically its potential beneficial effect in CAD. In summary, we demonstrate that a unique integration of protein-protein interaction network proximity and large-scale patient-level longitudinal data complemented by mechanistic in vitro studies can facilitate drug repurposing.


Is the social volcano still dormant? Trends in Chinese attitudes toward inequality.
Data from two China national surveys, in 2004 and 2009, focusing on popular attitudes toward current inequalities and mobility opportunities, are compared to examine two key questions: (1) Did the continued rise in income gaps and the impact within China of the global financial crisis lead to rising popular anger about the unfairness of current inequality patterns in 2009? and (2) Did the social contours of attitudes toward current inequalities shift over the five years between surveys? Through systematic comparisons of data from both surveys, we conclude that there is no general increase in anger about inequalities in the 2009 survey, and that the predictors of variations in these attitudes had changed relatively little, with the unexpectedly positive views of villagers still visible in 2009, although a bit muted. Trends in Chinese society between 2004 and 2009, and in the personal experience of survey respondents, are used to explain why popular acceptance of current inequalities remains widespread, despite continuing increases in China's income gaps.


Proarrhythmic remodelling of the right ventricle in a porcine model of repaired tetralogy of Fallot.
The growing adult population with surgically corrected tetralogy of Fallot (TOF) is at risk of arrhythmias and sudden cardiac death. We sought to investigate the contribution of right ventricular (RV) structural and electrophysiological remodelling to arrhythmia generation in a preclinical animal model of repaired TOF (rTOF). Pigs mimicking rTOF underwent cardiac MRI functional characterisation and presented with pulmonary regurgitation, RV hypertrophy, dilatation and dysfunction compared with Sham-operated animals (Sham). Optical mapping of rTOF RV-perfused wedges revealed a significant prolongation of RV activation time with slower conduction velocities and regions of conduction slowing well beyond the surgical scar. A reduced protein expression and lateralisation of Connexin-43 were identified in rTOF RVs. A remodelling of extracellular matrix-related gene expression and an increase in collagen content that correlated with prolonged RV activation time were also found in these animals. RV action potential duration (APD) was prolonged in the epicardial anterior region at early and late repolarisation level, thus contributing to a greater APD heterogeneity and to altered transmural and anteroposterior APD gradients in rTOF RVs. APD remodelling involved changes in Kv4.3 and MiRP1 expression. Spontaneous arrhythmias were more frequent in rTOF wedges and more complex in the anterior than in the posterior RV. Significant remodelling of RV conduction and repolarisation properties was found in pigs with rTOF. This remodelling generates a proarrhythmic substrate likely to facilitate re-entries and to contribute to sudden cardiac death in patients with rTOF.


A new role for the oncogenic high-mobility group A2 transcription factor in myogenesis of embryonic stem cells.
The high mobility group type A-2 (HMGA 2) transcription factor is involved in proliferation and differentiation, mainly during embryogenesis. Its activated form (HMGA 2/T) presents oncogenic activities both in vivo and in vitro. However, its precise role during embryogenesis is unknown. We investigated its role during the commitment of mouse embryonic stem (ES) cells by constructing cell lines expressing either wild type (wt) or HMGA 2/T forms of the gene. Following differentiation, control and wt HMGA 2 ES cells did not display myotubes; whereas HMGA 2/T ES cell lines massively formed contractile myotubes. Furthermore, as opposed to control cells, HMGA 2/T ES cells highly expressed the muscle myosin heavy chain (MHC) marker. Interestingly, in experimental conditions inhibitory for myogenesis, we observed a strong expression of MyoD and myogenin in HMGA 2/T cells. By contrast, commitment into adipocyte, neuron, and cardiomyocyte lineages was not affected. Teratocarcinomas induced by HMGA 2/T ES cell lines presented numerous skeletal muscle-differentiated tissues that were not observed in wt HMGA 2 or control tumours. Finally, rapamycin, an inhibitor of the mTOR kinase, downregulated endogenous HMGA-2 expression and inhibited myogenesis. This effect was prevented by overexpression of exogenous HMGA-2. Our results reveal a novel function of HMGA-2 in skeletal muscle differentiation.


Site dependent reactivity of Pt single atoms on anatase TiO2(101) in an aqueous environment.
The TiO2-Pt-water interface is of great relevance in photocatalysis where Pt is widely used as a co-catalyst for enhancing hydrogen evolution in aqueous TiO2. Using ab initio molecular dynamics, we investigated this interface focusing on Pt single atoms supported on anatase TiO2(101) in a water environment. Based on recent experiments showing a broad distribution of Pt coordination sites in TiO2, we examined six distinct single-Pt supported species with different nominal Pt oxidation states, namely: Pt, PtOH, and PtO2 species adsorbed on the stoichiometric surface; Pt adsorbed at a surface oxygen vacancy (Ov); and Pt substituting a surface Ti cation (PtTi), both without and with an accompanying Ov (PtTi + Ov). As found for the pristine anatase surface, interfacial water remained intact in the presence of a nearly neutral Pt adatom within the time duration of our simulations (∼15 ps). Similarly, no (or only temporary) water dissociation was observed at the PtTi + Ov and PtO2 interfaces, due to the formation of very stable planar Pt coordination structures that interact only weakly with water. In contrast, water dissociated with OH- (H+) on the Pt atom when this substituted a surface Ti (oxygen) ion as well as on PtOH. The significant proton affinity of Pt atoms at surface oxygen vacancies suggests that negatively charged Pt species are particularly efficient at catalyzing hydrogen evolution in aqueous TiO2.


Crystal structures of truncated alphaA and alphaB crystallins reveal structural mechanisms of polydispersity important for eye lens function.
Small heat shock proteins alphaA and alphaB crystallin form highly polydisperse oligomers that frustrate protein aggregation, crystallization, and amyloid formation. Here, we present the crystal structures of truncated forms of bovine alphaA crystallin (AAC(59-163)) and human alphaB crystallin (ABC(68-162)), both containing the C-terminal extension that functions in chaperone action and oligomeric assembly. In both structures, the C-terminal extensions swap into neighboring molecules, creating runaway domain swaps. This interface, termed DS, enables crystallin polydispersity because the C-terminal extension is palindromic and thereby allows the formation of equivalent residue interactions in both directions. That is, we observe that the extension binds in opposite directions at the DS interfaces of AAC(59-163) and ABC(68-162). A second dimeric interface, termed AP, also enables polydispersity by forming an antiparallel beta sheet with three distinct registration shifts. These two polymorphic interfaces enforce polydispersity of alpha crystallin. This evolved polydispersity suggests molecular mechanisms for chaperone action and for prevention of crystallization, both necessary for transparency of eye lenses.


A pilot telephone intervention to increase uptake of breast cancer screening in socially deprived areas in Scotland (TELBRECS): study protocol for a randomised controlled trial.
Breast cancer accounts for almost 30% of all cancers and is the second leading cause of cancer deaths in women in Scotland. Screening is key to early detection. The Scottish Breast Screening Programme is a nationwide, free at point of delivery screening service, to which all women aged between 50 and 70 years are invited to attend every 3 years. Currently over three-quarters of invited women regularly attend screening. However, women from more deprived areas are much less likely to attend: for example in the 3 years from 2010-2012 only 63% of women in the most deprived area attended the East of Scotland Breast Screening programme versus 81% in the least deprived. Research has suggested that reminders (telephone or letter) and brief, personalised interventions addressing barriers to attendance may be helpful in increasing uptake in low-income women. We will employ a brief telephone reminder and support intervention, whose purpose is to elicit and address any mistaken beliefs women have about breast screening, with the aim that the perceived benefits of screening come to outweigh any perceived barriers for individuals. We will test whether this intervention, plus a simple anticipated regret manipulation, will lead to an increase in the uptake of breast cancer screening amongst low-income women who have failed to attend a first appointment, in a randomised controlled trial with 600 women. Participants will be randomly allocated to one of four treatment arms i.e. 1) Letter reminder (i.e. Treatment as usual: CONTROL); 2) Telephone reminder (TEL), 3) Telephone reminder plus telephone support (TEL-SUPP) and 4) Telephone reminder plus support plus AR (TEL-SUPP-AR). The primary outcome will be attendance at breast screening within 3 months of the reminder letter. If this simple telephone support intervention (with or without AR intervention) leads to a significant increase in breast screening attendance, this would represent a rare example of a theoretically-driven, relatively simple psychological intervention that could result in earlier detection of breast cancer amongst an under-served group of lower socio-economic women. Current Controlled trials: ISRCTN06039270. Registered 16th January 2014.


Psychiatric manpower ratios. A beguiling numbers game?
Many characteristics of California's counties that correlate with physician-population ratios also correlate with psychiatrist-population ratios, with their changes through time and with rural counties' ability to attract psychiatrists. These same county characteristics seem to influence the uneven distribution of lawyers throughout the state, a fact that should help physicians help legislators understand problems in attempting to equalize manpower distribution. California's relatively high psychiatrist-population ratio and the presence of counties that are statistically anomalous should preclude the application of these findings to other states. Despite government interest in psychiatrist-population ratios as a device to estimate manpower needs, these ratios are a poor measure of access to services. Barriers to care such as lack of private insurance coverage and Medicaid and Medicare restrictions appear more powerful than uneven manpower distribution. Proposals for influencing psychiatrists' distribution should be compared with other methods of decreasing mental illness morbidity, such as mandating insurance coverage and increasing funds for preventive services and research.


A novel nuclear protein, Twa1, and Muskelin comprise a complex with RanBPM.
A truncated human RanBPM has been isolated as a protein binding to Ran, Ras-like nuclear small GTPase. Full-sized human RanBPM cDNA which was recently isolated, was found to encode a protein of 90 kDa which comprises a large protein complex. Consistent with this finding, several proteins were found to be co-precipitated with RanBPM by immunoprecipitation analysis. Accordingly, in the present study, we screened the human cDNA library by the two-hybrid method using RanBPM cDNA as bait. One novel protein designated as Twa1 (Two hybrid associated protein No. 1 with RanBPM), and two known proteins, a human homologue (hMuskelin) of mouse Muskelin and HSMpp8 were isolated repeatedly. Twa1 was well conserved through evolution and was localized within the nucleus. Interestingly, in addition to Muskelin and RanBPM, Twa1 was found to possess the LisH-CTLH motif which is detected in proteins involved in microtubule dynamics, cell migration, nucleokinesis and chromosome segregation. These functions overlap with functions suggested for the RanGTPase cycle. Immunoprecipitation and gel-filtration analyses indicated that both Twa1 and hMuskelin did indeed comprise a protein complex with RanBPM. Taken together with the fact that RanBPM interacts with Ran, our present findings suggested that there is an as yet uncovered function of the RanGTPase cycle.


The ability to accumulate deoxyuridine triphosphate and cellular response to thymidylate synthase (TS) inhibition.
Thymidylate synthase (TS) is an important enzyme catalysing the reductive methylation of dUMP to dTMP that is further metabolized to dTTP for DNA synthesis. Loss of viability following TS inhibition occurs as a consequence of depleted dTTP pools and at least in some cell lines, accumulation of dUTP and subsequent misincorporation of uracil into DNA. The expansion in dUTP pools is largely determined by the expression of the pyrophosphatase, dUTPase. Our previous work has shown that following TS inhibition the ability to accumulate dUTP was associated with an earlier growth inhibitory effect. 3 human lung tumour cell lines and HT29 human colon tumour cells transfected with dUTPase have been used to investigate the relationship between loss of viability following TS inhibition and dUTP accumulation. Cell cycle arrest typical of TS inhibition was an early event in all cell lines and occurred irrespective of the ability to accumulate dUTP or p53 function. However, a large expansion of dUTP pools was associated with mature DNA damage (4 h) and an earlier loss of viability following TS inhibition compared to cells in which dUTP pools were not expanded. In A549 cells damage to mature DNA may have been exacerbated by significantly higher activity of the excision repair enzyme, uracil-DNA glycosylase. Consistent with results using different inhibitors of TS, transfection of dUTPase into HT29 cells significantly reduced the cytotoxicity of a 24 h but not 48 h exposure to ZD9331. Although loss of viability can be mediated through dTTP deprivation alone, the uracil misincorporation pathway resulted in an earlier commitment to cell death. The relevance of this latter pathway in the clinical response to TS inhibitors deserves further investigation.


Force and velocity of sarcomere shortening in trabeculae from rat heart. Effects of temperature.
The effect of temperature on the force-sarcomere velocity relation (20 degrees, 25 degrees, and 30 degrees C) and maximum velocity of sarcomere shortening (Vo; range 15 degrees-35 degrees C) was studied in trabeculae from rat heart. Sarcomere length and Vo were measured by laser diffraction techniques. Sarcomere length and sarcomere velocity, determined from each of the first-order diffraction lines, differed by less than 4%. Slack sarcomere length in the trabeculae appeared to be 1.9 microns. Isovelocity release techniques were used to obtain sarcomere velocity and Vo directly. Sarcomere velocity was measured at SL = 1.9-2.0 microns for elimination of contributions of parallel elastic force and restoring force to the external load of the sarcomeres. Peak twitch force development (Fo) was maximal (Fo-max) at 25 degrees C at [Ca2+]o = 1.5 mM. Lowering of the temperature below 25 degrees C led to development of spontaneous sarcomere activity and depression of Fo; both responses could be prevented by the addition of 0.5 mM procaine. Increase of temperature above 25 degrees C reduced twitch duration and Fo. Hill's rectangular hyperbola fitted the force-velocity data if the load during shortening was less than 70% of Fo. Vo appeared to be independent of the level of activation at all temperatures when Fo was maintained above 90% of Fo-max, either by an increase of [Ca2+]o (to 3.0 mM) or by paired pulse stimulation. Vo increased with increasing temperature; the parameter a, calculated from force-velocity relations measured at 20 degrees, 25 degrees, and 30 degrees C, decreased with increasing temperature. The Arrhenius plot of Vo was studied in detail over a wider temperature range (15 degrees-35 degrees C) and in smaller temperature increments. The relation was linear between 18 degrees and 33 degrees C; the observed Q10, defined as the ratio of Vo measured at temperature (T) over Vo at T-10 degrees C, was 4.6 A Q10 of 4.6 for Vo is consistent with the reported temperature dependence of rat cardiac actin-activated myosin ATPase, which suggests that the same reaction step may limit the activity of the enzyme in vitro and during shortening of the cardiac sarcomeres at zero external load.


Factors associated with poor asthma control in children aged five to 13 years.
Most children with asthma should be able to achieve acceptable control. However, are there differences between those with acceptable and poor control, and if so, how can health care approaches be modified accordingly? To examine the characteristics of elementary school children aged five to 13 years with acceptable and poor levels of asthma control. The present cross-sectional study of children with asthma used five indicators of control, as outlined by the Canadian Asthma Consensus Report, to categorize acceptable and poor asthma control. Of 153 children, 115 (75%) were rated as having poorly controlled asthma. Of those with poor control, 65 (64%) children were currently using inhaled corticosteroids, and 65% of those reported using inhaled corticosteroids daily versus as needed. Fifty-one per cent of the children with poorly controlled asthma had exposure to tobacco smoke, whereas 79% of the children with asthma under acceptable control were from households with no smokers (P=0.002). The poor control group also had significantly worse parental perceptions of the psychosocial impact of asthma on their child. No significant difference was found in the percentage of those who had written action plans in the poor control group (28%) compared with the acceptable control group (26%), and similar percentages in each group stated that they used the plans. Despite the high use of inhaled corticosteroids, the majority of children had poorly controlled asthma. The poor control group had more exposure to tobacco smoke and a worse psychosocial impact due to asthma. Few children had past asthma education and action plans, suggesting that there is a need to improve access to and tools for education.


Clathrate hydrates of air in antarctic ice.
Measurements of the dissociation pressure of nitrogen hydrate and oxygen hydrate show that the clathrate hydrate of air with the formula (N(2), O(2)) 6H(2)O should exist below about 800 meters in the Antarctic ice sheet. This accounts for the disappearance of gas bubbles at depths greater than 1200 meters. The hydrate should exist from this depth to prise 0.06 percent of the ice.


Inpatient management of borderline personality disorder at Helen Joseph Hospital, Johannesburg.
The aim of this report was to establish a profile of patients with borderline personality disorder (BPD) admitted to the acute inpatient psychiatric assessment unit at the Helen Joseph Hospital, in Johannesburg, over the course of 1 year. A retrospective record review was conducted to investigate the prevalence, demographics, reasons for admission, treatment, length of stay and follow-up of a group of inpatients during 2010 with a diagnosis of BPD, based on DSM-IV-TR diagnostic criteria, allocated on discharge. Considering evidence retrospectively, the quality of the BPD diagnosis allocated appeared adequate. Statistical analysis revealed findings mainly in keeping with other reports, for example, that patients with BPD are above-average users of resources who make significantly more use of emergency services and that they generally do not adhere well to their scheduled outpatient follow-up arrangements. The longer average length of inpatient stay of this group with BPD, however, exceeded the typically brief period generally recommended for acute inpatient containment and emergency intervention. Implementation of targeted prevention and early intervention strategies, based on systematised programmes such as dialectical behavioural therapy and mentalisation based therapy, may be useful in addressing these problems experienced with integrating the in- and outpatient management of BPD.


Overexpression of STAT3 in HPV-mediated cervical cancer in a north Indian population.
The constitutively activated STAT family members, particularly STAT3, have been shown to possess transforming properties, and are strongly correlated with tumor development and progression. STAT3 transmits signals from many cytokines and growth factors to target genes in the nucleus through the Jak/Stat signaling pathway. HPV is the main etiological factor in the development of cervical cancer. In the current study, the expression of STAT3 was analyzed in various stages of HPV-mediated cervical carcinogenesis. Tissue biopsies from 100 patients with cervical cancer of different stages and normal tissues from patients undergoing hysterectomy were selected for studying the HPV status and STAT3 expression. HPV status of each corresponding biopsy was analyzed by PCR and typing. The mRNA expression was analyzed by reverse-transcriptase polymerase chain reaction (RT-PCR). HPV infection was detected in majority of cases: 75% (9/12) in precancer, 85% (34/40) stage I & II, and 95% (36/38) in stage III & IV of cervical cancer cases by L1 PCR. Further sub typing revealed HPV16 in 100% (9/9) of L1 positives in precancerous & 90% (63/70) in different stages of cancer. Significant level of STAT3 mRNA expression was predominantly found in cervical cancer cases as compared to normal controls (P = 0.001). We also found a significant correlation of STAT3 expression in cases infected with HPV (P = 0.001). Our results indicate a potentially interactive effect between HPV 16/18 and transcriptional activation of STAT3 gene in cervical carcinogenesis. To our knowledge, this is the first such study to be reported from India. Further investigations are needed to determine the influence of STAT3 expression on cervical carcinogenesis and its possible interaction with HPV infection status.


Purification and enzyme activity of ACK1.
The activated Cdc42 associated kinases (ACKs) are nonreceptor tyrosine kinases that are specific targets of Cdc42. To study the biochemical properties of ACK1, we expressed and purified the enzyme using the baculovirus/Sf9 cell system. This ACK1 construct contains (from N- to C-terminus) the kinase catalytic domain, SH3 domain, and Cdc42-binding CRIB domain. We describe enzyme activity assays based on synthetic peptide substrates. The best such substrate is a peptide derived from the site of ACK1-catalyzed phosphorylation of the Wiskott-Aldrich syndrome protein (WASP). Although the SH3 and CRIB domains of purified ACK1 are able to bind ligands (a polyproline peptide and Cdc42, respectively), the ligands did not stimulate in vitro tyrosine kinase activity. Purified ACK1 undergoes autophosphorylation at Tyr284, and autophosphorylation increases kinase activity.


Highly-dispersive transparency at optical frequencies in planar metamaterials based on two-bright-mode coupling.
Using a planar metamaterial, which consists of two silver strips, we theoretically demonstrate the plasmonic electromagnetically-induced transparency (EIT)-like spectral response at optical frequencies. The two silver strips serve as the bright modes, and are excited strongly by the incident wave. Based on the weak hybridization between the two bright modes, a highly-dispersive plasmonic EIT-like spectral response appears in our scheme. Moreover, the group index is higher than that of another scheme which utilizes the strong coupling between the bright and dark modes.


Fatal anaphylactic reaction to iron sucrose in pregnancy.
Iron-deficiency anemia in pregnancy can have serious deleterious effects for both mother and fetus. Parenteral iron therapy in iron-deficiency anemia is recommended in patients where oral iron therapy is ineffective due to malabsorption states and non-compliance. Compared to oral iron therapy, intravenous iron results in much more rapid resolution of iron-deficiency anemia with minimal adverse reactions. Iron sucrose has a favorable safety profile and is an alternative to other forms of parenteral iron therapy in correction of iron stores depletion. Immune mechanisms and iron agent releasing bioactive, partially unbound iron into the circulation, resulting in oxidative stress appears to cause severe adverse reactions. Although iron sucrose has a favorable safety profile in comparison to other parenteral iron preparations, this report highlights a fatal anaphylactic shock to iron sucrose in a pregnant woman with severe iron deficiency non-compliant to oral iron therapy.


Regulation of archaella expression by the FHA and von Willebrand domain-containing proteins ArnA and ArnB in Sulfolobus acidocaldarius.
The ability of microorganisms to sense and respond to sudden changes in their environment is often based on regulatory systems comprising reversible protein phosphorylation. The archaellum (former: archaeal flagellum) is used for motility in Archaea and therefore functionally analogous to the bacterial flagellum. In contrast with archaellum-mediated movement in certain members of the Euryarchaeota, this process, including its regulation, remains poorly studied in crenarchaeal organisms like Sulfolobus species. Recently, it was shown in Sulfolobus acidocaldarius that tryptone limiting conditions led to the induction of archaella expression and assembly. Here we have identified two proteins, the FHA domain-containing protein ArnA and the vWA domain-containing protein ArnB that are involved in regulating archaella expression in S. acidocaldarius. Both proteins are phosphorylated by protein kinases in vitro and interact strongly in vivo. Phenotypic analyses revealed that these two proteins are repressors of archaella expression. These results represent the first step in understanding the networks that underlie regulation of cellular motility in Crenarchaeota and emphasize the importance of protein phosphorylation in the regulation of cellular processes in the Archaea.


Impact of health facility-based insecticide treated bednet distribution in Malawi: progress and challenges towards achieving universal coverage.
High levels of insecticide treated bednet (ITN) use reduce malaria burden in countries with intense transmission such as Malawi. Since 2007 Malawi has implemented free health facility-based ITN distribution for pregnant women and children <5 years old (under-5s). We evaluated the progress of this targeted approach toward achieving universal ITN coverage. We conducted a cross-sectional household survey in eight districts in April 2009. We assessed household ITN possession, ITN use by all household members, and P. falciparum asexual parasitemia and anemia (hemoglobin <11 grams/deciliter) in under-5s. We surveyed 7,407 households containing 29,806 persons. Fifty-nine percent of all households (95% confidence interval [95% CI]: 56-62), 67% (95% CI: 64-70) of eligible households (i.e., households with pregnant women or under-5s), and 40% (95% CI: 36-45) of ineligible households owned an ITN. In households with at least one ITN, 76% (95% CI: 74-78) of all household members, 88% (95% CI: 87-90) of under-5s and 90% (95% CI: 85-94) of pregnant women used an ITN the previous night. Of 6,677 ITNs, 92% (95% CI: 90-94) were used the previous night with a mean of 2.4 persons sleeping under each ITN. In multivariable models adjusting for district, socioeconomic status and indoor residual spraying use, ITN use by under-5s was associated with a significant reduction in asexual parasitemia (adjusted odds ratio (aOR) 0.79; 95% CI: 0.64-0.98; p-value 0.03) and anemia (aOR 0.79; 95% CI 0.62-0.99; p-value 0.04). Of potential targeted and non-targeted mass distribution strategies, a campaign distributing 1 ITN per household might increase coverage to 2.1 household members per ITN, and thus achieve near universal coverage often defined as 2 household members per ITN. Malawi has substantially increased ITN coverage using health facility-based distribution targeting pregnant women and under-5s, but needs to supplement these activities with non-targeted mass distribution campaigns to achieve universal coverage and maximum public health impact.


Fiction or not? Fifty Shades is associated with health risks in adolescent and young adult females.
No prior study has empirically characterized the association between health risks and reading popular fiction depicting violence against women. Fifty Shades--a blockbuster fiction series--depicts pervasive violence against women, perpetuating a broader social narrative that normalizes these types of risks and behaviors in women's lives. The present study characterized the association between health risks in women who read and did not read Fifty Shades; while our cross-sectional study design precluded causal determinations, an empirical representation of the health risks in women consuming the problematic messages in Fifty Shades is made. Females ages 18 to 24 (n=715), who were enrolled in a large Midwestern university, completed a cross-sectional online survey about their health behaviors and Fifty Shades' readership. The analysis included 655 females (219 who read at least the first Fifty Shades novel and 436 who did not read any part of Fifty Shades). Age- and race-adjusted multivariable models characterized Fifty Shades' readers and nonreaders on intimate partner violence victimization (experiencing physical, sexual and psychological abuse, including cyber-abuse, at some point during their lifetime); binge drinking (consuming five or more alcoholic beverages on six or more days in the last month); sexual practices (having five or more intercourse partners and/or one or more anal sex partner during their lifetime); and using diet aids or fasting for 24 or more hours at some point during their lifetime. One-third of subjects read Fifty Shades (18.6%, or 122/655, read all three novels, and 14.8%, or 97/655, read at least the first novel but not all three). In age- and race-adjusted models, compared with nonreaders, females who read at least the first novel (but not all three) were more likely than nonreaders to have had, during their lifetime, a partner who shouted, yelled, or swore at them (relative risk [RR]=1.25) and who delivered unwanted calls/text messages (RR=1.34); they were also more likely to report fasting (RR=1.80) and using diet aids (RR=1.77) at some point during their lifetime. Compared with nonreaders, females who read all three novels were more likely to report binge drinking in the last month (RR=1.65) and to report using diet aids (RR=1.65) and having five or more intercourse partners during their lifetime (RR=1.63). Problematic depictions of violence against women in popular culture-such as in film, novels, music, or pornography-create a broader social narrative that normalizes these risks and behaviors in women's lives. Our study showed strong correlations between health risks in women's lives-including violence victimization-and consumption of Fifty Shades, a fiction series that portrays violence against women. While our cross-sectional study cannot determine temporality, the order of the relationship may be inconsequential; for example, if women experienced adverse health behaviors first (e.g., disordered eating), reading Fifty Shades might reaffirm those experiences and potentially aggravate related trauma. Likewise, if women read Fifty Shades before experiencing the health behaviors assessed in our study, it is possible that the book influenced the onset of these behaviors by creating an underlying context for the behaviors.


Temperature and atmospheric CO2 concentration estimates through the PETM using triple oxygen isotope analysis of mammalian bioapatite.
The Paleocene-Eocene Thermal Maximum (PETM) is a remarkable climatic and environmental event that occurred 56 Ma ago and has importance for understanding possible future climate change. The Paleocene-Eocene transition is marked by a rapid temperature rise contemporaneous with a large negative carbon isotope excursion (CIE). Both the temperature and the isotopic excursion are well-documented by terrestrial and marine proxies. The CIE was the result of a massive release of carbon into the atmosphere. However, the carbon source and quantities of CO2 and CH4 greenhouse gases that contributed to global warming are poorly constrained and highly debated. Here we combine an established oxygen isotope paleothermometer with a newly developed triple oxygen isotope paleo-CO2 barometer. We attempt to quantify the source of greenhouse gases released during the Paleocene-Eocene transition by analyzing bioapatite of terrestrial mammals. Our results are consistent with previous estimates of PETM temperature change and suggest that not only CO2 but also massive release of seabed methane was the driver for CIE and PETM.


Ontogenetic changes in the long bone microstructure in the nine-banded armadillo (Dasypus novemcinctus).
Analysis of ontogenetic changes in long bone microstructure aid in vertebrate life history reconstructions. Specifically, osteohistological examination of common fauna can be used to infer growth strategies of biologically uncommon, threatened, or extinct vertebrates. Although nine-banded armadillo biology has been studied extensively, work on growth history is limited. Here we describe long bone microstructure in tibiae and femora of a limited ontogenetic series of nine- banded armadillos (Dasypus novemcinctus) to elucidate patterns of bone growth. The cortex of the smallest individual is composed of compacted coarse cancellous bone (CCCB) and woven tissue. Extensive cortical drift is driven by periosteal erosion and further compaction of trabeculae resulting in an increase in the amount of CCCB. The cortex of the largest specimens is primarily CCCB with thickened endosteal bone and thin outer cortices of lamellar and parallel-fibered tissue. The outer cortices of the largest individuals are interpreted as an external fundamental system (EFS) indicating a cessation of appositional bone growth corresponding to skeletal maturity (i.e. asymptotic or adult size). The EFS forms in femora prior to tibiae, indicating femoral growth rates begin decreasing earlier than tibial in D. novemcinctus. Growth trends in common fauna like the nine-banded armadillo can be used as a foundation for understanding life histories of related, but uncommon or extinct, species of cingulates.


Repair of pars interarticularis defect with a modified cable-screw construct.
Operative treatment of symptomatic spondylolysis is not common. Multiple surgical techniques have been described for direct repairs of the pars defects. Reported success rates are high, although few reports describe successful return to sports in athletes. The purpose of the study was to assess the outcome after bone grafting and fixation of pars interarticularis defects utilizing a modification of the previously described techniques of Scott and of Songer. A retrospective single-arm cohort study was performed at a single center. This article reports on three athletes with symptomatic spondylolysis or grade I spondylolisthesis unresponsive to conservative management who were treated with bone grafting and a screw-cable repair. The outcome measure was the return to sports activities. A retrospective chart and radiographic analysis was conducted on three athletes. Patients were assessed for return to sports, clinical evidence of return to functional activities, and radiographic evidence of healing of the pars defects. All three patients proceeded to radiographic and clinical success. All patients reported resolution of their preoperative pain and return to sports. One patient did require occasional anti-inflammatory drugs for episodic low back pain. The use of this modified cable-screw technique for symptomatic spondylolysis provided excellent clinical, radiographic, and functional results in this small cohort.


Death and the retrovirus.
A flurry of new papers has shown that HIV reverse transcription is vulnerable to G-->A hypermutation. Apparently, cytidine bases in nascent DNA synthesis are lethally edited by the host cell molecule apolipoprotein B editing complex protein (APOBEC) 3G. This death mechanism is circumvented by the HIV viral infectivity factor protein, which prevents APOBEC3G from entering the virion.


The bleeding gastric ulcer--will it bleed again, and if so, why? A case for repeat endoscopy in evaluating stigmata.
Nine patients qualified for surgery for a bleeding gastric ulcer--all had a 'visible vessel'. Three of these vessels were thrombosed including 2 in patients who had been in shock. The smallest patent vessel was 0,35 mm in diameter, and 6 of the bleeding vessels were subserosal. The features thought to predispose to further bleeding were vessel size, a lateral hole in the main trunk of the vessel and, possibly, previous recanalization or ingestion of a drug which affected haemostasis. Five of 6 patent arteries had a cap of thrombus over the breach forming a false aneurysm. It is suggested that clinically these should pulsate, enlarge, leak--with persistent fresh thrombus in the ulcer crater on repeat endoscopy--and finally rupture. Where the underlying vessel is thrombosed the stigmata of a non-pulsatile 'visible vessel' or thrombus in the ulcer should disappear on repeat endoscopy. The sizes of the arteries in the normal antrum are tabulated.


Kilohertz frequency nerve block enhances anti-inflammatory effects of vagus nerve stimulation.
Efferent activation of the cervical vagus nerve (cVN) dampens systemic inflammatory processes, potentially modulating a wide-range of inflammatory pathological conditions. In contrast, afferent cVN activation amplifies systemic inflammatory processes, leading to activation of the hypothalamic-pituitary-adrenal (HPA) axis, the sympathetic nervous system through the greater splanchnic nerve (GSN), and elevation of pro-inflammatory cytokines. Ideally, to clinically implement anti-inflammatory therapy via cervical vagus nerve stimulation (cVNS) one should selectively activate the efferent pathway. Unfortunately, current implementations, in animal and clinical investigations, activate both afferent and efferent pathways. We paired cVNS with kilohertz electrical stimulation (KES) nerve block to preferentially activate efferent pathways while blocking afferent pathways. Selective efferent cVNS enhanced the anti-inflammatory effects of cVNS. Our results demonstrate that: (i) afferent, but not efferent, cVNS synchronously activates the GSN in a dose-dependent manner; (ii) efferent cVNS enabled by complete afferent KES nerve block enhances the anti-inflammatory benefits of cVNS; and (iii) incomplete afferent KES nerve block exacerbates systemic inflammation. Overall, these data demonstrate the utility of paired efferent cVNS and afferent KES nerve block for achieving selective efferent cVNS, specifically as it relates to neuromodulation of systemic inflammation.


Synaptic function is modulated by LRRK2 and glutamate release is increased in cortical neurons of G2019S LRRK2 knock-in mice.
Mutations in Leucine-Rich Repeat Kinase-2 (LRRK2) result in familial Parkinson's disease and the G2019S mutation alone accounts for up to 30% in some ethnicities. Despite this, the function of LRRK2 is largely undetermined although evidence suggests roles in phosphorylation, protein interactions, autophagy and endocytosis. Emerging reports link loss of LRRK2 to altered synaptic transmission, but the effects of the G2019S mutation upon synaptic release in mammalian neurons are unknown. To assess wild type and mutant LRRK2 in established neuronal networks, we conducted immunocytochemical, electrophysiological and biochemical characterization of >3 week old cortical cultures of LRRK2 knock-out, wild-type overexpressing and G2019S knock-in mice. Synaptic release and synapse numbers were grossly normal in LRRK2 knock-out cells, but discretely reduced glutamatergic activity and reduced synaptic protein levels were observed. Conversely, synapse density was modestly but significantly increased in wild-type LRRK2 overexpressing cultures although event frequency was not. In knock-in cultures, glutamate release was markedly elevated, in the absence of any change to synapse density, indicating that physiological levels of G2019S LRRK2 elevate probability of release. Several pre-synaptic regulatory proteins shown by others to interact with LRRK2 were expressed at normal levels in knock-in cultures; however, synapsin 1 phosphorylation was significantly reduced. Thus, perturbations to the pre-synaptic release machinery and elevated synaptic transmission are early neuronal effects of LRRK2 G2019S. Furthermore, the comparison of knock-in and overexpressing cultures suggests that one copy of the G2019S mutation has a more pronounced effect than an ~3-fold increase in LRRK2 protein. Mutant-induced increases in transmission may convey additional stressors to neuronal physiology that may eventually contribute to the pathogenesis of Parkinson's disease.


A Review on the Effect of Drying on Antioxidant Potential of Fruits and Vegetables.
The role of antioxidants in human nutrition has gained increased interest, especially due to their associated health beneficial effects for a number of chronic diseases, including cardiovascular diseases and certain types of cancer. Fruits and vegetables are perishable and difficult to preserve as fresh products. Dried fruits and vegetables can be easily stored, transported at relatively low cost, have reduced packing costs, and their low water content delays microbial spoilage. Air-, freeze-, microwave- and sun-drying are among the most thoroughly studied drying methods. This review provides an overview of recent findings on the effects of different drying techniques on major antioxidants of fruits and vegetables. In particular, changes in ascorbic acid, carotenoids, flavonoids, phenolic acids, total phenolics, and antioxidant activity are discussed in detail.


Emerging biomedical applications of synthetic biology.
Synthetic biology aims to create functional devices, systems and organisms with novel and useful functions on the basis of catalogued and standardized biological building blocks. Although they were initially constructed to elucidate the dynamics of simple processes, designed devices now contribute to the understanding of disease mechanisms, provide novel diagnostic tools, enable economic production of therapeutics and allow the design of novel strategies for the treatment of cancer, immune diseases and metabolic disorders, such as diabetes and gout, as well as a range of infectious diseases. In this Review, we cover the impact and potential of synthetic biology for biomedical applications.


Outcome following heart transplant assessment in adults with congenital heart disease.
Adults with congenital heart disease (ACHD) are a growing group with end-stage heart failure. We aim to describe the outcomes of ACHD patients undergoing assessment for orthotopic heart transplant (OHT). Case notes of consecutive ACHD patients (>16 years) assessed for OHT between 2000 and 2016 at our centre were reviewed. Decision and outcome were reported as of 2017. Data were analysed in three groups: systemic left ventricle (LV), systemic right ventricle (RV) and single ventricle (SV). 196 patients were assessed (31.8 years, 27% LV, 29% RV, 44% SV). 89 (45%) patients were listed for OHT and 67 (34%) were transplanted. 41 (21%) were unsuitable or too high risk and 36 (18%) were too well for listing. Conventional surgery was undertaken in 13 (7%) and ventricular assist device in 17 (9%) with 7 (4%) bridged to candidacy. Survival from assessment was 84.2% at 1 year and 69.7% at 5 years, with no difference between groups. Patients who were considered unsuitable for OHT (HR 11.199, p<0.001) and listed (HR 3.792, p=0.030) were more likely to die than those who were considered too well. Assessments increased over the study period. The number of ACHD patients assessed for OHT is increasing. A third are transplanted with a small number receiving conventional surgery. Those who are unsuitable have a poor prognosis.


High frequency of fumigants and other toxic gases in imported freight containers--an underestimated occupational and community health risk.
Residues of pesticide fumigants and toxic industrial chemicals in freight containers represent a health hazard to employees and consumers, especially since freight containers are sealed for transport and distributed widely throughout the importing countries before being opened for unloading. We investigated 2113 freight containers arriving at the second largest container terminal in Europe, Hamburg, Germany, over a 10-week period in 2006. The countries of origin, type of contents and the pesticide fumigation history declared on labels attached to the container were recorded. We determined that 1478 (70%) containers were contaminated with toxic chemicals above chronic reference exposure levels; 761 (36%) even exceeded the higher acute reference exposure level thresholds. Benzene and/or formaldehyde contamination was 4-times greater than for fumigants. Our findings indicate a health risk for dockworkers, container unloaders and even end-consumers, especially as many of the cancerogenic or toxic gases elude subjective detection.


Dexmedetomidine attenuates ethanol-induced inhibition of hippocampal neurogenesis in neonatal mice.
Ethanol (EtOH) exposure during a period comparable to the third trimester in human results in obvious neurotoxicity in the developing hippocampus and persistent deficits in hippocampal neurogenesis. Dexmedetomidine (DEX), a highly selective α-2-adrenergic agonist has been demonstrated to restore the impaired neurogenesis and neuronal plasticity in the dentate gyrus (DG) that follows neurological insult. However, the protective roles of DEX in the EtOH-induced deficits of postnatal neurogenesis in the hippocampus are still unknown. Mice were pretreated with DEX prior to EtOH exposure to determine its protective effects on impaired postnatal hippocampal neurogenesis. Six-day-old neonatal mice were treated with DEX (125 μg/kg) or saline, followed by EtOH at a total of 5 g/kg or an equivalent volume of saline on P7. Immunohistochemistry and immunofluorescence were used to evaluate the neurogenesis and activated microglia in the DG. Quantitative real time PCR (qRT-PCR) was utilized to assess the expression of inflammatory factors in the hippocampus. DEX pretreatment attenuated the inhibition of EtOH-mediated hippocampal neurogenesis and the reduction of hippocampal neural precursor cells (NPCs). We further confirmed that DEX pretreatment reversed the EtOH-induced microglia activation in the DG as well as the upregulation of the hippocampal TNFα, MCP-1, IL-6, and IL-1β mRNA levels. Our findings indicate that DEX pretreatment protects against EtOH-mediated inhibition of hippocampal neurogenesis in postnatal mice and reverses EtOH-induced neuroinflammation via repressing microglia activation and the expression of inflammatory cytokines.


Effect of macrophages on breast cancer cell proliferation, and on expression of hormone receptors, uPAR and HER-2.
Malignant tumors, including breast cancers, are frequently infiltrated with innate immune cells and tumor-associated macrophages (TAMs) represent the major inflammatory component in stroma of many tumors. In this study, we examined the immunoreactivity of the macrophage markers CD68 and CD163 as well as the hormone receptors estrogen receptor α (ERα), progesterone receptor (PR), estrogen receptor β1 (ERβ1), human epidermal growth factor receptor 2 (HER-2), matrix metalloproteinase 9 (MMP‑9), urokinase-type plasminogen activator receptor (uPAR) and the proliferations marker Ki67 in 17 breast cancer biopsies. The quantitative score for CD68+ and CD163+ strongly indicate M2 phenotype dominance in the currently investigated biopsies. We found that an increasing level of macrophages was negatively associated with ERα or PR, whereas a positive association was observed for Ki-67 or uPAR. No significant association could be seen between the level of macrophage and HER-2, ERβ1 or MMP-9 expression. Effect of conditioned media (CM) generated from cultured human M1 and M2 macrophage phenotypes were investigated on the proliferation and expression of selected markers in the T47D breast cancer cell line. We found that in contrast to the in vivo situation, in particularly the CM from M1 macrophages decreased the growth and Ki67 expression in T47D, and significantly increased ERβ1 mRNA levels. Moreover, in accordance to the in vivo situation the CM from the macrophages decreased the expression of ERα protein as well as ERα or PR mRNA. In conclusion our results show that macrophages alone have the capability to decrease the tumor cell expression of ERα and PR in vitro. In the tumor environment in vivo macrophages also contribute to an increase in tumor cell expression of uPAR and Ki67, suggesting that macrophages are involved in impairing the prognosis for breast cancer patients.


Early posterior neural tissue is induced by FGF in the chick embryo.
Signals that induce neural cell fate in amniote embryos emanate from a unique cell population found at the anterior end of the primitive streak. Cells in this region express a number of fibroblast growth factors (FGFs), a group of secreted proteins implicated in the induction and patterning of neural tissue in the amphibian embryo. Here we exploit the large size and accessibility of the early chick embryo to analyse the function of FGF signalling specifically during neural induction. Our results demonstrate that extraembryonic epiblast cells previously shown to be responsive to endogenous neural-inducing signals express early posterior neural genes in response to local, physiological levels of FGF signal. This neural tissue does not express anterior neural markers or undergo neuronal differentiation and forms in the absence of axial mesoderm. Prospective mesodermal tissue is, however, induced and we present evidence for both the direct and indirect action of FGFs on prospective posterior neural tissue. These findings suggest that FGF signalling underlies a specific aspect of neural induction, the initiation of the programme that leads to the generation of the posterior central nervous system.


Semi-Supervised Approach to Monitoring Clinical Depressive Symptoms in Social Media.
With the rise of social media, millions of people are routinely expressing their moods, feelings, and daily struggles with mental health issues on social media platforms like Twitter. Unlike traditional observational cohort studies conducted through questionnaires and self-reported surveys, we explore the reliable detection of clinical depression from tweets obtained unobtrusively. Based on the analysis of tweets crawled from users with self-reported depressive symptoms in their Twitter profiles, we demonstrate the potential for detecting clinical depression symptoms which emulate the PHQ-9 questionnaire clinicians use today. Our study uses a semi-supervised statistical model to evaluate how the duration of these symptoms and their expression on Twitter (in terms of word usage patterns and topical preferences) align with the medical findings reported via the PHQ-9. Our proactive and automatic screening tool is able to identify clinical depressive symptoms with an accuracy of 68% and precision of 72%.


Sudden death: ACE inhibitors and beta-blockers.
Sudden death is extremely common in patients suffering from cardiovascular diseases. At least one third of those with hypertension and probably about half of those who survive a myocardial infarction or suffer from cardiac failure who die in a clinical trial, die suddenly. Beta-blockers reduce the risk of sudden death in patients with cardiovascular disease, particularly in those who have had a myocardial infarction or heart failure. ACE inhibitors are perhaps less effective. Other cardiovascular drugs have not been shown to reduce the risk of sudden death.


Sharp injuries and their determinants among health care workers at first-level care facilities in Sindh Province, Pakistan.
To assess the rate and determinants of sharp injuries during the previous 6 months among health care workers at first-level care facilities in two districts of Pakistan. Cross-sectional survey at public, general practitioners and non-licensed private practitioners selected through stratified random sampling. At each facility, we interviewed a prescriber and a dispenser/injection provider about knowledge of bloodborne pathogens transmission and preventive practices, risk perception, and use of precautions and sharp injuries received during the previous 6 months. Multivariable Poisson regression was used to assess the factors associated with the number of sharp injuries. Fifty-four percentage of the 233 workers had at least one injury during the previous 6 months. The overall rate of sharp injuries per person per year was 3.7; among non-physician prescribers (9%), it was 4.3; among dispensers (69%), it was 3.7, and among physicians (18%), it was 2.1. In the multivariable model, work experience, risk perception and type of health care worker were significantly associated with receiving sharp injuries during the previous 6 months. In the model including dispensers only, a higher knowledge score was associated with fewer sharp injuries, while perceived severity of disease and lack of professional qualification were associated with more. Sharp injuries are common in Pakistan. Better knowledge about modes of bloodborne pathogen transmission and professional qualification may reduce their incidence.


Treatment of chronic conditions with traditional Chinese medicine: findings from traditional Chinese medicine hospitals in Hubei, China.
This study aimed to document clinical use of Traditional Chinese Medicine (TCM) for chronic conditions in all TCM hospitals in a Chinese province and to recommend treatments most in need of evaluation for use in community health centers. A cross-sectional survey was conducted in the summer of 2010. It included 119 of 132 TCM hospitals in Hubei Province, China. TCM physicians were asked to recommend specific TCM treatments for common chronic conditions. Nine types of chronic conditions recommended more than 3.7 times (mean of frequencies of chronic conditions) are included in this analysis. Frequency of each TCM treatment and the number of visits by type of chronic conditions were calculated. The total number of recommendations by TCM physicians was 411. For seven types of treatments, six were recommended for musculoskeletal pain, five for soft tissue injuries, four for visceral pain and fractures, three for stroke and asthma, two for hemorrhoids, and one for hypertension. The most frequently recommended treatments for specific conditions include orally ingested herbs for visceral pain (n=3), type 2 diabetes (n=5), and hypertension (n=7); herbs for external use for soft tissue injuries (n=10), asthma (n=6), and hemorrhoids (n=8); acupuncture for musculoskeletal pains (n=43) and for stroke (n=10); and Chinese external fixation for fractures (n=24). The number of visits for recommended treatments per year of was 671,759. The most frequently recommended treatments for specific chronic conditions have most visits, except for chronic conditions such as musculoskeletal pains, visceral pains, soft tissue injuries, and asthma. Patients with musculoskeletal pain have more treatment options than other patients. Herbal medicine is the option most commonly used for chronic conditions. These treatments for these conditions should be targeted for further evaluation of effectiveness and, only if found effective, considered for use in primary care settings.


Effect of human leukocyte antigen heterozygosity on infectious disease outcome: the need for allele-specific measures.
Doherty and Zinkernagel, who discovered that antigen presentation is restricted by the major histocompatibility complex (MHC, called HLA in humans), hypothesized that individuals heterozygous at particular MHC loci might be more resistant to particular infectious diseases than the corresponding homozygotes because heterozygotes could present a wider repertoire of antigens. The superiority of heterozygotes over either corresponding homozygote, which we term allele-specific overdominance, is of direct biological interest for understanding the mechanisms of immune response; it is also a leading explanation for the observation that MHC loci are extremely polymorphic and that these polymorphisms have been maintained through extremely long evolutionary periods. Recent studies have shown that in particular viral infections, heterozygosity at HLA loci was associated with a favorable disease outcome, and such findings have been interpreted as supporting the allele-specific overdominance hypothesis in humans. An algebraic model is used to define the expected population-wide findings of an epidemiologic study of HLA heterozygosity and disease outcome as a function of allele-specific effects and population genetic parameters of the study population. We show that overrepresentation of HLA heterozygotes among individuals with favorable disease outcomes (which we term population heterozygote advantage) need not indicate allele-specific overdominance. On the contrary, partly due to a form of confounding by allele frequencies, population heterozygote advantage can occur under a very wide range of assumptions about the relationship between homozygote risk and heterozygote risk. In certain extreme cases, population heterozygote advantage can occur even when every heterozygote is at greater risk of being a case than either corresponding homozygote. To demonstrate allele-specific overdominance for specific infections in human populations, improved analytic tools and/or larger studies (or studies in populations with limited HLA diversity) are necessary.


Activation of the neuregulin/ErbB system during physiological ventricular remodeling in pregnancy.
The neuregulin-1 (NRG1)/ErbB system has emerged as a paracrine endothelium-controlled system in the heart, which preserves left ventricular (LV) performance in pathophysiological conditions. Here, we analyze the activity and function of this system in pregnancy, which imparts a physiological condition of LV hemodynamic overload. NRG1 expression and ErbB receptor activation were studied by Western blot analyses in rats and mice at different stages of pregnancy. LV performance was evaluated by transthoracic echocardiography, and myocardial performance was assessed from twitches of isolated papillary muscles. NRG1/ErbB signaling was inhibited by oral treatment of animals with the dual ErbB1/ErbB2 tyrosine kinase inhibitor lapatinib. Analyses of LV tissue revealed that protein expression of different NRG1 isoforms and levels of phosphorylated ErbB2 and ErbB4 significantly increased after 1-2 wk of pregnancy. Lapatinib prevented phosphorylation of ErbB2 and ERK1/2, but not of ErbB4 and protein kinase B (Akt), revealing that lapatinib only partially inhibited NRG1/ErbB signaling in the LV. Lapatinib did not prevent pregnancy-induced changes in LV mass and did not cause apoptotic cell death or fibrosis in the LV. Nevertheless, lapatinib led to premature maternal death of ∼25% during pregnancy and it accentuated pregnancy-induced LV dilatation, significantly reduced LV fractional shortening, and induced abnormalities of twitch relaxation (but not twitch amplitude) of isolated papillary muscles. This is the first study showing that the NRG1/ErbB system is activated, and plays a modulatory role, during physiological hemodynamic overload associated with pregnancy. Inhibiting this system during physiological overload may cause LV dysfunction in the absence of myocardial cell death.


Relationship between subdomains of total physical activity and mortality.
The purpose of this study was to describe the association of the overall and domain-specific physical activity on all-cause and cardiovascular mortality. A large body of epidemiological evidence suggests a strong and consistent inverse association between physical activity and mortality risk. However, it is unclear how this association varies according to the domain of life in which the activity takes place. In an English population-based cohort of 14,903 participants (mean age = 63 yr), total and domain-specific physical activity was assessed using a validated questionnaire (EPAQ2). After a median follow-up of 7 yr, there were 1128 deaths, with 370 from cardiovascular disease. The relative risks (95% confidence interval) for all-cause mortality due to physical activity undertaken at home, during exercise, at work, for transport, and in total were 0.81 (0.66-0.99), 0.66 (0.54-0.80), 0.84 (0.55-1.30), 0.82 (0.67-1.00), and 0.77 (0.61-0.98), respectively, after adjustment for baseline age, sex, social class, alcohol consumption, smoking status, history of diabetes, history of cancer, and history of cardiovascular disease and stroke. Cardiovascular mortality was inversely associated with physical activity undertaken at home (P for trend = 0.03), during exercise (P for trend = 0.001), and in total (P for trend = 0.007). The results were unchanged after excluding individuals with a history of heart disease, stroke, and cancer at baseline and those who died within the first 2 yr of follow-up. In this study, physical activities at home and during exercise are associated with lower risk of mortality, whereas occupational and transportation-related activities are not. Promoting the potential benefits of physical activity undertaken at home and during exercise may be an important public health message for aging populations.


Increased intensity of Ecstasy and polydrug usage in the more experienced recreational Ecstasy/MDMA users: a WWW study.
Recreational Ecstasy/MDMA (3,4-methylenedioxymethamphetamine) users often take a variety of psychoactive drugs, but there is little empirical data on how these drug consumption patterns change with greater experience of Ecstasy. The aim of this study was to compare the polydrug usage patterns reported by non-Ecstasy users, novice Ecstasy users, moderate Ecstasy users, and heavy Ecstasy users. In a WWW study of 763 unpaid volunteers, 481 had never taken Ecstasy, whereas 282 reported they had taken it. The Ecstasy users comprised 109 novice users (1-9 occasions), 136 moderate Ecstasy users (10-99 occasions), and 36 heavy Ecstasy users (+100 occasions). Each participant also reported their experience with a range of other psychoactive drugs. The Ecstasy users reported significantly greater psychoactive drug usage than the non-Ecstasy users. The novice, moderate, and heavy Ecstasy users also differed significantly from each other in the use of cocaine, amphetamine, LSD, and psilocybin mushrooms, but not of alcohol, cannabis, or cigarettes/nicotine. Experienced Ecstasy users also took significantly more MDMA tablets on each occasion, and reported a higher maximum weekly intake. The increased use of Ecstasy is associated with more intensive patterns of Ecstasy/MDMA intake, and the greater use of illicit CNS stimulants and hallucinogens, but not of alcohol, nicotine, or cannabis. These results are discussed in the context of cross-tolerance and drug predisposition/preference.


Risk-Need Profiles of Serious and Chronic Female Juvenile Offenders: Implications for Female Juvenile Correctional Programming.
Understanding differences and similarities between male and female juvenile offenders is critically important for determining the treatment needs of each group. Less is known, however, about the similarities and differences among female juvenile offenders and the variation in their needs, risks, and psychosocial profiles. Understanding the variation among female juvenile offenders could lead to improvements in gender-responsive interventions and treatment. Latent profile analysis was conducted to construct risk-need profiles in a state-based sample of incarcerated girls ( N = 203) based on a range of psychosocial subscales covering family, peer, school and cognitive and emotional processes, psychopathology, and antisocial outcomes. Findings revealed four distinct groups/profiles with varying levels of risk-needs- Aggression Only (51%), Alcohol and Drug Use (19%), Socioemotional and Family Relationship Problems (24%), and Severe Alcohol and Drug Use (6%)-warranting the need for varying levels of treatment intensity and different treatment components across subgroups, ranging from less to more extensive.


Neutrophils are essential for induction of vaccine-like effects by antiviral monoclonal antibody immunotherapies.
Using a mouse retroviral model, we have shown that mAb-based immunotherapy can induce life-long endogenous protective immunity (vaccine-like effects). This observation has potentially important consequences for treating life-threatening human viral infections. Here, we investigated the role of neutrophils in this effect. Neutrophils are innate immunity effector cells with well-established microbe-killing activities that are rapidly mobilized upon infection. They are also emerging as orchestrators of innate and adaptive immunities. However, their immunomodulatory activity during antiviral mAb immunotherapies has never been studied. Our data reveal that neutrophils have an essential role in immunotherapy-induced immune protection of infected mice. Unexpectedly, neutrophils have a limited effect in controlling viral propagation upon passive immunotherapy administration, which is mostly mediated by NK cells. Instead, neutrophils operate as essential inducers of a potent host humoral antiviral response. Thus, neutrophils play an unexpected key role in protective immunity induction by antiviral mAbs. Our work opens approaches to improve antiviral immunotherapies, as it suggests that preserving neutrophil functions and counts might be required for achieving mAb-induced protective immunity.


Immunohistochemical staining of radixin and moesin in prostatic adenocarcinoma.
Some members of the Protein 4.1 superfamily are believed to be involved in cell proliferation and growth, or in the regulation of these processes. While the expression levels of two members of this family, radixin and moesin, have been studied in many tumor types, to our knowledge they have not been investigated in prostate cancer. Tissue microarrays were immunohistochemically stained for either radixin or moesin, with the staining intensities subsequently quantified and statistically analyzed using One-Way ANOVA or nonparametric equivalent with subsequent Student-Newman-Keuls tests for multiple comparisons. There were 11 cases of normal donor prostates (NDP), 14 cases of benign prostatic hyperplasia (BPH), 23 cases of high-grade prostatic intraepithelial neoplasia (HGPIN), 88 cases of prostatic adenocarcinoma (PCa), and 25 cases of normal tissue adjacent to adenocarcinoma (NAC) analyzed in the microarrays. NDP, BPH, and HGPIN had higher absolute staining scores for radixin than PCa and NAC, but with a significant difference observed between only HGPIN and PCa (p = < 0.001) and HGPIN and NAC (p = 0.001). In the moesin-stained specimens, PCa, NAC, HGPIN, and BPH all received absolute higher staining scores than NDP, but the differences were not significant. Stage 4 moesin-stained PCa had a significantly reduced staining intensity compared to Stage 2 (p = 0.003). To our knowledge, these studies represent the first reports on the expression profiles of radixin and moesin in prostatic adenocarcinoma. The current study has shown that there were statistically significant differences observed between HGPIN and PCa and HGPIN and NAC in terms of radixin expression. The differences in the moesin profiles by tissue type were not statistically significant. Additional larger studies with these markers may further elucidate their potential roles in prostatic neoplasia progression.


HPV 16 and cigarette smoking as risk factors for high-grade cervical intra-epithelial neoplasia.
Although genital human papillomavirus (HPV) infection is well established as the etiologic agent for cervical intraepithelial neoplasia (CIN), little is known about the cofactors involved in the development of high-grade lesions or the progression of low-grade to high-grade lesions. In our study of HPV-infected women with CIN (163 CIN I, 51 CIN II and 44 CIN III), women with CIN II or III were compared with those with CIN I for risk factors associated with high-grade lesions. After controlling for age, education, ethnicity and frequency of Pap smear screening, infection with HPV 16, but not high viral load or infection with multiple types, was associated with high-grade lesions (OR for CIN II = 11.96, OR for CIN III = 23.74). Risk of CIN III, but not CIN II, increased with number of cigarettes smoked per day (ORs = 1.49 and 3.35 for < or = 10 and > 10 cigarettes per day, respectively) and decreased with frequency of condom use during sex (ORs = 0.60 and 0.32 for women who used condoms occasionally/sometimes and most/all of the time, respectively). There were no associations between high-grade lesions and plasma levels of micronutrients (retinol, beta-carotene, alpha-tocopherol and reduced ascorbic acid). Our results indicate that infection with HPV 16 is associated with high-grade lesions. Additional cofactors, such as cigarette smoking, may be required as a carcinogen to advance HPV-infected cells toward neoplastic progression.


HIV treatment cascade in tuberculosis patients.
Globally, the number of deaths associated with tuberculosis (TB) and HIV coinfection remains unacceptably high. We review the evidence around the impact of strengthening the HIV treatment cascade in TB patients and explore recent findings about how best to deliver integrated TB/HIV services. There is clear evidence that the timely provision of antiretroviral therapy (ART) reduces mortality in TB/HIV coinfected adults. Despite this, globally in 2013, only around a third of known HIV-positive TB cases were treated with ART. Although there is some recent evidence exploring the barriers to achieve high coverage of HIV testing and ART initiation in TB patients, our understanding of which factors are most important and how best to address these within different health systems remains incomplete. There are some examples of good practice in the delivery of integrated TB/HIV services to improve the HIV treatment cascade. However, evidence of the impact of such strategies is of relatively low quality for informing integrated TB/HIV programming more broadly. In most settings, there remain barriers to higher-level organizational and functional integration. There remains a need for commitment to patient-centred integrated TB/HIV care in countries affected by the dual epidemic. There is a need for better quality evidence around how best to deliver integrated services to strengthen the HIV treatment cascade in TB patients, both at primary healthcare level and within community settings.