Concordance between Dash Diet and Hypertension: Results from the Mediators of Atherosclerosis in South Asians Living in America (MASALA) Study.
High blood pressure is an important predictor of atherosclerotic cardiovascular disease (ASCVD), particularly among South Asians, who are at higher risk for ASCVD when compared to other population groups. The Dietary Approaches to Stop Hypertension (DASH) dietary pattern is established as the best proven nonpharmacological approach to preventing hypertension in adults. Using data from the Mediators of Atherosclerosis in South Asians Living in America (MASALA) cohort, we calculated a DASH dietary score to examine the association between adherence to the DASH diet and its components, and prevalent and incident hypertension and systolic and diastolic blood pressure, after five years of follow-up. We found that the relative risk ratio (RRR) of incident hypertension was 67% lower among participants in the highest DASH diet score category (aRRR: 0.33; 95% CI: 0.13, 0.82; ptrend = 0.02) compared with those in the lowest DASH diet score category in fully adjusted models. These findings are consistent with previous clinical trials and large prospective cohort studies, adding to evidence that supports the diet-disease relationship established between DASH diet and hypertension. This study is the first to examine DASH diet adherence and hypertension among South Asian adults in the U.S.


Histopathological and immunohistochemical studies of infective dermatitis associated with HTLV-I.
Infective dermatitis associated with HTLV-I (IDH) is a chronic, recurrent, exudative eczema occurring in childhood which is considered to be a risk factor for the development of lymphoma and HTLV-I-associated myelopathy/tropical spastic paraparesis. Skin biopsies from 19 patients with IDH were studied histologically and immunohistochemically using the following antibodies: anti-CD3, CD45RO, CD20, CD79a, CD4, CD8, CD56, CD57, TIA-1, granzyme-B, and perforin. A chronic dermatitis similar to atopic and seborrheic dermatitis was observed in 15 cases, whereas architectural aspects mimicking mycosis fungoides were observed in the remaining four. The infiltrate consisted predominantly of CD8+ lymphocytes and of CD57+ cells in the dermis and epidermis. TIA-1 and granzyme-B were expressed in 15/18 cases and 5/19 cases at the proportion of < or = 15% and < or = 3%, respectively. All cases were negative for perforin and CD56. Like other dermatites, histologically IDH may represent a benign simulator of mycosis fungoides. IDH shows a predominance of CD8+ cells and a low percentage of cells with cytotoxic granules, indicating that most CD8+ lymphocytes are not activated. These findings differ from the immunohistochemical pattern of atopic and seborrheic dermatitis, possibly representing additional means of differentiation between IDH and these dermatites. The distribution of CD57+ cells suggests that they play a role in the inflammatory process.


Lessons from the skin--cutaneous features of familial cancer.
As the molecular basis of disease continues to be elucidated, familial cancer syndromes, which consist of a range of neoplastic and non-neoplastic features, are emerging. The usual pathway of referral to a genetics clinic or familial cancer centre is via an oncologist, when high-risk features that suggest a possible hereditary basis for the presenting cancer are recognised. Traditionally, these high-risk features include more than two family members with similar cancers over two or more generations, a young age of onset, and more than one synchronous or metachronous tumour. These features are effective in ascertaining a substantial proportion of families with hereditary breast and ovarian cancer due to a BRCA mutation, or the more common bowel-cancer predisposition syndromes, such as hereditary non-polyposis colon cancer and familial adenomatous polyposis. However, there are a range of familial cancer syndromes that are not easily detected and that can remain undiagnosed when history and examination are not extended to include non-malignant features. The identification of cutaneous signs associated with rare familial-cancer syndromes provides individuals and their families with the opportunity to undertake early surveillance for malignant and non-malignant complications that might in time be shown to improve outcomes.


Differential Functions of Individual Transcription Factor Binding Sites in the Tandem Repeats Found in Clinically Relevant cyp51A Promoters in Aspergillus fumigatus.
Aspergillus fumigatus is the major filamentous fungal pathogen in humans. The gold standard treatment of A. fumigatus is based on azole drug use, but the appearance of azole-resistant isolates is increasing at an alarming rate. The cyp51A gene encodes the enzymatic target of azole drugs, and azole-resistant alleles of cyp51A often have an unusual genetic structure containing a duplication of a 34- or 46-bp region in the promoter causing enhanced gene transcription. These tandem repeats are called TR34 and TR46 and produce duplicated binding sites for the SrbA and AtrR transcription factors. Using site-directed mutagenesis, we demonstrate that both the SrbA (sterol response element [SRE]) and AtrR binding sites (AtrR response element [ATRE]) are required for normal cyp51A gene expression. Loss of either the SRE or ATRE from the distal 34-bp repeat of the TR34 promoter (further 5' from the transcription start site) caused loss of expression of cyp51A and decreased voriconazole resistance. Surprisingly, loss of these same binding sites from the proximal 34- or 46-bp repeat led to increased cyp51A expression and voriconazole resistance. These data indicate that these duplicated regions in the cyp51A promoter function differently. Our findings suggest that the proximal 34- or 46-bp repeat in cyp51A recruits a corepressor that requires multiple factors to act while the distal repeat is free of this repression and provides the elevated cyp51A expression caused by these promoter duplications. IMPORTANCE Aspergillus fumigatus is the most common human filamentous fungal pathogen. Azole drugs are the current therapy of choice for A. fumigatus, but the prevalence of azole resistance is increasing. The main genetic alteration causing azole resistance is a change in the cyp51A gene, which encodes the target of these drugs. Azole-resistant cyp51A alleles routinely contain duplications in their promoter regions that cause increased gene transcription. Here, we demonstrate that clinical isolates containing a 34- or 46-bp duplication in the cyp51A promoter required the presence of the transcription factor-encoding atrR gene to exhibit elevated azole resistance. Eliminations of transcription factor binding sites in the cyp51A gene have differential actions on expression of the resulting mutant allele. These data dissect the molecular inputs to cyp51A transcription and reveal a complicated function of the promoter of this gene that is critical in azole resistance.


Cost-effectiveness of decompressive craniectomy as a lifesaving rescue procedure for patients with severe traumatic brain injury.
Decompressive craniectomy has been traditionally used as a lifesaving rescue procedure for patients with refractory intracranial hypertension after severe traumatic brain injury (TBI), but its cost-effectiveness remains uncertain. Using data on length of stay in hospital, rehabilitation facility, procedural costs, and Glasgow Outcome Scale (GOS) up to 18 months after surgery, the average total hospital costs per life-year and quality-adjusted life-year (QALY) were calculated for patients who had decompressive craniectomy for TBI between 2004 and 2010 in Western Australia. The Corticosteroid Randomisation After Significant Head Injury prediction model was used to quantify the severity of TBI. Of the 168 patients who had 18-month follow-up data available after the procedure, 70 (42%) achieved a good outcome (GOS-5), 27 (16%) had moderate disability (GOS-4), 34 (20%) had severe disability (GOS-3), 5 (3%) were in vegetative state (GOS-2), and 32 (19%) died (GOS-1). The hospital costs increased with the severity of TBI and peaked when the predicted risk of an unfavorable outcome was about 80%. The average cost per life-year gained (US$671,000 per life-year) and QALY (US$682,000 per QALY) increased substantially and became much more than the usual acceptable cost-effective limit (US$100,000 per QALY) when the predicted risk of an unfavorable outcome was >80%. Changing different underlying assumptions of the analysis did not change the results significantly. Severity of TBI had an important effect on cost-effectiveness of decompressive craniectomy. As a lifesaving procedure, decompressive craniectomy was not cost-effective for patients with extremely severe TBI.


Spatiotemporal Distribution of Chinavia hilaris (Hemiptera: Pentatomidae) in Peanut-Cotton Farmscapes.
The green stink bug, Chinavia hilaris (Say) (Hemiptera: Pentatomidae), is a pest of cotton in the southeastern United States, but little is known concerning its spatiotemporal distribution in agricultural farmscapes. Therefore, spatiotemporal distribution of C. hilaris in farmscapes where cotton fields adjoined peanut was examined weekly. Spatial patterns of C. hilaris counts were analyzed using SADIE (Spatial Analysis by Distance Indices) methodology. Interpolated maps of C. hilaris density were used to visualize abundance and distribution of C. hilaris in crops. For the six peanut-cotton farmscapes studied, the frequency of C. hilaris in cotton (94.8%) was significantly higher than in peanut (5.2%), and nymphs were rarely detected in peanut, indicating that peanut was not a source of C. hilaris into cotton. Significantly, aggregated spatial distributions were detected in cotton. Maps of local clustering indices depicted patches of C. hilaris in cotton, mainly at field edges including the peanut-to-cotton interface. Black cherry (Prunus serotina Ehrh.) and elderberry (Sambucus nigra subsp. canadensis [L.] R. Bolli) grew in habitats adjacent to crops, C. hilaris were captured in pheromone-baited stink bug traps in these habitats, and in most instances, C. hilaris were observed feeding on black cherry and elderberry in these habitats before colonization of cotton. Spatial distribution of C. hilaris in these farmscapes revealed that C. hilaris colonized cotton field edges near these two noncrop hosts. Altogether, these findings suggest that black cherry and elderberry were sources of C. hilaris into cotton. Factors affecting the spatiotemporal dynamics of C. hilaris in peanut-cotton farmscapes are discussed.


Retinoic acid mediates regulation of network formation by COUP-TFII and VE-cadherin expression by TGFbeta receptor kinase in breast cancer cells.
Tumor development, growth, and metastasis depend on the provision of an adequate vascular supply. This can be due to regulated angiogenesis, recruitment of circulating endothelial progenitors, and/or vascular transdifferentiation. Our previous studies showed that retinoic acid (RA) treatment converts a subset of breast cancer cells into cells with significant endothelial genotypic and phenotypic elements including marked induction of VE-cadherin, which was responsible for some but not all morphological changes. The present study demonstrates that of the endothelial-related genes induced by RA treatment, only a few were affected by knockdown of VE-cadherin, ruling it out as a regulator of the RA-induced endothelial genotypic switch. In contrast, knockdown of the RA-induced gene COUP-TFII prevented the formation of networks in Matrigel but had no effect on VE-cadherin induction or cell fusion. Two pan-kinase inhibitors markedly blocked RA-induced VE-cadherin expression and cell fusion. However, RA treatment resulted in a marked and broad reduction in tyrosine kinase activity. Several genes in the TGFbeta signaling pathway were induced by RA, and specific inhibition of the TGFbeta type I receptor blocked both RA-induced VE-cadherin expression and cell fusion. Together these data indicate a role for the TGFbeta pathway and COUP-TFII in mediating the endothelial transdifferentiating properties of RA.


Dithione, the antipodal redox partner of ene-1,2-dithiol ligands and their metal complexes.
Defining the oxidation state of the central atom in a coordination compound is fundamental in understanding the electronic structure and provides a starting point for elucidating molecular properties. The presence of non-innocent ligand(s) can obscure the oxidation state of the central atom as the ligand contribution to the electronic structure is difficult to ascertain. Redox-active ligands, such as dithiolene ligands, are well known non-innocent ligands that can exist in both a fully reduced (Dt2-) and fully oxidized (Dt0) states. Complexes containing the fully oxidized dithione state of the ligand are uncommon and only a few have been completely characterized. Dithione ligands are of interest due to their electron-deficient nature and ability to act as an electron acceptor for more electron-rich moieties, such as other dithiolene ligands or metal centers. This article focuses the syntheses, structures, and metal coordination, particularly coordination compounds, of dithione ligands. Various examples of mono, bis, and tris dithione complexes are discussed.


Torsional control of double-stranded DNA branch migration.
DNA branched junctions are analogues of Holliday junction recombination intermediates. Partially mobile junctions contain a limited amount of homology flanking the branch point. A partially mobile DNA branched junction has been incorporated into a synthetic double-stranded circular DNA molecule. The junction is flanked by four homologous nucleotide pairs, so that there are five possible locations for the branch point. Two opposite arms of the branched junction are joined to form the circular molecule, which contains 262 nucleotides to the base of the junction. This molecule represents a system whereby torque applied to the circular molecule can have an impact on the junction, by relocating its branch point. Ligation of the molecule produces two topoisomers; about 87% of the product is a relaxed molecule, and the rest is a molecule with one positive supercoil. The position of the branch point is assayed by cleaving the molecule with endonuclease VII. We find that the major site of the branch point in the relaxed topoisomer is at the maximally extruded position in the relaxed molecule. Upon the addition of ethidium, the major site of the branch point migrates to the minimally extruded position.


Host microbiota dictates the proinflammatory impact of LPS in the murine liver.
Gut microbiota can impact liver disease development via the gut-liver axis. Liver inflammation is a shared pathological event in various liver diseases and gut microbiota might influence this pathological process. In this study, we studied the influence of gut microbiota on the inflammatory response of the liver to lipopolysaccharide (LPS). The inflammatory response to LPS (1-10 μg/ml) of livers of specific-pathogen-free (SPF) or germ-free (GF) mice was evaluated ex vivo, using precision-cut liver slices (PCLS). LPS induced a more pronounced inflammatory response in GF PCLS than in SPF PCLS. Baseline TNF-α gene expression was significantly higher in GF slices as compared to SPF slices. LPS treatment induced TNF-α, IL-1β, IL-6 and iNOS expression in both SPF and GF PCLS, but the increase was more intense in GF slices. The anti-inflammatory markers SOCS3 and IRAK-M gene expression was significantly higher in GF PCLS than SPF PCLS at 24h with 1 µg/ml LPS treatment, and IL-10 was not differently expressed in GF PCLS than SPF PCLS. In addition, TLR-4 mRNA, but not protein, at basal level was higher in GF slices than in SPF slices. Taken together, this study shows that, in mice, the host microbiota attenuates the pro-inflammatory impact of LPS in the liver, indicating a positive role of the gut microbiota on the immune homeostasis of the liver.


Foreign Body Granuloma Following Hwangryunhaedok-tang Pharmacopuncture for Postherpetic Neuralgia.
Foreign body granuloma can be caused by endogenous compounds as well as various injectable materials. In oriental medicine, pharmacopuncture combining herbal medicine administration and injection is one of the commonly used procedures. Hwangryunhaedok-tang (HHT, a.k.a., Huang-Lian-Jie-Du-Tang in China), an oriental medicinal herb known to produce anti-inflammatory effects, has been recently made in pharmacopuncture products and commonly used for various disorders. An 88-year-old female presented with multiple tender nodules on the left parietal scalp and forehead. The diagnosis of foreign body granuloma caused by HHT pharmacopuncture was revealed by more detailed previous treatment history of postherpetic neuralgia and histopathologic examination. Herein, we report a foreign body granuloma as a delayed adverse reaction caused by non-standard administration of herbal extracts, considered biologically inert.


Vertebroplasty and kyphoplasty for osteolytic vertebral collapse.
As many as 70% of patients with cancer and multiple myeloma initially present with osteolytic involvement of the spine. These vertebral fractures are associated with significant morbidity and mortality and represent a tremendous personal and societal burden. Traditional medical and surgical options often are inadequate or too invasive for this population debilitated by cancer. Vertebroplasty involves the injection of polymethylmethaerylate to strengthen a vertebra. This minimally invasive method, which has been adopted by practitioners during the past decade to treat symptomatic osteoporotic compression fractures is reported to provide quick pain relief in 90% of patients, with only infrequent, mostly minor, complications. In patients with osteolytic fractures, vertebroplasty is associated with an increased rate of cement leak and less predictable pain relief. Kyphoplasty is an extension of vertebroplasty that uses an inflatable bone tamp to restore the vertebral body toward its original height while creating a cavity to be filled with bone cement. Preliminary data indicate that kyphoplasty is a safe procedure associated with a lower risk of cement leak, restoration of vertebral body height, and sagittal spinal alignment. In patients with osteolytic fractures secondary to multiple myeloma, kyphoplasty yields quick pain relief, and is associated with a statistically significant improvement in generic health outcome measures.


Association of Plasmodium falciparum isolates encoding the p. Falciparum chloroquine resistance transporter gene K76T polymorphism with anemia and splenomegaly, but not with multiple infections.
The aim of the study was to assess whether infections with Plasmodium falciparum isolates encoding the P. falciparum chloroquine resistance transporter (pfcrt) gene K76T polymorphism, a molecular marker for chloroquine resistance, are associated with multiple infections, age, or clinical signs of malaria in a semi-immune population in a holoendemic area of Burkina Faso. The parameters of interest were investigated in 210 P. falciparum-positive inhabitants. Logistic regression analysis showed that pfcrt K76T-carrying isolates are significantly more likely to cause anemia and splenomegaly. Furthermore, we found that infections with P. falciparum isolates encoding pfcrt K76T are dependent on age rather than multiple infections. Our findings suggest that pfcrt K76T might serve as a valuable marker for assessing the long-term clinical effect of chronic infections with chloroquine-resistant P. falciparum isolates in populations, without the need of drug efficacy trials.


Hyaluronic Acid (HA)-Based Silk Fibroin/Zinc Oxide Core-Shell Electrospun Dressing for Burn Wound Management.
Burn injuries represent a major life-threatening event that impacts the quality of life of patients, and places enormous demands on the global healthcare systems. This study introduces the fabrication and characterization of a novel wound dressing made of core-shell hyaluronic acid-silk fibroin/zinc oxide (ZO) nanofibers for treatment of burn injuries. The core-shell configuration enables loading ZO-an antibacterial agent-in the core of nanofibers, which in return improves the sustained release of the drug and maintains its bioactivity. Successful formation of core-shell nanofibers and loading of zinc oxide are confirmed by transmission electron microscopy, Fourier-transform infrared spectroscopy, and energy dispersive X-ray. The antibacterial activity of the dressings are examined against Escherichia coli and Staphylococcus aureus and it is shown that addition of ZO improves the antibacterial property of the dressing in a dose-dependent fashion. However, in vitro cytotoxicity studies show that high concentration of ZO (>3 wt%) is toxic to the cells. In vivo studies indicate that the wound dressings loaded with ZO (3 wt%) substantially improves the wound healing procedure and significantly reduces the inflammatory response at the wound site. Overall, the dressing introduced herein holds great promise for the management of burn injuries.


Early use of inhaled corticosteroids in the emergency department treatment of acute asthma.
Systemic corticosteroids therapy is central to the management of acute asthma The use of inhaled steroids may also be beneficial in this setting. To determine the benefit of ICS for the treatment of patients with acute asthma managed in the emergency department (ED). Randomised controlled trials (RCTs) were identified from the Cochrane Airways Review Group register. Bibliographies from included studies, known reviews, and texts also were searched. Only RCTs or quasi-randomised trials were eligible for inclusion. Studies were included if patients presented with acute asthma to the ED or its equivalent, and were treated with ICS or placebo, in addition to standard therapy. Two reviewers independently selected potentially relevant articles, and then independently selected articles for inclusion. Methodological quality was independently assessed by two reviewers. Data were extracted independently by two reviewers if the authors were unable to verify the validity of extracted information. Missing data were obtained from the authors or calculated from other data presented in the paper. Seven trials were selected for inclusion, but data were not available for one of them. In the six usable rials, (4 adult, 2 paediatric), a total of 352 patients were studied (179 ICS, 173 non-ICS treated). Patients treated with ICS were less likely to be admitted to hospital (OR: 0.30; 95% CI: 0.16, 0.57). This benefit was confined to patients not receiving concomitant systemic steroids. Such patients showed the same, but non-significant, trend towards reduced admissions compared to placebo treatment (OR 0.46; 95% CI: 0. 19, 1.11). In children, ICS appeared to be at least as effective as systemic steroids (OR 0.5; 95% CI: 0.24, 1.06). Patients receiving ICS demonstrated small, significant improvements in peak expiratory flows (PEFR WMD: 7%; 95% CI: 3, 13) and forced expiratory volumes (FEV-FEV1 WMD: 5.0%; 95% CI: 0.4, 9.7). The treatment was well tolerated, with few reported adverse side effects. Inhaled steroids reduced admission rates in patients with acute asthma who were not receiving concomitant systemic steroids. In children, inhaled steroids appear to be at least as effective as systemic steroids. Further research is needed to clarify the effect of ICS when used in addition to systemic corticosteroids, and to determine the optimal dose, agent, and frequency of ICS administration.


Telomere length variation in normal epithelial cells adjacent to tumor: potential biomarker for breast cancer local recurrence.
A better understanding of the risk of local recurrence (LR) will facilitate therapeutic decision making in the management of early breast cancers. In the present study, we investigated whether telomere length in the normal breast epithelial cells surrounding the tumor is predictive of breast cancer LR; 152 women who were diagnosed with breast cancer at the Lombardi Comprehensive Cancer Center were included in this nested case-control study. Cases (patients had LR) and controls (patients had no LR) were matched on year of surgery, age at diagnosis and type of surgery. Telomere fluorescent in situ hybridization was used to determine the telomere length using formalin fixed paraffin-embedded breast tissues. Small telomere length variation (TLV), defined as the coefficient variation of telomere lengths among examined cells, in normal epithelial cells adjacent to the tumor was significantly associated with a 5-fold (95% confidence interval = 1.2-22.2) increased risk of breast cancer LR. When the subjects were categorized into quartiles, a significant inverse dose-response relationship was observed with lowest versus highest quartile odds ratio of 15.3 (P(trend) = 0.012). Patients who had large TLV had significantly better 10 year recurrence free survival rate compared with patients who had small TLV (80 versus 33%). The present study revealed that TLV in normal epithelial cells adjacent to tumor is a strong predictor of breast cancer LR. If confirmed by future studies, TLV in normal epithelial cells adjacent to tumor has the potential to become a promising biomarker for predicting breast cancer LR after breast conserving surgery.


Insulin-like growth factor-I regulates GPER expression and function in cancer cells.
Functional cross talk between insulin-like growth factor-I (IGF-I) system and estrogen signaling has been largely reported, although the underlying molecular mechanisms remain to be fully elucidated. As GPR30/GPER mediates rapid cell responses to estrogens, we evaluated the potential of IGF-I to regulate GPER expression and function in estrogen receptor (ER)α-positive breast (MCF-7) and endometrial (Ishikawa) cancer cells. We found that IGF-I transactivates the GPER promoter sequence and upregulates GPER mRNA and protein levels in both cells types. Similar data were found, at least in part, in carcinoma-associated fibroblasts. The upregulation of GPER expression by IGF-I involved the IGF-IR/PKCδ/ERK/c-fos/AP1 transduction pathway and required ERα, as ascertained by specific pharmacological inhibitors and gene-silencing. In both MCF-7 and Ishikawa cancer cells, the IGF-I-dependent cell migration required GPER and its main target gene CTGF, whereas the IGF-I-induced proliferation required both GPER and cyclin D1. Our data demonstrate that the IGF-I system regulates GPER expression and function, triggering the activation of a signaling network that leads to the migration and proliferation of cancer cells.


In vivo aminoacylation of human and Xenopus suppressor tRNAs constructed by site-specific mutagenesis.
Amber suppressor tRNA genes were constructed by site-specific mutagenesis of the anticodons of human lysine-inserting tRNA (tRNA(Lys)) and glutamine-inserting tRNA (tRNA(Gln)) genes, and a Xenopus laevis tyrosine-inserting tRNA (tRNA(Tyr)) gene. As previous in vitro studies in prokaryotes have shown that substitution of nucleotides in the anticodon region can profoundly affect tRNA aminoacylation, it is important to determine whether the mutation affects aminoacylation of these eukaryotic tRNAs. We present a method for quantitating the tRNA aminoacylation in vivo in mammalian cells, and we have determined that the suppressor tRNA(Tyr) is fully aminoacylated and suppressor tRNA(Lys) and tRNA(Gln) are aminoacylated 40-50% and 80%, respectively. This in vivo method of estimating aminoacylation may be applied to other mutations in the tRNA genes.


An atrioventricular node model incorporating autonomic tone.
The response to atrial fibrillation (AF) treatment is differing widely among patients, and a better understanding of the factors that contribute to these differences is needed. One important factor may be differences in the autonomic nervous system (ANS) activity. The atrioventricular (AV) node plays an important role during AF in modulating heart rate. To study the effect of the ANS-induced activity on the AV nodal function in AF, mathematical modelling is a valuable tool. In this study, we present an extended AV node model that incorporates changes in autonomic tone. The extension was guided by a distribution-based sensitivity analysis and incorporates the ANS-induced changes in the refractoriness and conduction delay. Simulated RR series from the extended model driven by atrial impulse series obtained from clinical tilt test data were qualitatively evaluated against clinical RR series in terms of heart rate, RR series variability and RR series irregularity. The changes to the RR series characteristics during head-down tilt were replicated by a 10% decrease in conduction delay, while the changes during head-up tilt were replicated by a 5% decrease in the refractory period and a 10% decrease in the conduction delay. We demonstrate that the model extension is needed to replicate ANS-induced changes during tilt, indicating that the changes in RR series characteristics could not be explained by changes in atrial activity alone.


Changing patterns of propagation in a super-refractory status of the temporal lobe. Over 900 seizures recorded over nearly one year.
Our goals were to study the propagation models in a situation of persistent temporal epileptic seizures with varying degrees of bitemporal excitability and to analyze which propagation models were found at times of high temporal excitability and which occurred with lower levels of excitability. A patient with super-refractory status arising from the temporal lobes was studied daily using video-electroencephalography (VEEG), with a large number of electroclinical seizures recorded. The analysis focused on the method and type of seizure propagation and classified them either according to the propagation models described in the literature or as undetermined. Video-EEG monitoring was carried out daily for 310 days. A total of 990 electroclinical seizures were recorded; 135 seizures were recorded during the first week, and 523 were recorded in the first month. From the beginning, the interictal recording showed independent discharges over both temporal lobes. The seizures showed independent onset in both temporal lobes. During periods of the highest number of seizures, certain models of propagation begin to predominate through switch of lateralization, temporal asynchrony, early remote propagation, total contralateral propagation, seizures with nonlocalized onset, or models that are difficult to classify. Conversely, when the condition was brought relatively under control, we observed fewer propagation models with predominantly simple patterns: only hemispheric propagation or graduated sequential propagation with a few nonlateralized onset seizures. Upon analyzing the seizures, we found that the propagation models vary as the status evolved, with the change reflecting the degree of excitability in the mesial temporal-limbic network at a given time. In clinical practice, these changes in propagation models are more likely to be observed in temporal status that extends over time and with an onset of the seizures in both temporal lobes. The analysis of the propagation models may provide information about the excitability of the mesial temporal-limbic network.


Low-power noncontact photoacoustic microscope for bioimaging applications.
An inexpensive noncontact photoacoustic (PA) imaging system using a low-power continuous wave laser and a kilohertz-range microphone has been developed. The system operates in both optical and PA imaging modes and is designed to be compatible with conventional optical microscopes. Aqueous coupling fluids are not required for the detection of the PA signals; air is used as the coupling medium. The main component of the PA system is a custom designed PA imaging sensor that consists of an air-filled sample chamber and a resonator chamber that isolates a standard kilohertz frequency microphone from the input laser. A sample to be examined is placed on the glass substrate inside the chamber. A laser focused to a small spot by a 40 × objective onto the substrate enables generation of PA signals from the sample. Raster scanning the laser over the sample with micrometer-sized steps enables high-resolution PA images to be generated. A lateral resolution of 1.37 ?? ? m was achieved in this proof of concept study, which can be further improved using a higher numerical aperture objective. The application of the system was investigated on a red blood cell, with a noise-equivalent detection sensitivity of 43,887 hemoglobin molecules ( 72.88 × 10 ? 21 ?? mol or 72.88 zeptomol). The minimum pressure detectable limit of the system was 19.1 ?? ? Pa . This inexpensive, compact noncontact PA sensor is easily integrated with existing commercial optical microscopes, enabling optical and PA imaging of the same sample. Applications include forensic measurements, blood coagulation tests, and monitoring the penetration of drugs into human membrane.


The changing epidemiology of hepatitis A in Arizona following intensive immunization programs (1988-2007).
Arizona had the highest hepatitis A incidence of any U.S. state during 1987-1997. In 1995, the first hepatitis A vaccines became available in the U.S. A series of hepatitis A vaccination policies and recommendations were implemented in 1996-2006. Our objective was to examine the shifting epidemiologic patterns in hepatitis A in Arizona from 1988 to 2007. Passive surveillance reports to the Arizona Department of Health Services were used to compare hepatitis A rates by age, race/ethnicity and geographic area, before and after widespread vaccination. Reported risk factors and possible sources of infection were compared for two time periods. Age-adjusted incidence during three periods was mapped. Overall hepatitis A incidence in Arizona fell from 58 cases per 100,000 in 1988 to 2 per 100,000 in 2007. The proportion of reported cases among children dropped from 62% in 1994-1995 to 32% in 2006-2007. Racial/ethnic disparities between American Indians and non-Hispanic White populations have been eliminated. The geographic distribution of cases within the state has shifted. Earlier cases were likely to report contact with another hepatitis A case or childcare facilities, while later cases indicated recent international travel. A major shift in the overall burden of hepatitis A and hepatitis A transmission has occurred in Arizona since the widespread implementation of immunization policies and the concomitant rise in vaccination rates in the state. Current transmission has shifted to older age groups and disparities by race/ethnicity are now highest in Hispanic populations. Future strategies to further reduce hepatitis A transmission may require broadening recommendations to include general adult populations without previous vaccination history.


Quantifying surface albedo and other direct biogeophysical climate forcings of forestry activities.
By altering fluxes of heat, momentum, and moisture exchanges between the land surface and atmosphere, forestry and other land-use activities affect climate. Although long recognized scientifically as being important, these so-called biogeophysical forcings are rarely included in climate policies for forestry and other land management projects due to the many challenges associated with their quantification. Here, we review the scientific literature in the fields of atmospheric science and terrestrial ecology in light of three main objectives: (i) to elucidate the challenges associated with quantifying biogeophysical climate forcings connected to land use and land management, with a focus on the forestry sector; (ii) to identify and describe scientific approaches and/or metrics facilitating the quantification and interpretation of direct biogeophysical climate forcings; and (iii) to identify and recommend research priorities that can help overcome the challenges of their attribution to specific land-use activities, bridging the knowledge gap between the climate modeling, forest ecology, and resource management communities. We find that ignoring surface biogeophysics may mislead climate mitigation policies, yet existing metrics are unlikely to be sufficient. Successful metrics ought to (i) include both radiative and nonradiative climate forcings; (ii) reconcile disparities between biogeophysical and biogeochemical forcings, and (iii) acknowledge trade-offs between global and local climate benefits. We call for more coordinated research among terrestrial ecologists, resource managers, and coupled climate modelers to harmonize datasets, refine analytical techniques, and corroborate and validate metrics that are more amenable to analyses at the scale of an individual site or region.


Host resistance selects for traits unrelated to resistance-breaking that affect fitness in a plant virus.
The acquisition by parasites of the capacity to infect resistant host genotypes, that is, resistance-breaking, is predicted to be hindered by across-host fitness trade-offs. All analyses of costs of resistance-breaking in plant viruses have focused on within-host multiplication without considering other fitness components, which may limit understanding of virus evolution. We have reported that host range expansion of tobamoviruses on L-gene resistant pepper genotypes was associated with severe within-host multiplication penalties. Here, we analyze whether resistance-breaking costs might affect virus survival in the environment by comparing tobamovirus pathotypes differing in infectivity on L-gene resistance alleles. We predicted particle stability from structural models, analyzed particle stability in vitro, and quantified virus accumulation in different plant organs and virus survival in the soil. Survival in the soil differed among tobamovirus pathotypes and depended on differential stability of virus particles. Structure model analyses showed that amino acid changes in the virus coat protein (CP) responsible for resistance-breaking affected the strength of the axial interactions among CP subunits in the rod-shaped particle, thus determining its stability and survival. Pathotypes ranked differently for particle stability/survival and for within-host accumulation. Resistance-breaking costs in survival add to, or subtract from, costs in multiplication according to pathotype. Hence, differential pathotype survival should be considered along with differential multiplication to understand the evolution of the virus populations. Results also show that plant resistance, in addition to selecting for resistance-breaking and for decreased multiplication, also selects for changes in survival, a trait unrelated to the host-pathogen interaction that may condition host range expansion.


The generation of multiple co-existing mal-regulatory mutations through polygenic evolution in glucose-limited populations of Escherichia coli.
The multicomponent glucose transport system of Escherichia coli was used to study the polygenic basis of increased fitness in prolonged nutrient-limited, continuous cultures. After 280 generations of glucose-limited growth, nearly all bacteria in four independent chemostat populations exhibited increased glucose transport and contained multiple, stable mutations. Fitter bacteria increased outer membrane permeability for glucose through overexpression of the LamB glycoporin. Three classes of mutation influenced LamB levels as well as regulation of other mal genes. Low-level mal/lamB constitutivity resulted from mlc mutations acquired in all populations as well as changes at another uncharacterized locus. Larger increases in transporter content resulted from widespread acquisition of a regulatory malT-con mutation in fit isolates. The malT mutations sequenced from 67 adapted isolates were all single base substitutions resulting in amino acid replacements in the N-terminal third of the MalT activator protein. Analysis of malT-con sequences revealed a mutational spectrum distinct from that found in plate-selected malT mutants, suggesting that mutational pathways were affected by environmental factors. A second major finding was the remarkable allele diversity in malT within a population derived from a single clone, with at least 11 different alleles co-existing in a population. The multiplicity of alleles (as well as those found in adaptive mgl changes in the accompanying study) suggest that the periodic selection events observed previously in such populations are not a major factor in reducing genetic diversity. A simple model is presented for the generation of genetic heterogeneity in bacterial populations undergoing polygenic selection.


The association between atrial fibrillation and stroke in patients with obstructive sleep apnea: a population-based case-control study.
Obstructive sleep apnea (OSA) has been shown to be an independent risk factor for ischemic stroke and may increase the risk of atrial fibrillation (AF) by up to fourfold. Given these relationships, it is possible that OSA may provide a link between stroke and AF. A case-control study was conducted to examine the association between AF and stroke in patients with OSA. Olmsted County, MN, USA, residents with a new diagnosis of OSA based on polysomnography (PSG) between 2005 and 2010 (N = 2980) who suffered a first-time ischemic stroke during the same period were identified as cases. Controls with no history of stroke were randomly chosen from the same database. Univariate and multiple logistic regression analyses were performed with age, gender, body mass index (BMI), smoking, hypertension, hyperlipidemia, diabetes mellitus, apnea-hypopnea index (AHI) and coronary artery disease (CAD) as co-variates, with the diagnosis of AF as the variable of interest. A total of 108 subjects were studied. Mean age of cases (n = 34) was 73 ± 12 years and 53% were men. Among controls (n = 74), mean age was 61 ± 16 years and 55% were male. On univariate analyses, AF was significantly more common in the cases than among controls (50.0% vs 10.8%, p < 0.01). On multivariate regression analyses, the association between AF and stroke was significant after controlling for age, BMI, coronary artery disease, hypertension, diabetes mellitus, hyperlipidemia and smoking status (corrected odds ratio (OR): 5.34; 95% confidence interval (CI): 1.79-17.29). Patients with OSA who had a stroke had higher rates of AF even after accounting for potential confounders.


Histologic differential diagnosis of focal liver lesions by ultrasonically guided fine needle biopsy.
Ultrasonically guided fine needle biopsies were carried out in 84 patients with focal liver lesions and were subsequently evaluated histologically. A correct diagnosis of malignancy was made in 46 of 52 patients with proven hepatic malignancy, showing an overall accuracy of 93%. The specificity of the procedure was 100%. Such histological examination not only enables the differentiation between primary and secondary hepatic malignancy; it has the additional advantage of making a more precise tumour description and at the same time it pinpoints the primary site of the tumour.


The use of alkaline phosphatase and possible alternative testing to verify pasteurisation of raw milk, colostrum, dairy and colostrum-based products.
Pasteurisation of raw milk, colostrum, dairy or colostrum-based products must be achieved using at least 72°C for 15 s, at least 63°C for 30 min or any equivalent combination, such that the alkaline phosphatase (ALP) test immediately after such treatment gives a negative result. For cows' milk, a negative result is when the measured activity is ≤ 350 milliunits of enzyme activity per litre (mU/L) using the ISO standard 11816-1. The use and limitations of an ALP test and possible alternative methods for verifying pasteurisation of those products from other animal species (in particular sheep and goats) were evaluated. The current limitations of ALP testing of bovine products also apply. ALP activity in raw ovine milk appears to be about three times higher and in caprine milk about five times lower than in bovine milk and is highly variable between breeds. It is influenced by season, lactation stage and fat content. Assuming a similar pathogen inactivation rate to cows' milk and based on the available data, there is 95-99% probability (extremely likely) that pasteurised goat milk and pasteurised sheep milk would have an ALP activity below a limit of 300 and 500 mU/L, respectively. The main alternative methods currently used are temperature monitoring using data loggers (which cannot detect other process failures such as cracked or leaking plates) and the enumeration of Enterobacteriaceae (which is not suitable for pasteurisation verification but is relevant for hygiene monitoring). The inactivation of certain enzymes other than ALP may be more suitable for the verification of pasteurisation but requires further study. Secondary products of heat treatment are not suitable as pasteurisation markers due to the high temperatures needed for their production. More research is needed to facilitate a definitive conclusion on the applicability of changes in native whey proteins as pasteurisation markers.


Intrajejunal levodopa versus conventional therapy in Parkinson disease: motor and nonmotor effects.
Seventeen patients with advanced Parkinson disease (PD) were treated with intrajejunal L-dopa infusion (IJL) and compared with a matched group of 9 patients (termed comparator [C]) not given IJL because of funding restriction by primary care trusts (PCTs) in the UK, although considered to be clinically eligible for IJL. Assessments were baseline and follow-up (6 months) with Hoehn and Yahr staging, unified PD rating scale (UPDRS-III and UPDRS-IV), Parkinson disease questionnaire (PDQ-8, quality of life [QoL]) and nonmotor symptom scale (NMSS).Baseline characteristics were comparable between the groups. The IJL-treated group showed highly significant improvements in UPDRS-III (P = 0.005), UPDRS-IV (P = 0.0004), total NMSS score (P = 0.004), and QoL (P = 0.01), whereas the C group showed no change in these parameters. A large effect size of IJL was seen in treated patients for UPDRS-III (1.13), UPDRS-IV (1.52), NMSS score (0.82), and QoL (1.12), whereas continuing conventional treatment registered no effect in C.This study confirms the robust effect of IJL on motor and, in particular, nonmotor symptoms and QoL in advanced PD as described in open-label studies but additionally points to the need for such treatment in those denied this therapy because of centrally dictated funding policies leading to inequalities in health care.


[Clinical trial of mepiprazol in the treatment of neurotic inpatients (author's transl)].
Within a controlled double-blind clinical trial the psychopharmacological effect of mepiprazole was tested against placebo in the treatment of neurotic inpatients. Some results of the recorded psychophysiological parameters (tremor, reaction time and flicker fusion threshold) as well as the scores on a symptom checklist for neurotic patients (post hoc divided into three scales by means of factor analysis: anxiety, depression and weaping) indicate a tranquilizing effect of mepiprazol. These findings are discussed critically with regard of methodological problems of testing tranquilizers in psychiatric hospitals.


Harmaline and its Derivatives Against the Infectious Multi-Drug Resistant Escherichia coli.
Multidrug resistance (MDR) is a major challenge in the treatment of infectious diseases. The MDR in urinary tract infection causing bacteria, such as Escherichia coli, has made treatment of UTI very difficult. The aims of the current study were to synthesize a library of harmaline derivatives, and to evaluate their activity against various strains of multi-drug resistance (MDR) E. coli. Harmaline derivatives were synthesized by the reaction of harmaline (1) with various acid halides and anhydrides. These compounds were subjected to susceptibility determination by in vitro MTT assay. The changes in morphology of the bacterial cells after the treatment with harmaline (1) and its new derivatives 2 and 3 were studied through scanning electron, atomic force and fluorescence microscopy. Effect of harmaline and its derivatives on the production of Reactive Oxygen Species (ROS) in MDR E. coli was assessed through lucigenin chemiluminescence assays. The selected compounds assisted the fluorescently labeled dye DiBAC4(3) to bind to the lipid rich intra-cellular entities, and thus produced a sharp green fluorescence by easily penetrating into the compound-induced depolarized membrane of MDR E. coli. These compounds have also triggered a significant generation of ROS from bacterial cells as compared to the conventional antibiotics. The current study demonstrated that harmaline (1), and its derivatives 2 and 3 were identified as anti-MDR agents against MDR strains of E. coli. Antibacterial effect of compounds 1-3 on MDR E. coli is possibly due to membrane depolarization due to ROS-induced damage to the bacterial cell membrane. Harmaline and its derivatives were identified as anti-MDR agents against various highly resistant and Pakistani MDR clinical isolates of E. coli. These compounds may serve as the leads for further studies towards the development of treatment against the infections caused by MDR E. coli.


Galleria mellonella (greater wax moth) as an eco-friendly in vivo approach for the assessment of the acute toxicity of medicinal plants: Application to some plants from Cameroon.
The evaluation of medicinal plants' toxicity is a prerequisite prior to their usage. The vertebrate models used for this purpose are often the object of ethical consideration. Though invertebrate models including Galleria mellonella (GM) have demonstrated the ability to be used to assess the toxicity of various products. To the authors' knowledge, GM has never been exploited to determine the toxicity of medicinal plants. The aim of this study was to demonstrate the potential of GM larvae as a simple, inexpensive, and rapid model for the evaluation of the toxicity of herbal medicines. In this study, the toxicity of aqueous and ethanolic (80%, v/v) extracts of seven well known plants from Cameroon namely leaves of Cymbopogon citratus (DC.) Stapf, Moringa oleifera Lam and Vernonia amygdalina Delile; barks of Cinchona officinalis and Enantia chlorantha Oliv; barks and seeds of Garcinia lucida Vesque and leaves and seeds of Azadirachta indica (Neem) was evaluated using the larval form of GM. The median lethal doses (LD50), 90% (LD90), and 100% (LD100) were determined using the spline cubic survival curves and equations from the data obtained on the survival rate of GM 24 hours after the injection with the extracts. We found that distilled water extracted a more important mass of phytochemical compounds (7.4%-21.2%) compared to ethanolic solution (5.8%-12.4%). LD varied depending on the plant materials and ethanolic extracts (hydroalcoholic extract, (HAE)) were more toxic to GM than aqueous ones. The LD50 (mg/ml) of the tested extracts varied from 4.87 [3.90 g/kg body weight (bw)] to >200 (> 166.67 g/kg bw), the LD90 (mg/ml) from 25.00 (18.52 g/kg bw) to >200 (> 181.82 g/kg bw) and LD100 (mg/ml) from 45.00 (40.91 g/kg bw) to > 200 (>181.82 g/kg bw). The HAE of A. indica seed and C. officinalis bark exhibited the highest toxicity with LD50 (g/kg bw) of 3.90 and 4.81, respectively. The results obtained in this study suggest that GM can be used as a sensitive, reliable, and robust eco-friendly model to gauge the toxicity of medicinal plants. Thus, avoid the sacrifice of vertebrate models often used for this purpose to limit ethical concerns.


Developmental patterns of serum 3 alpha-androstanediol glucuronide.
3 alpha-androstanediol glucuronide (3 alpha diolG) is a marker of peripheral tissue androgen metabolism. There are no previous data regarding complete paediatric reference ranges for 3 alpha diolG. In order to obtain reference values for 3 alpha diolG we have measured serum levels of 3 alpha diolG in 283 healthy children and adolescents, 146 boys and 137 girls, age 1 month to 20 years and 28 adults. A non-extraction, solid phase radioimmunoassay employing a polyclonal antiserum that is specific for 3 alpha diolG was used to measure serum 3 alpha diolG levels (intra assay variation 5.1-10.1%, inter assay variation 2.7-9.0%). There was a strong sex and age dependence (r = 0.8; p < 0.0001) of 3 alpha diolG levels throughout childhood and adolescence with males showing significantly higher levels of the androgen than females (p < 0.05). 3 alpha diolG serum levels (nmol/l +/- SD) correlated significantly with pubertal stage (p < 0.01). Interestingly, in 35 children with CAH serum 3 alpha diolG levels correlated well with clinical and metabolic status, i.e. 17OHP serum levels. In summary, we have established percentile curves for 3 alpha diolG levels in healthy children and adolescents. We hypothesize that on the basis of our reference values the single measurement of serum 3 alpha diolG could serve as a means to determine androgen status in children with disorders of puberty and sexual development.


Determining optimal therapy--randomized trials in individual patients.
Although the treatment of an individual patient in routine clinical practice has been likened to an experiment, the method is so susceptible to bias that we have come to demand multi-patient, double-blind, randomized controlled trials on matters of efficacy. Unfortunately, such trials have not or cannot be carried out for many clinical disorders; even when they have been executed their results may be difficult to extrapolate to individual patients. To resolve this problem, we have begun to use double-blind randomized trials in which a single patient undergoes a series of pairs of treatments, consisting of one active and one placebo or alternative treatment per pair, with the order determined by random allocation. Appropriate treatment targets (signs, symptoms, or laboratory tests) are used as the measure of efficacy, and the trial is continued until efficacy is established or disproved. We describe such a trial, which resulted in a dramatically beneficial modification of treatment in a patient with partially reversible airflow limitation. We have established a clinical service that facilitates the widespread use of the method in our community.


Terminalia catappa leaf extracts inhibited metastasis of A2058 and A375 melanoma cells via downregulating p-Src and β-catenin pathway in vitro.
Background: Melanoma is a highly aggressive, lethal, and malignant cancer. Once diagnosed early, it can be easily removed and cured with satisfaction. Although many methods such as surgery, chemotherapy, radiotherapy, and immunotherapy have been used to treat this disease at an advanced stage, the outcomes are poor. Terminalia catappa leaves have been shown to have various biological benefits, including antitumor activity. The specific effects and molecular mechanisms of Terminalia catappa leaf in treating A2058 and A375 melanoma cells in vitro need to be clarified. Methods: The A2058 and A375 melanoma cancer cells were treated with Terminalia catappa leaf extracts, and then the effect of Terminalia catappa leaf extracts on migration and invasion was examined. The cell migration/invasion capacities of A2058 and A375 cells were investigated by a modified Boyden chamber assay. Zymography was used to clarify the activities of matrix metalloproteinases-2 and urinary type plasminogen activator. We performed a Western blot to verify the related expression of phospho-Src (Tyr416), phospho-Focal adhesion kinase (Tyr397), Vimentin, and β-catenin. Results: Modified Boyden chamber assays demonstrated that treatment of Terminalia catappa leaf extracts significantly inhibited A2058 and A375 cell migration/invasion capacities. In the zymography results, we showed that Terminalia catappa leaf extracts negatively modulated the activities of matrix metalloproteinases-2 and urinary type plasminogen activator. Western blot indicated that Terminalia catappa leaf extracts reduced the expression of phospho-Src (Tyr416), phospho-Focal adhesion kinase (Tyr397), Vimentin, and β-catenin. Conclusion: Terminalia catappa leaf extracts affected the antimetastasis of the A2058 and A375 melanoma cell lines by inhibiting the Focal adhesion kinase/Src interaction and Wingless-int1/β-catenin pathways in vitro. Terminalia catappa leaf extracts may serve as an effective chemopreventive agent against metastasis of melanoma cancer.


Excretion of beta-phenethylamine is elevated in humans after profound stress.
The urinary excretion rate of the endogenous, amphetamine-like substance beta-phenethylamine was markedly elevated in human subjects in association with an initial parachuting experience. The increases were delayed in most subjects and were not correlated with changes in urinary pH or creatinine excretion. The data suggest a stress-related role for beta-phenethylamine.


HIV non-occupational postexposure prophylaxis (nPEP) usage among five key populations in China.
To examine the feasibility of non-occupational postexposure prophylaxis (nPEP) as a national strategy for HIV prevention in China, we investigated nPEP usage and related sociodemographic and behavioural factors among five key populations at high risk of contracting HIV. We conducted a cross-sectional study among five key populations from November 2018 to September 2019 in China using convenience sampling to recruit participants aged ≥18 years, self-reporting HIV status as either negative or unknown and providing written informed consent. Univariable and multivariable logistic regression models were fitted. Our analysis included data from 2022 participants with a mean age of 35 years (SD=11.62). Only 57 (2.82%) participants had ever used nPEP. Sociodemographic and behavioural factors related to nPEP usage included populations (p<0.0001), age (p<0.05), education (p<0.05), nPEP knowledge (p<0.01), receiving conventional HIV prevention services (p<0.05) and HIV testing (p<0.05). A significant percentage (26%) of nPEP users used nPEP medication more than once. Challenges and concerns, such as multiple use of nPEP and syndemic conditions, were emerging. Key populations in China had low nPEP usage rates. Female sex workers, people who use drugs, older and illiterate individuals with poor nPEP knowledge, not using HIV prevention services or never tested for HIV should be emphasised. Implementing nPEP services would be an important way to access high-risk individuals for intensive and tailored HIV prevention and intervention. Challenges of providing nPEP services and future study foci are highlighted.


Conformational analysis of the major DNA adduct derived from the food mutagen 2-amino-3-methylimidazo[4,5-f]quinoline.
The heterocyclic amine 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) is one of a number of carcinogens found in barbecued meat and fish. It is mutagenic in bacterial and mammalian assays and induces tumors in mammals. IQ is biochemically activated to a derivative which reacts with DNA to form a major covalent adduct at carbon 8 of guanine. This adduct may deform the DNA and consequently cause a mutation, which may be responsible for initiating IQ's carcinogenicity. Atomic resolution structures of the IQ-damaged DNA are not yet available experimentally. We have carried out an extensive molecular mechanics energy minimization search to locate feasible structures for the major IQ-DNA adduct in the representative sequence d(5'-G1-G2-C3-G4-C5-C6-A7-3'). d(5'-T8-G9-G10-C11-G12-C13-C14-3') with IQ modification at G4; this contains the GGCGCC mutational hotspot sequence known as NarI. The molecular mechanics program AMBER 5.0 with the force field of Cornell et al. [(1995) J. Am. Chem. Soc. 117, 5179-5197] was employed, including explicit Na(+) counterions and an implicit treatment for solvation. However, key parameters, the partial charges, bond lengths, bond angles, and dihedral parameters of the modified residue, are not available in the AMBER database. We carefully parametrized the force field, created 800 starting conformations which uniformly sampled at 18 degrees intervals each of the three flexible torsion angles that govern the IQ-DNA orientation, and minimized their energy. A conformational mix of structural types, including major groove, minor groove, and base-displaced intercalated carcinogen positions, was generated. This mixture may be related to the diversity of mutational outcomes induced by IQ.


Identification and Analysis of Imaging-Genomic Signatures to Study Recurrence in Breast Cancers.
One of the main causes of breast cancer related death is its recurrence. In this study, we investigate the association of gene expression and pathological image features to understand breast cancer recurrence. A total of 172 breast cancer patient data was downloaded from the TCGA-BRCA database. The dataset contained diagnostic whole slide images and RNA-seq data of 80 recurrent and 92 disease-free breast cancer patients. We performed genomic analysis on RNA-seq data to obtain the hub genes related to recurrent breast cancer. We extracted relevant pathomic features from histopathology images. The discriminative ability of the hub genes and pathomic features were evaluated using machine learning classifiers. We used Spearman rank correlation analysis to find statistically significant association between gene expression and pathomic features. We identified that, genes which are related to breast cancer progression is significantly associated (adjusted p-value<0.05) with several pathomic features.Clinical Relevance- Histopathology is the gold standard for cancer detection. It provides us with cellular level information. A strong association between a pathomic feature and a gene expression will help clinicians understand the cellular and molecular mechanism of cancer for better prognosis.


Fluorescent Nanohybrids from ZnS/CdSe Quantum Dots Functionalized with Triantennary, N-Hydroxy-p-(4-arylbutanamido)benzamide/Gallamide Dendrons That Act as Inhibitors of Histone Deacetylase for Lung Cancer.
N-Hydroxy-p-(4-arylbutanamido)benzamides (HABAB) belong to one class of histone deacetylase inhibitors (HDACi), which regulate deacetylation of lysine residue's amino group in histone, which results in chromatin constriction. In addition, transcriptional knockdown of the genetic loci possessing the suppressor genes of tumor occurs. A tripodal, HABAB-capped gallamide dendron possessing thiol anchoring unit was prepared by the click method. The resultant hydrophilic dendritic unit was easily attached on the outer layer of CdSe/ZnS (i.e., core/shell type) quantum dots by thiolate-Zn interaction, as supported via 1H NMR spectroscopic analysis of the conjugate with its original property of fluorescence. The resulting, water-miscible nanohybrid (nano-HTPB) which bore trivalent, peripheral HABABs as the HDACi was efficiently taken up by cells of lung cancer and transported into the nuclei of cells in 3 h, as confirmed by confocal microscopy analysis. The concentration levels of 50% inhibition (IC50) after 48 h incubation of the nano-HTPB for A549 and H1299 lung cancer cell lines were 14 and 18 nM, respectively, which were about 150-fold lower than those of the parent HTPB analogues. Nano-HTPB at 20 nM induced the knockdown of cell cycle at second growth/mitosis (i.e., G2/M) transition, which eventually led to apoptosis of lung cancer cells, demonstrating that the nano-HTPB was much more potent in inhibiting lung cancer cell growth in a synergistic manner than the parent HTPB analogues. In addition, the dendritic HABAB-capped nanohybrid, nano-HTPB, is more effective than the parent HTPB analogues both in vitro and in vivo. Furthermore, the nano-HTPB is more effective than the parent HTPB to increase the acetylation level of proteins related to histone and nonhistone like p53 and tubulin. Our results confirmed that covalent encapsulation of quantum dots with peripheral, triantennary HDACis represented a feasible strategy for synergistic drug delivery with enhanced biological effects.


Activation of Gi-like proteins, a receptor-independent effect of kinins in mast cells.
The peptide hormones bradykinin and kallidin (Lys-bradykinin), as well as their analogues [des-Arg9]-bradykinin, a selective B1 agonist, [des-Arg9,Leu8]-bradykinin, a selective B1 antagonist, and [Thi5,8,D-Phe7]-bradykinin and D-Arg0-[Hyp3,D-Phe7]-bradykinin, two selective B2 antagonists, induced rapid histamine release from purified rat peritoneal mast cells. In contrast, the N-terminal fragment bradykinin-(1-5) was inactive. These peptides also activate the GTPase activity of GTP-binding proteins (G proteins) (Go/Gi) purified from calf brain, with an order of potency identical to that observed on mast cells, [Thi5,8,D-Phe7]-bradykinin much greater than kallidin greater than bradykinin greater than D-Arg0-[Hyp3,D-Phe7]-bradykinin greater than [des-Arg9]-bradykinin greater than [des-Arg9,Leu8]-bradykinin greater than bradykinin-(1-5). This correlation suggested that G proteins are the targets of kinins in mast cells. Accordingly, the concomitant increase in inositol trisphosphates and release of histamine elicited by kinins were inhibited by pertussis toxin pretreatment of mast cells. The inhibitory effect of benzalkonium chloride showed that the G proteins involved belong to the Gi type. GTPase activity was measured in the supernatant of homogenized mast cells but not in the membranous fraction. This activity was stimulated by kinins and by the venom peptide mastoparan. The potency of peptides was similar to that observed with purified bovine G proteins. Sodium dodecyl sulfate-gel electrophoresis of mast cell supernatant revealed pertussis toxin-induced ADP-ribosylation of two proteins, in the Mr 41,000 and 40,000 range, i.e., similar to purified alpha-subunits of Gi1 and Gi2 or Gi3 subtypes. The data support the proposal that bradykinin and analogues act like mastoparan, substance P, and compound 48/80, interacting first with sialic acid residues of the cell surface and then with Gi-like proteins, inducing phospholipase C activation and intracellular calcium mobilization.


Clinical features of the hospitalized patients with 2009 pandemic influenza A (H1N1) in Santa Fe, Argentina.
During 2009 occurred the emergence and global spread of a novel influenza A (H1N1) virus. We describe the clinical and epidemiologic features of hospitalized patients who survived and patients who died because of pandemic 2009 influenza A (H1N1) infection reported in Santa Fe, Argentina, from May to July 2009. Using medical charts, we collected data on 242 patients who were hospitalized with confirmed laboratory results (defined as positive by specific PCR for pandemic 2009 influenza A H1N1). During the study period, there were 242 cases of hospitalization or death. Of the 242, 46% were admitted to an intensive care unit (ICU) and 33·5% died. The mean age was 27·8 years for surviving and 39·6 for those who died. Twenty-eight percent of hospitalizations involved persons under the age of 15 years; 33% of the patients were between the age of 15 and 44 years; and only 3·3% were 65 years of age or older. Sixty-seven percent had an underlying medical conditions, including diabetes, obesity, heart and lung diseases, and pregnancy. Of the 242 patients, 68% had findings consistent with pneumonia. Treatment with oseltamivir was administered to 227 (93·8%) patients from which 38 received oseltamivir within 48 hours after the onset of symptoms. The pandemic strain caused severe illness, including pneumonia and acute respiratory distress syndrome, and resulted in ICU admissions in 46% of patients and death in 33·5%. The mean age of hospitalized infected cases was lower than is common with seasonal influenza. Underlying medical conditions were common in the 67% the evaluated patients. Patients who died had a higher prevalence of comorbidities (86·4%) than those who survived (57%), suggesting that the presence of chronic illness may increase the likelihood of death. However, the severe illness was also identified among young, healthy persons.


Childhood adversity and subsequent mental health status in adulthood: screening for associations using two linked surveys.
Accumulating evidence links childhood adversity to negative health outcomes in adulthood. However, most of the available evidence is retrospective and subject to recall bias. Published reports have sometimes focused on specific childhood exposures (e.g. abuse) and/or specific outcomes (e.g. major depression). Other studies have linked childhood adversity to a large and diverse number of adult risk factors and health outcomes such as cardiovascular disease. To advance this literature, we undertook a broad examination of data from two linked surveys. The goal was to avoid retrospective distortion and to provide a descriptive overview of patterns of association. A baseline interview for the Canadian National Longitudinal Study of Children and Youth collected information about childhood adversities affecting children aged 0-11 in 1994. The sampling procedures employed in a subsequent study called the National Population Health Survey (NPHS) made it possible to link n = 1977 of these respondents to follow-up data collected later when respondents were between the ages of 14 and 27. Outcomes included major depressive episodes (MDE), some risk factors and educational attainment. Cross-tabulations were used to examine these associations and adjusted estimates were made using the regression models. As the NPHS was a longitudinal study with multiple interviews, for most analyses generalized estimating equations (GEE) were used. As there were multiple exposures and outcomes, a statistical procedure to control the false discovery rate (Benjamini-Hochberg) was employed. Childhood adversities were consistently associated with a cluster of potentially related outcomes: MDE, psychotropic medication use and smoking. These outcomes may be related to one another since psychotropic medications are used in the treatment of major depression, and smoking is strongly associated with major depression. However, no consistent associations were observed for other outcomes examined: physical inactivity, excessive alcohol consumption, binge drinking or educational attainment. The conditions found to be the most strongly associated with childhood adversities were a cluster of outcomes that potentially share pathophysiological connections. Although prior literature has suggested that a very large number of adult outcomes, including physical inactivity and alcohol-related outcomes follow childhood adversity, this analysis suggests a degree of specificity with outcomes potentially related to depression. Some of the other reported adverse outcomes (e.g. those related to alcohol use, physical inactivity or more distal outcomes such as obesity and cardiovascular disease) may emerge later in life and in some cases may be secondary to depression, psychotropic medication use and smoking.


Management of severe rheumatological disease in the burn center.
In recent years, Burn Center has evolved to become a "wound intensive care unit" treating disease processes other than those due to thermal injury. Recent data have shown that more than 16% of admissions to Burn Centers are for nonburn injuries, particularly severe dermatologic diseases. The role of the Burn Center has been expanded to include treatment of patients with severe cutaneous manifestations of rheumatologic diseases. This approach has not been described before. All collagen vascular disease admissions to the Burn Center from 2005 to 2010 have been reviewed. There were 16 admissions where intensive wound management was a major component of the disease management. Disease processes included systemic lupus erythematosus, progressive systemic sclerosis, Raynaud's phenomenon, antiphospholipid syndrome, and dermatomyositis, among others. The authors describe five of these cases in detail. Comanagement of these patients by the Rheumatology and Burn services led to outstanding, successful outcomes. Collagen vascular diseases represent another area where the Burn Center may be the appropriate site for therapy.


Aberrant methylation and silencing of the calponin gene in human sarcoma cells.
We have recently developed a new strategy for the treatment of sarcomas by using human calponin promoter to drive replication and oncolysis of herpes simplex virus (HSV-1). In order to apply this therapy to a broad spectrum of sarcoma cells, it is essential to elucidate silencing mechanisms of the calponin promoter in a subset of sarcoma cells: In this study, we investigated the mechanisms of calponin inactivation in human sarcoma tissues and cell lines through the analysis of CpG methylation of promoter region by bisulfite modification, because the 5'-flanking region of the human calponin gene was originally identified as a DNA fragment bound to the conserved methyl-CpG binding domain (MBD) of MeCP2. Furthermore, we examined the correlation between DNA methylation and expression of the calponin gene by treatment with the demethylating agent 5-Aza-CdR, and in vitro 5'CpG methylation in a luciferase reporter gene construct. Here, we have provided evidence that DNA hypermethylation of the specific 5'CpG sites in exon 1 is a mechanism accompanying decreased calponin expression in both human sarcoma tissues and cell lines. These results suggest that DNA methylation may be an important mechanism regulating calponin transcription in human sarcoma cells, and thus could potentially affect the efficacies of treatment of this malignancy utilizing the human calponin promoter.


A Novel Fic (Filamentation Induced by cAMP) Protein from Clostridium difficile Reveals an Inhibitory Motif-independent Adenylylation/AMPylation Mechanism.
Filamentation induced by cAMP (Fic) domain proteins have been shown to catalyze the transfer of the AMP moiety from ATP onto a protein target. This type of post-translational modification was recently shown to play a crucial role in pathogenicity mediated by two bacterial virulence factors. Herein we characterize a novel Fic domain protein that we identified from the human pathogen Clostridium difficile The crystal structure shows that the protein adopts a classical all-helical Fic fold, which belongs to class II of Fic domain proteins characterized by an intrinsic N-terminal autoinhibitory α-helix. A conserved glutamate residue in the inhibitory helix motif was previously shown in other Fic domain proteins to prevent proper binding of the ATP γ-phosphate. However, here we demonstrate that both ATP binding and autoadenylylation activity of the C. difficile Fic domain protein are independent of the inhibitory motif. In support of this, the crystal structure of a mutant of this Fic protein in complex with ATP reveals that the γ-phosphate adopts a conformation unique among Fic domains that seems to override the effect of the inhibitory helix. These results provide important structural insight into the adenylylation reaction mechanism catalyzed by Fic domains. Our findings reveal the presence of a class II Fic domain protein in the human pathogen C. difficile that is not regulated by autoinhibition and challenge the current dogma that all class I-III Fic domain proteins are inhibited by the inhibitory α-helix.


Validation of a novel estrogen receptor-based microtitration plate assay for the determination of phytoestrogens in soy-based foods.
A novel, nonisotopic microtitration plate assay based on the human estrogen receptor has been used to screen soy-based and soy-containing foods for their phytoestrogen content (measured as genistein equivalents). The validation of the assay for use with food extracts has been demonstrated by investigation of recoveries after acidic and enzymic hydrolysis, by investigation of matrix effects, and by comparison of results with HPLC analysis. Phytoestrogen levels in soy products analyzed ranged between 520 and 1872 microgram of genistein equiv/g of soy flour, 5-282 microgram/g of soy concentrates, 503-1292 microgram/g of soy-protein isolates, and 108-226 microgram/g of soy-based infant formulas. Samples of textured vegetable protein and bread containing soy and linseed gave values of 1114 and 68 microgram/g, respectively. Comparison of results for 12 samples analyzed both by the receptor assay and by HPLC showed good correlation (r(2) = 0.905). The assay, which is rapid and simple to perform, is suitable for screening phytoestrogen-containing foods in order to assess human exposure to these bioactive compounds. The assay sensitivity is 3.4 microgram/g, and 14 samples/plate can be analyzed in 4 h following hydrolysis.


ALV-J GP37 molecular analysis reveals novel virus-adapted sites and three tyrosine-based Env species.
Compared to other avian leukosis viruses (ALV), ALV-J primarily induces myeloid leukemia and hemangioma and causes significant economic loss for the poultry industry. The ALV-J Env protein is hypothesized to be related to its unique pathogenesis. However, the molecular determinants of Env for ALV-J pathogenesis are unclear. In this study, we compared and analyzed GP37 of ALV-J Env and the EAV-HP sequence, which has high homology to that of ALV-J Env. Phylogenetic analysis revealed five groups of ALV-J GP37 and two novel ALV-J Envs with endemic GP85 and EAV-HP-like GP37. Furthermore, at least 15 virus-adapted mutations were detected in GP37 compared to the EAV-HP sequence. Further analysis demonstrated that three tyrosine-based motifs (YxxM, ITIM (immune tyrosine-based inhibitory motif) and ITAM-like (immune tyrosine-based active motif like)) associated with immune disease and oncogenesis were found in the cytoplasmic tail of GP37. Based on the potential function and distribution of these motifs in GP37, ALV-J Env was grouped into three species, inhibitory Env, bifunctional Env and active Env. Accordingly, 36.91%, 61.74% and 1.34% of ALV-J Env sequences from GenBank are classified as inhibitory, bifunctional and active Env, respectively. Additionally, the Env of the ALV-J prototype strain, HPRS-103, and 17 of 18 EAV-HP sequences belong to the inhibitory Env. And models for signal transduction of the three ALV-J Env species were predicted. Our findings and models provide novel insights for identifying the roles and molecular mechanism of ALV-J Env in the unique pathogenesis of ALV-J.


Pediatric uveitis secondary to probable, presumed, and biopsy-proven sarcoidosis.
To describe pediatric patients with uveitis diagnosed as having sarcoidosis. Medical records of pediatric patients evaluated between 1987 and 2008 were reviewed to identify those with ocular inflammation in whom a diagnosis of sarcoidosis was considered. A classification system including ocular findings and results of laboratory testing was devised and used to classify likelihood of sarcoidosis. Four hundred sixty children younger than 17 years were evaluated. Based on the classification system designed, 13 patients (2.8%) had probable, presumed, or definite sarcoidosis. The mean age was 11.6 years (range: 5 to 16 years). Elevated angiotensin-converting enzyme was measured in 6 patients and lysozyme in 5 patients. Five of 12 patients in whom chest imaging was performed had signs of sarcoidosis. Anterior segment involvement was non-granulomatous more often than granulomatous. Seven patients had multifocal choroiditis and 4 patients had retinal periphlebitis. Ocular sarcoidosis is uncommon in children, even at a tertiary referral center. Pulmonary involvement was detected in slightly less than half of the patients who had imaging, in contrast to previous reports of almost universal lung involvement in children 8 to 15 years old. The classification system of presumed, probable, and definite sarcoidosis presented may be useful in clinical practice.


Action plan for improving cardiac rehabilitation-related outcomes in a university hospital based on a review of previous interventions.
Although referral to cardiac rehabilitation (CR) is considered the standard of care and demonstrably reduces both mortality rates and hospital admissions after cardiac events, rates of referral continue to be suboptimal. In fact, national reports reveal rates ranging from approximately 60% to 85% depending on the type of cardiac event. At an urban teaching hospital in Tennessee, efforts to increase referral rates were launched during the first quarter of 2018 as part of the Define, Measure, Analyze, Improve, Control (DMAIC) Project: Acute Myocardial Infarction (AMI) Transition of Care. The goal of this Action Plan is to review the interventions taken and the outcomes data from this project in order to propose future deliverables that can address areas of improvement within the DMAIC project. A list of the DMAIC project's interventions, which were varied and multidisciplinary, were obtained from the university hospital as well as the project's data. Data from the National Cardiovascular Data Registry (NCDR)-ACTION Registry show that referral rates at this hospital have been on the rise since the initiation of the DMAIC project. Peak referral rates in the year before the interventions were implemented were approximately 39%; whereas, the peak referral rate in the year these interventions were launched rose to 86.4%. While the interventions of the DMAIC project are hypothesized to have contributed to this increase in referral rates, based on their collaborative nature and the types of referral strategies employed, there are still opportunities for improvement and growth. Thus, this Action Plan proposes future projects to increase inclusivity of CR referral pathways, improve physician education, and establish support for outpatient CR programs.


[Prognostic value of markers for proliferative activity and apoptotic regulation in laryngeal squamous cell carcinoma].
Prognosis for patients with laryngeal squamous cell carcinoma depends on many factors, among which molecular biological markers receive ever increasing attention. The purpose of this study was to determine the prognostic value of the expression of the proteins p53 and bcl-2 and the proliferation markers Ki-67 and cyclin D1 in laryngeal squamous cell carcinoma. Biopsy specimens from 64 patients aged 34 to 77 years (mean age 56+1.2 years) with invasive laryngeal squamous cell carcinoma, who received combination therapy at the Medical Radiology Research Center, Russian Academy of Medical Sciences, were studied. The level of Ki-67 and the expression of cyclin D1, p53, and bcl-2 were compared with clinical and anatomic parameters (T stage, tumor grade, and the presence of regional metastases), using Student's t-test and fourfold table analysis (X2 or Fisher's exact test). Survival rates were analyzed by the Kaplan-Meier method; the significance of differences between survival curves was confirmed by Cox's F-test. The value p0.05 was taken to be significant. Ki-67 is an important prognostic marker for the N status (p=0.03) and recurrence (p=0.04) and a marker for tumor grading (p<0.01). Cyclin D1 expression is associated with low overall and relapse-free survival rates (p=0.05 and 0.03, respectively). The prognostic marker for a recurrence is p53 (p=0.01) that is related to the N status at the trend level (p=0.08). The marker bcl-2 is associated with high overall survival (p=0.01) and N status at the trend level (p=0.08).


[Evaluation of a new technology for the detection of enterovirus in sewage].
This paper reported the appraisal of a novel technology for the detection of enterovirus in sewage based on a viral recovery method using polyethylenglycol as a concentrating agent and on the combined use of viral isolation and polymerase chain reaction as viral detection and identification techniques. It was also confirmed that the viral recovery method is highly efficient since it allows to recover all viruses present in sewage and to preserve their infective capacity. It was proved that the polymerase chain reaction (PCR) is less sensitive than cell culture for detecting enteroviruses in sewage. It is also possible to use guadinine isothiocyanate, whose components can be prepared in the lab, as an alternative method for taking out and purifying nucleic acids instead of using the conventional TRIZOL method which is the one recommended in these cases by the World Health Organization.


Stress-induced body dissatisfaction in women with binge eating disorder.
Stress is known to be a trigger for binge eating in individuals with binge eating disorder (BED). However, the influence of stressful situations on BED patients' body image is less understood. Our study objective was to gain insight into the effects of inducing psychosocial stress on body dissatisfaction in women with BED. Overweight women with BED (n = 29) and without an eating disorder (control group, CG; n = 38) underwent the Trier Social Stress Test for Groups (TSST-G stress) and a nonstressful control task (TSST-G no stress). Additionally, to test for the influence of body salience, participants were either exposed or not exposed to a mirror. Participants repeatedly rated their current body dissatisfaction and psychological distress. Simultaneously, biological stress reactivity was measured using salivary cortisol and alpha-amylase (sAA). Participants responded to TSST-G stress with significantly higher psychological and biological stress compared to the TSST-G control task. The psychological distress response was significantly greater in women with BED than the CG. As hypothesized, exposure to acute socioevaluative stress led to exacerbated body dissatisfaction in the BED group only. The findings of the present study suggest that acute socioevaluative stress may play an influential role in BED patients' body dissatisfaction. Body image programs might benefit from targeting stress management or coping skills in patients with BED. (PsycINFO Database Record


Multifocal neuroblastoma: biologic behavior and surgical aspects.
Although multifocal neuroblastoma is rare, its incidence has increased because of recent improvements in diagnostic tools and the introduction of mass screening. Among the 106 neuroblastoma cases treated at the authors' hospital between 1984 and 1998, 8 were multifocal neuroblastoma. The authors examined clinicopathologic findings and biologic features, including MYCN amplification, NTRK1 and Ha-ras p21 expression, cellular DNA content, and telomerase activity in these 8 multifocal neuroblastoma cases. Moreover, clinicopathologic findings were investigated with a review of 53 published cases of multiple neuroblastoma in the literature published in English between 1966 and 1999. Among these eight cases, five were detected by mass screening and three were incidental neuroblastomas. Histologically, all tumors were classified as ganglioneuroma or favorable neuroblastoma except one advanced case. All tumors lacked the MYCN gene amplification and expressed NTRAK1 mRNA and Ha-ras p21 protein. Cellular DNA content showed that half of these tumors were near-triploid, and the proliferative index (%S-phase) of all tumors was less than 25%. High telomerase activity was detected in none of these cases. Four patients underwent multistage operation and five patients with bilateral adrenal neuroblastomas underwent tumor enucleation to preserve adrenal function. Currently, all patients are disease free and none have required corticosteroid replacement therapy. Among the previously reported 53 cases with multifocal neuroblastoma, 25 were incidentally detected, 18 had familiar history, and most patients without other major complications also had extremely good prognoses. These findings suggested that most multifocal neuroblastomas have favorable biologic features. Clinically, surgical approaches should be attempted to preserve organ function, especially adrenal function, and minimal invasive surgery should be performed. In cases of thoracoabdominal neuroblastoma, multistage surgery is effective and safe.


Follow-up height after discontinuation of growth hormone treatment in children with intrauterine growth retardation.
Growth hormone (GH) treatment has been used in children with intrauterine growth retardation (IUGR) to promote growth with success in several short- and long-term clinical trials. Intermittent GH therapy has also been advocated in children with IUGR. This study was designed to evaluate the growth of children with IUGR after discontinuation of a two-year trial of GH treatment. Sixteen children (12 F, 4 M) who had received GH (Genotropin) at age 5.3 (1.3) years at a dose of 0.2 IU/kg/day for 2 years (Group 1) and 10 (6 F, 4 M) controls of age 4.3 (1.7) years without treatment (Group 2) were followed after completion of the trial over a median period of 4 years. Height SDS of the GH-treated group showed an increase from -3.0 (0.5) to -1.9 (0.7) (p <0.001) over 2 years of therapy. Off therapy, height SDS decreased to -3.5 (0.5) at a mean age of 11.2 (1.6) years. The difference between the initial and recent height SDS in this group was significantly different (p = 0.02). Height SDS of the control group, -2.7 (1.4) initially, did not change over the two-year observation period. At follow-up, seven control children received GH in a similar fashion for one year. In spite of an insignificant increase in height SDS on one year of GH, it decreased to -2.9 (1.6) at age 11.0 (2.1) years at the latest visit. There was no significant difference between the recent heights of the two groups at final examination. One girl in Group 1 developed acanthosis nigricans and type 2 diabetes mellitus at age 13.3 years, after the follow-up period. A second patient developed osteosarcoma in the left tibia at age 9.9 years, for which she received chemotherapy and surgery. In conclusion, height SDS showed a significant increase on GH therapy for 2 years in children with IUGR; however, it decelerated after discontinuation of therapy. At the final visit, GH therapy did not seem to have had any effect on height prognosis. This finding shows that GH should be given continuously to improve final height in children with IUGR.


Vascular Imaging Techniques of the Spinal Cord.
The various imaging techniques used to depict vascular lesions of the spinal cord are described in this article with particular emphasis on magnetic resonance imaging (MRI), vascular sequences, and advantages of high-field MRI. Technical vascular protocols are discussed in computed tomography, MRI, and conventional angiography. The diverse magnetic resonance angiography protocols are presented as well as their findings, specificities, and pitfalls. A review of the vascular anatomy and the most common pathologies analyzed by magnetic resonance angiography and conventional angiography is described.


A multibiomarker approach in clams (Ruditapes philippinarum) for a toxicological evaluation of dredged sediments.
The Lagoon of Venice is often dredged for channel maintenance. To avoid harmful consequences to the ecosystem, a proper disposal of bottom sediments requires a preliminary evaluation of its potential toxicity before excavation. Here we evaluated the effects of polluted sediments on clams (Ruditapes philippinarum) using a multibiomarker approach. Bivalves were exposed for 3 and 14 days to five sediment samples collected along a navigation canal between Venice historical centre and the industrial area of Porto Marghera. Immunological, antioxidant, detoxification, and neurotoxicity biomarkers were analysed in haemolymph, gill, and digestive gland. As a control, sediments collected far from pollution sources was used. Two experiments were performed to assess potential seasonal/gametogenic influence in clam sensitivity. A different response of clam biomarkers was observed during the two experiments and among sampling sites. Clams' digestive gland resulted to be the most sensitive tissue analysed showing significant differences among sites in all biomarkers analysed. Greater differences were present due to seasonality rather than exposure. The concentrations of metals and organic pollutants increased from the city centre to the industrial area, highlighting the influence that industrial activities had on the lagoon ecosystem. However, bioaccumulation in clams did not follow the same clear pattern, suggesting low bioavailability of compounds due to relatively high organic matter content. Biomarkers modulation was mainly driven by metals, both present in sediments and bioaccumulated. In comparison, effects of organic pollutants on the biomarkers tested were negligible. Other sources of contamination not investigated (e.g. pesticides) were suggested by neurotoxicity biomarkers alteration.


Treating the Deviated or Wide Nasal Dorsum.
Both deviation and excessive width of the nasal dorsum result in conspicuous facial disharmony and are often attended by nasal airway dysfunction. Whether the result of developmental growth disturbances, nasal trauma, failed nasal surgery, or combinations therein, deviation and splaying of the nasal dorsum can be exceedingly difficult to treat. Individualized treatment is paramount because contour variations are seemingly endless, and a careful preoperative assessment of the anatomic, physiologic, cosmetic, and psychosocial factors that characterize the deformity is necessary to devise an effective patient-specific treatment plan. Ensuring the linearity, strength, alignment, and aesthetically pleasing profile dimensions of the nasal L-strut is the requisite first step in successful treatment. Releasing all deformed components in a controlled and precise manner using powered instrumentation (whenever possible) to facilitate minimally traumatic and effective repositioning, followed by structural reconstitution of the skeletal framework using autologous graft materials, and then consolidation of the newly created construct with suture fixation completes the transformation to normalcy. Paying equal attention to both cosmetic and functional wellness, while simultaneously seeking to maximize structural stability, serves to optimize the final outcome.


Training and simulation for patient safety.
Simulation-based medical education enables knowledge, skills and attitudes to be acquired for all healthcare professionals in a safe, educationally orientated and efficient manner. Procedure-based skills, communication, leadership and team working can be learnt, be measured and have the potential to be used as a mode of certification to become an independent practitioner. Simulation-based training initially began with life-like manikins and now encompasses an entire range of systems, from synthetic models through to high fidelity simulation suites. These models can also be used for training in new technologies, for the application of existing technologies to new environments and in prototype testing. The level of simulation must be appropriate to the learners' needs and can range from focused tuition to mass trauma scenarios. The development of simulation centres is a global phenomenon which should be encouraged, although the facilities should be used within appropriate curricula that are methodologically sound and cost-effective. A review of current techniques reveals that simulation can successfully promote the competencies of medical expert, communicator and collaborator. Further work is required to develop the exact role of simulation as a training mechanism for scholarly skills, professionalism, management and health advocacy.


Evaluation of estrogen receptor Beta binding of pruni cortex and its constituents.
The bark of Prunus jamasakura Siebold (Pruni Cortex) has long been used in Japan as a folk remedy and is one of ingredients of the Kampo formula, Jumi-haidoku-to (JHT). JHT is used for treatment of skin diseases such as acne (acne vulgaris). According to Kampo medicinal sources, Quercus Cortex can be used in place of Pruni Cortex. In this study, we found that water extracts of Pruni Cortex, not Quercus Cortex showed a binding effect on estrogen receptor beta (ERbeta). Thus, their chemical analysis was carried out by GC-MS and found that five unique constituents (i.e., sakuranetin, naringenin, genistein, genkwanin and arctigenin) were detected in Pruni Cortex. The ERbeta binding capacity of these constituents was examined using 70 ng/ml 17beta-estradiol, as the positive control with 100% ERbeta binding. Among them, genistein (60% at 10 ng/ml) showed the strongest binding capacity than naringenin (60% at 1000 ng/ml) and sakuranetin (40% at 1000 ng/ml). These results suggested that Pruni Cortex in JHT could play an important role in treatment of acne. In addition, those of Pruni Cortex from different harvest places were also examined in their chemical contents and ERbeta binding capacity. The extracts of Pruni Cortex from Kyushu in Japan and Anhui Province in China showed higher contents of genistein and stronger ERbeta binding capacity than that of Pruni Cortex from Tokushima Prefecture in Japan.


Ethnic differences in problem perception and perceived need as determinants of referral in young children with problem behaviour.
An underrepresentation of ethnic minority children in mental health care settings is consistently reported. Parents of ethnic minority children are, however, less likely to perceive problem behaviour in their children. Our hypothesis was that, as a result of ethnic differences in problem perception, referral to care by a child health professional (CHP) would be lower for 5- to 6-year-old (high-risk) children from ethnic minority backgrounds than for their peers from the ethnic majority (Dutch origin). For 10,951 children in grade two of elementary school, parents and/or teachers completed the Strengths and Difficulties Questionnaire (SDQ) as well as questions on problem perception (PP) and perceived need for professional care (PN). Referral information was obtained from the Electronic Child Records (ECR) for 1,034 of these children. These children had a high (>90th percentile) SDQ score, and were not receiving mental health care. CHP's referred 144 children (14 %) during the routine health assessments. A lower problem perception was reported by parents of ethnic minority children (40-72 %) than by parents of the ethnic majority group (80 %; p < 0.001), but there were no ethnic differences in referral (OR range 0.9-1.9-p > 0.05). No ethnic differences were found for parental PN, nor for teacher's PP or PN. Despite a lower problem perception in ethnic minority parents when compared to ethnic majority parents, no ethnic differences were found in referral of children with problem behaviour in a preventive health care setting.