Biological characteristics of adrenocortical carcinoma: a study of p53, IGF, EGF-r, Ki-67 and PCNA in 17 adrenocortical carcinomas.
Adrenocortical carcinoma (ACC) is a rare neoplasm with a poor prognosis. Prognostic factors are needed to identify patients who should be treated aggressively and those for which a less aggressive approach is warranted. As a result of advances within the field of immunohistochemistry, investigations of Ki-67, PCNA, IGF, EGF-r and p53 were performed in 17 ACC. The aim of this study was to clarify the role of Ki-67, PCNA, EGF-r, IGF and p53 in correlation to tumour behaviour and outcome. This retrospective study includes 16 patients, 10 women and 6 men, with a median age of 46 years. Nine tumours were hormonally functioning and 7 were non-functioning. The results obtained revealed that all tumours expressed PCNA and Ki-67 with median values of 59% and 14%, respectively, while p53 was negative in 88%, IGF negative in 82% and EGF-r positive in 94% of the tumours. No correlation was found between p53, IGF, EGF-r and survival rate. There was no interdependence between PCNA and Ki-67, or between PCNA, Ki-67 and the survival rate.


Prediction of Retinal Ganglion Cell Counts Considering Various Displacement Methods From OCT-Derived Ganglion Cell-Inner Plexiform Layer Thickness.
To compare various displacement models using midget retinal ganglion cell to cone (mRGC:C) ratios and to determine viability of estimating RGC counts from optical coherence tomography (OCT)-derived ganglion cell-inner plexiform layer (GCIPL) measurements. Four Drasdo model variations were applied to macular visual field (VF) stimulus locations: (1) using meridian-specific Henle fiber length along the stimulus circumference; (2) using meridian-specific differences in RGC receptive field and counts along the stimulus circumference; (3) per method (2), averaged across principal meridians; and (4) per method (3), with the stimulus center displaced only. The Sjöstrand model was applied (5) along the stimulus circumference and (6) to the stimulus center only. Eccentricity-dependent mRGC:C ratios were computed over displaced areas, with comparisons to previous models using sum of squares of the residuals (SSR) and root mean square error (RMSE). RGC counts estimated from OCT-derived ganglion cell layer (GCL) and GCIPL measurements, from 143 healthy participants, were compared using Bland-Altman analyses. Methods 1, 2, and 5 produced mRGC:C ratios most consistent with previous models (SSR 3.82, 4.07, and 3.02; RMSE 0.22, 0.23, and 0.20), while central mRGC:C ratios were overestimated by method 3 and underestimated by methods 4 and 6. RGC counts predicted from GCIPL measurements were within 16% of GCL-based counts, with no notable bias with increasing RGC counts. Sjöstrand displacement and meridian-specific Drasdo displacement applied to VF stimulus circumferences produce mRGC:C ratios consistent with previous models. RGC counts can be estimated from OCT-derived GCIPL measurements. Implementing appropriate displacement methods and deriving RGC estimates from relevant OCT parameters enables calculation of the number of RGCs responding to VF stimuli from commercial instrumentation.


A model for predicting postoperative persistent acute kidney injury (AKI) in AKI after cardiac surgery patients with normal baseline renal function.
Persistent acute kidney injury (AKI) after cardiac surgery is not uncommon and linked to poor outcomes. The purpose was to develop a model for predicting postoperative persistent AKI in patients with normal baseline renal function who experienced AKI after cardiac surgery. Data from 5368 patients with normal renal function at baseline who experienced AKI after cardiopulmonary bypass cardiac surgery in our hospital were retrospectively evaluated. Among them, 3768 patients were randomly assigned to develop the model, while the remaining patients were used to validate the model. The new model was developed using logistic regression with variables selected using least absolute shrinkage and selection operator regression. The incidence of persistent AKI was 50.6% in the development group. Nine variables were selected for the model, including age, hypertension, diabetes, coronary heart disease, cardiopulmonary bypass time, AKI stage at initial diagnosis after cardiac surgery, postoperative serum magnesium level of <0.8 mmol/L, postoperative duration of mechanical ventilation, and postoperative intra-aortic balloon pump use. The model's performance was good in the validation group. The area under the receiver operating characteristic curve was 0.761 (95% confidence interval: 0.737-0.784). Observations and predictions from the model agreed well in the calibration plot. The model was also clinically useful based on decision curve analysis. It is feasible by using the model to identify persistent AKI after cardiac surgery in patients with normal baseline renal function who experienced postoperative AKI, which may aid in patient stratification and individualized precision treatment strategy.


Variant ALDH2 is associated with accelerated progression of bone marrow failure in Japanese Fanconi anemia patients.
Fanconi anemia (FA) is a severe hereditary disorder with defective DNA damage response and repair. It is characterized by phenotypes including progressive bone marrow failure (BMF), developmental abnormalities, and increased occurrence of leukemia and cancer. Recent studies in mice have suggested that the FA proteins might counteract aldehyde-induced genotoxicity in hematopoietic stem cells. Nearly half of the Japanese population carries a dominant-negative allele (rs671) of the aldehyde-catalyzing enzyme ALDH2 (acetaldehyde dehydrogenase 2), providing an opportunity to test this hypothesis in humans. We examined 64 Japanese FA patients, and found that the ALDH2 variant is associated with accelerated progression of BMF, while birth weight or the number of physical abnormalities was not affected. Moreover, malformations at some specific anatomic locations were observed more frequently in ALDH2-deficient patients. Our current data indicate that the level of ALDH2 activity impacts pathogenesis in FA, suggesting the possibility of a novel therapeutic approach.


Self-assembly of light-harvesting crystalline nanosheets in aqueous media.
A methodology leading to facile self-assembly of crystalline aromatic arrays in dilute aqueous solutions would enable efficient fabrication and processing of organic photonic and electronic materials in water. In particular, soluble 2D crystalline nanosheets may mimic the properties of photoactive thin films and self-assembled monolayers, covering large areas with ordered nanometer-thick material. We designed such solution-phase arrays using hierarchical self-assembly of amphiphilic perylene diimides in aqueous media. The assemblies were characterized by cryogenic transmission electron microscopy (cryo-TEM), revealing crystalline order and 2D morphology (confirmed by AFM studies). The order and morphology are preserved upon drying as evidenced by TEM and AFM. The 2D crystalline-like structures exhibit broadening and red-shifted absorption bands in UV-vis spectra, typical for PDI crystals and liquid crystals. Photophysical studies including femtosecond transient absorption spectroscopy reveal that two of the assemblies are superior light-harvesters due to excellent solar spectrum coverage and fast exciton transfer, in one case showing exciton diffusion comparable to solid-state crystalline systems based on perylene tetracarboxylic dianhidride (PTCDA).


Recurrence and Driving Factors of Visceral Leishmaniasis in Central China.
Visceral leishmaniasis (VL) is an important vector-borne zoonosis caused by Leishmania spp. that has been spreading in China. It has been posing a significant risk to public health in central China due to its recurrence in recent decades. Yet, the spatiotemporal patterns and the driving factors of VL in central China remain unclear at present. The purpose of this study was to analyse spatiotemporal distribution, explore driving factors, and provide novel insight into prevention and control countermeasures of the VL spreading in central China. Based on data of human VL cases from 2006 to 2019 obtained from the Chinese Centres for Disease Control and Prevention (CDC), we depicted the map showing the spatiotemporal distribution of VL in central China. We further explored the driving factors contributing to the spread of VL through the general additive model (GAM) by combining maps of environmental, meteorological, and socioeconomic correlates. Most VL cases were reported in Shaanxi and Shanxi provinces, the number of which has been increasing every year in the last 14 years, from 3 new cases in 2006 to 101 new cases in 2019. The results of GAM revealed that environmental (i.e., changes in grasslands/forests), meteorological (i.e., temperature and relative humidity), and socioeconomic (i.e., population density) factors are significantly associated with the prevalence of VL in central China. Our results provide a better understanding regarding the current situation and the driving factors of VL in central China, assisting in developing the disease prevention and control strategies implemented by public health authorities.


Sleeping site selection of Francois's langur (Trachypithecus francoisi) in two habitats in Mayanghe National Nature Reserve, Guizhou, China.
Sleeping site selection is an important aspect of the behavioral biology of primates. Comparison of different habitats for the same species in this context enhances understanding of their adaptation to altered environments. We collected data on sleep-related behaviors for 6 groups of Francois's langur (Trachypithecus francoisi) in two habitats, in Mayanghe National Nature Reserve, Guizhou, China. Regardless of habitat, all sleeping sites were located in areas of steep terrain of ≥60°. In undisturbed habitat, sleeping sites were located only in evergreen broadleaf forest with rock caves and crevices surrounded mainly by a vegetation layer of shrub + rock. In disturbed habitat, sleeping sites were also located in mixed evergreen and deciduous broadleaf forest and in grassland, including rock caves, crevices, and pits, surrounded mainly by arbor + shrub and shrub + rock. Wild food availability was higher in undisturbed habitat than disturbed habitat, but food abundance around sleeping sites was lower. Water sources included river and seasonal gully or pond. There was strong positive correlation between use of sleeping sites away from the river valley and occurrence of seasonal water sources. The number of sleeping sites varied across groups, numbering 6, 7, and 10 for three specific groups. Few sleeping sites were used all year round. Six consecutive nights was the longest recorded run. Francois's langurs' sleeping habits differed between two habitats. In undisturbed habitat, minimizing predation risk appeared to predominate, expressed by choosing steep terrain, open visual field, and inconspicuous presleeping behavior. In disturbed habitat, along with predation avoidance, food resources may strongly influence sleeping site selection, as demonstrated by the richer food abundance and greater foraging activity around the site. Finally, water resources may influence choice of sites distant from the river; such sites were used less frequently during water shortages.


Masking repeats while clustering ESTs.
A problem in EST clustering is the presence of repeat sequences. To avoid false matches, repeats have to be masked. This can be a time-consuming process, and it depends on available repeat libraries. We present a fast and effective method that aims to eliminate the problems repeats cause in the process of clustering. Unlike traditional methods, repeats are inferred directly from the EST data, we do not rely on any external library of known repeats. This makes the method especially suitable for analysing the ESTs from organisms without good repeat libraries. We demonstrate that the result is very similar to performing standard repeat masking before clustering.


Modulation of DNA-dependent protein kinase activity in chlorambucil-treated cells.
DNA-dependent protein kinase (DNA-PK) is activated in a two-step process whereby the Ku heterodimer first binds to the DNA double-strand breaks (dsbs) and then the DNA-PK catalytic subunit (cs) is recruited to form a repair complex. Oxidative stress is simultaneously generated along with DNA damage by ionizing radiation or chemotherapeutic agents whose impact on the DNA-PK activity has not previously been investigated. Here we show that the DNA damage-induced kinase activity of DNA-PK was modulated by oxidative stress, which was induced along with DNA dsbs in chlorambucil (Cbl)-exposed cells. Pretreatment with the antioxidants, 2(3)-t-butyl-4-hydroxyanisole or N-acetyl-l-cysteine enhanced the amount of DNA-PKcs phosphorylated at threonine 2609 (DNA-PK(pThr2609)) at the DNA dsbs and DNA-PK activity. Conversely, oxidative stress induced by l-buthionine (SR)-sulfoximine or glucose oxidase decreased the DNA-PK activity in Cbl-exposed cells. In addition, DNA-PK(pThr2609) was poorly detectable at the site of DNA dsbs, as shown by colocalization to DNA-end-binding pH2AX or p53BP1. There was no change in the protein levels of DNA-PKcs, Ku70, or Ku86. Data from these studies provide the first evidence that oxidative stress effects posttranslational modification and assembly of DNA-PK complex at DNA dsbs, and thereby repair of DNA dsbs.


Conducting a financial analysis of capitation arrangements.
There is no doubt that capitation contracts are risky business. There are many issues to consider carefully that have implications in every area of the healthcare industry. However, there are many additional issues that should be considered such as hospital facility capacity, incremental cost of services, physician relations, and emergency services. The contract structure and other legal issues should also be thoroughly discussed. While there will always be an element of risk in capitation arrangements, the only hope of that risk being at a reasonable and manageable level is to be prepared both financially and operationally if and when market conditions force you to consider an at-risk healthcare delivery system.


Arbuscular mycorrhizal fungi elicit a novel intracellular apparatus in Medicago truncatula root epidermal cells before infection.
The penetration of arbuscular mycorrhizal (AM) fungi through the outermost root tissues of the host plant is a critical step in root colonization, ultimately leading to the establishment of this ecologically important endosymbiotic association. To evaluate the role played by the host plant during AM infection, we have studied in vivo cellular dynamics within Medicago truncatula root epidermal cells using green fluorescent protein labeling of both the plant cytoskeleton and the endoplasmic reticulum. Targeting roots with Gigaspora hyphae has revealed that, before infection, the epidermal cell assembles a transient intracellular structure with a novel cytoskeletal organization. Real-time monitoring suggests that this structure, designated the prepenetration apparatus (PPA), plays a central role in the elaboration of the apoplastic interface compartment through which the fungus grows when it penetrates the cell lumen. The importance of the PPA is underlined by the fact that M. truncatula dmi (for doesn't make infections) mutants fail to assemble this structure. Furthermore, PPA formation in the epidermis can be correlated with DMI-dependent transcriptional activation of the Medicago early nodulin gene ENOD11. These findings demonstrate how the host plant prepares and organizes AM infection of the root, and both the plant-fungal signaling mechanisms involved and the mechanistic parallels with Rhizobium infection in legume root hairs are discussed.


[Proliferation of anaerobic flora in the small intestine of infants with acute and protracted diarrhea].
Bacterial proliferation in the small intestine can induce the protraction of diarrhea due to malabsorption of the nutrients. We performed the culture of the small intestine juice for the aerobic and anaerobic flora in 40 infants with persistent and acute diarrhea. Bacterial proliferation was observed in 32 (80%) patients, being 30 (75%) due to the aerobic microflora and 17 (43%) due to the anaerobic microflora. There was no statistical difference in the bacterial growth between acute and persistent diarrhea. The aerobic bacteria most frequently isolated was E. coli in 23 patients, and Bacteroides sp was the most prevalent anaerobic bacteria, isolated in 9 cases. The transitory flora was significantly more abundant in patients with persistent diarrhea.


Dusp26 phosphatase regulates mitochondrial respiration and oxidative stress and protects neuronal cell death.
The dual specificity protein phosphatases (Dusps) control dephosphorylation of mitogen-activated protein kinases (MAPKs) as well as other substrates. Here, we report that Dusp26, which is highly expressed in neuroblastoma cells and primary neurons is targeted to the mitochondrial outer membrane via its NH2-terminal mitochondrial targeting sequence. Loss of Dusp26 has a significant impact on mitochondrial function that is associated with increased levels of reactive oxygen species (ROS), reduction in ATP generation, reduction in mitochondria motility and release of mitochondrial HtrA2 protease into the cytoplasm. The mitochondrial dysregulation in dusp26-deficient neuroblastoma cells leads to the inhibition of cell proliferation and cell death. In vivo, Dusp26 is highly expressed in neurons in different brain regions, including cortex and midbrain (MB). Ablation of Dusp26 in mouse model leads to dopaminergic (DA) neuronal cell loss in the substantia nigra par compacta (SNpc), inflammatory response in MB and striatum, and phenotypes that are normally associated with Neurodegenerative diseases. Consistent with the data from our mouse model, Dusp26 expressing cells are significantly reduced in the SNpc of Parkinson's Disease patients. The underlying mechanism of DA neuronal death is that loss of Dusp26 in neurons increases mitochondrial ROS and concurrent activation of MAPK/p38 signaling pathway and inflammatory response. Our results suggest that regulation of mitochondrial-associated protein phosphorylation is essential for the maintenance of mitochondrial homeostasis and dysregulation of this process may contribute to the initiation and development of neurodegenerative diseases.


Novel single component tri-rare-earth emitting MOF for warm white light LEDs.
Single-phase white phosphors could overcome many drawbacks of traditional phosphors, and warm white light phosphors have been considered suitable for indoor illumination applications. Thus, synthesizing new single-phase warm white phosphors is significant for the production of LEDs. Based on the above considerations, a novel single component warm white light phosphor SmxTbyDy0.2-x-y-metal organic frameworks (MOFs) has been prepared successfully in this study. The compound Sm0.1Tb0.04Dy0.06-MOF shows ideal warm white light emission with CIE coordinates (0.333, 0.3522), a color rendering index (CRI) value of 86.7, a low correlated color temperature (CCT) value of 4444 K, and good heating/cooling circulation. In addition, the LED devices fabricated with this novel warm white light phosphor have excellent warm white light quality even at high temperatures, which is necessary for its practical application.


Ovarian kisspeptin expression is related to age and to monocyte chemoattractant protein-1.
The objective of this study was to test the hypothesis that ovarian kisspeptin (kiss1) and its receptor (kiss1r) expression are affected by age, obesity, and the age- and obesity-related chemokine monocyte chemoattractant protein-1 (MCP-1). Ovaries from reproductive-aged and older C57BL/6J mice fed normal chow (NC) or high-fat (HF) diet, ovaries from age-matched young MCP-1 knockout and young control mice on NC, and finally, cumulus and mural granulosa cells (GCs) from women who underwent in vitro fertilization (IVF) were collected. Kiss1, kiss1r, anti-Mullerian hormone (AMH), and AMH receptor (AMHR-II) messenger RNA (mRNA) expression levels were quantified using real-time polymerase chain reaction (RT-PCR). In mouse ovaries, kiss1 and kiss1r mRNA levels were significantly higher in old compared to reproductive-aged mice, and diet-induced obesity did not alter kiss1 or kiss1r mRNA levels. Compared to young control mice, young MCP-1 knockout mice had significantly lower ovarian kiss1 mRNA but significantly higher AMH and AMHR-II mRNA levels. In human cumulus GCs, kiss1r mRNA levels were positively correlated with age but not with BMI. There was no expression of kiss1 mRNA in either cumulus or mural GCs. These data suggest a possible age-related physiologic role for the kisspeptinergic system in ovarian physiology. Additionally, the inflammatory MCP-1 may be associated with kiss1 and AMH genes, which are important in ovulation and folliculogenesis, respectively.


The peroxisome proliferator-activated receptor interacts with the retinoid X receptor in vivo.
The peroxisome proliferator-activated receptor (PPAR) binds cooperatively to cognate peroxisome proliferator-responsive elements (PPRE) in vitro through heterodimerization with retinoid X receptors (RXR). We used the yeast two-hybrid system to determine whether these two nuclear receptors physically interact in vivo. Mouse (m) PPAR and human (h) RXR alpha were synthesized as fusion proteins to either the DNA-binding domain (GBD) or the transactivation domain (GAD) of the yeast GAL4 transcription-activator protein, and were tested for their ability to activate expression of a GAL1::lacZ reporter gene. Strong activation was observed only in yeast transformed with combinations of GBD::mPPAR and GAD::hRXR alpha or with GAD::mPPAR and GBD::hRXR alpha. Homodimeric interaction by mPPAR was not detected. These results provide evidence for the interaction of PPAR and RXR alpha in vivo in the absence of a PPRE target site or exogenously added ligands.


The stability, electronic structure, and optical absorption of boron-nitride diamondoids predicted with first-principles calculations.
Although diamondoids are broadly studied for their fundamental properties and applications, boron-nitride-based diamondoids are scarcely explored. Here we predict the stability, electronic structure, and optical absorption spectra of six boron-nitride (BN) diamondoids with first-principles methods based on pseudopotential density functional theory and many-body perturbation methods implemented with a real-space formalism. We find that four of them are thermodynamically stable at room temperature, while B10N8H24 and B6N4H16 show thermodynamic instability in molecular dynamics simulations. With the GW approximation, we predicted the ionization energies and electron affinities of BN-diamondoids and find that the evolution of the electronic structure with size does not follow the same trend as diamondoids, owing to the unbalanced numbers of boron and nitrogen atoms. We show strong photoabsorption of BN-triamantane and BN-adamantane in the infrared and visible ranges and analyze the features of low-energy absorption by examining the characteristics of related orbitals.


[Tuberculosis among socially predisposed groups of the population].
Low incidence rates of tuberculosis are directly related to social factors, including higher morbidity among such groups as migrants, vagabonds, ex-convicts and alcohol abusers. In view of that it seems necessary to solve a problem of organizing tuberculosis-oriented treatment-and-labor preventoria to render health care to the vagabonds and other patients refusing medical intervention. Since presently there exists a wide diversity of tuberculosis morbidity rates among different community groups, tuberculosis control tactics should be based on the awareness of the associated risk factors, the existing level of epidemiological data and social and economic situation in a certain region.


Meiotic competent human germ cell-like cells derived from human embryonic stem cells induced by BMP4/WNT3A signaling and OCT4/EpCAM (epithelial cell adhesion molecule) selection.
The establishment of an effective germ cell selection/enrichment platform from in vitro differentiating human embryonic stem cells (hESCs) is crucial for studying the molecular and signaling processes governing human germ cell specification and development. In this study, we developed a germ cell-enriching system that enables us to identify signaling factors involved in germ cell-fate induction from differentiating hESCs in vitro. First, we demonstrated that selection through an OCT4-EGFP reporter system can successfully increase the percentage of meiotic-competent, germ cell-like cells from spontaneously differentiating hESCs. Furthermore, we showed that the pluripotency associated surface marker, epithelial cell adhesion molecule (EpCAM), is also expressed in human fetal gonads and can be used as an effective selection marker for germ cell enrichment from differentiating hESCs. Combining OCT4 and EpCAM selection can further enrich the meiotic-competent germ cell-like cell population. Also, with the percentage of OCT4(+)/EpCAM(+) cells as readout, we demonstrated the synergistic effect of BMP4/pSMAD1/5/8 and WNT3A/β-CATENIN in promoting hESCs toward the germline fate. Combining BMP4/WNT3A induction and OCT4/EpCAM selection can significantly increase the putative germ cell population with meiotic competency. Co-transplantation of these cells with dissociated mouse neonatal ovary cells into SCID mice resulted in a homogenous germ cell cluster formation in vivo. The stepwise platform established in this study provides a useful tool to elucidate the molecular mechanisms of human germ cell development, which has implications not only for human fertility research but regenerative medicine in general.


What is a troland?
Trolands are a widely used measure of retinal illuminance in vision science and visual optics, but disagreements exist for the definition and interpretation of this photometric unit. The purpose of this communication is to resolve the confusion by providing a sound conceptual basis for interpreting trolands as a measure of angular flux density incident upon the retina. Using a simplified optical analysis, we show that the troland value of an extended source is the intensity in micro-candelas of an equivalent point source located at the eye's posterior nodal point that produces the same illuminance in the retinal image as does the extended source. This optical interpretation of trolands reveals that total light flux in the image of an extended object is the product of the troland value of the source and the solid angle subtended by the source at the first nodal point, independent of eye size.


Prevalence, genetics, and clinical features of patients carrying podocin mutations in steroid-resistant nonfamilial focal segmental glomerulosclerosis.
Podocin mutations (NPHS2 gene) are responsible for the autosomal recessive form of steroid-resistant nephrotic syndrome. As a result of a screening for these gene alterations in a cohort of Italian patients with nonfamilial nephrotic syndrome and histologic focal segmental glomerulosclerosis (FSGS), nine patients with NPHS2 gene homozygous or composite heterozygous mutations were found. In addition to the previously described defects, two novel mutations at exon 4 were identified (frameshift, L169P); four single nucleotide polymorphisms (SNPs) and one dinucleotide repeat were also identified. On the basis of haplotype analysis, a founder effect was suggested for the 419delG mutation, the most frequently observed in the patients studied. Patients carrying NPHS2 mutations and without a family history of nephrotic syndrome were indistinguishable from those with idiopathic FSGS on the basis of the clinical phenotype. Two of the nine patients had normal renal function at 3 and 10 yr of age, despite the presence of the nephrotic syndrome. The other seven had reached end-stage renal failure at a mean age of 9.6 yr (range, 4 to 17 yr) and had received renal allografts. In those presenting with end-stage renal failure, the clinical and laboratory features both before and after transplantation were similar, including the age at onset, the amount of proteinuria, and the absence of any response to steroids and other immunosuppressants. Finally, two children presented recurrence of mild proteinuria after transplantation, which promptly remitted after plasmapheresis combined with cyclophosphamide. These data demonstrate that podocin mutations in nonfamilial cases of steroid-resistant nephrotic syndrome are frequent and may be due in one case to a founder effect. The pretransplantation and posttransplantation outcomes in the group of patients with mutations of the podocin gene are similar to classical idiopathic FSGS, including the possibility of recurrence of proteinuria that is mild and responsive to plasmapheresis. These observations support a role of molecular screening of the podocin gene in patients with nephrotic syndrome before immunosuppressive treatment is started.


On the inadequacy of nominal assortativity for assessing homophily in networks.
Nominal assortativity (or discrete assortativity) is widely used to characterize group mixing patterns and homophily in networks, enabling researchers to analyze how groups interact with one another. Here we demonstrate that the measure presents severe shortcomings when applied to networks with unequal group sizes and asymmetric mixing. We characterize these shortcomings analytically and use synthetic and empirical networks to show that nominal assortativity fails to account for group imbalance and asymmetric group interactions, thereby producing an inaccurate characterization of mixing patterns. We propose the adjusted nominal assortativity and show that this adjustment recovers the expected assortativity in networks with various level of mixing. Furthermore, we propose an analytical method to assess asymmetric mixing by estimating the tendency of inter- and intra-group connectivities. Finally, we discuss how this approach enables uncovering hidden mixing patterns in real-world networks.


Inhibition of the synthesis and secretion of extracellular glucosyl- and fructosyltransferase in Streptococcus sanguis by sodium ions.
The influence of Na+ and K+ on the synthesis and secretion of extracellular glucosyltransferase (GTF; EC 22.214.171.124) and fructosyltransferase (FTF; EC 184.108.40.206) by Streptococcus sanguis NCTC 7865 and Streptococcus sanguis Challis NCTC 7868 has been determined. No FTF and little or no mutansucrase (GTF-I) activities were detectable during growth on glucose or sucrose unless the Na+/K+ ratio of the cultures was kept low. Increasing K+ concentrations stimulated the production of FTF and dextransucrase (GTF-S), but all glycosyltransferase activities decreased in high K+ media when the growth pH was maintained with NaOH instead of KOH, indicating that the Na+/K+ ratio effect was due principally to Na+ inhibition. Significant GTF and FTF activities were detected in a putative GTF- mutant of strain Challis grown in high K+ medium but not in high Na+ medium, suggesting that the mutant might be defective in a regulatory gene.


Fishing activity, health characteristics and mercury exposure of Amerindian women living alongside the Beni River (Amazonian Bolivia).
Populations in Bolivian Amazonia are exposed to mercury contamination through fish ingestion. A group of 170 Amerindian women living along the banks of the Beni River were examined in order to detect any adverse effects on their health consistent with the toxic effects of mercury. The mercury content of the women's hair (H-Hg) was used as the bio-indicator of mercury exposure. The women answered a 24-h food recall questionnaire on the frequency of their fish consumption. They also underwent a clinical examination with their weight, stature, hemoglobin concentration in blood, and blood pressure being recorded. Significant relationships were found between fishing practices, the frequency of fish consumption and H-Hg levels with mercury contaminated women (H-Hg>5μg/g) being more likely to present neurological abnormalities (paresthesia, static and dynamic imbalance, poor motor coordination) than non-contaminated women. No relationship was found between blood pressure and mercury levels. Women with higher H-Hg reported more infant deaths than did women with lower levels. A logistic regression analysis which included socio-cultural traits, fish consumption habits and health characteristics was performed in order to determine the risks of contamination. Contaminated women were more likely to belong to those communities pursuing traditional fishing activities; moreover these women tended to be younger and frailer than other. They also exhibited mild neurological abnormalities and reported more infant deaths. These findings should stimulate local communities to take preventive actions directed towards the more "traditional" and vulnerable groups of population.


A Data-Driven Personalized Model of Glucose Dynamics Taking Account of the Effects of Physical Activity for Type 1 Diabetes: An In Silico Study.
This paper aims to develop a data-driven model for glucose dynamics taking into account the effects of physical activity (PA) through a numerical study. It intends to investigate PA's immediate effect on insulin-independent glucose variation and PA's prolonged effect on insulin sensitivity. We proposed a nonlinear model with PA (NLPA), consisting of a linear regression of PA and a bilinear regression of insulin and PA. The model was identified and evaluated using data generated from a physiological PA-glucose model by Dalla Man et al. integrated with the uva/padova Simulator. Three metrics were computed to compare blood glucose (BG) predictions by NLPA, a linear model with PA (LPA), and a linear model with no PA (LOPA). For PA's immediate effect on glucose, NLPA and LPA showed 45-160% higher mean goodness of fit (FIT) than LOPA under 30 min-ahead glucose prediction (P < 0.05). For the prolonged PA effect on glucose, NLPA showed 87% higher FIT than LPA (P < 0.05) for simulations using no previous measurements. NLPA had 25-37% and 31-54% higher sensitivity in predicting postexercise hypoglycemia than LPA and LOPA, respectively. This study demonstrated the following qualitative trends: (1) for moderate-intensity exercise, accuracy of BG prediction was improved by explicitly accounting for PA's effect; and (2) accounting for PA's prolonged effect on insulin sensitivity can increase the chance of early prediction of postexercise hypoglycemia. Such observations will need to be further evaluated through human subjects in the future.


Use of vegetated agricultural drainage ditches to decrease toxicity of irrigation runoff from tomato and alfalfa fields in California, USA.
The current study investigated the potential of vegetated drainage ditches for mitigating the impact of agricultural irrigation runoff on downstream aquatic ecosystems. Water column toxicity to larval fathead minnow (Pimephales promelas),and the amphipod Hyalella azteca was measured for 12 h or less at the ditch inflow and outflow, using custom-built in situ exposure systems. In addition, water and sediment samples were subject to standard toxicity tests with Ceriodaphnia dubia and H. azteca, respectively. No acute toxicity to larval fathead minnow was observed; however, runoff was highly toxic to invertebrates. Passage through a 389- to 402-m section of vegetated ditch had a mitigating effect and reduced toxicity to some degree. However, runoff from an alfalfa field treated with chlorpyrifos remained highly toxic to both invertebrate species, and runoff from a tomato field treated with permethrin remained highly toxic to H. azteca after passage through the ditch. Predicted toxic units calculated from insecticide concentrations in runoff and 96-h median lethal concentration (LC50) values generally agreed with C. dubia toxicity measured in the laboratory but significantly underestimated in situ toxicity to H. azteca. Sediments collected near the ditch outflow were toxic to H. azteca. Results from the current study demonstrate that experimental vegetated ditches were unable to eliminate the risk of irrigation runoff to aquatic ecosystems. In addition, protective measures based on chemical concentrations or laboratory toxicity tests with C. dubia do not ensure adequate protection of aquatic ecosystems from pyrethroid-associated toxicity.


[Bladder catheter or suprapubic fistula? Indications and contraindications].
Even in closed sterile transurethral catheter drainage, infections of the lower urinary tract are documented in 50% of cases after 1 week of indwelling catheter. Not all of these cases develop symptomatic catheter-associated urinary tract infection. Suprapubic catheter drainage of the bladder results in markedly later urinary tract infection, presenting 50% of patients infected on day 40. The markedly later onset of catheter-associated urinary tract infection makes the suprapubic approach to bladder drainage suitable for all those patients, who may need catheters for more than 3 days postoperatively. Transfusion-dependent bleeding after puncture in 2-4% of cases and perforation of adjacent organs in 0.3% are the main complications. Suprapubic insertion of a catheter is contraindicted in patients with bleeding disorders and in those with bladder cancer in their history.


Repetitive Aerosol Exposure Promotes Cavitary Tuberculosis and Enables Screening for Targeted Inhibitors of Extensive Lung Destruction.
Cavitation is a serious consequence of tuberculosis. We tested the hypothesis that repetitive exposure to the same total bacterial burden of Mycobacterium tuberculosis drives greater lung destruction than a single exposure. We also tested whether inhibition of endogenous matrix metalloproteinase-1 (MMP-1) may inhibit cavitation during tuberculosis. Over a 3-week interval, we infected rabbits with either 5 aerosols of 500 colony-forming units (CFU) of M. tuberculosis or a single aerosol of 2500 CFU plus 4 sham aerosols. We administered the MMP-1 inhibitor cipemastat (100 mg/kg daily) during weeks 5-10 to a subset of the animals. Repetitive aerosol infection produced greater lung inflammation and more cavities than a single aerosol infection of the same bacterial burden (75% of animals vs 25%). Necropsies confirmed greater lung pathology in repetitively exposed animals. For cipemastat-treated animals, there was no significant difference in cavity counts, cavity volume, or disease severity compared to controls. Our data show that repetitive aerosol exposure with M. tuberculosis drives greater lung damage and cavitation than a single exposure. This suggests that human lung destruction due to tuberculosis may be exacerbated in settings where individuals are repeatedly exposed. MMP-1 inhibition with cipemastat did not prevent the development of cavitation in our model.


Multiscale resistant kernel surfaces derived from inferred gene flow: An application with vernal pool breeding salamanders.
The importance of assessing spatial data at multiple scales when modelling species-environment relationships has been highlighted by several empirical studies. However, no landscape genetics studies have optimized landscape resistance surfaces by evaluating relevant spatial predictors at multiple spatial scales. Here, we model multiscale/layer landscape resistance surfaces to estimate resistance to inferred gene flow for two vernal pool breeding salamander species, spotted (Ambystoma maculatum) and marbled (A. opacum) salamanders. Multiscale resistance surface models outperformed spatial layers modelled at their original spatial scale. A resistance surface with forest land cover at a 500-m Gaussian kernel bandwidth and normalized vegetation index at a 100-m Gaussian kernel bandwidth was the top optimized resistance surface for A. maculatum, while a resistance surface with traffic rate and topographic curvature, both at a 500-m Gaussian kernel bandwidth, was the top optimized resistance surface for A. opacum. Species-specific resistant kernels were fit at all vernal pools in our study area with the optimized multiscale/layer resistance surface controlling kernel spread. Vernal pools were then evaluated and scored based on surrounding upland habitat (local score) and connectivity with other vernal pools on the landscape, with resistant kernels driving vernal pool connectivity scores. As expected, vernal pools that scored highest were in areas within forested habitats and with high vernal pool densities and low species-specific landscape resistance. Our findings highlight the success of using a novel analytical approach in a multiscale framework with applications beyond vernal pool amphibian conservation.


The "secret" in secretions: methodological considerations in deciphering primate olfactory communication.
Olfactory communication in primates is gaining recognition; however, studies on the production and perception of primate scent signals are still scant. In general, there are five tasks to be accomplished when deciphering the chemical signals contained in excretions and secretions: (1) obtaining the appropriate samples; (2) extracting the target organic compounds from the biological matrix; (3) separating the extracted compounds from one another (by gas chromatography, GC or liquid chromatography, LC); (4) identifying the compounds (by mass spectrometry, MS and associated procedures); and (5) revealing biologically meaningful patterns in the data. Ultimately, because some of the compounds identified in odorants may not be relevant, associated steps in understanding signal function involve verifying the perception or biological activity of putative semiochemicals via (6) behavioral bioassays or (7) receptor response studies. This review will focus on the chemical analyses and behavioral bioassays of volatile, primate scent signals. Throughout, we highlight the potential pitfalls of working with highly complex, chemical matrices and suggest ways for minimizing problems. A recurring theme in this review is that multiple approaches and instrumentation are required to characterize the full range of information contained in the complex mixtures that typify primate or, indeed, many vertebrate olfactory cues. Only by integrating studies of signal production with those verifying signal perception will we better understand the function of olfactory communication.


Preventing neonatal sepsis in rural Uganda: a cross-over study comparing the tolerance and acceptability of three alcohol-based hand rub formulations.
Neonatal sepsis causes 0.5 million deaths annually, mostly in low resource settings. Babies born in African rural homes without running water or toilet facilities are especially vulnerable. Alcohol-based hand rub (ABHR) may be used by mothers and carers as an alternative to hand washing with soap to prevent neonatal infection. However, no definite study has established the preferred formulation of hand rub for the mothers. This study aimed to assess the effects of addition of bitterants and perfume towards the acceptability of the alcohol-based hand rubs by the mothers in their homes after childbirth. This was a 3-way blinded cross-over study design. Mothers with children aged ≤3 months were recruited from immunisation clinics at 3 local health facilities in rural eastern Uganda and received 3-different ABHR formulations (in the order plain, bitterant and perfumed) packed in 100 ml bottles. Each ABHR was used for 5 consecutive days followed by a 2-day 'washout' period (evaluation period). Overall satisfaction with each hand rub was evaluated at the end of each week using a 7-point Likert scale. A total of 43 women were recruited, whose ages ranged from 16 to 45 years (mean 26.2 years old). None of the participants normally used a hand protective lotion/cream. The three formulations were used for a mean of 5 (range 3-7) days. A significantly greater volume of the "bitterant" and "perfumed" formulations (mean 91 and 83 ml respectively) were used in comparison to the "plain" formulation (mean 64 ml). Overall satisfaction was high with all the hand rubs, but the perfumed formulation had a significantly higher overall satisfaction score [mean 6.7, range 4-7] compared with the plain [6.4, 3-7] and bitterant [6.2, 2-7] formulations. All the 3 ABHR formulations were well accepted with little to choose between them. The ABHR with added perfume scored highest on overall satisfaction and was used significantly more often than plain ABHR. ABHR with bitterant additive did, however, score highly and may be a preferable choice to those with concern over alcohol misuse. ISRCTN67852437 , prospectively registered on 18/03/2018.


Phytotoxic fungal secondary metabolites as herbicides.
Among the alternatives to synthetic plant protection products, biocontrol appears as a promising method. This review reports on the diversity of fungal secondary metabolites phytotoxic to weeds and on the approach generally used to extract, characterize, identify and exploit them for weed management. The 183 phytotoxic fungal secondary metabolites discussed in this review fall into five main classes of molecules: 61 polyketides, 53 terpenoids, 36 nitrogenous metabolites, 18 phenols and phenolic acids, and 15 miscellaneous. They are mainly produced by the genera Drechslera, Fusarium and Alternaria. The phytotoxic effects, more often described by the symptoms they produce on plants than by their mode of action, range from inhibition of germination to inhibition of root and vegetative growth, including tissue and organ alterations. The biochemical characterization of fungal secondary metabolites requires expertise and tools to carry out fungal cultivation and metabolite extraction, phytotoxicity tests, purification and fractionation of the extracts, and chemical identification procedures. Phytotoxicity tests are mainly carried out under controlled laboratory conditions (not always on whole plants), while effectiveness against targeted weeds and environmental impacts must be assessed in greenhouses and open fields. These steps are necessary for the formulation of effective, environment-friendly fungal secondary metabolites-derived bioherbicides using new technologies such as nanomaterials. © 2023 Society of Chemical Industry.


Imaging Spatial Reorganization of a MAPK Signaling Pathway Using the Tobacco Transient Expression System.
Visualization of dynamic signaling events in live cells has been a challenge. We expanded an established transient expression system, the biomolecular fluorescent complementation (BiFC) assay in tobacco epidermal cells, from testing protein-protein interaction to monitoring spatial distribution of signal transduction in plant cells. In this protocol, we used the BiFC assay to show that the interaction and the signaling between the Arabidopsis MAPKKK YODA and MAPK6 occur at the plasma membrane. When the scaffold protein BASL was co-expressed, the YODA-MAPK interaction redistributed and spatially co-polarized with CFP-BASL. This modified tobacco expression system allows for quick examination of signaling localization and dynamic changes (less than 4 days) and can accommodate multiple of fluorescent protein colors (at least three). We also presented detailed methods to quantify protein distribution (asymmetric spatial localization, or "polarization") in tobacco cells. This advanced tobacco expression system has a potential to be used widely for quick testing of dynamic signaling events in live plant cells.


Variation induced by a three-days application of the artificial beta-cell on glucagon, growth hormone and catecholamine secretion, glycosylated hemoglobin, and erythrocyte 2,3-diphosphoglycerate concentration.
Five insulin-dependent diabetics with poor metabolic control were examined at the beginning and after a three-day application of artificial endocrine pancreas (AEP). Pancreatic alpha cell function evaluated by arginine infusion (0.5 g/Kg b.w. over 30 minutes) showed no significant differences between the beginning and during artificial beta cell aplication, but the increment in plasma glucagon level over basal values observed in both tests appeared significantly higher at 30 and 60 min in comparison with a control group. Growth hormone response to arginine infusion was clearly reduced in the second test. C-peptide concentration appeared very low in basal conditions and during arginine infusion; no improvement was observed after three days of AEP application. Urinary excretion of norepinephrine markedly increased at the beginning of the study, reversed almost to normal during AEP treatment, while minor changes were observed in urinary excretion of epinephrine. The Concentration of glycosylated hemoglobin, markedly higher than normally before the connection with AEP, showed a slight but significant decrease during glucose-controlled insulin infusion. Finally, 2,3-diphosphoglycerate was normal and no modifications were observed in the course of the study.


Nonpuerperal inversion of the uterus by endometrial stromal sarcoma of the uterine fundus.
Nonpuerperal inversion of the uterus is rare; the 69th such case in the English literature is reported. Although caused most frequently by submucous leiomyoma, nonpuerperal uterine inversion may be caused by carcinoma or, as in this report, a sarcoma of the uterine fundus. For optimal therapy and to reduce surgical complications, the correct preoperative diagnosis of uterine inversion and any concomitant disease is mandatory.


Composition, antimicrobial activity and in vitro cytotoxicity of essential oil from Cinnamomum zeylanicum Blume (Lauraceae).
The essential oil from the bark of Cinnamomum zeylanicum Blume was analyzed by GC-MS and bioassays were carried out. Nine constituents representing 99.24% of the oil were identified by GC-MS. The major compounds in the oil were (E)-cinnamaldehyde (68.95%), benzaldehyde (9.94%) and (E)-cinnamyl acetate (7.44%). The antimicrobial activity of the oil was investigated in order to evaluate its efficacy against 21 bacteria and 4 Candida species, using disc diffusion and minimum inhibitory concentration methods. The essential oil showed strong antimicrobial activity against all microorganisms tested. The cytotoxic and apoptotic effects of the essential oil on ras active (5RP7) and normal (F2408) fibroblasts were examined by MTT assay and acridine orange/ethidium bromide staining, respectively. The cytotoxicity of the oil was quite strong with IC(50) values less than 20 μg/mL for both cell lines. 5RP7 cells were affected stronger than normal cells. Morphological observation of apoptotic cells indicated the induction of apoptosis at the high level of the oil, especially in 5RP7 cells. The present study showed the potential antimicrobial and anticarcinogenic properties of the essential oil of cinnamon bark, indicating the possibilities of its potential use in the formula of natural remedies for the topical treatment of infections and neoplasms.


Perspectives on the U.S. FDA Bioresearch Monitoring Program.
An overview is presented of the U.S. FDA Bioresearch Monitoring Program from the field perspective. The presentation includes current insight as to how FDA conducts field audits in various program areas and observations regarding shared responsibilities for ensuring both quality data and patient safety during the preclinical and clinical investigation processes.


The origin and nature of tightly clustered BTG1 deletions in precursor B-cell acute lymphoblastic leukemia support a model of multiclonal evolution.
Recurrent submicroscopic deletions in genes affecting key cellular pathways are a hallmark of pediatric acute lymphoblastic leukemia (ALL). To gain more insight into the mechanism underlying these deletions, we have studied the occurrence and nature of abnormalities in one of these genes, the B-cell translocation gene 1 (BTG1), in a large cohort of pediatric ALL cases. BTG1 was found to be exclusively affected by genomic deletions, which were detected in 65 out of 722 B-cell precursor ALL (BCP-ALL) patient samples (9%), but not in 109 T-ALL cases. Eight different deletion sizes were identified, which all clustered at the telomeric site in a hotspot region within the second (and last) exon of the BTG1 gene, resulting in the expression of truncated BTG1 read-through transcripts. The presence of V(D)J recombination signal sequences at both sites of virtually all deletions strongly suggests illegitimate RAG1/RAG2-mediated recombination as the responsible mechanism. Moreover, high levels of histone H3 lysine 4 trimethylation (H3K4me3), which is known to tether the RAG enzyme complex to DNA, were found within the BTG1 gene body in BCP-ALL cells, but not T-ALL cells. BTG1 deletions were rarely found in hyperdiploid BCP-ALLs, but were predominant in other cytogenetic subgroups, including the ETV6-RUNX1 and BCR-ABL1 positive BCP-ALL subgroups. Through sensitive PCR-based screening, we identified multiple additional BTG1 deletions at the subclonal level in BCP-ALL, with equal cytogenetic distribution which, in some cases, grew out into the major clone at relapse. Taken together, our results indicate that BTG1 deletions may act as "drivers" of leukemogenesis in specific BCP-ALL subgroups, in which they can arise independently in multiple subclones at sites that are prone to aberrant RAG1/RAG2-mediated recombination events. These findings provide further evidence for a complex and multiclonal evolution of ALL.


Highly Selective and Sensitive Voltammetric Method for the Detection of Catechol in Tea and Water Samples Using Poly(gibberellic acid)-Modified Carbon Paste Electrode.
Despite the wide range of applications of catechol (CC) in agrochemical, petrochemical, textile, cosmetics, and pharmaceutical industries, its exposure to the environment leads to health issues as it is carcinogenic. This increased the concern over the risk of exposure level of CC in the environment, and monitoring its level has become critical. In this work, we report the fabrication of poly-gibberellic acid-modified carbon paste electrode (PGBAMCPE) to be a simple, viable, and effective electrochemical electrode for the determination of CC. This was synthesized by a simple electropolymerization method by the cyclic voltammetry (CV) technique. The electrodes were characterized by field emission electron microscopy, energy-dispersive X-ray spectroscopy, and electrochemical impedance spectroscopy. Compared to the bare carbon paste electrode, the sensitivity for CC fortified at PGBAMCPE in both CV and differential pulse voltammetry (DPV). We succeeded attaining a lower detection limit of 0.57 μM by the DPV method. The developed electrode was observed to be highly conductive, transducing, stable, and reproducible and was highly selective with anti-interfering properties from the determination of CC with hydroquinone simultaneously. The applicability of the electrode was confirmed from the detection CC in tea and water samples with good recoveries. This substantiates that PGBAMCPE is promising and consistent for the rapid monitoring of CC-contaminated area and clinical diagnosis.


Investigation of OH-proline contents of hernia sacs in children and comparison with adults.
One of the factors suggested to be causative in hernia formation is defective collagen metabolism. In this study, we investigated whether there is any relationship between the collagen contents of indirect hernial sacs and certain demographic and anatomic parameters. Hernial sac hydroxyproline levels were measured in 100 pediatric and 23 adult indirect inguinal hernia cases as indicators of collagen concentrations. Hydroxyproline levels were compared between boys and girls, right and left sided hernias, unilateral and bilateral cases, children and adults. Whether there was any relationship between patient age and hydroxyproline level was also investigated. No difference was found between males and females (p > 0.05), right and left sided hernias (p > 0.05) or unilateral and bilateral cases (p > 0.05). Hydroxyproline levels of adults were found to be significantly higher than those of children (p = 0.000). There was also a positive correlation between age and hydroxyproline levels of boys (r = 0.285, p = 0.023). Although a relationship between direct inguinal hernia and collagen structure has been shown by some investigators, we were unable to point to any significant findings which would indicate such a relationship in indirect inguinal hernia cases. Further studies on hydroxyproline levels in peritoneal samples will be necessary to understand the role of peritoneal hydroxyproline levels in hernia formation.


Pattern of milk feeding and family size as risk factors for iron deficiency anemia among poor Egyptian infants 6 to 24 months old.
Infants between 6 and 24 months of age are at the highest risk of development of iron deficiency anemia (IDA) in developing countries. Consuming unmodified cow's milk, delayed introduction of solid foods after 6 months, and high birth order could be predictors of the presence of IDA. Three hundred infants between the ages of 6 and 24 months (mean, 13.94 ± 6.17 months) from Ain Shams University Children's Hospital were enrolled in the study. Data collected included demographic information and dietary assessment including the type of milk feeding, introduction of solid foods, and daily iron intake. The infants were examined, and anthropometric measurements were recorded. Anemic infants (hemoglobin level <11 g/dL) were further evaluated by complete blood count, hemoglobin electrophoresis, and iron profile. Anemia was diagnosed among 198 infants (66%), of whom 129 (43%) had IDA. Red cell distribution width at a cutoff value of 15.8% was 86% sensitive and 74% specific in predicting IDA. The main risk factors for IDA included being between 6 and 18 months of age, of the male sex, birth order above the second order, consuming cow's milk, predominant breast-feeding beyond 6 months of age, and low daily iron intake. We conclude that IDA is the most common cause of anemia among Egyptian infants 6 to 24 months old of low socioeconomic standard. Independent clinical predictors were consuming cow's milk during the first 6 months, delayed introduction of solid foods after 6 months, and birth order beyond the second order.


Persistence of desertified ecosystems: Explanations and implications.
Studies of rainfall partitioning by shrubs, responses of shrub-dominated ecosystems to herbicide treatment, and experiments using drought and supplemental rainfall were conducted to test the hypothesis that the shrub-dominated ecosystems that have replaced desert grasslands are resistant and resilient to disturbance. Between 16 and 25% of the intercepted rainfall is channelized to deep soil storage by stemflow and root channelization. Stemflow water is nutrient enriched and contributes to the "islands of fertility" that develop under desert shrubs. Drought and rainfall augmentation experiments during the growing season after 5 consecutive years of summer drought found that (1) growth of creosotebushes, Larrea tridentata, was not significantly affected, (2) perennial grasses and forbs disappeared on droughted plots, (3) nitrogen mineralization increased in the short term, and (4) densities and biomass of spring annual plants increased on the droughted plots. Doubling summer rainfall for 5 consecutive years had less-significant effects. Coppice dunes treated with herbicide in 1979 to kill mesquite (Prosopis glandulosa) had the same frequency of occurrence of the shrub as the untreated dunes when remeasured in 1993. These data indicate that the shrub-dominated ecosystems persist because they are resistant and resilient to climatic and anthropogenic stresses.


Treatment of pilocarpine-induced epileptic seizures in adult male mice.
Epilepsy is one of the most common neurological disorders affecting most social, economic and biological aspects of human life. Most patients with epilepsy have uncontrolled seizures and drug side effects despite the medications. Patients with epilepsy often have problems with attention, memory, and information processing speed, which may be due to seizures, underlying causes, or anticonvulsants. Therefore, improving seizure control and reducing or changing the anti-epileptic drugs can solve these problems, but these problems will not be solved in most cases. In this work, we looked at the effects of pioglitazone, a Peroxisome Proliferator-Activated Receptor agonist used to treat type 2 diabetes, on pilocarpine-induced seizures in mice. The Racine scale was used to classify pilocarpine-induced convulsions. After that, all of the animals were beheaded, and the brain and hippocampus were dissected. Finally, biochemical techniques were used to determine the levels of Malondialdehyde and Catalase activity, as well as Superoxide Dismutase and Glutathione Reductase in the hippocampus. The results of this investigation suggest that pioglitazone's antioxidant action may play a key role in its neuroprotective properties against pilocarpine-induced seizure neuronal damage.


Short in-Frame Insertions/Deletions in the Coding Sequence of the α-Globin Gene. Consequences of the 3D Structure and Resulting Phenotypes: Hb Choisy as an Example.
A small group of hemoglobin (Hb) variants result from 'in-frame' deletion/insertion (del/ins). We describe a new variant of this group (Hb Choisy), found on the α1 gene, which is the exact counterpart of a previously published deletional variant, Hb J-Biskra [codons 51-58 (or codons 52-59) (-24 bp) (-TCTGCCCAGGTTAAGGGCCACGGC); HBA1: c.157_180del (or HBA2)]. In Hb J-Biskra, the sequence Ser-Ala-Gln-Val-Lys-Gly-His-Gly located from positions α52(E1) to α59(E8) is deleted, while in Hb Choisy the same sequence (Ser-Ala-Gln-Val-Lys-Gly-His-Gly) is inserted at position α52(E1). The variant carrying the insertion appears to be less damaging than the one with the deletion. A possible explanation could be that the additional sequence is located in the C to E interhelical region, and is less disturbing to the general structure of the globin chain. This insertion/deletion (ins/del) is likely favored by the repetition, at an interval of 16 nucleotides, of an eight nucleotide sequence. Comparison of variants of this group, found in the HbVar database, shows that structural modifications resulting from insertions are frequently less damaging than that caused by deletions.


C7β-methyl analogues of the orvinols: the discovery of kappa opioid antagonists with nociceptin/orphanin FQ peptide (NOP) receptor partial agonism and low, or zero, efficacy at mu opioid receptors.
Buprenorphine is a successful analgesic and treatment for opioid abuse, with both activities relying on its partial agonist activity at mu opioid receptors. However, there is substantial interest in its activities at the kappa opioid and nociceptin/orphanin FQ peptide receptors. This has led to an interest in developing compounds with a buprenorphine-like pharmacological profile but with lower efficacy at mu opioid receptors. The present article describes aryl ring analogues of buprenorphine in which the standard C20-methyl group has been moved to the C7β position, resulting in ligands with the desired profile. In particular, moving the methyl group has resulted in far more robust kappa opioid antagonist activity than seen in the standard orvinol series. Of the compounds synthesized, a number, including 15a, have a profile of interest for the development of drug abuse relapse prevention therapies or antidepressants and others (e.g., 8c), as analgesics with a reduced side-effect profile.


Emergency legal preparedness for hospitals and health care personnel.
During the past decade, hospital emergency preparedness has become a focus of local, state, and federal governments seeking to address emergencies or disasters that affect the public health. Integral to hospital emergency preparedness are numerous legal challenges that hospitals and their health care personnel face during declared states of emergencies. In this article, we evaluate legal requirements for hospital emergency preparedness, key legal concerns that hospitals should consider in emergency preparedness activities, and how the changing legal landscape during emergencies necessitates real-time decision making. We then analyze legal issues including negligence, discrimination, and criminal culpability that may arise during or after medical triage. Finally, we examine the legal risks of evading preparedness, specifically asking how a hospital and its personnel may be held liable for failing to plan or prepare for an emergency.


Microfluidic isoform sequencing shows widespread splicing coordination in the human transcriptome.
Understanding transcriptome complexity is crucial for understanding human biology and disease. Technologies such as Synthetic long-read RNA sequencing (SLR-RNA-seq) delivered 5 million isoforms and allowed assessing splicing coordination. Pacific Biosciences and Oxford Nanopore increase throughput also but require high input amounts or amplification. Our new droplet-based method, sparse isoform sequencing (spISO-seq), sequences 100k-200k partitions of 10-200 molecules at a time, enabling analysis of 10-100 million RNA molecules. SpISO-seq requires less than 1 ng of input cDNA, limiting or removing the need for prior amplification with its associated biases. Adjusting the number of reads devoted to each molecule reduces sequencing lanes and cost, with little loss in detection power. The increased number of molecules expands our understanding of isoform complexity. In addition to confirming our previously published cases of splicing coordination (e.g., BIN1), the greater depth reveals many new cases, such as MAPT Coordination of internal exons is found to be extensive among protein coding genes: 23.5%-59.3% (95% confidence interval) of highly expressed genes with distant alternative exons exhibit coordination, showcasing the need for long-read transcriptomics. However, coordination is less frequent for noncoding sequences, suggesting a larger role of splicing coordination in shaping proteins. Groups of genes with coordination are involved in protein-protein interactions with each other, raising the possibility that coordination facilitates complex formation and/or function. We also find new splicing coordination types, involving initial and terminal exons. Our results provide a more comprehensive understanding of the human transcriptome and a general, cost-effective method to analyze it.


Assessment of Resident Knowledge in Pediatric Rheumatology.
Pediatric Rheumatic illnesses are complex, chronic, and often multi-systemic. Our goal was to assess the efficacy of 2 standardized pediatric rheumatology lectures, administered to pediatric residents, in improving the pediatric residents' knowledge and confidence in pediatric rheumatology. Two lectures, 1 hour each, were delivered by 2 residents and given 1 week apart to 28 pediatric residents. Pre- and post-tests assessed knowledge and residents' self-rated competence. Change in knowledge was assessed using paired t-tests. Twenty-eight residents participated in the study. Sixty-three percent (17/27) had an improvement in score from pre-test to post-test. Thirty-seven percent (10/27) reported increased competence from pre-test to post-test. Ninety-six percent (22/23) of the residents found the lectures to be beneficial. Residents in the third post-graduate year (PGY3) cohort had the most significant improvement in scores. The lectures given to the pediatric residents increased pediatric knowledge and the pediatric residents found these lectures to be beneficial.


Dynamics of the Type I Interferon Response During Immunosuppressive Therapy in Rheumatoid Arthritis.
Objective: The type I interferon (IFN) response in rheumatoid arthritis (RA) has been extensively studied in relation to therapy with biological DMARDs (bDMARDs). However, the effect of conventional synthetic (cs)DMARDs and glucocorticoids (GCs) on IFN response gene (IRG) expression remains largely unknown, even though csDMARDS are used throughout all disease phases, including simultaneously with biologic therapy. This study was aimed to determine the dynamics of IFN response upon immunosuppressive treatment. Methods: Whole blood was collected in PAXgene tubes from 35 RA patients who received either COBRA therapy (combination of prednisone, initially 60 mg, methotrexate and sulfasalazine) (n = 14) or COBRA-light therapy (prednisone, initially 30 mg, and methotrexate) (n = 21). Expression of 10 IRGs was determined by real-time PCR at baseline (T0), after 4 weeks (T4), and 13 weeks (T13) of treatment. IRG selection was based on the differential presence of transcription factor binding sites (TFBS), in order to study the therapy effect on different pathway components involved in IFN signaling. Results: Seven of the 10 IRGs displayed significant changes during treatment (p ≤ 0.016). These 7 IRGs all displayed a particularly pronounced decrease between T0 and T4 (≥1.6-fold, p ≤ 0.0059). The differences between IRG sensitivity to the treatment appeared related to the presence of TFBS for STAT1 and IRF proteins within the genes. The extent of the decreases between T0 and T4 was similar for the COBRA- and COBRA-light-treated group, despite the differences in drug combination and doses in those groups. Between T4 and T13, however, IRG expression in the COBRA-light-treated group displayed a significant increase, whereas it remained stable or decreased even further in most COBRA-treated patients (comparison of mean fold changes, p = 0.011). A significant association between IRG dynamics and clinical response to therapy was not detected. Conclusions: Immunosuppressive treatment with csDMARDs, in this case a combination of prednisolone, methotrexate and sulfasalazine, substantially downregulates the IFN response in RA patients. The dynamics of this downregulation were partly dependent on the presence of TFBS within the IRGs and the combination and dosages of agents, but they were irrespective of the clinical response to therapy.


New Sex Chromosomes in Lake Victoria Cichlid Fishes (Cichlidae: Haplochromini).
African cichlid fishes harbor an extraordinary diversity of sex-chromosome systems. Within just one lineage, the tribe Haplochromini, at least 6 unique sex-chromosome systems have been identified. Here we focus on characterizing sex chromosomes in cichlids from the Lake Victoria basin. In Haplochromis chilotes, we identified a new ZW system associated with the white blotch color pattern, which shows substantial sequence differentiation over most of LG16, and is likely to be present in related species. In Haplochromis sauvagei, we found a coding polymorphism in amh that may be responsible for an XY system on LG23. In Pundamilia nyererei, we identified a feminizing effect of B chromosomes together with XY- and ZW-patterned differentiation on LG23. In Haplochromis latifasciatus, we identified a duplication of amh that may be present in other species of the Lake Victoria superflock. We further characterized the LG5-14 XY system in Astatotilapia burtoni and identified the oldest stratum on LG14. This species also showed ZW differentiation on LG2. Finally, we characterized an XY system on LG7 in Astatoreochromis alluaudi. This report brings the number of distinct sex-chromosome systems in haplochromine cichlids to at least 13, and highlights the dynamic evolution of sex determination and sex chromosomes in this young lineage.


Exploring Scoring Function Space: Developing Computational Models for Drug Discovery.
The idea of scoring function space established a systems-level approach to address the development of models to predict the affinity of drug molecules by those interested in drug discovery. Our goal here is to review the concept of scoring function space and how to explore it to develop machine learning models to address protein-ligand binding affinity. We searched the articles available in PubMed related to the scoring function space. We also utilized crystallographic structures found in the protein data bank (PDB) to represent the protein space. The application of systems-level approaches to address receptor-drug interactions allows us to have a holistic view of the process of drug discovery. The scoring function space adds flexibility to the process since it makes it possible to see drug discovery as a relationship involving mathematical spaces. The application of the concept of scoring function space has provided us with an integrated view of drug discovery methods. This concept is useful during drug discovery, where we see the process as a computational search of the scoring function space to find an adequate model to predict receptor-drug binding affinity.


Cystic fibrosis mortality: registry data of cystic fibrosis.
The Cystic Fibrosis Foundation has been collecting mortality and other data on cystic fibrosis patients from over 100 U.S. clinical centers since 1966, and publishes annual reports of the data. Cystic fibrosis is an important autosomal recessive genetic disease, affecting multiple body systems, with disability and early mortality as very common complications. Observed data by age in the 1994 and 1995 REports are compared with the earliest Registry experience. 1966-1972, after age-matching observed with expected mortality in the U.S. population. Observed and expected results are given in four tables of comparative mortality. Excess mortality as a rate difference has shown a marked decrease during this time period, ranging from 96% at age 0-1 to 52% at ages 20-25 years. This can be attributed to improvements in medical treatment.


[Freshwater snails of the Campus of Manguinhos, Oswaldo Cruz Foundation, Rio de Janeiro, RJ].
A survey of freshwater gastropods of the Campus of Manguinhos, Fundação Oswaldo Cruz, Rio de Janeiro, was carried out during the last two years aiming to compare the current species with those found at the beginning of this century. Among 18 breeding sites in 880,000m2 of the surveyed area, 13 showed the following species: Antillorbis nordestensis; Biomphalaria glabrata; Biomphalaria straminea; Lymnaea columella; Melanoides tuberculatus; Physa cubensis; Pomacea glauca and Pomacea lineata. Notably, Biomphalaria tenagophila reported by Lutz in 1918, had disappeared and B. straminea and the Asiatic thiarid M. tuberculatus had been introduced. No specimens infected with Schistosoma mansoni were found.


Can the tall cell variant of papillary thyroid carcinoma be distinguished from the conventional type in fine needle aspirates? A cytomorphologic study with assessment of diagnostic accuracy.
The tall cell variant of papillary thyroid carcinoma (TCV-PTC) is an aggressive variant of PTC requiring accurate cytopathologic diagnosis for early aggressive management. Twenty-five cases of TCV-PTC in which the tall cells comprised at least 30% of surgically resected tumor were included in the study. The direct smears from a preoperative fine needle aspiration (FNA) and available hematoxylin and eosin cell block sections were reviewed. Ten cases of TCV-PTC were randomly selected and blinded with an equal number of conventional PTC cases. Representative slides were independently reviewed by 7 cytologists. In a majority of the cases, the FNA direct smears were hypercellular and displayed flat monolayer sheets of cells. Tall columnar cells with cytoplasmic tails were seen in 56% of cases. The presence of large polygonal follicular cells with abundant granular oncocytic cytoplasm and distinct cell borders was the most common feature seen in all cases. Seventeen (68%) cases displayed intranuclear pseudoinclusions in cells with abundant granular cytoplasm. A correct diagnosis of TCV-PTC was made in 30-40% of cases by 7 study participants. The correct recognition of TCV-PTC features in preoperative FNA is important for clinical management, and reporting these features in a cytopathology report is suggested.


The association between age, sex, and hospital-acquired infection rates: results from the 2009-2011 National Medicare Patient Safety Monitoring System.
To define the relationships between age, sex and hospital-acquired infection (HAI) rates in a national cohort of hospitalized patients. Analysis of chart-abstracted Medicare Patient Safety Monitoring System data from randomly selected medical records of patients hospitalized between January 1, 2009, and December 31, 2011, for acute cardiovascular disease, pneumonia, or major surgery associated with 1 of 6 HAIs. Patients were stratified into 6 groups. We then analyzed the association of age, sex, and 2 outcomes; the rate of occurrence of HAI for patients who were at risk and the rate of patients having at least 1 HAI. Among 85,461 patients, all groups except younger female surgical patients had higher catheter-associated urinary tract infection (CAUTI) rates than male patients. After adjustment for comorbidities, there was no overall evidence of higher HAI rates among elderly patients. In patients with acute cardiovascular disease, women had higher rates of HAIs. Among patients with pneumonia, there was no significant difference in the rate of HAIs among most age and sex groups. Among surgical patients, all age and sex groups had a significantly higher adjusted rate of developing at least 1 HAI except females 65 years of age or older. Similar results were seen for the outcome of the occurrence rate of HAIs. There was not an overall increased risk of HAIs among older patients hospitalized for acute cardiovascular disease, pneumonia, and major surgery after adjustment for comorbidities. The relationship between sex and the rate of HAIs varied depending upon the underlying acute reason for hospitalization.


Lymphoid organ-resident dendritic cells exhibit unique transcriptional fingerprints based on subset and site.
Lymphoid organ-resident DC subsets are thought to play unique roles in determining the fate of T cell responses. Recent studies focusing on a single lymphoid organ identified molecular pathways that are differentially operative in each DC subset and led to the assumption that a given DC subset would more or less exhibit the same genomic and functional profiles throughout the body. Whether the local milieu in different anatomical sites can also influence the transcriptome of DC subsets has remained largely unexplored. Here, we interrogated the transcriptional relationships between lymphoid organ-resident DC subsets from spleen, gut- and skin-draining lymph nodes, and thymus of C57BL/6 mice. For this purpose, major resident DC subsets including CD4 and CD8 DCs were sorted at high purity and gene expression profiles were compared using microarray analysis. This investigation revealed that lymphoid organ-resident DC subsets exhibit divergent genomic programs across lymphoid organs. Interestingly, we also found that transcriptional and biochemical properties of a given DC subset can differ between lymphoid organs for lymphoid organ-resident DC subsets, but not plasmacytoid DCs, suggesting that determinants of the tissue milieu program resident DCs for essential site-specific functions.


The nucleotide sequence of RNA-1 of raspberry bushy dwarf virus.
Raspberry bushy dwarf virus (RBDV) has isometric, 33 nm diameter particles and a bipartite RNA genome. Sequencing of the larger component (RNA-1) showed that it consists of 5449 nucleotides and contains one large open reading frame encoding a putative translation product with a calculated M(r) of 190,000. Comparisons of this polypeptide with non-structural proteins of other plant viruses revealed significant homologies with those of alfalfa mosaic virus (AlMV), brome mosaic virus (BMV), cucumber mosaic virus (CMV) and tobacco mosaic virus (TMV). Thus RBDV belongs to the supergroup of 'Sindbis-like' plant viruses. The translation product of RBDV RNA-1 contains motifs characteristic of proteins with polymerase, methyltransferase and helicase activities, suggesting that this protein is involved in the replication of the viral RNA. Thus in RBDV, as in TMV, all three functional domains are combined in the single protein, whereas in AlMV, BMV and CMV these domains are distributed over the proteins encoded by RNA-1 and RNA-2. These findings support the idea that RBDV should be placed in a distinct virus genus for which the name idaeovirus has been proposed.


Astroglial modulation of transient potassium current development in cultured mouse hippocampal neurons.
Hippocampal neurons exhibit three voltage-gated potassium currents, two transient currents and a delayed rectifier, that influence numerous aspects of electrogenesis including action potential duration and accommodation to sustained depolarization. These currents, termed A-, D-, and K-currents, respectively, can be distinguished based on kinetics, steady state inactivation characteristics, and sensitivity to 4-aminopyridine (see Wu and Barish, 1992b). We have compared the voltage-gated potassium currents in voltage-clamped pyramidally shaped cultured hippocampal neurons growing on or touching glial fibrillary acidic protein-expressing astroglia (termed on-glia or touching-glia neurons, respectively) with those in similar neurons growing directly on a coated glass substrate (termed off-glia neurons). We observed differences in the wave forms of total potassium current that correlated with the extent of astroglial contact. After 5-7 d in culture, A-current amplitude in off-glial neurons was approximately 19% of that of neurons growing in the normal (for culture) on-glia configuration. D-current amplitude tended to be larger in these off-glia neurons. Neurons in contact with astroglia had greater membrane area than off-glia neurons. Comparison of current densities (current at a fixed voltage normalized to capacitance and expressed in units of pA/pF) indicated that A-currents were the major component of transient potassium current in on- and touching-glia neurons, while D-currents were more dominant in off-glia neurons. Astroglia influenced membrane currents by a surface- or extracellular matrix-associated mechanism, rather than by free diffusion of a soluble factor, as differences were observed between closely adjacent neurons on the same coverslip. Living glia were required, as potassium currents in neurons grown on dried or methanol-fixed glia resembled those of off-glia neurons. On-glia neurons in cultures treated with an RNA synthesis inhibitor [DRB (5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole)] for 5-7 d had reduced whole-cell capacitance and A-current amplitude. This effect was localized to DRB actions on underlying astroglia, not on the neurons. Action potentials elicited by current injection varied with astroglial contact. In on-glia neurons with relatively larger A-currents a delay was seen in the onset of firing after depolarization. In contrast, action potentials in off-glia neurons rose smoothly after initiation of depolarization. We conclude that astrocytes modulate the appearance of transient potassium currents in hippocampal pyramidal neurons by inducing development of A-current.(ABSTRACT TRUNCATED AT 400 WORDS)


Bleeding patterns after immediate initiation of an oral compared with a vaginal hormonal contraceptive.
This study compared 84-day bleeding patterns after immediate initiation of a triphasic oral contraceptive with a 25-mug daily dose of ethinyl estradiol (E2) compared with the contraceptive vaginal ring, which has a 15-mug daily dose of ethinyl E2. This was an open-label controlled trial. We randomly assigned 201 women to immediate start of a contraceptive pill or immediate start of the ring in a 1:1 allocation ratio. Our primary outcome was difference in mean bleeding-spotting days per woman according to treatment assignment. Secondary outcomes were differences in World Health Organization-defined menstrual indices, differences in perceived bleeding changes, and differences in bleeding according to cycle day at the start of method. The mean bleeding-spotting days in the 84-day reference period for all subjects was 19.2 days (17.0 days for ring users and 21.4 days for pill users, mean difference 4.4 days). Using the World Health Organization menstrual indices, the ring users experienced fewer days or episodes of bleeding-spotting and shorter intervals. Among ring users, no baseline characteristics were associated with bleeding outcomes. Older nulliparous pill users, however, reported more bleeding-spotting days. Significantly more ring users reported a decrease in duration of bleeding compared with pill users (P < .01). We found no significant differences in bleeding patterns based on analysis of cycle day at study enrollment. Our study shows advantageous bleeding patterns for subjects using the contraceptive vaginal ring. It also confirms our previous findings that immediate start of hormonal contraception is an acceptable alternative to waiting for menses. II-1.


Bone health in diabetes: considerations for clinical management.
The metabolic and endocrine alterations of diabetes adversely affect bone quantity and/or quality and may increase fracture risk. A survey of the scientific literature on diabetes and bone cited on PubMed/MEDLINE and published in English from January 1970 to November 2008. Subjects with type 1 diabetes have reduced bone mass and increased risk of fragility fracture, while those with type 2 diabetes, despite having normal or above-normal bone mineral density (BMD), are susceptible to low-trauma fractures, especially hip fractures. A recent meta-analysis, involving 836 000 subjects and 139 000 incident cases of fracture, found that type 2 diabetes was associated with significantly increased risks of non-vertebral (relative risk 1.2), hip (relative risk 1.7) and foot (relative risk 1.3) fracture. The association with hip fracture persisted after adjustment for age, physical activity and body weight, and was more pronounced in men and in those with long-standing diabetes. Insulin has an anabolic effect on bone, and the qualitatively different effects of type 1 and type 2 diabetes on bone mass are consistent with the opposing insulin-secretory states (hypoinsulinaemia vs. hyperinsulinaemia). However, the existence of an elevated fracture risk in type 2 diabetes, despite the underlying hyperinsulinaemia, suggests the involvement of other potential pathogenic influences (e.g., hyperglycaemia, diabetic complications and lifestyle factors) on bone. Animal studies suggest that diabetic bone may be more fragile than non-diabetic bone. Falls arising from diabetes-related comorbidities are another possible cause of low-trauma fracture. Clinical trial findings, supported by bone marker and bone density data, suggest that the oral antidiabetic agents metformin and glibenclamide significantly lower fracture risk, whereas the thiazolidinediones slightly increase fracture risk in postmenopausal women, but not in men, with type 2 diabetes. Recent preclinical studies have helped elucidate the mechanisms underlying the dynamics of bone remodelling, but more research is needed to improve outcomes for patients. Bone health is an important consideration in diabetes, and caution should be exercised in prescribing thiazolidinediones to postmenopausal women with low BMD and patients with prior fracture.


CD28 expression in sentinel node biopsies from breast cancer patients in comparison with CD3-zeta chain expression.
BACKGROUND: Immunosuppression is documented in several malignant diseases, including breast cancer. Subsequently, future therapeutic concepts might include immunological approaches. However, detailed knowledge about tumor immunogenicity and host immunoreactivity, and how to assess these adequately, is still limited. We studied CD28 and CD3-zeta expression in sentinel node biopsies (SNB) from breast cancer patients to analyze tumor-related changes in T cell activity. METHOD: 25 women underwent surgery for primary breast cancer, including SNB. Frozen sections from 21 sentinel nodes could be analyzed with a double-staining technique. CD28 expression was studied in CD4+ and CD8+ T-lymphocyte subsets and compared with CD3-zeta expression in three specified nodal regions. RESULTS: The degree of CD28 expression varied between the different lymph node areas. The lowest degree of CD28 expression was observed in CD4+ T-lymphocytes in the paracortex and germinal centers. Here, a good agreement with CD3-zeta expression was found. A higher CD28 expression was noted in CD4+ T-cells in the primary follicles, where concordance with CD3-zeta expression was weaker. The CD8+ T-lymphocyte subset displayed generally a higher degree of CD28 expression than the CD4+ subset. CONCLUSION: Sentinel lymph nodes from breast cancer patients displayed local immunosuppression of varying extent. In the areas with the lowest degree of CD28 expression an accordingly low CD3-zeta expression was found. The SNB might prove an important diagnostic tool for the evaluation of interactions between tumor and the host immune system, helping to select patients who might benefit from adjuvant immunotherapy.


The effects of a controlled energy storage and return prototype prosthetic foot on transtibial amputee ambulation.
The lack of functional ankle musculature in lower limb amputees contributes to the reduced prosthetic ankle push-off, compensations at other joints and more energetically costly gait commonly observed in comparison to non-amputees. A variety of energy storing and return prosthetic feet have been developed to address these issues but have not been shown to sufficiently improve amputee biomechanics and energetic cost, perhaps because the timing and magnitude of energy return is not controlled. The goal of this study was to examine how a prototype microprocessor-controlled prosthetic foot designed to store some of the energy during loading and return it during push-off affects amputee gait. Unilateral transtibial amputees wore the Controlled Energy Storage and Return prosthetic foot (CESR), a conventional foot (CONV), and their previously prescribed foot (PRES) in random order. Three-dimensional gait analysis and net oxygen consumption were collected as participants walked at constant speed. The CESR foot demonstrated increased energy storage during early stance, increased prosthetic foot peak push-off power and work, increased prosthetic limb center of mass (COM) push-off work and decreased intact limb COM collision work compared to CONV and PRES. The biological contribution of the positive COM work for CESR was reduced compared to CONV and PRES. However, the net metabolic cost for CESR did not change compared to CONV and increased compared to PRES, which may partially reflect the greater weight, lack of individualized size and stiffness and relatively less familiarity for CESR and CONV. Controlled energy storage and return enhanced prosthetic push-off, but requires further design modifications to improve amputee walking economy.


Cytoreductive Surgery and Normothermic Intraperitoneal Chemotherapy for Signet Ring Cell Appendiceal Adenocarcinoma With Peritoneal Metastases in the Setting of Cirrhosis.
Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are combined to treat peritoneal surface malignancies (PSM). The objective of cytoreduction is to eradicate macroscopic disease, while HIPEC addresses residual microscopic disease. Currently, there are no protocols guiding treatment of cirrhotic patients with PSM. We report the case of a cirrhotic patient with signet ring cell (SRC) appendiceal adenocarcinoma who underwent normothermic, as opposed to hyperthermic intraperitoneal chemotherapy (IPC). A 50-year-old woman with compensated class A cirrhosis and chronic hepatitis B and C underwent a right hemicolectomy in 2007 and adjuvant chemotherapy in 2008 for appendiceal SRC adenocarcinoma. In 2011, she was found to have peritoneal disease after a laparotomy. She subsequently experienced intolerance to chemotherapy, with stable disease on serial restaging. In light of her cirrhosis, the decision was made to perform CRS and IPC without hyperthermia to treat her residual disease. In 2012, she underwent CRS (omentectomy, total abdominal hysterectomy, left salpingo-oophorectomy) and IPC with mitomycin C. Thirty-day postoperative morbidity included delayed abdominal closure (Clavien-Dindo Grade IIIb), prolonged ventilator support (IIIa), vasopressor requirements (II), and confusion (II). The patient's liver function remained stable. Eight months later, she had evidence of recurrence on computed tomography. Twenty-two months later, she developed an extrinsic compression secondary to evolving disease, requiring a palliative endoscopic stent. The patient expired from her disease 29 months after her CRS and IPC. The criteria guiding selection of suitable candidates for CRS continues to evolve. Concomitant compensated cirrhosis in patients with PSM should not constitute a reason independently to exclude CRS with intraperitoneal chemotherapy, given the oncologic benefits of the procedure.


Evaluating Potentials of Species Rich Taxonomic Groups in Cosmetics and Dermatology: Clustering and Dispersion of Skin Efficacy of Asteraceae and Ranunculales Plants on the Species Phylogenetic Tree.
The medicinal properties of plants can be predicted by virtue of phylogenetic methods, which nevertheless have not been utilized to explore the regularity of skin-related bioactivities of ethnomedicinal plants. We aim to investigate the distribution of skin efficacy of Asteraceae and Ranunculales plants on the species-level Tree of Life. The clinical efficacy data of 551 ethnomedicinal species belonging to Ranunculales, as well as 579 ethnomedicinal species of Asteraceae, were systematically collected and collated; these therapeutic data fell into 15 categories, including skin disease/cosmeceutical. The large phylogenetic tree of all China angiosperm species was used to detect the phylogenetic signals of ethnomedicinal plants by calculating the D statistic, phylogenetic diversity (PD), net relatedness index (NRI), and nearest taxon index (NTI). Of all Chinese ethnomedicinal plants of Ranunculales and Asteraceae, 339 (61.5% of all ethnomedicinal species) and 382 (66.0% of all) are used for skin problems. In Ranunculales, a clustered structure was suggested by the NRI value for skin uses. In Asteraceae, the skin utility was not clustered; Artemisia, Aster, Cremanthodium, Ligularia, and Saussurea are the most used Asteraceae genera for skin issues. The clustering structure was identified in Artemisia, and the skin efficacy in other genera was of overdispersion (NRI < 0). NTI values and D statistics largely agree with NRI. When compared with PD values of different therapeutic categories, the PD value of the skin category was relatively high in Cremanthodium, Ranunculales, Asteraceae, and Artemisia, suggesting the enormous efficacy space in the new taxa of these taxonomic groups. By resolving the distribution of therapeutic effects of Ranunculales/Asteraceae taxa, the importance of phylogenetic methods in mining botanical resources with skin utilities is validated.


Hepatoma-derived growth factor is expressed after vascular injury in the rat and stimulates smooth muscle cell migration.
The role of hepatoma-derived growth factor (HDGF), a novel nuclear-targeted vascular smooth muscle cell (SMC) mitogen in vascular injury is unknown. We hypothesized that HDGF plays a role in SMC proliferation and migration in formation of the neointima after balloon injury of the rat carotid. Using co-immunohistochemical staining, HDGF and proliferating cell nuclear antigen (PCNA) were co-expressed in 80% of nuclei of neointimal cells 7 d post carotid balloon injury with HDGF. The HDGF-positive medial and neointimal cells were smooth muscle actin negative and therefore likely represented a subgroup of SMC that have undergone phenotypic switching. Utilizing modified Boyden chamber migration assays, adenoviral-expressed HDGF in mouse SMC increased migration 10-fold (20 versus 2). HDGF gene silencing reduced both SMC proliferation and migration. In conclusion, HDGF is highly expressed in the media and neointima post balloon injury, a SMC mitogen and positive regulator of cell migration. We speculate that HDGF is involved in the SMC proliferative and migratory response to injury resulting in neointimal formation.


The T1D Exchange clinic registry.
The T1D Exchange includes a clinic-based registry, a patient-centric web site called Glu, and a biobank. The aim of the study was to describe the T1D Exchange clinic registry and provide an overview of participant characteristics. Data obtained through participant completion of a questionnaire and chart extraction include diabetes history, management, and monitoring; general health; lifestyle; family history; socioeconomic factors; medications; acute and chronic diabetic complications; other medical conditions; and laboratory results. Data were collected from 67 endocrinology centers throughout the United States. We studied 25,833 adults and children with presumed autoimmune type 1 diabetes (T1D). Participants ranged in age from less than 1 to 93 yr, 50% were female, 82% were Caucasian, 50% used an insulin pump, 6% used continuous glucose monitoring, and 16% had a first-degree family member with T1D. Glycosylated hemoglobin at enrollment averaged 8.3% and was highest in 13 to 25 yr olds. The prevalence of renal disease was ≤4% until T1D was present for at least 10 yr, and retinopathy treatment was ≤2% until T1D was present for at least 20 yr. A severe hypoglycemic event (seizure or coma) in the prior 12 months was reported by 7% of participants and diabetic ketoacidosis in the prior 12 months by 8%. The T1D Exchange clinic registry provides a database of important information on individuals with T1D in the United States. The rich dataset of the registry provides an opportunity to address numerous issues of relevance to clinicians and patients, including assessments of associations between patient characteristics and diabetes management factors with outcomes.