The nature of hyaline (eosinophilic) globules and vascular slits of Kaposi's sarcoma.
Ultrastructural studies of Kaposi's sarcoma (KS) from skin biopsies of 24 patients (eight with acquired immunodeficiency syndrome (AIDS) and 16 without) were performed to delineate the nature of hyaline globules and vascular slits. These structures have been regarded as one of the important criteria for the recognition of KS under light microscopy. Histochemical and immunochemical studies were also performed to correlate with the electron microscopic (EM) observations. The most remarkable EM findings of KS were the intracytoplasmic lumen formation and erythrophagocytic activities of the neoplastic cells, particularly in the mature nodular, or neoplastic stage. The spindle-shaped or ovoid neoplastic cells frequently contained one to several intact and fragmented red blood cells. The intracellular and extravasated erythrocytes were often arranged in single files, giving these vascular slits an elongated appearance on longitudinal sections. The phagocytic activities of the neoplastic cells were demonstrated by the presence of membrane-bound lysosomes containing phagocytized erythrocytes and their partially digested forms (erythrophagosomes) adjacent to pinocytotic vesicles, prominent rough endoplasmic reticulum, and Golgi apparatus, as well as scattered, small, membrane-bound lysosomal granules, some of which were attached to the erythrophagosomes. The erythrophagosomes underwent various stages of disintegration. The partially digested red cells varied from 0.4 to 10 microns in diameter. The results of histochemical and immunochemical findings also strongly suggested that erythrophagosomes were most likely the hyaline globules (bodies) seen in light microscopy. The exact mechanism of erythrophagocytosis is uncertain. However, its consequences, erythrophagosomes, and intracytoplasmic lumen formation, particularly in the nodular or neoplastic stage in patients with and without AIDS, are among the important histologic features of KS.


Molecular and biochemical characterization of a distinct type of fructose-1,6-bisphosphatase from Pyrococcus furiosus.
The Pyrococcus furiosus fbpA gene was cloned and expressed in Escherichia coli, and the fructose-1,6-bisphosphatase produced was subsequently purified and characterized. The dimeric enzyme showed a preference for fructose-1,6-bisphosphate, with a K(m) of 0.32 mM and a V(max) of 12.2 U/mg. The P. furiosus fructose-1,6-bisphosphatase was strongly inhibited by Li(+) (50% inhibitory concentration, 1 mM). Based on the presence of conserved sequence motifs and the substrate specificity of the P. furiosus fructose-1,6-bisphosphatase, we propose that this enzyme belongs to a new family, class IV fructose-1,6-bisphosphatase.


[Immediate results of surgical treatment of esophageal and gastric cancer].
The immediate results of surgical treatment of 279 patients are presented. Of these patients, 15.8% developed complications at the postoperative period. The lethality was 6.8%. In 89.2% of the patients, the operation was performed, using the abdominal approach, in 48.1% of cases, sagittal diaphragmotomy was added. Formation of a muff-like esophagojejunoanastomosis contributed to performance of satisfactory surgical treatment.


Morphological and ultrastructural characterization of the alimentary canal in Japanese wax scale (Ceroplastes japonicus Green).
The morphology and ultrastructure of the alimentary canal in the adult female of the Japanese wax scale, Ceroplastes japonicus Green (Hemiptera: Coccoidea: Coccidae), was investigated using light microscopy, scanning electron microscopy and transmission electron microscopy. The results showed that the foregut was subdivided into a sclerotized pharynx and an oesophagus. A pair of salivary glands attached in the middle of the foregut. The loop-shaped midgut was narrow and longer than the foregut and its inner wall lined with a thick layer of epithelia. The hindgut was divided into a narrower ileum and a broader rectum, with the well-developed filter chamber enclosed in the anterior rectum. Malpighian tubules consisted of two brownish-yellow moniliform tubules with pores, approximately 1 μm in diameter, scattered on the outer surface and many spherical crystals inside the tubules.


The role of vascular endothelial growth factor in proliferation of odontogenic cysts and tumors: An immunohistochemical study.
Vascular endothelial growth factor (VEGF) is capable of initiating angiogenesis in blood vessels and may act as mitogenic agent for epithelium of odontogenic cysts and tumors. This study was conducted to evaluate the role of epithelial VEGF expression in odontogenic cysts and ameloblastoma and its correlation with argyrophilic nucleolar organizer region counts to assess its role in their biological behavior. In this retrospective cross-sectional study, 45 histologically confirmed cases, 15 cases of each of keratocystic odontogenic tumors (KCOTs), dentigerous cysts, and ameloblastomas were examined for immunohistochemical expression for epithelial VEGF, and argyrophilic nucleolar organizer regions (AgNORs) (used as secondary marker in this study) staining was done for comparing the proliferative capacity with VEGF. KCOT shows mild expression within the basal layers and strong expression in the suprabasal layer whereas, in dentigerous cysts, a majority showed no VEGF expression whereas ameloblastomas showed strong expression in all cases by stellate reticulum-like cells at the center of the follicles and suprabasal layers of epithelium. The results of AgNOR counts were higher in KCOTs as compared to ameloblastoma and least in dentigerous cysts. VEGF expression by the epithelium of odontogenic cysts and tumors may play a role in epithelial proliferation via autocrine mechanism as reflected by increased AgNOR counts. The angiogenic activity via paracrine pathway may be responsible for the difference in growth rate and neoplastic behavior of the lesions.


Cutaneous squamous cell carcinoma of the scalp extending to the skull: A case report and review of the literature.
Squamous cell carcinoma (SCC) of the scalp has increased prevalence in older patients and often presents later in life. Mohs micrographic surgery remains the most effective treatment in most cases. Delayed presentation may result in localized bony invasion or distant metastases. We present a case of an elderly woman presenting with extension of SCC into the parietal bone of the skull.


Proteasome-dependent proteolysis has a critical role in fine-tuning the feedback inhibition of cytokinin signaling.
The ubiquitin/26S proteasome-dependent proteolysis of response regulators is a critical element of many plant hormone signaling pathways. We have recently shown that cytokinin signaling requires the AXR1 component of the related to ubiquitin (RUB) protein modification pathway to promote the proteasome-dependent degradation of the cytokinin response inhibitor ARR5. Here, we show that ARR5 also accumulates in the 26S proteasome mutant rpn12a-1, and leads to a marked resistance to cytokinins. Collectively, these results suggest that proteasome-dependent proteolysis of feedback inhibitors such as ARR5 is essential for the maintenance of optimal responsivity and plasticity in cytokinin signaling.


Pharmaceutical analysis beyond compendial requirements.
Recent ICH recommendations on test procedures and acceptance criteria for new drug substances of synthetic chemical origin and new drug products produced from them (Q6A) sets the frame for registration of new chemical entities. These requirements are automatically applied by all pharmaceutical companies to products in late developmental phases. Furthermore, and justifiably so, they do not provide any guideline for setting specifications other than those for residual solvents and residues of heavy metal catalysts. During development of new chemical entities, ICH requirements represent a minimum beyond which additional testing has to be carried out in order to accumulate a body of scientific data which may ultimately permit simplified testing. This information is furthermore needed for drafting of registration files. This presentation will provide information on salt and polymorph selection, as well as morphology of particles. The need for more sophisticated techniques for assay of trace impurities by LC/MS will be illustrated with examples of alkylating agents. Complementary information from techniques such as CE, orthogonal to HPLC, is often needed to ensure absence of additional impurities. Finally, beyond compendial characterisation of hydroxypropylmethylcellulose, a commonly used excipient, by size exclusion chromatography with triple detection will be described.


Effect of furosemide on urinary acidification in distal renal tubular acidosis.
Furosemide stimulates urinary acidification in normal humans probably by increasing distal Na delivery and transport, thus creating a favorable electric gradient for H+ and K secretion. Therefore, furosemide should stimulate urinary acidification in patients with distal renal tubular acidosis, provided the distal nephron is capable of transporting Na and the H+ pumps can respond to the favorable electric gradient. We examined the effect of short-term furosemide administration on urinary acidification in five normal participants and 12 patients with normokalemic, hypokalemic, or hyperkalemic distal renal tubular acidosis. In controls, furosemide decreased urine pH and increased net acid and K excretion. In six of eight patients with normokalemic or hypokalemic renal tubular acidosis, furosemide decreased urine pH and increased net acid and K excretion to levels not significantly different from control values. The patients that had normal responses were interpreted as having a rate-dependent or gradient distal renal tubular acidosis, and thus increased distal Na delivery created a favorable electric gradient for H+ and K secretion. The normokalemic patients who did not have a response were considered to have a defect in the pumps (secretory defect). Of the four hyperkalemic patients, two had a voltage-dependent defect and the other two had aldosterone deficiency. The patients with selective aldosterone deficiency had low baseline urine pH values that did not change with furosemide administration, but net acid and K excretion did increase significantly. The patients with voltage-dependent defect did not lower urine pH or increase net acid and K excretion. Our data demonstrate that administration of furosemide enhances urinary acidification in certain patients with distal renal tubular acidosis. We suggest that furosemide administration may be useful in the characterization of the mechanism responsible for distal renal tubular acidosis and in the treatment of distal renal tubular acidosis in selected patients.


AIDS knowledge and measurement considerations with unacculturated Latinos.
Likert-type scales are frequently used in research with different ethnic groups. Differences in cultural response styles and understanding of the scale have long been noted but rarely explored in research. This article presents the authors' experiences in using a Likert-type questionnaire to measure AIDS knowledge among recently arrived Mexican immigrants in the southeastern United States. The questionnaire findings were compared to a qualitative assessment using vignettes to ascertain knowledge of AIDS casual transmission. It was found that a lack of association existed between the respondents' answers to the quantitative AIDS Likert-type scale and the qualitative vignettes. In-depth interviews to understand the problems respondents were having with the scaling (linguistics, format, and wording of the AIDS questionnaire) supported the findings of a lack of association between the two methods of knowledge assessment. The findings suggest that the Likert-type format is confusing for, and does not accurately reflect knowledge in, recently arrived Mexican immigrants.


Failure properties of cervical spinal ligaments under fast strain rate deformations.
The failure responses of the anterior longitudinal ligament, posterior longitudinal ligament, and ligamentum flavum were examined in vitro under large strain-rate mechanical loading. To quantify the failure properties for 3 cervical spinal ligaments at strain rates associated with traumatic events. There exists little experimentation literature for fast-rate loading of the cervical spine ligaments. The small amount of available information is framed only in extensive experimental coordinates, and not in the context of strains. Bone-ligament-bone complexes were strained at fast rates, in an incrementally increasing loading protocol using a servohydraulic mechanical test frame. Failure loads and displacements were converted to engineering and true stress and strain values, and compared for the different ligaments (anterior longitudinal ligament, posterior longitudinal ligament, and ligamentum flavum), spinal levels (C3-C4, C5-C6, and C7-T1), and for male versus female specimens. There were no significant differences in force or true stress for gender or spinal level. There was a significant difference in force and true stress for ligament type. A difference was found between the posterior longitudinal ligament and ligamentum flavum for failure force, and between the ligamentum flavum and both the anterior and posterior longitudinal ligaments for failure true stress. No significant differences were found in true strain for ligament, gender, or spinal level. The mean ligament failure true strain was 0.81. Failure true strains were approximately 57% of the failure engineering strains. Once the injury mechanisms of the cervical spine are fully understood, computational models can be employed to understand the potentially traumatic effects of clinical procedures, and mitigate injury in impact, falls, and other high-rate scenarios. The soft tissue failure properties in this study can be used to develop failure tolerances in fast-rate loading scenarios. Failure properties of the anterior and posterior longitudinal ligaments were similar, and the same properties can be used to model both ligaments.


FDA-iRISK--a comparative risk assessment system for evaluating and ranking food-hazard pairs: case studies on microbial hazards.
Stakeholders in the system of food safety, in particular federal agencies, need evidence-based, transparent, and rigorous approaches to estimate and compare the risk of foodborne illness from microbial and chemical hazards and the public health impact of interventions. FDA-iRISK (referred to here as iRISK), a Web-based quantitative risk assessment system, was developed to meet this need. The modeling tool enables users to assess, compare, and rank the risks posed by multiple food-hazard pairs at all stages of the food supply system, from primary production, through manufacturing and processing, to retail distribution and, ultimately, to the consumer. Using standard data entry templates, built-in mathematical functions, and Monte Carlo simulation techniques, iRISK integrates data and assumptions from seven components: the food, the hazard, the population of consumers, process models describing the introduction and fate of the hazard up to the point of consumption, consumption patterns, dose-response curves, and health effects. Beyond risk ranking, iRISK enables users to estimate and compare the impact of interventions and control measures on public health risk. iRISK provides estimates of the impact of proposed interventions in various ways, including changes in the mean risk of illness and burden of disease metrics, such as losses in disability-adjusted life years. Case studies for Listeria monocytogenes and Salmonella were developed to demonstrate the application of iRISK for the estimation of risks and the impact of interventions for microbial hazards. iRISK was made available to the public at http://irisk.foodrisk.org in October 2012.


Islet expression of the DNA repair enzyme 8-oxoguanosine DNA glycosylase (Ogg1) in human type 2 diabetes.
BACKGROUND: It has become increasingly clear that beta-cell failure plays a critical role in the pathogenesis of type 2 diabetes. Free-radical mediated beta-cell damage has been intensively studied in type 1 diabetes, but not in human type 2 diabetes. Therefore, we studied the protein expression of the DNA repair enzyme Ogg1 in pancreases from type 2 diabetics. Ogg1 was studied because it is the major enzyme involved in repairing 7,8-dihydro-8-oxoguanosine DNA adducts, a lesion previously observed in a rat model of type 2 diabetes. Moreover, in a gene expression screen, Ogg1 was over-expressed in islets from a human type 2 diabetic. METHODS: Immunofluorescent staining of Ogg1 was performed on pancreatic specimens from healthy controls and patients with diabetes for 2-23 years. The intensity and islet area stained for Ogg1 was evaluated by semi-quantitative scoring. RESULTS: Both the intensity and the area of islet Ogg1 staining were significantly increased in islets from the type 2 diabetic subjects compared to the healthy controls. A correlation between increased Ogg1 fluorescent staining intensity and duration of diabetes was also found. Most of the staining observed was cytoplasmic, suggesting that mitochondrial Ogg1 accounts primarily for the increased Ogg1 expression. CONCLUSION: We conclude that oxidative stress related DNA damage may be a novel important factor in the pathogenesis of human type 2 diabetes. An increase of Ogg1 in islet cell mitochondria is consistent with a model in which hyperglycemia and consequent increased beta-cell oxidative metabolism lead to DNA damage and the induction of Ogg1 expression.


Depolarization and neurotransmitter regulation of vasopressin gene expression in the rat suprachiasmatic nucleus in vitro.
Vasopressin (VP) transcription in the rat suprachiasmatic nucleus (SCN) in organotypic culture was studied by in situ hybridization histochemistry using an intron-specific VP heteronuclear RNA probe. The circadian peak of VP gene transcription in the SCN in vitro is completely blocked by a 2 h exposure to tetrodotoxin (TTX) in the culture medium, and this TTX inhibition of VP gene transcription is reversed by exposure of the SCN to either forskolin or potassium depolarization. This suggests that an intrinsic, spontaneously active neuronal mechanism in the SCN is responsible for the cAMP- and depolarization-dependent pathways involved in maintaining peak VP gene transcription. In this paper, we evaluate a variety of neurotransmitter candidates, membrane receptors, and signal-transduction cascades that might constitute the mechanisms responsible for the peak of VP gene transcription. We find that vasoactive intestinal peptide (VIP) and a VPAC2 (VIP receptor subtype 2) receptor-specific agonist, Ro-25-1553, are the most effective ligands tested in evoking a cAMP-mitogen-activated protein kinase signal transduction cascade leading to an increase in VP gene transcription in the SCN. In addition, a second independent pathway involving depolarization activating L-type voltage-gated calcium channels and a Ca-dependent kinase pathway [inhibited by KN62 (1-[N,O-bis(5-isoquinolinesulphonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine)] rescues VP gene transcription in the presence of TTX. In the absence of TTX, these independent pathways appear to act in a cooperative manner to generate the circadian peak of VP gene transcription in the SCN.


Subtotal arthrodeses of the wrist joint.
The goal of subtotal arthrodesis of the wrist is to provide a stable and pain-free joint, with preservation of a limited but useful range of motion. Experience indicates that the available mobility of the joints that are left unfused tends to increase with time and use of the extremity, and that accelerated wear of these joints has not been a problem. Subtotal arthrodeses of the wrist are indicated for: painful arthritis involving one or two radiocarpal or intracarpal joint surfaces, stabilization of carpal collapse deformities, failed ligament reconstructions or repairs, bone tumors with partial carpal involvement, and supplementation of carpal implants, when their insertion alone could precipitate or increase potential carpal instability.


Improved brushing durability of titanium dioxide coating on polymethylmethacrylate substrate by prior treatment with acryloxypropyl trimethoxysilane-based agent for denture application.
The purpose of this study was to determine whether the brushing durability of a titanium dioxide coating on a polymethyl methacrylate (PMMA) substrate was improved by prior treatment with an acryloxypropyl trimethoxysilane-based agent. Titanium dioxide coatings were obtained by spray-coating substrates with or without prior treatment. Structure was investigated using IR, SEM, and an EPMA. Effect on durability against brushing was determined with a brush-wear test machine utilizing a commercial denture brush. A thin layer comprised of siloxane and TiO(2) was formed on a PMMA substrate by prior treatment with an acryloxypropyl trimethoxysilane-based agent and spray-coating of TiO(2). Prior treatment demonstrated improved stability against brushing, whereas the titanium coating was removed after less than 1x10(5) brushing cycles without prior treatment. This suggests that prior treatment with an acryloxypropyl trimethoxysilane-based agent would confer improved durability against brushing-induced stress on a TiO(2) coating in its application to dentures.


Wurtzite CuInS₂ and CuInxGa₁-xS₂ nanoribbons: synthesis, optical and photoelectrical properties.
Single crystalline wurtzite ternary and quaternary semiconductor nanoribbons (CuInS(2), CuIn(x)Ga(1-x)S(2)) were synthesized through a solution-based method. The structure and composition of the nanoribbons were characterized by X-ray diffraction (XRD), high resolution transmission electron microscopy (HRTEM), the corresponding fast Fourier transform (FFT) and nanoscale-resolved elemental mapping. Detailed investigation of the growth mechanism by monitoring the structures and morphologies of the nanoribbons during the growth indicates that Cu(1.75)S nanocrystals are formed first and act as a catalyst for the further growth of the nanoribbons. The high mobility of Cu(+) promotes the generation of Cu(+) vacancies in Cu(1.75)S, which will facilitate the diffusion of Cu, In or Ga species from solution into Cu(1.75)S to reach supersaturated states. The supersaturated species in the Cu(1.75)S catalyst, Cu-In-S and Cu-In-Ga-S species, start to condense and crystallize to form wurtzite CuInS(2) or CuIn(x)Ga(1-x)S(2) phases, firstly resulting in two-sided nanoparticles. Successive crystallizations gradually impel the Cu(1.75)S catalyst head forward and prolong the length of the CuInS(2) or CuIn(x)Ga(1-x)S(2) body, forming heterostructured nanorods and thus nanoribbons. The optical band gaps of CuIn(x)Ga(1-x)S(2) nanoribbons can be continuously adjusted between 1.44 eV and 1.91 eV, depending on the Ga concentration in nanoribbons. The successful preparation of those ternary and quaternary semiconductor nanoribbons provide us an opportunity to study their photovoltaic properties. The primary photoresponsive current measurements demonstrate that wurtzite CuIn(x)Ga(1-x)S(2) nanoribbons are excellent photoactive materials. Furthermore, this facile method could open a new way to synthesize other various nano-structured ternary and quaternary semiconductors, such as CuInSe(2) and CuIn(x)Ga(1-x)Se(2), for applications in solar cells and other fields.


Clinical applications of circulating tumor DNA in central nervous system lymphoma.
Detection and characterization of circulating tumor DNA (ctDNA) in body fluids have the potential to revolutionize management of patients with lymphoma. Minimal access to malignant DNA through a simple blood draw or lumbar puncture is particularly appealing for CNS lymphomas (CNSL), which cannot be easily or repeatedly sampled without invasive surgeries. Profiling of ctDNA provides a real-time snapshot of the genetic composition in patients with CNSL and enables ultrasensitive quantification of lymphoma burden at any given time point during the course of the disease. Here, we broadly review technical challenges of ctDNA identification in CNSL, recent advances of innovative liquid biopsy technologies, potential clinical applications of ctDNA and how it may improve CNSL risk stratification, outcome prediction, and monitoring of measurable residual disease. Finally, we discuss clinical trials and scenarios in which ctDNA could be implemented to guide risk-adapted and personalized treatment decisions.


The impact of complement activation on tumor oxygenation during photodynamic therapy.
The response to photodynamic therapy (PDT) mediated by photosensitizer Photofrin was examined with Lewis lung carcinomas growing in either complement-proficient C57BL/6 (B6) or complement-deficient complement C3 knockout (C3KO) mice. The results reveal that Photofrin-PDT was more effective in attaining cures of tumors in C3KO than in B6 hosts. Colony-forming ability of cells from tumors excised immediately after Photofrin-PDT confirmed that the direct cell killing effect was more pronounced in C3KO than in B6 hosts. In contrast, PDT mediated by photosensitizer benzoporphyrin derivative (BPD) produced higher cure rates of tumors in B6 hosts than those in C3KO hosts. Determination of tumor C3 levels by ELISA showed that Photofrin-PDT induced markedly more pronounced complement activation than BPD-PDT. Measurements of tumor oxygen tension immediately after PDT by Eppendorf pO2 histograph showed that Photofrin-PDT induced a marked decline in the oxygenation of tumors growing in B6 mice that was much less pronounced in C3KO hosts. With BPD-PDT the oxygen tensions in tumors in B6 and C3KO hosts decreased to a similar extent. This study indicates that complement activation in PDT-treated tumors that varies with different photosensitizers is an important determinant of tumor oxygen limitation effects directly associated with photodynamic action.


Screening procedures for neuroblastoma: false-negative results.
Since elevation of 3-methoxy-4-hydroxymandelic acid (VMA) excretion frequently occurs in patients with neuroblastoma, simpler methods have been developed to differentiate between high and low levels of VMA in the urine, namely the LaBrosse spot test and VMA test strips. Sensitivity of these two procedures depends upon the concentration of VMA in the urine rather than total amount of VMA excreted. VMA excretion data from patients with neuroblastoma show that even though the total amount of VMA excreted in a 24-hour period may definitely be elevated, the concentration of VMA in the 24-hour urine samples may vary greatly from one day to the next and from one patient to another. Therefore, these rapid screening methods for urinary VMA would appear to be too insensitive to use as the sole means of detection or follow-up of patients with neuroblastoma since these techniques require a high concentration of VMA.


Clinical consequences of the lipophilicity and plasma protein binding of antiarrhythmic drugs and active metabolites in man.
In two series of antiarrhythmic drugs tested, as the octanol/water partition coefficient increases so do the following: elimination from the body by biotransformation, first-pass biotransformation in the liver and gastrointestinal tract after oral administration, protein binding to some extent, and penetration into brain tissue. Patients receiving lipophilic beta-adrenoreceptor blocking drugs may experience more central nervous system side effects than those receiving hydrophilic beta blockers. Structural modification of a drug, guided by the concept of bioisosterism, may allow the disassociation of therapeutic from toxic activities. Alpha-1 acid glycoprotein is the major plasma protein that binds the basic antiarrhythmic drugs. Antiarrhythmic drug metabolites are generally more polar (less lipophilic) and less plasma protein-bound than the parent drugs.


Review on ultrasound-guided photoacoustic imaging for complementary analyses of biological systems in vivo.
Photoacoustic imaging has been developed as a new biomedical molecular imaging modality. Due to its similarity to conventional ultrasound imaging in terms of signal detection and image generation, dual-modal photoacoustic and ultrasound imaging has been applied to visualize physiological and morphological information in biological systems in vivo. By complementing each other, dual-modal photoacoustic and ultrasound imaging showed synergistic advances in photoacoustic imaging with the guidance of ultrasound images. In this review, we introduce our recent progresses in dual-modal photoacoustic and ultrasound imaging systems at various scales of study, from preclinical small animals to clinical humans. A summary of the works reveals various strategies for combining the structural information of ultrasound images with the molecular information of photoacoustic images.


Qinghua decoction improves chronic nonbacterial prostatitis possibly regulating the chromogranin A/nerve growth factor/tyrosine kinase A signaling pathway mediated by inflammatory factors.
To explore the mechanism by which Qinghua decoction regulates neuroendocrine inflammation in chronic nonbacterial prostatitis (CNP) model rats and provide an experimental basis for clinical treatment. The rats were randomly divided into six groups: normal control, model, Qianlie Tongyu capsule, low-dose Qinghua decoction, medium-dose Qinghua decoction, and high-dose Qinghua decoction group with six rats in each group. Rats in each group were sacrificed on the 29th day of treatment, and blood and prostate tissues were collected. Serum levels of tumor necrosis factor-alpha and interleukins 1-beta, 6, 8, and 10 (TNF-α and IL-1β, -6, -8, and -10, respectively) were measured using enzyme-linked immunosorbent assay. The pathological changes in the rat prostate tissue in each group were observed under a light microscope. The expression levels of chromogranin A (CgA), nerve growth factor (NGF), and tyrosine kinase A (TrkA) were detected using reverse transcription quantitative polymerase chain reaction. Western blotting was used to detect protein expression of CgA, NGF, and TrkA. In the model group, the prostate capsule membrane and stroma were significantly dilated with more inflammatory cells infiltrating the stroma and perivessels. TNF-α, IL-1β, -6, and -8, CgA, NGF, and TrkA levels increased, whereas the content of IL-10 decreased, which was statistically significant compared to that in the normal control group ( < 0.05). Prostate tissue cells in the high-dose group were neatly arranged with no obvious inflammatory cell infiltration. When compared with the model group, the high-dose Qinghua decoction group showed a significant improvement in these indices ( < 0.05). Qinghua decoction led to inhibition of pathological changes in the prostate tissue of rats with CNP, regulation of inflammatory cytokine expression, and inhibition in the expression of CgA, NGF, and TrkA. This mechanism may be primarily related to regulation of the CgA/NGF/TrkA signaling pathway mediated by various inflammatory factors.


Paediatrics Brain Imaging In Epilepsy: Common Presenting Symptoms And Spectrum Of Abnormalities Detected On MRI.
Epilepsy, a common neurological disorder can present at any age and has a number of aetiologies with underlying brain disease being the most common aetiology. Brain imaging becomes important and mandatory in the work up for epilepsy in localization and lateralization of the seizure focus. This cross-sectional study was conducted in the department of Radiology Ayub Medical Teaching Institution Abbottabad from 1st March 2015 to 31st March 2016. A total of 209 children aged 28 days to 14 years were included in the study who presented with seizures to clinicians. Information obtained from history, clinical examination and investigations especially MRI brains were recorded in a prescribed pro forma. The data was analysed in SPSS 20. MRI examination was unremarkable in 44.01% (n=92) and mild generalized brain atrophy was noted in 12.91% (n=27). Arachnoid cysts, mild unilateral brain atrophy and hydrocephalous due to aqueduct stenosis were recorded in 3.82% (n=8) of each group. Neoplastic lesions were the second most common abnormal MRI finding and constituted 5.74% (n=12). Leukodystrophy was diagnosed in 4.78% (n=10). MRI examination showed ring enhancing lesions (tuberculomas) and AVM in 1.43% (n=3) of each group. Perinatal ischemia and intracranial infection, (focal or generalized) were recorded in 2.87% (n=6) of each group. A 0.95% (n=2) of children in each group had agenesis of corpus callosum and cavernoma. The radiological MRI diagnosis of Raussmussen encephalitis was made in 3.34% (n=7). Single case, each of mesial temporal sclerosis, subdural haemorrhage, infarct and craniopharyngioma was recorded making 0.47% of the total patients in each case. MRI examination was abnormal in significant number of patients (55.86%), so therefore if properly utilized, in a good clinical context, this can identify most of the structural brain abnormalities in paediatric patients presenting with seizures.


Isotope angiography: technique, validation and value in the assessment of arterial reconstruction.
Isotope angiography performed by intravenous injection of technetium 99m pertechnetate has been demonstrated to be of value in the diagnosis and management of a variety of disorders of the large arteries. An improved technique of isotope angiography is described and the technique validated (53 cases) in normal and diseased arteries by correlating it with conventional contrast arteriography and/or operative findings. Peripheral arteries as far distal as the wrist or mid-calf have been accurately visualized and quantitation of isotope arrival times and total isotope activity in different parts of the arterial tree has provided a means of evaluating the hemodynamic significance of stenosing lesions. Thirty-nine arterial reconstructions were studied by this technique. Seven of 27 (26%) clinically patent arterial reconstructions were found to be harboring significant and potentially dangerous imperfections which were clinically unsuspected. Nine of 12 (75%) arterial reconstructions thought clinically to be occluded were demonstrated to be patent, obviating the need for invasive contrast arteriography. Isotope angiography may be used with no risk for the immediate postoperative and long-term evaluation of arterial reconstructions. Only those patients with abnormalities identified on isotope angiography need have conventional contrast arteriography for further delineation of the abnormality so that it may be repaired before it causes failure of the reconstruction.


PEGylated trimethylchitosan emulsomes conjugated to octreotide for targeted delivery of sorafenib to hepatocellular carcinoma cells of HepG2.
The current study aimed to develop PEGylated trimethyl chitosan (TMC) coated emulsomes (EMs) conjugated with octreotide for targeted delivery of sorafenib to hepatocellular carcinoma cells (HCC) of HepG2. Sorafenib loaded TMC coated EMs were prepared by the emulsion evaporation method and characterized concerning particle size, zeta potential, drug encapsulation efficiency, and in vitro drug release. Synthesized EMs were then conjugated to octreotide. The cytotoxicity of the targeted and non-targeted EMs was determined by cellular uptake and MTT assay on HepG2 cell. Cell cycle assay was also studied using flow cytometry. The results showed the optimized EMs had the particle size of 127 nm, zeta potential of -5.41 mV, loading efficiency of 95%, and drug release efficiency of 62% within 52 h. Octreotide was attached efficiently to the surface of EMs as much as 71%. MTT assay and cellular uptake studies showed that targeted EMs had more cytotoxicity than free sorafenib and non-targeted EMs. Cell cycle analyses revealed that there was a significant more accumulation of targeted EMs treated HepG2 cells in the G1 phase than free sorafenib and non-targeted EMs. The results indicate that designed EMs may be promising for the treatment of hepatocellular carcinoma.


Aging and rapid aiming arm movement control.
The authors explored the motor control of target-oriented arm movements across 3 age groups: 20 20- to 30-year-olds, 2 groups (n = 38) of older adults (54 to 64, and 65 to 80). Each individual completed 2 arm movement tasks that had the same movement difficulty but different movement directions. A mixed design was used to examine the differences among age groups and movement directions in reaction time (RT), variability in RT, movement time (MT), timing variability, and inter-segment-interval (ISI). Comparing to the young participants, the senior adults initiated movement tasks slower (RT) and with more RT variability, and executed the arm movements slower and less consistently. The two older groups had greater timing variability in their movements, showed more delays (longer ISI) when reversing arm movement direction, and had lower correlations among segments of the movements than the younger group. The quality of the elderly's control of rapid aiming arm movements showed a regression, which suggests a lack of movement planning, resulting in greater use of visual feedback during movement execution.


Task-specific training reduces trip-related fall risk in women.
The potential of task-specific training as a fall-prevention intervention was studied. The primary purpose of the study was to determine the extent to which a task-specific training protocol decreased the number of falls by middle-age and older women after a laboratory-induced trip. Secondary purposes were to explore the ability of trunk kinematics during the initial recovery step and the length of the initial recovery step to correctly classify the trip outcome and to quantify the extent to which the training protocol affected these variables. Healthy community-dwelling women (n = 52) were assigned to either a training group or a control group that received no training. Training group women participated in an individually tailored, task-specific training protocol during which forward-directed stepping responses were necessary to avoid a fall after treadmill-delivered postural disturbances. Following the protocol, the ability to avoid a fall after a laboratory-induced trip was assessed. The primary outcome variable was the success (recover) or failure (fall) of the posttrip stepping response. Compared with the control group, there were fewer falls by the trained women after the laboratory-induced trip (P < 0.001; odds ratio = 0.13). Using logistic regression, falls and recoveries after the trip were sensitively classified by trunk flexion angle at the completion of the initial recovery step and the length of the initial recovery step (sensitivity = 0.67, specificity = 0.98), the former of which improved as a result of the task-specific training protocol. The task-specific training protocol significantly reduced the number of falls after a laboratory-induced trip. Prospective study is required to determine whether this task-specific training reduces falls in the community and, consequently, may complement currently used exercise-based fall prevention intervention methods.


Ostwald ripening in multiple-bubble nuclei.
The Ostwald ripening of bubbles is studied by molecular dynamics simulations involving up to 679 × 10(6) Lennard-Jones particles. Many bubbles appear after depressurizing a system that is initially maintained in the pure-liquid phase, and the coarsening of bubbles follows. The self-similarity of the bubble-size distribution function predicted by Lifshitz-Slyozov-Wagner theory is directly confirmed. The total number of bubbles decreases asymptotically as t(-x) with scaling exponent x. As the initial temperature increases, the exponent changes from x = 3/2 to 1, which implies that the growth of bubbles changes from interface-limited (the t(1/2) law) to diffusion-limited (the t(1/3) law) growth.


The case of the wandering kidney.
Nephroptosis is a controversial phenomenon well described in the literature. In this case report, we present a patient whose right kidney had "wandered" from its normal anatomic position in the retroperitoneum anteriorly and was in a fixed position anterior to the liver secondary to hydronephrosis. As opposed to the suspected mechanism of nephroptosis, we offer a hydraulic theory as to the origin of the energy required to cause this translocation. The work required to move the patient's kidney was generated by her cardiac output.


A population-based approach to the estimation of diabetes prevalence and health resource utilisation.
This study estimated diabetes prevalence and utilisation of healthcare services in Counties Manukau using routinely collected administrative data and compared estimates with findings for three other district health boards (DHBs) in close geographic proximity. Records of subsidy claims for pharmaceuticals and laboratory investigations were linked to records in a national hospital admissions database to 'reconstruct' populations of four DHBs--Counties Manukau, Northland, Waitemata and Auckland. Individuals were included in reconstructed populations if they had health events recorded between January 2006 and December 2007. Diabetes cases were identified using an algorithm based on claims for monitoring tests and pharmaceuticals, as well as clinical codes for diabetes in hospital admissions. Reconstructed populations were only 6% lower than census population counts indicating that the vast majority of the population use health services in a two year period. The age- and sex-standardised prevalence of diabetes was 7.1% in Counties Manukau and 5.2% in the other three DHBs combined. Prevalence of diabetes was highest amongst Māori (10.6% in women and 12.2% in men) and Pacific peoples (15.0% for women and 13.5% for men). Maori diabetes cases had the highest hospital discharge rate of any ethnic group. Community pharmaceutical prescribing patterns and laboratory test frequency were similar between diabetes cases by ethnicity and deprivation. Estimates of diabetes prevalence using linkage of routinely collected administrative data were consistent with epidemiological surveys, suggesting that linkage of pharmaceutical and laboratory subsidy databases with hospital admissions data can be used as an alternative to traditional surveys for estimating the prevalence of some long-term conditions. This study demonstrated substantial differences in the prevalence of diabetes and in hospitalisation rates by ethnicity, but measures of community diabetes care were similar by ethnicity and deprivation.


Diffusion and flow across nanoporous polydicyclopentadiene-based membranes.
We report gas and liquid transport measurements through membranes that have 40% voids made of 14 nm pores. A reactive polylactide-polynorbornenylethylstyrene block polymer is used as a structural template in the polymerization of dicyclopentadiene during the membrane formation process. After the membrane is cast, the pore structure is formed by etching the polylactide component using dilute aqueous base. The pore structure is isotropic; therefore, there is no need for special alignment techniques. Knudsen diffusion experiments and water flow experiments show pores with a tortuosity of 1.81 and a size of 14 nm, a diameter consistent with nitrogen adsorption and small-angle X-ray scattering measurements. These membranes are effective for ultrafiltration, with molecular weight cutoffs (MWCO) consistent with theoretical predictions with no adjustable parameters. These MWCO's can be tuned by changing the size of the constituent blocks in the templating copolymer.


A circulating extracellular vesicles-based novel screening tool for colorectal cancer revealed by shotgun and data-independent acquisition mass spectrometry.
Background: Early screening for colorectal cancer (CRC) is essential to improve its prognosis. Liquid biopsies are increasingly being considered for diagnosing cancer due to low invasiveness and high reproducibility. In addition, circulating extracellular vesicles (crEVs, extracellular vesicles isolated from plasma) expressing tumour-specific proteins are potential biomarkers for various cancers. Here, we present a data-independent acquisition (DIA)-mass spectrometry (MS)-based diagnostic method for liquid biopsies. Methods: Extracellular vesicles (EVs) were isolated from culture supernatants of human CRC cell lines, and plasma of patients with CRC at different tumour stages, by overnight ultracentrifugation coupled with sucrose density gradient centrifugation. Tumour-specific EV proteins were prioritized using Tandem Mass Tag (TMT)-based shotgun proteomics and phosphoproteomics. The results were verified in a second independent cohort and a mouse tumour-bearing model using Western blotting (WB). The candidate biomarkers were further validated in a third cohort by DIA-MS. Finally, the DIA-MS methodology was accelerated to permit high-throughput detection of EV biomarkers in another independent cohort of patients with CRC and healthy controls. Results: High levels of total and phosphorylated fibronectin 1 (FN1) in crEVs, haptoglobin (HP), S100A9 and fibrinogen α chain (FGA) were significantly associated with cancer progression. FGA was the most dominant biomarker candidate. Analysis of the human CRC cell lines and the mouse model indicated that FGA+ crEVs were likely released by CRC cells. Furthermore, fast DIA-MS and parallel reaction monitoring (PRM)-MS both confirmed that FGA+ crEVs could distinguish colon adenoma with an area of curve (AUC) in the receiver operating characteristic (ROC) curve of 0.949 and patients with CRC (AUC of ROC is 1.000) from healthy individuals. The performance outperformed conventional tumour biomarkers. The DIA-MS quantification of FGA+ crEVs among three groups agreed with that from PRM-MS. Conclusion: DIA-MS detection of FGA+ crEVs is a potential rapid and non-invasive screening tool to identify early stage CRC. Abbreviations: FGA: fibrinogen α chain; CRC: colorectal cancer; crEVs: circulating extracellular vesicles; EV: extracellular vesicles;MS: mass spectrometry; WB: Western blotting; ROC: receiver operating characteristic; PRM: Parallel Reaction Monitoring; GPC1: Glypican-1; GO: Gene ontology; TEM: transmission electron microscopy; FN1: Fibronectin 1; HP: haptoglobin; TMT: Tandem Mass Tag; LC-MS/MS: liquid chromatography coupled to tandem mass spectrometry; DIA: data-independent acquisition; DDA: data-dependent acquisition; CiRT: Common internal Retention Time standards;AGC: Automatic gain control; AUC: area under curve.


Low amplified spontaneous emission threshold from 2-thiophenemethylammonium quasi-2D perovskites via phase engineering.
Quasi-2D Ruddlesden-Popper perovskites attract great attention as an optical gain media in lasing applications due to their excellent optoelectronic properties. Herein, a novel quasi-2D Ruddlesden-Popper perovskite based on 2-thiophenemethylammonium (ThMA) is synthesized by a facile solution-processed method. In addition, an anti-solvent treatment method is proposed to tune the phase distribution, and preferential orientation of quasi-2D (ThMA)2Csn-1PbnBr3n+1 thin films. The large-n-dominated narrow domain distribution improves the energy transfer efficiency from small-n to large-n phases. Also, the highly oriented nanocrystals facilitate the efficient Förster energy transfer, beneficial for the carrier population transfer. Furthermore, a green amplified spontaneous emission with a low threshold of 13.92 µJ/cm2 is obtained and a single-mode vertical-cavity laser with an 0.4 nm linewidth emission is fabricated. These findings provide insights into the design of the domain distribution to realize low-threshold multicolor continuous-wave or electrically driven quasi-2D perovskites laser.


[Diagnostic imaging in acute pulmonary embolism. The use of spiral computed tomography, lung scintigraphy and echocardiography].
Acute pulmonary embolism is an underdiagnosed and potentially lethal condition. Treatment may be lifesaving but is associated with severe side effects. Thus, reliable diagnostic imaging is essential. We conducted a literature review on the use of spiral computed tomography, lung scintigraphy and echocardiography in acute pulmonary embolism and identified 562 articles, of which 16 original papers met our inclusion criteria. From these, we concluded that none of the modalities is applicable in every situation. Spiral computed tomography can confirm the diagnosis but cannot rule out subsegmental embolism. With lung scintigraphy, perfusion imaging alone is probably sufficient and suited to both confirming and ruling out the diagnosis. Echocardiography should be reserved for patients with an emergent need for treatment and cannot rule out the diagnosis.


Vortex-assisted surfactant-enhanced emulsification microextraction based on solidification of floating organic drop followed by electrothermal atomic absorption spectrometry for speciation of antimony (ΙΙΙ, V).
Vortex-assisted surfactant-enhanced emulsification microextraction based on solidification of floating organic drop (VASEME-SFO) was used for preconcentration and speciation of antimony (ΙΙΙ, V) followed by electrothermal atomic absorption spectrometry (ETAAS). In this procedure, Triton X-114 was used as emulsifier and 1-undecanol was used as extraction solvent. This method is based on the complexation of Sb(ΙΙΙ) with dithizone (as complexing agent) at pH 2 and extraction of the resulting hydrophobic complex into the extraction solvent (1-undecanol) with vortex-assisted liquid phase microextraction, whereas Sb(V) remained in solution. Sb(ΙΙΙ) in extraction solvent was directly analyzed by ETAAS after dilution with ethanol, and Sb(V) was calculated by subtracting Sb(ΙΙΙ) from the total antimony after reducing Sb(V) to Sb(ΙΙΙ) by L-cysteine. Under the optimized condition, the calibration curve was linear in the range of 0.4-8 μg L(-1) of Sb(ΙΙΙ) with a correlation coefficient of 0.9995. The detection limit based on three times of the standard deviation of the blank (n = 8) was 0.09 μg L(-1). The validation and the recovery of the proposed method were performed by the analysis of a certified reference material and spike method. The obtained results were in very good agreements with certified values. The proposed method was successfully applied for the determination of antimony species at trace levels in different water samples.


Delta-tocotrienol inhibits non-small-cell lung cancer cell invasion via the inhibition of NF-κB, uPA activator, and MMP-9.
Delta-tocotrienol (δT), an isomer of vitamin E, exhibits anticancer properties in different cancer types including non-small-cell lung cancer (NSCLC). Yet, anti-invasive effects of δT and its underlying cellular mechanism in NSCLC have not been fully explored. Matrix metalloproteinase 9 (MMP-9)-based cell migration and invasion are critical cellular mechanisms in cancer development. The current evidence indicates that MMP-9 is upregulated in most patients, and the inhibition of MMPs is involved in decreasing invasion and metastasis in NSCLC. Therefore, its suppression is a promising strategy for attenuating cell invasion and metastasis processes in NSCLC. The aim of this study was to evaluate the possibility of MMP-9 inhibition as the underlying mechanism behind the antimetastatic properties of δT on NSCLC cells. The effects of δT on cell proliferation, migration, invasion, adhesion, and aggregation capabilities were investigated using different cell-based assays. An inhibitory effect of MMP-9 enzyme activity with δT was also identified using gel zymography. Using real-time PCR and Western blot analysis, a number of cellular proteins, regulatory genes, and miRNA involved in the Notch-1 and urokinase-type plasminogen activator (uPA)-mediated MMP-9 pathways were examined. The study found that δT inhibited cell proliferation, cell migration, invasion, aggregation, and adhesion in a concentration-dependent manner and reduced MMP-9 activities. Real-time PCR and Western blot analysis data revealed that δT increased miR-451 expressions and downregulated Notch-1-mediated nuclear factor-κB (NF-κB), which led to the repressed expression of MMP-9 and uPA proteins. δT attenuated tumor invasion and metastasis by the repression of MMP-9/uPA via downregulation of Notch-1 and NF-κB pathways and upregulation of miR-451. The data suggest that δT may have potential therapeutic benefit against NSCLC metastasis.


[Benefits of Affirm VPIII and L-PAP in the diagnosis of bacterial vaginosis].
Bacterial vaginosis is a syndrome occurring in women of reproductive age, characterized by abnormal vaginal discharge and associated with gynecological and obstetric problems during pregnancy. This study assesses the value of proline aminopeptidase (L-Pap) detection and DNA hybridization with the Affirm VPIII microbial identification test, as analytical tools for the diagnosis of bacterial vaginosis. Vaginal secretions from 406 women were collected and analyzed to investigate bacterial vaginosis with the Affirm VPIII commercial kit and the L-Pap reaction. The criteria of Nugent et al, and Amsel et al. were used to characterize patients with bacterial vaginosis syndrome. Results were analyzed with a 2 x 2 contingency table and evaluated by the chi-square test, at a significance level of P < 0.05. L-Pap showed a sensitivity of 92.2%, specificity of 93.4%, PPV of 91.7% and NPV of 93.8%. The Affirm VPIII method had a sensitivity of 91.1%, specificity of 94.7%, PPV of 93.1% and NPV of 93.8%. The diagnostic performance of the two tests showed no statistical differences. CONCLUSION. L-Pap and Affirm VPIII are both suitable tests for fast, accurate diagnosis of bacterial vaginosis.


Venous thromboembolism prophylaxis in urology: A review.
Venous thromboembolism is potentially a lethal problem, and is associated with chronic morbidity. Venous thromboembolism is frequently diagnosed after urological surgery, yet the role of perioperative venous thromboembolism prophylaxis is not clearly defined. Any current recommendations are largely based on evidence derived from other surgical specialties. Even within different guidelines, there remains significant variation, suggesting a consensus is required. The present review aims to define the problem of venous thromboembolism within the urological population, and identifies patients at risk. It evaluates the role of various types of mechanical and pharmacological prophylaxis, along with its timing and duration of administration in common urological operations. The current guidelines are summarized and compared in order to give the reader a better perspective of this vital condition.


Simulated data-driven hospital selection for surgical treatment of well-differentiated thyroid cancer in older adults.
Thyroid surgery at high-quality hospitals is associated with fewer complications. We evaluated the impact of referring older adults with thyroid cancer to higher-performing local hospitals. We performed a simulation study of Surveillance, Epidemiology, and End Results-Medicare patients, aged ≥66 years, who underwent a thyroidectomy for well-differentiated thyroid cancer (2013-2017). An 80% sample was used to calculate each hospital's risk-standardized 30-day serious adverse event rate, dividing hospitals into quartiles by performance. Hospitals located ≤30 miles of the remaining 20% of patients were compared, and 30-day serious adverse event rates and costs were simulated as if patients were treated at higher-quality hospitals using logistic regression with each alternative hospital's fixed-effect. We identified 8,946 patients who underwent thyroid resection at 843 hospitals. Average risk-adjusted serious adverse event rates ranged from 13.9% to 52.9% between quartile 1 and 4 hospitals (P < .001). We identified higher-quality hospitals for 43.7% of patients. Simulating care at the best local hospital reduced predicted serious adverse event rates from 25.6% (95% confidence interval, 24.7-26.4) to 16.2% (95% confidence interval, 15.5-16.8; P < .001), while modestly lowering average costs from $12,883 (95% confidence interval, 12,500-13,267) to $12,679 (95% confidence interval, 12,304-13,056; P = .029). Simulated care at higher-performing hospitals decreased serious adverse event rates after thyroid resection. Optimizing hospital selection may reduce postoperative morbidity without compromising preferences for local treatment.


From soil to blood: first human case of Sphingobacterium hotanense bacteraemia.
This report describes a case of Sphingobacterium hotanense bacteraemia in a patient scratched by a rooster on the right arm. Diagnostic, clinical and therapeutic features are discussed. To the best of our knowledge, this is the first case of Sphingobacterium hotanense bacteremia reported in the medical literature.


[DEK-targeting aptamer DTA-64 inhibits epithelial-mesenchymal transition of airway epithelial cells in bronchial asthmatic mice via blocking TGF-β1 signaling pathway].
Objective To investigate the inhibitory effect of DEK targeting aptamer 64 (DTA-64) on airway inflammation and epithelial to mesenchymal transition (EMT) induced by ovalbumin (OVA) in asthmatic mice. Methods Thirty-two female BALB/c mice (8 weeks old) were randomly divided into PBS group, OVA model group, DTA-64 group (1 μg/mouse), and control aptamer group, with 8 in each. HE staining of lung tissues was used to detect inflammatory cell infiltration around the airways; immunohistochemical staining was used to detect DEK expression around the airways; ELISA was used to detect serum IgE, and Th2-type cytokines IL-4, IL-5, IL-13 and Th1-type cytokine IFN-γ in bronchoalveolar lavage fluid (BALF); Western blot was applied to detect the EMT-related proteins α-SMA, Snail+Slug, vimentin, and E-cadherin, and TGF-β1/Smad, MAPK, PI3K, AKT, as well as mTOR in lung; and flow cytometry was used to observe the α-SMA expression in the lung single cell suspensions. Results DEK protein was highly expressed in the lung tissues of OVA group mice and decreased in the DTA-64 group mice; DTA-64 reduced the infiltration of eosinophils and neutrophils around the airways, down-regulated serum OVA-specific IgE and IL-4, IL-5, IL-13 in BALF, and up-regulated IFN-γ; DTA-64 also reduced the expressions of vimentin, α-SMA, Snail+Slug in the lung tissue, and up-regulated epithelial marker E-cadherin. DTA-64 inhibited the expressions of TGF-β1 and its downstream canonical pathways Smad2/3 and Smad4, as well as the phosphorylation of non-canonical TGF-β1 pathways ERK1/2, p38 MAPK, JNK and PI3K/AKT/mTOR. Conclusion DTA-64 may inhibit the airway inflammation and EMT induced by OVA in asthmatic mice via blocking TGF-β1/Smad, MAPK and PI3K signaling pathways, thereby alleviating airway remodeling in asthma.


Histone variant H3.3-mediated chromatin remodeling is essential for paternal genome activation in mouse preimplantation embryos.
Derepression of chromatin-mediated transcriptional repression of paternal and maternal genomes is considered the first major step that initiates zygotic gene expression after fertilization. The histone variant H3.3 is present in both male and female gametes and is thought to be important for remodeling the paternal and maternal genomes for activation during both fertilization and embryogenesis. However, the underlying mechanisms remain poorly understood. Using our H3.3B-HA-tagged mouse model, engineered to report H3.3 expression in live animals and to distinguish different sources of H3.3 protein in embryos, we show here that sperm-derived H3.3 (sH3.3) protein is removed from the sperm genome shortly after fertilization and extruded from the zygotes via the second polar bodies (PBII) during embryogenesis. We also found that the maternal H3.3 (mH3.3) protein is incorporated into the paternal genome as early as 2 h postfertilization and is detectable in the paternal genome until the morula stage. Knockdown of maternal H3.3 resulted in compromised embryonic development both of fertilized embryos and of androgenetic haploid embryos. Furthermore, we report that mH3.3 depletion in oocytes impairs both activation of the Oct4 pluripotency marker gene and global de novo transcription from the paternal genome important for early embryonic development. Our results suggest that H3.3-mediated paternal chromatin remodeling is essential for the development of preimplantation embryos and the activation of the paternal genome during embryogenesis.


Acute limb ischemia as manifestation of a pheochromocytoma.
A case is described of a woman admitted to the emergency room with myocardial infarction and acute leg ischemia and suspected thromboembolism. Surgical exploration of the common femoral artery and its branches was performed. The surgical outcome and the subsequent clinical course suggested the diagnosis of pheochromocytoma which was supported by isotopic red-cell labelling study and catecholamine measurement. The very high values of catecholamine production explained the marked and persistent arterial vasospasm which led to marked and irreversible ischemia.


Advances and changes in the treatment of children with nephroblastoma.
Wilms' tumor or nephroblastoma is the most common malignant tumor stemming from kidney cells and second only to neuroblastoma when it comes to extracranial solid tumors in children. The results of nephroblastoma treatment are a perfect example of therapeutic success resulting from an interdisciplinary approach to the problem and the cooperation of pediatric surgeons, pediatric oncologists, pathologists, radiologists and radiotherapists leading to precise diagnoses and the selection of the optimal treatment. At the end of the sixties, international research teams began studying the best treatment for this tumor in children. In Europe, it was the International Society of Paediatric Oncology (SIOP), which has used the working name SIOP- RTSG (Renal Tumor Study Group - Group for the Study of Kidney tumors) since 2008 and in North America NWTS (National Wilms' Tumor Study - The National Committee for Research on Wilms' tumor). Summarizing the experience and knowledge on the treatment of nephroblastoma, it should be noted that, despite years of research and information exchange, uniform guidelines have not yet been developed, and there are still differences in treatment of this tumor. The biggest differences are between the "American" treatment recommended by the NWTS and the "European" by SIOP. In the first it is recommended to start treatment from the surgical removal of the tumor, even in the case of disseminated disease with the presence of metastases in the lungs. The treatment method is chosen by the institution managing the patient; for this reason on the American continent in Brazil, Wilms' tumor is treated according to the recommendations of "European" protocols (SIOP) and some institutions in Europe, for example in Italy, treat patients with nephroblastoma according to the "American" protocols recommended by the NWTS; until recently, focal disease was treated with primary nephrectomy in the UK.


Identification of novel long non-coding RNA biomarkers for prognosis prediction of papillary thyroid cancer.
Papillary thyroid carcinoma (PTC) is the most frequent type of malignant thyroid tumor. Several lncRNA signatures have been established for prognosis prediction in some cancers. However, the prognostic value of lncRNAs has not been investigated in PTC yet. In this study, we performed genome-wide analysis of lncRNA expression profiles in a large cohort of PTC patients from The Cancer Genome Atlas and identified 111 differentially expressed lncRNAs between tumor and non-tumor samples and between recurrent and recurrence-free samples. From the 111 differentially expressed lncRNAs, four independent lncRNA biomarkers associated with prognosis were identified and were integrated into a four-lncRNA signature which classified the patients of training dataset into the high-risk group and low-risk group with significantly different overall survival (p=0.016, log-rank test). The prognostic value of the four-lncRNA signature was validated in the independent testing dataset. Multivariate analysis indicated that the four-lncRNA signature was an independent prognostic predictor. Moreover, identified four lncRNA biomarkers demonstrates good performance in predicting disease recurrence with AUC of 0.833 using leave one out cross-validation. Our study not only highlighted the potential role for lncRNAs to improve clinical prognosis prediction in patients with PTC and but also provided alternative biomarkers and therapeutic targets for PTC patients.


Synergetic DNA-cleaving activities of the metal complexes of a polyether-tethered pyrrole-polyamide dimer.
A simple polyether-tethered pyrrole-polyamide dimer 1 was synthesized in 50% yield from the reaction of 2,2,2-trichloro-1-(1-methyl-4-nitro-1H-pyrrol-2-yl)ethanone with 2,2'-[1,2-ethanediylbis(oxy)]bisethanamine, and fully characterized on the basis of ¹H- and ¹³C-NMR, MS, HR-MS, and IR data. Agarose gel-electrophoresis study of the cleavage of plasmid pBR322 DNA by the complexes of compound 1 with seven metal ions indicated that most of the metal complexes were capable of efficiently cleaving DNA at pH 7.0 and 37°. Among them, the Cu(II) complex exhibited the highest activity, with the maximal catalytic rate constant k(max) and Michaelis constant K(M) being 5.61 h⁻¹ and 7.30 mM, respectively. Spectroscopic, ESI-MS, ethidium-bromide (EB) displacement, and viscosity experiments indicated that compound 1 could form a 1 : 1 complex with Cu(II) ion, and that this complex showed moderate binding affinity toward calf-thymus DNA.


Detection of HBV Covalently Closed Circular DNA.
Chronic hepatitis B virus (HBV) infection affects approximately 240 million people worldwide and remains a serious public health concern because its complete cure is impossible with current treatments. Covalently closed circular DNA (cccDNA) in the nucleus of infected cells cannot be eliminated by present therapeutics and may result in persistence and relapse. Drug development targeting cccDNA formation and maintenance is hindered by the lack of efficient cccDNA models and reliable cccDNA detection methods. Southern blotting is regarded as the gold standard for quantitative cccDNA detection, but it is complicated and not suitable for high-throughput drug screening, so more sensitive and simple methods, including polymerase chain reaction (PCR)-based methods, Invader assays, in situ hybridization and surrogates, have been developed for cccDNA detection. However, most methods are not reliable enough, and there are no unified standards for these approaches. This review will summarize available methods for cccDNA detection. It is hoped that more robust methods for cccDNA monitoring will be developed and that standard operation procedures for routine cccDNA detection in scientific research and clinical monitoring will be established.


The infinitesimal model with dominance.
The classical infinitesimal model is a simple and robust model for the inheritance of quantitative traits. In this model, a quantitative trait is expressed as the sum of a genetic and an environmental component, and the genetic component of offspring traits within a family follows a normal distribution around the average of the parents' trait values, and has a variance that is independent of the parental traits. In previous work, we showed that when trait values are determined by the sum of a large number of additive Mendelian factors, each of small effect, one can justify the infinitesimal model as a limit of Mendelian inheritance. In this paper, we show that this result extends to include dominance. We define the model in terms of classical quantities of quantitative genetics, before justifying it as a limit of Mendelian inheritance as the number, M, of underlying loci tends to infinity. As in the additive case, the multivariate normal distribution of trait values across the pedigree can be expressed in terms of variance components in an ancestral population and probabilities of identity by descent determined by the pedigree. Now, with just first-order dominance effects, we require two-, three-, and four-way identities. We also show that, even if we condition on parental trait values, the "shared" and "residual" components of trait values within each family will be asymptotically normally distributed as the number of loci tends to infinity, with an error of order 1/M. We illustrate our results with some numerical examples.


Detection of Antimicrobial Resistance and Biofilm Production Among Staphylococcus pseudintermedius from Canine Skin Lesions.
Aims: Staphylococcus pseudintermedius is an opportunistic pathogen also indicated as one of the major causes of skin infections in dogs. This study aimed to identify S. pseudintermedius isolated from canine skin lesions, evaluate their antibiotic resistance profile and biofilm production ability. Methodology: Lesions from 50 rural dogs with different skin lesions were sampled after pyoderma diagnosis by private practices. Bacterial species determination was investigated and susceptibility to nine antimicrobials were determined by means of Kirby-Bauer assay. Then seven antibiotic resistance genes, including mecA, blaZ, tetK, tetM, blaSHV, blaOXA-1, and blaTEM were screened by PCR. Moreover, biofilm formation ability of the strains was determined using the microtiter plate assay along with the presence of icaADBC genes. Results: A total of 37 (74%) isolates were identified as S. pseudintermedius. All S. pseudintermedius isolates were resistant to multiple drugs. Resistance to penicillin, amoxicillin-clavulanic acid, and cefazolin were higher than other antimicrobials. All the beta-lactam-resistant isolates carried blaZ, whereas mecA was found in 6 (16.21%) of them. Among tetracycline-resistant strains, the frequency of tetK and tetM determinants were 19 (90.47%) and 21 (100%), respectively. Finally, most cefazolin-resistant strains 31 (91.89%) were positive for blaTEM gene. The rate of biofilm production ability among S. pseudintermedius isolates was 35 (94.59%). Furthermore, the presence of icaA/D genes was detected in 35 (100%) and 29 (82.85%) of S. pseudintermedius strains, respectively. Conclusion: The high rates of antimicrobial resistance and biofilm production ability among S. pseudintermedius isolates, emphasize the urgent need to use more effective infection control policies and guidelines for antimicrobial use.


Induction of drug-metabolizing enzymes by polycyclic aromatic hydrocarbons: mechanisms, and some implications in environmental health research.
The mechanisms by which administration of polycyclic aromatic hydrocarbons (PAH) stimulates drug-metabolizing enzymes are summarized. The hepatic monooxygenase system of marine and freshwater fish is also induced by PAH-type compounds, including chlorinated dioxins and certain polychlorinated and polybrominated biphenyl isomers, and these chemicals are, or are suspected to be, toxic to humans. Consequently, there is considerable interest in whether or not PAH-type induction in fish can be used as a sentinel or early warning indicator for certain classes of toxic pollutants in the aquatic environment. We have investigated various aspects of PAH-type induction in marine fish and have found that approximately 50% of the winter flounder (Pseudopleuronectes americanus), captured near Mount Desert Island, Maine, appear to have induced hepatic monooxygenase systems, which suggests that they are exposed to PAH-type chemicals in the environment. The potential advantages and limitations of using PAH-type enzyme induction as a sentinel system for pollutants in aquatic ecosystems are discussed.


Supporting special needs in the mainstream classroom: children's perceptions of the adult role.
Inclusion of children with significant special educational needs within the ordinary classroom frequently involves additional human resources. In the UK, specialist teachers and classroom assistants (teachers' aides) are now a regular feature of many classrooms. Their purpose is to provide advice and support to the teacher and/or specifically to assist the child with special educational needs in accessing the mainstream curriculum. There has been little research into the impact of these additional adults on children not designated as having special educational needs, although their attitudes and responses are likely to prove critical to the success of any policy of inclusive education. This study examines the responses of 713 children (ages 7-14+) attending 27 schools in London to questions relating to the role of adults supporting special educational needs (SEN) children in their classrooms and to the social desirability of being singled out for support. The findings suggest that the majority of those responding saw the support being directed towards the teacher's needs. The recognition of pupils' needs was less frequently expressed. The desirability of support became challenged by some children in the upper age range of the sample. Reasons for this and the implications for inclusive education are considered.


Thrombospondin-1 expression is increased during follicular atresia in the primate ovary.
Thrombospondin (TSP)-1 is an antiangiogenic extracellular matrix glycoprotein that modulates several aspects of cellular function. The aim of this study was to determine the pattern of TSP-1 mRNA and protein expression as well as expression of its receptor CD36 in the marmoset ovary and to investigate the effects of inhibition of gonadotropins or VEGF activity on TSP-1 and CD36 expression in vivo. GnRH antagonist or VEGF Trap, a soluble decoy receptor, was administered on d 0 of the follicular phase of the cycle, and ovaries were collected at the end of the follicular phase (d 10). TSP-1 mRNA and protein were present in granulosa cells of preantral and antral follicles, with the highest staining at the late secondary and tertiary stages. Moreover, expression of TSP-1 mRNA and protein was significantly increased in tertiary follicles undergoing atresia. CD36 protein was detected in granulosa cells of preantral and antral follicles as well as in endothelial cells of large vessels. Inhibition of gonadotropin secretion or VEGF activity had no effect on TSP-1 expression; however, expression of CD36 protein was inhibited by the VEGF Trap. In conclusion, TSP-1 may be involved in the cessation of angiogenesis in follicles undergoing atresia; alternatively, TSP-1 may act on granulosa and/or endothelial cells to promote follicular atresia in the ovary. Angiogenesis is likely to involve a balance between pro- and antiangiogenic factors. Our results suggest that loss of VEGF activity does not regulate TSP-1 expression directly but may influence TSP-1 activity via down-regulation of the CD36 receptor.


[Hormone replacement therapy following breast carcinoma].
Additional advantages of hormone suppletion therapy (HST) in women with climacteric complaints are the reduced risks of development of cardiovascular disease and osteoporosis. A disadvantage is the enhanced risk of breast cancer. More and more women with a treated primary breast cancer nowadays have a relatively favourable prognosis; they might also profit by HST, especially if chemotherapy for breast cancer has led to an early menopause. Recent pilot studies of the connection between HST and recurrence of breast cancer are inadequate as to methodology and size to permit definite conclusions. There are numerous arguments for a connection between exposure to oestrogens and development of breast cancer. As long as it has not been demonstrated that HST does not lead to enhanced risk of breast cancer recurrence, the general recommendation should be not to administer HST to patients with treated breast carcinoma.


Face recognition is similarly affected by viewpoint in school-aged children and adults.
There is an ongoing debate on the question when face processing abilities mature. One aspect that has been part of this debate is the ability to recognize faces in and across different viewpoints. Here, we tested 128 participants consisting of school-age children (ages, 5-10 years) and adults (ages, 19-37 years) in two experiments to investigate the effects of different viewpoints (including front, three-quarter, profile view) on face recognition during development. Furthermore, we compared recognition performance for faces to that of another object category (cars). In the first experiment (n = 88) we tested if the pattern of performance for faces presented in different viewpoints is similar in school-aged children and adults. Participants completed a two-alternative-forced-choice (2AFC) memory task comprising images of both faces and cars in front, three-quarter and profile view, which were presented in the same viewpoint during learning and testing. In the second experiment (n = 40) we tested if face recognition is similarly affected by viewpoint changes in children and adults. In this experiment the 2AFC memory task included a change of viewpoint between learning and testing. While in both experiments we found higher recognition performance for faces with increasing age, the overall pattern of both viewpoint and viewpoint-change-effects and also the difference between view-change- and no-change-conditions was similar across age groups. In contrast to faces, no viewpoint effects were observed in cars (experiment 1), viewpoint change effects, however, were similar for cars and faces (experiment 2). In sum, our results suggest early maturity of the ability to recognize faces in and across different viewpoints.


The C-terminus of alpha2-antiplasmin interacts with endothelial cells.
The serpin, alpha(2)-antiplasmin (alpha(2)AP), has an extended C-terminus relative to other inhibitors. This 51-residue region contains an RGD sequence; such sequences constitute a key recognition sequence for cell adhesion, mediated through integrins. In the present study, this sequence was expressed in Escherichia coli and its binding to endothelial cells and whether binding depends on the RGD sequence was investigated. Binding to the surface of human umbilical vein endothelial cells (HUVEC-C) was observed by flow cytometry and immunohistochemistry. Binding studies on immobilised cells showed specific and RGD-dependent binding of the peptides to HUVEC-C. The binding of the wild-type peptide to the HUVEC-C was significantly higher than that of a mutant peptide, in which RGD was replaced by SAA (P < 0.05, n = 4). Similarly, ethylenediaminetetraacetic acid decreased the binding of the wild-type peptide (P < 0.05, n = 4). The binding was competed out by full-length alpha(2)AP, fibronectin and anti-alpha(5)beta(1). This is the first evidence of binding of the C-terminus of alpha(2)AP to endothelial cells via its RGD sequence, with most but not all of the binding being integrin-mediated. We speculate that this interaction with alpha(2)AP may potentially play a role in the control of cellular fibrinolysis by regulating local plasmin activity on cell surfaces.


Intercellular junctions of methylcholanthrene-induced rat skin basocellular and squamous carcinomas.
The occurrence of different intercellular junctions in epithelial rat skin tumours induced by methylcholanthrene was investigated using thin sections and freeze-fracture replicas examined by electron microscopy. Tumours which appeared first were basal cell carcinomas. Later, different tumours of hair follicle and of sebaceous gland origin were formed. Finally, in the majority of tumours a squamous component evolved. Metastases developed from the squamous carcinomas exclusively. Desmosomes and gap junctions were detected in basal cell carcinomas whereas, in squamous carcinomas, tight junctions were also seen. While all three types of junction were found in the primary squamous tumours, the tumour metastases in lymph nodes and lungs contained only desmosomes.


Prospective study of polyomavirus type BK replication and nephropathy in renal-transplant recipients.
Nephropathy associated with the polyomavirus type BK (BKV) nephropathy has emerged as a cause of allograft failure linked to immunosuppressive regimens containing tacrolimus or mycophenolate mofetil. The presence of viral inclusions, known as "decoy cells," in urine and the presence of BKV DNA in plasma have been proposed as markers for the replication of BKV and associated nephropathy, but data from prospective studies have been lacking. In a prospective, single-center study, we followed 78 renal-transplant recipients who were receiving immunosuppressive therapy that included tacrolimus (37 patients) or mycophenolate mofetil (41 patients). Urine was tested for the presence of decoy cells at routine visits. BKV DNA was measured 3, 6, and 12 months after transplantation and whenever decoy cells were detected. The viral load in plasma was quantified with the use of a real-time polymerase-chain-reaction method. Renal biopsy was performed if allograft function deteriorated. Twenty-three patients had decoy-cell shedding a median of 16 weeks after transplantation (range, 2 to 69), 10 patients had BKV viremia at a median of 23 weeks (range, 4 to 73), and 5 had BKV nephropathy at a median of 28 weeks (range, 8 to 86). Kaplan-Meier estimates of the probability of decoy-cell shedding, viremia, and nephropathy were 30 percent (95 percent confidence interval, 20 to 40 percent), 13 percent (95 percent confidence interval, 5 to 21 percent), and 8 percent (95 percent confidence interval, 1 to 15 percent), respectively. Antirejection treatment, particularly with corticosteroids, was associated with BKV replication and nephropathy. The viral load in plasma was higher in patients with BKV nephropathy than in those without nephropathy (P<0.001 by the Mann-Whitney test). BKV antibodies were detected in 77 percent of the 78 patients before transplantation, including 4 of 5 with BKV nephropathy. BKV nephropathy in renal-transplant recipients represents a secondary infection associated with rejection and its treatment in most cases and could be monitored by measuring the viral load in plasma.


Effects of fipronil on dogs over Triatoma infestans, the main vector of Trypanosoma cruzi, causative agent of Chagas disease.
Chagas disease is the most important endemic disease in Latin America, mainly transmitted by Triatoma infestans in the Southern Cone countries of South America. Dogs are one of the main domestic reservoirs of Trypanosoma cruzi, the etiological agent of Chagas disease. The presence of dogs in rural households of endemic areas significantly increases the likelihood of the vectorial transmission of the parasite. We studied the mortality and blood intake of T. infestans exposed to dogs treated with different doses and formulations of fipronil. Two doses, two formulations, and different distances to the application point of fipronil were compared. Third instar nymphs of T. infestans were fed at different time intervals after the insecticide application up to 45 days post-application. No significant difference was found between the blood intake of nymphs fed on control and treated dogs with different doses and formulations (p > 0.05). The spray formulation showed lower effect and persistence than the spot-on formulation. The mortality rate caused by the spot-on formulation in the 26.8-mg active ingredient (a.i.)/kg dose was higher (48%) than with the 13.4-mg a.i./kg dose (25%), 24 h after the insecticide application. The effect was highly heterogeneous among replicates of the same treatment. The mortality rate of nymphs fed over the point of the insecticide application was higher than the mortality of nymphs fed over places 12 cm apart from the fipronil application point, suggesting that the distribution of fipronil over the dog body is lower than the needed one to obtain a persistent triatomicide effect.


Tissue-type plasminogen activator and neuroserpin: a well-balanced act in the nervous system?
Tissue-type plasmingen activator (tPA) is a highly specific serine proteinase that activates the zymogen plasminogen to the broad-specificity proteinase plasmin. tPA is found in the blood, where its primary function is as a thrombolytic enzyme, as well as in the central nervous system (CNS), where it promotes events associated with synaptic plasticity and cell death in a number of settings, such as cerebral ischemia and seizures. Neuroserpin is a fully inhibitory serine proteinase inhibitor (serpin) that reacts preferentially with tPA, and is located in regions of the brain where either tPA message or tPA protein are also found, suggesting that neuroserpin is the selective inhibitor of tPA in the CNS. There is a growing body of evidence demonstrating the participation of tPA in a number of physiologic and pathologic events in the CNS, and the role of neuroserpin as the natural regulator of tPA's activity in these processes.


Coffee intake and risk of type 2 diabetes: the Multiethnic Cohort.
We evaluated the influence of coffee consumption on diabetes incidence among the Hawaii component of the Multiethnic Cohort (MEC). Prospective cohort. Population-based sample residing in Hawaii. After exclusions, 75 140 men and women of Caucasian, Japanese American and Native Hawaiian ancestry aged 45-75 years were part of the current analysis. All participants provided information on diet and lifestyle through an FFQ. After 14 years of follow-up 8582 incident diabetes cases were identified using self-reports, medication questionnaires and health plan linkages. Hazard ratios (HR) and 95 % confidence intervals were calculated using Cox regression while adjusting for known covariates. The risk for diabetes associated with total coffee consumption differed by sex (P interaction < 0·0001). Women consuming ≥3 cups of any type of coffee daily had a significantly lower risk (HR = 0·66; 95 % CI 0·58, 0·77; P trend < 0·0001) than those reporting <1 cup/d, whereas the relationship in men was borderline (HR = 0·89; 95 % CI 0·80, 0·99; P trend = 0·09). The same difference by sex was seen for regular coffee consumption, with HR of 0·65 (95 % CI 0·54, 0·78; P trend < 0·0001) and 0·86 (95 % CI 0·75, 0·98; P trend = 0·09) in men and women, respectively. No significant association with diabetes was apparent for decaffeinated coffee in women (HR = 0·85; 95 % CI 0·72, 1·01; P trend = 0·73) or men (HR = 1·07; 95 % CI 0·93, 1·23; P trend = 0·71). Despite small differences by ethnicity, the interaction terms between coffee intake and ethnicity were not significant. In this multiethnic population, regular, but not decaffeinated, coffee intake was much more protective against diabetes in women of all ethnic groups than in men.


Hypoxia-targeted cupric-tirapazamine liposomes potentiate radiotherapy in prostate cancer spheroids.
In this study, novel cupric-tirapazamine [Cu(TPZ)2]-liposomes were developed as an effective hypoxia-targeted therapeutic, which potentiated radiotherapy in a three dimensional (3D) prostate cancer (PCa) model. To overcome the low water solubility of the Cu(TPZ)2, a remote loading method was developed to efficiently load the lipophilic complex into different liposomal formulations. The effect of pH, temperature, PEGylation, lipid composition, liposome size, lipid: complex ratio on the liposome properties, and drug loading was evaluated. The highest loading efficiency was obtained at neutral pH, which was independent of lipid composition and incubation time. In addition, enhanced drug loading was achieved upon decreasing the lipid:complex molar ratio with minimal effects on liposomes' morphology. Interestingly, the in vitro potency of the developed liposomes was easily manipulated by changing the lipid composition. The hydrophilic nature of our liposomal formulations improved the complex's solubility, leading to enhanced cellular uptake and toxicity, both in PCa monolayers and tumour spheroids. Moreover, Cu(TPZ)2-loaded liposomes combined with radiation, showed a significant reduction in PCa spheroids growth rate, compared to the free complex or radiation alone, which could potentiate radiotherapy in patients with localised advanced PCa.


Regulation of renal sodium and water excretion in the nephrotic syndrome and cirrhosis of the liver.
Atrial natriuretic peptide (ANP) produced in the heart and prostaglandin E2 (PGE2) synthesised in the kidneys facilitate renal excretion of sodium and water, and thus oppose the actions of angiotensin II, aldosterone, arginine vasopressin (AVP), endothelin, and the renal sympathetic nerves. In the present work we studied the contributions and interactions of these substances in the regulation of blood volume (BV), renal haemodynamics, renal sodium and water handling and blood pressure (BP) in patients with glomerulonephritis and cirrhosis. The aim was through a better understanding of the pathophysiology to improve the treatment of fluid retention in these patients, which occurs as development of the nephrotic syndrome and accumulation of ascites, respectively. Normotensive patients with glomerulonephritis but without the nephrotic syndrome had normal baseline BV values measured as the sum of plasma volume and red cell volume; they responded to BV expansion after infusion of albumin and BV depletion after administration of furosemide with appropriate counterregulatory hormonal changes. However, they tended to hold more fluid within the intravascular phase after both manipulations than did the healthy subjects. The acutely induced increase in BV did not affect the BP, which was likely attributable to the changes in plasma values of angiotensin II and ANP shown. ANP could be expected to be a tool in the management of fluid accumulation in patients with the nephrotic syndrome and cirrhosis. The non-renal effects of high-dose ANP were studied for the first time in dialysis patients without excretory kidney function. A reversible shift of fluid away from the intravascular phase was demonstrated. The BV was maximally reduced 30 min after ANP had been given. The BP was reduced before fluid displacement occurred and to the same extent in patients and healthy subjects. The reduction in the BV was negatively correlated to the reduction in BP. From that study it is inferred that the BP reducing effect of ANP is not mediated by its diuretic effect or ability to displace fluid from the intravascular to the interstitial fluid compartment. As a pharmacological dose of ANP was given, it can only be suggested that endogenous ANP, by altering transcapillary Starling mechanisms, assists in buffering intravascular fluid expansion until renal excretion or dialysis can take place. The same dose of ANP was given to patients with the nephrotic syndrome and cirrhosis. The ability of ANP to increase sodium excretion through inhibition of sodium reabsorption in the distal tubules and to increase the glomerular filtration rate (GFR) was blunted in both patient groups, but the BP was reduced to the same extent as in the healthy controls. Patients with the nephrotic syndrome tended to have a slightly elevated BP. We only studied patients with normal or slightly reduced GFR. They had a normal BV, reduced renal filtration fraction, suppressed aldosterone, increased ANP, but normal plasma values of angiotensin II, endothelin, and AVP, and normal urinary excretion of PGE2. Thus, neither haemodynamic nor hormonal factors can easily explain the spontaneous sodium retention or the resistance to the effects of ANP and furosemide. An interesting finding, not previously reported in nephrotic humans, was the low cyclic guanosine 3'5'-monophosphate (cGMP) in plasma and urine in relation to ANP, both before and after administration of ANP. It is hypothesised that renal resistance to ANP, exaggerated renal cGMP degradation, or preponderance of clearance receptors in nephrotic kidneys may contribute to sodium retention and the low filtration fraction. Elevation of ANP in these patients is connected with increased albuminuria, and probably an increase in intraglomerular capillary pressure. The resistance to furosemide could not be attributed to delayed passage of fluid from the interstitial to the intravascular fluid phase, but is most likely due to renal tubular resistan


Diversity and host specificity of coccidia (Apicomplexa: Eimeriidae) in native and introduced squirrel species.
Introduction of alien species into new areas can have detrimental effects on native ecosystems and impact the native species. The present study aims to identify coccidia infecting native and introduced squirrels in Italy, to gain insight into possible transmission patterns and role of monoxenous coccidia in mediating the competition between alien and native hosts. We collected 540 faecal samples of native red squirrels, Sciurus vulgaris, invasive alien grey squirrels, S. carolinensis, and introduced Pallas's squirrels, Callosciurus erythraeus. Total prevalence of Eimeria spp. was 95.6% in S. vulgaris, 95.7% in S. carolinensis and only 4.1% in C. erythraeus. Morphological examination revealed 3 Eimeria morphotypes. Phylogenetic analyses of Eimeria DNA based on 18S, ITS, cox I markers displayed fairly distinct monophyletic clades in the microscopically indistinguishable E2 morphotype, proving indisputable distinction between the isolates from red and grey squirrels. Grey squirrels successfully introduced E. lancasterensis from their native range, but this species does not spill over to native red squirrels. Similarly, there is no evidence for the transmission of E. sciurorum from red to grey squirrels. The possible transmission and the potential role of monoxenous coccidia in mediating the competition between native and invasive squirrels in Italy were not confirmed.


Complement system proteins which interact with C3b or C4b A superfamily of structurally related proteins.
Recent cDNA sequencing data has allowed the prediction of the entire amino acid sequences of complement components factor B and C2, the complement control proteins factor H and C4b-binding protein and a partial sequence for the Cab/C4b receptor CR1. These proteins all contain internal repeating units of approximately 60 amino acids, each repeating unit having a characteristic framework of highly conserved residues. The N-terminal Ba and CA portions of factor B and C2 both contain 3 repeating units and the chains of C4b-binding protein and factor H contain 8 and 20 repeating units, respectively, while the precise number of units in CR1 is not known yet. These structurally homologous complement proteins are also functionally related as they all interact with C3b and C4b during activation of the cascade. The repeating units also occur in the functionally unrelated proteins subcomponent C1r, β2-glycoprotein 1, blood clotting factor XIII and interleukin-2 receptor. In this review Ken Reid and his colleagues propose that this could be a general feature of a superfamily of structurally related proteins.


Quantitative study of new bone formation in distraction osteogenesis of craniofacial bones by bone scintigraphy.
Although distraction osteogenesis is widely accepted as a technique to augment the craniofacial skeleton, timing to start distraction after an osteotomy or to remove distractors is basically based on studies on long bones. Because bone scintigraphy is well known to be the gold standard for quantitative measurement of bone formation, we conducted this pilot study to evaluate its feasibility as a tool for assessing new bone formation by distraction osteogenesis. Five patients with midface hypoplasia and four with mandibular hypoplasia were studied. Each patient had five bone scans: before surgery, 3 and 30 days after stopping distraction, and 3 days before and 3 months after distractor removal. Radiotracer uptake values at distraction sites were measured at 1 and 3 hours. Each uptake value was compared with preoperative study as uptake ratio. A typical pattern of radiotracer uptake ratio was observed in all cases with successful distraction. Uptake rose to the maximum during the consolidation period and remained at or above the preoperative level until the study end point. In one patient who had mandibular distraction and nonunion of the right ramus, there was no uptake peak during early consolidation as seen in the successfully distracted body and in the other cases. Bone scintigraphy was found to be a useful investigation in craniofacial distraction. It showed the dynamic of new bone formation by demonstrating the osteoblastic activity, which is important objective information for determining distraction rate and consolidation duration in each case. It may also be a tool that can predict the outcome of distraction osteogenesis.


Structural and Thermal Disorder of Solution-Processed CH3NH3PbBr3 Hybrid Perovskite Thin Films.
We extracted the electronic disorder energy of the organic-inorganic lead-halide hybrid perovskite CH3NH3PbBr3 from temperature-dependent absorption data. We showed that the disorder at room temperature is ∼30 meV and is due to strong electron-phonon coupling with the longitudinal-optical mode of energy 16 meV. This mode can be attributed to longitudinal-optical phonons of the inorganic PbBr6 frame; this conclusion highlights the polaronic nature of electronic excitations in CH3NH3PbBr3. We showed that structural disorder is of the same impact as thermal disorder. A temperature-dependence of the exciton binding energy was observed close to the orthorhombic-to-tetragonal phase-transition temperature.


The Effect of MCM3AP-AS1/miR-211/KLF5/AGGF1 Axis Regulating Glioblastoma Angiogenesis.
Glioblastoma (GBM) is the most aggressive and malignant primary tumor. Angiogenesis plays a critical role in the progression of GBM. Previous studies have indicated that long non-coding RNAs (lncRNAs) are abnormally expressed in various cancers and participate in the regulation of the malignant behaviors of tumors. The present study demonstrated that lncRNA antisense 1 to Micro-chromosome maintenance protein 3-associated protein (MCM3AP-AS1) was upregulated whereas miR-211 was downregulated in glioma-associated endothelial cells (GECs). Knockdown of MCM3AP-AS1 suppressed the cell viability, migration, and tube formation of GECs and played a role in inhibiting angiogenesis of GBM in vitro. Furthermore, knockdown of MCM3AP-AS1 increased the expression of miR-211. Luciferase reporter assay implicated that miR-211 targeted KLF5 3'-UTR and consequently inhibited KLF5 expression. Besides, in this study we found that MCM3AP-AS1 knockdown decreased KLF5 and AGGF1 expression by upregulating miR-211. In addition, KLF5 was associated with the promoter region of AGGF1. Knockdown of KLF5 decreased AGGF1 expression by transcriptional repression, and also inhibited the activation of PI3K/AKT and ERK1/2 signaling pathways. Overall, this study reveals that MCM3AP-AS1/miR-211/KLF5/AGGF1 axis plays a prominent role in the regulation of GBM angiogenesis and also serves as new therapeutic target for the anti-angiogenic therapy of glioma.