Rates of species introduction to a remote oceanic island.
The introduction of species to areas beyond the limits of their natural distributions has a major homogenizing influence, making previously distinct biotas more similar. The scale of introductions has frequently been commented on, but their rate and spatial pervasiveness have been less well quantified. Here, we report the findings of a detailed study of pterygote insect introductions to Gough Island, one of the most remote and supposedly pristine temperate oceanic islands, and estimate the rate at which introduced species have successfully established. Out of 99 species recorded from Gough Island, 71 are established introductions, the highest proportion documented for any Southern Ocean island. Estimating a total of approximately 233 landings on Gough Island since first human landfall, this equates to one successful establishment for every three to four landings. Generalizations drawn from other areas suggest that this may be only one-tenth of the number of pterygote species that have arrived at the island, implying that most landings may lead to the arrival of at least one alien. These rates of introduction of new species are estimated to be two to three orders of magnitude greater than background levels for Gough Island, an increase comparable to that estimated for global species extinctions (many of which occur on islands) as a consequence of human activities.


Cognitive reserve in neuropsychiatry.
The idea that superior cognitive function acts as a protective factor against dementia and the consequences of head injury is well established. Here we suggest the hypothesis that cognitive reserve is also important in neuropsychiatric disorders including schizophrenia, bipolar disorder and depression. We review the history of passive and active models of reserve, and apply the concept to neuropsychiatric disorders. Schizophrenia is used as an exemplar because the effects of premorbid IQ and cognitive function in this disorder have been extensively studied. Cognitive reserve may impact on neuropsychiatric disorders in three ways: by affecting the risk for developing the disorder, in the expression of symptoms within disorders, and in patients' functional outcome. Cognitive failure below a certain threshold may alone, or in combination with common psychiatric symptoms, produce neuropsychiatric syndromes. Consideration of cognitive reserve may considerably improve our understanding of individual differences in the causes and consequences of neuropsychiatric disorders. For these reasons, the concept of cognitive reserve should be incorporated in future studies of neuropsychiatric disorder. It may be possible to enhance cognitive reserve through pharmacological or non-pharmacological means, such as education, neurocognitive activation or other treatment programmes.


Emotion in language and speech: methodological issues in naturalistic approaches.
Researchers currently seek to improve validity in speech and language studies by adopting naturalistic procedures In emotion-display research, validity is threatened by standard experimental controls which diminish the naturalism of stimuli and response ranges. We report two experiments comparing the adequacy of naturalistic with standard procedures. Experiment 1 had 158 judges code 89 samples of naturally-occurring emotional speech with free-choice emotion labels, and later with labels from a standard set. When free-choice labels were similar across judges, they were consistent with standard labels, but showed a range of intensity and contextual relevance. We recommend that future studies include wider options for judges when coding emotions. Experiment 2 compared valency ratings of words when presented in, or out of, context. Standard procedures score lexical valencies using affective dictionaries, disregarding natural contexts. Experiment 2 compared 23 judges' valency ratings of words presented individually, and later in their original context. Between 30% and 44% of words were rated differently in context (depending on the statistical significance level adopted). We concluded from Experiment 2 that, where small corpora adequately model a domain, the improved accuracy of valency rating achieved by presenting words in their natural context justifies the extra procedures required.


Studies on the therapeutic effect of propolis along with standard antibacterial drug in Salmonella enterica serovar Typhimurium infected BALB/c mice.
Antibiotic resistance is an emerging public health problem. Centers for Disease Control and Prevention (CDC) has described antibiotic resistance as one of the world's most pressing health problems in 21st century. WHO rated antibiotic resistance as "one of the three greatest threats to human health". One important strategy employed to overcome this resistance is the use of combination of drugs. Many plants, natural extracts have been shown to exhibit synergistic response with standard drugs against microorganisms. The present study focused on the antibacterial potential of propolis in combination with the standard antibiotic Cefixime against the typhoid causing bacteria i.e. Salmonella. Ethanolic extract of propolis was taken for the present work. For the experiment BALB/c mice were taken as animal model and divided into ten groups. Along with normal and infected control groups, four different combinations of cefixime and propolis were used. Biochemical, hematological and histopathological indices were studied by following the standard protocols. In BALB/c mice, Salmonella causes severe biochemical, hematological and histopathological alterations by 5th day of infection. Ethanolic extract of propolis at a dose of 300 mg/kg body weight of mice when used alone to treat Salmonella infection in mice gave significant results by 30th day of treatment. Similarly, when cefixime (4 mg/kg body weight of mice) was used to treat infection in mice, significant results as compared to infected control were observed after 5th day. But when propolis and cefixime were used together in different concentrations in combination therapy, evident results were observed after 5 days of treatment. The levels of various liver and kidney function enzymes, blood indices and the histopathology of liver, spleen and kidney were restored to near normal after 5 days of treatment and at much lower doses as compared to the effective dose when used alone. The study confirmed that significant results were observed in three combinations of cefixime and propolis as compared to infected controls. Propolis acted synergistically with cefixime and enhanced the efficacy of antibiotic and reduced its effective dose in combined therapy.


Disordered (pathologic or problem) gambling and axis I psychiatric disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions.
The authors' objective in this study was to examine the role of disordered gambling as a risk factor for the subsequent occurrence of specific Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Axis I psychiatric disorders after adjusting for medical conditions, health-related quality of life, and stressful life events. Community-dwelling respondents from nationally representative US samples (n = 33,231) were interviewed in 2000-2001 and 2004-2005. Past-year disordered gambling at baseline was associated with the subsequent occurrence of any Axis I psychiatric disorder, any mood disorder, bipolar disorder, generalized anxiety disorder, posttraumatic stress disorder, any substance use disorder, alcohol use disorders, and alcohol dependence disorder after adjustment for sociodemographic variables. After simultaneous adjustment for medical conditions, health-related quality of life, and recent stressful life events, disordered gambling remained significantly related to any mood disorder, generalized anxiety disorder, posttraumatic stress disorder, alcohol use disorders, and alcohol dependence. The clinical implications of these findings are that treatment providers need to screen gambling patients for mood, anxiety, and substance use problems and monitor the possible development of later comorbid conditions.


[Maternal transition in mothers with high risk newborns].
The purpose of this study was a comprehensive understanding about maternal transition in mothers with high risk newborns according to the degree of situational meaning. A methodological triangulation that combines qualitative and quantitative methods was used. The situational meaning of a high risk newborn mother was identified using a Family Meaning Attribution Scale. According to the degree of situational meaning, in-depth interviews were conducted at 3 time periods postpartum : between 3-10 days after childbirth, around the time of the newborn's discharge, and between 10-12 weeks after childbirth. Quantitative data was analyzed using descriptive statistics and t-test. Qualitative data was analyzed using Tutty, Rothery, & Grinnell's methodology. The average score of the situational meaning in high the risk newborn mother was 53.57(possible score is between 0-96) and the average score of each item was 1.67. A Maternal transition process in the mother that has a positive situational meaning was conceptualized in three distinctive phases : confusion, accepting, and shaping phases. The Maternal transition process in the mother that has a negative situational meaning was also conceptualized in three distinctive phases : avoiding, conflicting, and accepting phases. It is necessary that the nurses provide high risk newborn mothers with individualized care considering both the situational meaning that is attributed to them and the maternal transition phase that they are faced with.


Biodiversity hotspots house most undiscovered plant species.
For most organisms, the number of described species considerably underestimates how many exist. This is itself a problem and causes secondary complications given present high rates of species extinction. Known numbers of flowering plants form the basis of biodiversity "hotspots"--places where high levels of endemism and habitat loss coincide to produce high extinction rates. How different would conservation priorities be if the catalog were complete? Approximately 15% more species of flowering plant are likely still undiscovered. They are almost certainly rare, and depending on where they live, suffer high risks of extinction from habitat loss and global climate disruption. By using a model that incorporates taxonomic effort over time, regions predicted to contain large numbers of undiscovered species are already conservation priorities. Our results leave global conservation priorities more or less intact, but suggest considerably higher levels of species imperilment than previously acknowledged.


The left cradling bias: An evolutionary facilitator of social cognition?
A robust left side cradling bias (LCB) in humans is argued to reflect an evolutionarily old left visual field bias and right hemisphere dominance for processing social stimuli. A left visual field bias for face processing, invoked via the LCB, is known to reflect a human population-level right cerebral hemisphere specialization for processing social stimuli. We explored the relationship between cradling side biases, hand dominance and socio-communicative abilities. Four and five year old typically-developing children (N = 98) participated in a battery of manual motor tasks interspersed by cradling trials comprising a(n): infant human doll, infant primate doll, proto-face pillow and no-face pillow. Mean social and communication ability scores were obtained via a survey completed by each child's key teacher. We found a population-level LCB for holding an infant human doll that was not influenced by hand dominance, sex, age or experience of having a younger sibling. Children demonstrating a LCB, did however, obtain a significantly higher mean social ability score compared with their right side cradling counterparts. Like the infant human doll, the proto-face pillow's schematic face symbol was sufficient to elicit a population-level LCB. By contrast, the infant primate doll elicited a population-level right side cradling bias, influenced by both hand dominance and sex. The findings suggest that the LCB is present and visible early in development and is likely therefore, to represent evolutionarily old domain-specific organization and function of the right cerebral hemisphere. Additionally, results suggest that a LCB requires minimal triggering but can be reversed in some situations, possibly in response to species-type or levels of novelty or stress as perceived by the viewer. Patterns of behavioral biases within the context of social stimuli and their associations with cognitive ability are important for understanding how socio-communication abilities emerge in developing children.


Dietary Inulin Fibers Prevent Proton-Pump Inhibitor (PPI)-Induced Hypocalcemia in Mice.
Proton-pump inhibitor-induced hypomagnesemia (PPIH) is the most recognized side effect of proton-pump inhibitors (PPIs). Additionally, PPIH is associated with hypocalcemia and hypokalemia. It is hypothesized that PPIs reduce epithelial proton secretion and thereby increase the pH in the colon, which may explain the reduced absorption of and Mg2+ and Ca2+. Fermentation of dietary oligofructose-enriched inulin fibers by the microflora leads to acidification of the intestinal lumen and by this enhances mineral uptake. This study aimed, therefore, to improve mineral absorption by application of dietary inulin to counteract PPIH. Here, C57BL/J6 mice were supplemented with omeprazole and/or inulin. Subsequently, Mg2+ and Ca2+ homeostasis was assessed by means of serum, urine and fecal electrolyte measurements. Moreover, the mRNA levels of magnesiotropic and calciotropic genes were examined in the large intestine and kidney by real-time PCR. Treatment with omeprazole significantly reduced serum Mg2+ and Ca2+ levels. However, concomitant addition of dietary inulin fibers normalized serum Ca2+ but not serum Mg2+ concentrations. Inulin abolished enhanced expression of Trpv6 and S100g in the colon by omeprazole. Additionally, intestinal and renal mRNA levels of the Trpm6 gene were reduced after inulin intake. This study suggests that dietary inulin counteracts reduced intestinal Ca2+ absorption upon PPI treatment. In contrast, inulin did not increase intestinal absorption of Mg2+ sufficiently to recover serum Mg2+. The clinical potential of dietary inulin treatment should be the subject of future studies.


White Matter Lesions in Femoral Head Osteonecrosis patients: Manifestation of vascular disease or not?
Osteonecrosis has been associated with the presence of white matter lesions. The objective of this study was to investigate the association between macro- and micro- vascular disease and white matter lesions. Sixty-four patients with femoral head osteonecrosis were assessed during a cross sectional study in our university-based hospital. A vascular 'profile' was obtained for each patient and included measurement of plasma lipids, fundoscopic examination and common carotid artery triplex ultrasonography. All patients had brain MRI to assess for presence of white matter lesions. The two groups formed, with and without white matter lesions, were compared in order to define the association between white matter lesions and vascular disease. Patients without white matter lesions had more frequently corticosteroid induced osteonecrosis. There was no difference in the two groups with respect to intima media thickness and ApoB/ApoA1 ratio. Only one of our patients demonstrated retinopathy. There is no evidence of concurrent macro- and micro- vascular pathology in young patients with white matter lesions and femoral head osteonecrosis. Cortisone appears to have a 'protective' effect against occurrence of white matter lesions.


Prevalence of sexual dysfunction and impact of contraception in female German medical students.
Female sexual dysfunction (FSD) is a very common disorder, with an estimated prevalence of having at least one sexual dysfunction of about 40%. To investigate the prevalence and types of FSD and the relationship between hormonal contraception (HC) and FSD in female German medical students. Female Sexual Function Index (FSFI) with additional questions on contraception, sexual activity, and other factors that may influence sexual function. An online questionnaire based on the FSFI was completed by students from six medical schools. Obtained data were screened for inconsistencies by programmed algorithms. A total of 1,219 completed questionnaires were received, and 1,086 were included in the analyses after screening. The mean total FSFI score was 28.6 +/- 4.5. 32.4% of women were at risk for FSD according to FSFI definitions. Based on domain scores, 8.7% for were at risk for FSD concerning orgasm, 5.8% for desire, 2.6% for satisfaction, 1.2% for lubrication, 1.1% for pain and 1.0% for arousal. The method of contraception and smoking were factors with significant effect on the total FSFI score whereby hormonal contraception was associated with lower total FSFI scores and lower desire and arousal scores than no contraception and non-hormonal contraception only. Other variables such as stress, pregnancy, smoking, relationship and wish for children had an important impact on sexual function as expected according to earlier studies. The prevalence of students at high risk for FSD was consistent with the literature although domain subscores differed from samples previously described. The contraception method has a significant effect on the sexual functioning score and women using contraception, especially hormonal contraception, had lower sexual functioning scores. Stress and relationship among other variables were found to be associated with sexual function and may thus provide insight into the etiology of sexual disorders.


Quantitation of the rates of hepatic and intestinal cholesterol synthesis in lysosomal acid lipase-deficient mice before and during treatment with ezetimibe.
Esterified cholesterol (EC) and triglycerides, contained within lipoproteins taken up by cells, are hydrolysed by lysosomal acid lipase (LAL) in the late endosomal/lysosomal (E/L) compartment. The resulting unesterified cholesterol (UC) is transported via Niemann-Pick type C2 and C1 into the cytosolic compartment where it enters a putative pool of metabolically active cholesterol that is utilized in accordance with cellular needs. Loss-of-function mutations in LIPA, the gene encoding LAL, result in dramatic increases in tissue concentrations of EC, a hallmark feature of Wolman disease and cholesteryl ester storage disease (CESD). The lysosomal sequestration of EC causes cells to respond to a perceived deficit of sterol by increasing their rate of cholesterol synthesis, particularly in the liver. A similar compensatory response occurs with treatments that disrupt the enterohepatic movement of cholesterol or bile acids. Here we measured rates of cholesterol synthesis in vivo in the liver and small intestine of a mouse model for CESD given the cholesterol absorption inhibitor ezetimibe from weaning until early adulthood. Consistent with previous findings, this treatment significantly reduced the amount of EC sequestered in the liver (from 132.43±7.35 to 70.07±6.04mg/organ) and small intestine (from 2.78±0.21 to 1.34±0.09mg/organ) in the LAL-deficient mice even though their rates of hepatic and intestinal cholesterol synthesis were either comparable to, or exceeded those in matching untreated Lal-/- mice. These data reveal the role of intestinal cholesterol absorption in driving the expansion of tissue EC content and disease progression in LAL deficiency.


Optimal signal processing of nonlinearity in swept-source and spectral-domain optical coherence tomography.
We demonstrate the efficiency of the convolution using an optimized Kaiser-Bessel window to resample nonlinear data in wavenumber for Fourier-domain optical coherence tomography (OCT). We extend our previous experimental demonstration that was performed with a specific swept-source nonlinearity. The method is now applied to swept-source OCT data obtained for various simulated swept-source nonlinearities as well as spectral-domain OCT data obtained from both simulations and experiments. Results show that the new optimized method is the most efficient for handling all the different types of nonlinearities in the wavenumber domain that one can encounter in normal practice. The efficiency of the method is evaluated through comparison with common methods using resampling through interpolation prior to performing a fast-Fourier transform and with the accurate but time-consuming discrete Fourier transform for unequally spaced data, which involves Vandermonde matrices.


Experimental Validation of Model-Based Prognostics for Pneumatic Valves.
Because valves control many critical operations, they are prime candidates for deployment of prognostic algorithms. But, similar to the situation with most other components, examples of failures experienced in the field are hard to come by. This lack of data impacts the ability to test and validate prognostic algorithms. A solution sometimes employed to overcome this shortcoming is to perform run-to-failure experiments in a lab. However, the mean time to failure of valves is typically very high (possibly lasting decades), preventing evaluation within a reasonable time frame. Therefore, a mechanism to observe development of fault signatures considerably faster is sought. Described here is a testbed that addresses these issues by allowing the physical injection of leakage faults (which are the most common fault mode) into pneumatic valves. What makes this testbed stand out is the ability to modulate the magnitude of the fault almost arbitrarily fast. With that, the performance of end-of-life estimation algorithms can be tested. Further, the testbed is mobile and can be connected to valves in the field. This mobility helps to bring the overall process of prognostic algorithm development for this valve a step closer to validation. The paper illustrates the development of a model-based prognostic approach that uses data from the testbed for partial validation.


Effect of cyclodextrin and transformer oil amendments on the chemical extractability of aged [14C]polychlorinated biphenyl and [14C]polycyclic aromatic hydrocarbon residues in soil.
Sequestration of hydrophobic organic contaminants (HOCs) in soils limits chemical and biological availability. Concerns exist regarding the long-term stability of sequestered contaminants in the environment, and stability needs to be demonstrated if bioavailability considerations are to be adopted into the risk assessment and remediation of contaminated land. The aim of the present study was to test the short-term influence of two organic amendments on the chemical extractability of HOC residues that had been present in soils for more than 12 years. The amendments investigated were cyclodextrin and transformer oil (a light, nonaqueous phase liquid [LNAPL]). The contaminants investigated were fluoranthene and benzo[a]pyrene in one soil and the polychlorinated biphenyls (PCBs) 28 and 52 in a second soil. The addition of cyclodextrin to the soils did not result in a significant increase in chemical extractability of the residues after a 36-d contact time. The addition of transformer oil resulted in an increase in chemical extractability of the PCBs after a 14-d soil-LNAPL contact time and a further increase after a 36-d contact time. The present study demonstrates that the chemical availability of aged HOCs in soil may be influenced by the presence of other chemicals and has implications for the long-term management of contaminated land.


Redefining Relative Biological Effectiveness in the Context of the EQDX Formalism: Implications for Alpha-Particle Emitter Therapy.
Alpha-particle radiopharmaceutical therapy (αRPT) is currently enjoying increasing attention as a viable alternative to chemotherapy for targeting of disseminated micrometastatic disease. In theory, αRPT can be personalized through pre-therapeutic imaging and dosimetry. However, in practice, given the particularities of α-particle emissions, a dosimetric methodology that accurately predicts the thresholds for organ toxicity has not been reported. This is in part due to the fact that the biological effects caused by α-particle radiation differ markedly from the effects caused by traditional external beam (photon or electron) radiation or β-particle emitting radiopharmaceuticals. The concept of relative biological effectiveness (RBE) is used to quantify the ratio of absorbed doses required to achieve a given biological response with alpha particles versus a reference radiation (typically a beta emitter or external beam radiation). However, as conventionally defined, the RBE varies as a function of absorbed dose and therefore a single RBE value is limited in its utility because it cannot be used to predict response over a wide range of absorbed doses. Therefore, efforts are underway to standardize bioeffect modeling for different fractionation schemes and dose rates for both nuclear medicine and external beam radiotherapy. Given the preponderant use of external beams of radiation compared to nuclear medicine in cancer therapy, the more clinically relevant quantity, the 2 Gy equieffective dose, EQD2(α/β), has recently been proposed by the ICRU. In concert with EQD2(α/β), we introduce a new, redefined RBE quantity, named RBE2(α/β), as the ratio of the two linear coefficients that characterize the α particle absorbed dose-response curve and the low-LET megavoltage photon 2 Gy fraction equieffective dose-response curve. The theoretical framework for the proposed new formalism is presented along with its application to experimental data obtained from irradiation of a breast cancer cell line. Radiobiological parameters are obtained using the linear quadratic model to fit cell survival data for MDA-MB-231 human breast cancer cells that were irradiated with either α particles or a single fraction of low-LET 137Cs γ rays. From these, the linear coefficient for both the biologically effective dose (BED) and the EQD2(α/β) response lines were derived for fractionated irradiation. The standard RBE calculation, using the traditional single fraction reference radiation, gave RBE values that ranged from 2.4 for a surviving fraction of 0.82-6.0 for a surviving fraction of 0.02, while the dose-independent RBE2(4.6) value was 4.5 for all surviving fraction values. Furthermore, bioeffect modeling with RBE2(α/β) and EQD2(α/β) demonstrated the capacity to predict the surviving fraction of cells irradiated with acute and fractionated low-LET radiation, α particles and chronic exponentially decreasing dose rates of low-LET radiation. RBE2(α/β) is independent of absorbed dose for α-particle emitters and it provides a more logical framework for data reporting and conversion to equieffective dose than the conventional dose-dependent definition of RBE. Moreover, it provides a much needed foundation for the ongoing development of an α-particle dosimetry paradigm and will facilitate the use of tolerance dose data available from external beam radiation therapy, thereby helping to develop αRPT as a single modality as well as for combination therapies.


Replacing 14C with stable isotopes in drug metabolism studies.
After administration of a mixed dose of both radioisotope and stable-isotope-labeled tirilazad, we carried out a parallel set of HPLC analyses for drug metabolites in bile samples from monkeys and dogs using either radioactivity monitoring (RAM) for 14C or the chemical reaction interface mass spectrometry technique (CRIMS) to detect 13C or 15N. CRIMS is a novel method where analytes are decomposed in a microwave-induced plasma and the elements contained in the analytes are reformulated into small gaseous species that are detected by a mass spectrometer. The comprehensiveness of detection, chromatographic resolution, sensitivity, signal/noise, and quantitative abilities of CRIMS were compared with RAM and in no case was RAM superior. This implies that stable isotopes may be substituted for radioisotopes in studies of drug metabolism where the ability of the latter approach to detect a label independent of the structures in which the label appears has been the primary reason for continuing to use a hazardous and expensive tracer. With HPLC-CRIMS, stable isotopes such as 13C and 15N can be comprehensively detected and quantitative patterns of drug metabolism from biological fluids can be produced that mirror the results when 14C is used.


Differential distribution of cardiac ion channel expression as a basis for regional specialization in electrical function.
The cardiac electrical system is designed to ensure the appropriate rate and timing of contraction in all regions of the heart, which are essential for effective cardiac function. Well-controlled cardiac electrical activity depends on specialized properties of various components of the system, including the sinoatrial node, atria, atrioventricular node, His-Purkinje system, and ventricles. Cardiac electrical specialization was first recognized in the mid 1800s, but over the past 15 years, an enormous amount has been learned about how specialization is achieved by differential expression of cardiac ion channels. More recently, many aspects of the molecular basis have been revealed. Although the field is potentially vast, an appreciation of key elements is essential for any clinician or researcher wishing to understand modern cardiac electrophysiology. This article reviews the major regionally determined features of cardiac electrical function, discusses underlying ionic bases, and summarizes present knowledge of ion channel subunit distribution in relation to functional specialization.


Activation of cell cycle arrest and apoptosis by the proto-oncogene Pim-2.
Potent survival effects have been ascribed to the serine/threonine kinase proto-oncogene PIM-2. Elevated levels of PIM-2 are associated with various malignancies. In human cells, a single Pim-2 transcript gives rise mainly to two protein isoforms (34, 41 kDa) that share an identical catalytic site but differ at their N-terminus, due to in-frame alternative translation initiation sites. In this study we observed that the 34 kDa PIM-2 isoform has differential nuclear and cytoplasmic forms in all tested cell lines, suggesting a possible role for the balance between these forms for PIM-2's function. To further study the cellular role of the 34 kDa isoform of PIM-2, an N-terminally HA-tagged form of this isoform was transiently expressed in HeLa cells. Surprisingly, this resulted in increased level of G1 arrested cells, as well as of apoptotic cells. These effects could not be obtained by a Flag-tagged form of the 41 kDa isoform. The G1 arrest and apoptotic effects were associated with an increase in T14/Y15 phosphorylation of CDK2 and proteasom-dependent down-regulation of CDC25A, as well as with up-regulation of p57, E2F-1, and p73. No such effects were obtained upon over-expression of a kinase-dead form of the HA-tagged 34 kDa PIM-2. By either using a dominant negative form of p73, or by over-expressing the 34 kDa PIM-2 in p73-silenced cells, we demonstrated that these effects were p73-dependent. These results demonstrate that while PIM-2 can function as a potent survival factor, it can, under certain circumstances, exhibit pro-apoptotic effects as well.


Zyzzyzus rubusidaeus (Cnidaria, Hydrozoa, Tubulariidae), a new species of anthoathecate hydroid from the coast of British Columbia, Canada.
Zyzzyzus rubusidaeus, sp. nov., is described from inshore waters near the northern tip of Vancouver Island, British Columbia, Canada. Specimens were collected on rocky bottoms amongst barnacles, sponges, and compound ascidians at a depth of 18 m in Weynton Passage, Broughton Strait, during March, July, and October 2012. Polyps tend to grow in dense aggregations, often covering several square centimetres. Hydroids of Z. rubusidaeus most closely resemble those of Z. robustus Petersen, 1990 from Greenland, but differ in having aboral tentacles that are scattered in a narrow band around the base of the hydranth rather than occurring in a single whorl, thin and transparent instead of thick and stiff perisarc around hydrocaulus and tubers, and gonophores that arise from simple pedicels instead of short, stout branches. Possible embryos were present in female gonophores, although structures recognizable as actinula larvae have not been observed. The cnidome comprises small and large stenoteles, desmonemes, microbasic euryteles, basitrichs, and isorhizas. Polyps are a raspberry colour in life, a hue that has faded but little in our formalin-preserved material. Discovery of this hydroid brings the number of species currently recognized in genus Zyzzyzus Stechow, 1921 to seven.


Contralateral acute subdural hematoma after surgical evacuation of the initial hematoma: two case reports and review of the literature.
Remote intracranial hemorrhages after craniotomy or craniectomy may rarely develop. As the sparse literature on this phenomenon has focused on contralateral intraparenchymal and epidural clots, only seven cases of postoperative contralateral acute subdural hematomas have been reported in the literature. We presented two patients who developed contralateral acute subdural hematomas after surgical evacuation of their initial hematomas. Case 1: A 19-year-old male fell from a height. CT scan revealed a left parietal acute epidural hematoma. A left craniotomy and epidural hematoma evacuation were performed; however, the brain expanded towards the craniotomy site. Dural incision revealed a thick subdural hematoma. Evacuation of the subdural hematoma was performed. The bone flap was not replaced. An emergency CT scan revealed a right acute subdural hematoma, and a right decompressive craniectomy and hematoma evacuation were performed. Case 2: A 7-year-old boy was hit by a motor vehicle. CT scan revealed a right frontotemporal acute subdural hematoma. A right decompressive craniectomy and subdural hematoma evacuation were performed; however, the brain expanded towards the craniectomy site. An emergency CT scan revealed a left acute subdural hematoma. We also reviewed the literature and discussed about these characteristics.


Damnacanthal inhibits the NF-κB/RIP-2/caspase-1 signal pathway by inhibiting p56lck tyrosine kinase.
Damnacanthal is a major constituent of Morinda citrifolia L. (noni) and exhibits anti-cancer and anti-inflammatory activities. However, the effects of damnacanthal on allergic diseases have not been determined. In this study, we investigated the effect of damnacanthal on mast cell-mediated allergic inflammatory responses. Damnacanthal significantly and dose-dependently inhibited compound 48/80-induced systemic anaphylactic shock, histamine release and intracellular calcium levels. In particular, IgE-mediated passive cutaneous anaphylaxis was significantly inhibited by the oral administration of damnacanthal. In addition, we report for the first time that p56lck tyrosine kinase was expressed in phorbol 12-myristate 13-acetate and calcium ionophore A23187 (PMACI)-stimulated mast cells. Furthermore, damnacanthal inhibited the up-regulation of p56lck tyrosine kinase activity by PMACI and repressed PMACI-induced histidine decarboxylase expression and activity. Damnacanthal also inhibited PMACI-induced interleukin (IL)-1β, IL-6 and tumor necrosis factor-α expressions by suppressing nuclear factor-kappa B (NF-κB) activation and suppressed the activation of caspase-1 and the expression of receptor interacting protein-2. This study shows damnacanthal inhibits the NF-κB/receptor-interacting protein-2/caspase-1 signal pathway by inhibiting p56lck tyrosine kinase and suggests that damnacanthal has potential for the treatment of mast cell-mediated allergic disorders.


Treatment trends and Medicare reimbursements for localized prostate cancer in elderly patients.
The absolute and proportional numbers of elderly patients diagnosed with localized prostate cancer (PCa) are on the rise. We examined treatment trends and reimbursement figures in localized PCa patients aged ≥80 years. Between 2000 and 2008, we identified 30 217 localized PCa patients aged ≥80 years in Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database. Alternative treatment modalities consisted of conservative management (CM), radiation therapy (RT), radical prostatectomy (RP), and primary androgen-deprivation therapy (PADT). For all four modalities, utilization and reimbursements were examined. PADT was the most frequently used treatment modality between 2000 and 2005. CM became the dominant treatment modality from 2006-2008. RP rates were marginal. RT ranked third, and its annual rate increased from 20.77% in 2000 to 29.13% in 2008. Median individual reimbursement of RT was highest and ranged from $29 343 in 2000 to $31 090 in 2008, followed by RP (from $20 560 in 2000 to $19 580 in 2008), PADT (from $18 901 in 2000 to $8000 in 2008), and CM (from $1824 in 2000 to $1938 in 2008). RT contributed to most of the cumulative annual reimbursements from 2003 (49.24%) to 2008 (72.97%). PADT ranked first from 2000 (54.56%) to 2002 (50.49%), but decreased by 19.40% in 2008. CM's contribution increased from 4.42% in 2000 to 6.96% in 2008. RP's share of reimbursements was stable during the study period. Our results, focusing on localized PCa treatment in patients aged ≥80 years, showed an important increase in rates, median cost, and proportion of cumulative cost related to RT.


The community of Hymenoptera parasitizing necrophagous Diptera in an urban biotope.
Most reports published in the field of forensic entomology are focused on Diptera and neglect the Hymenoptera community. However, Hymenoptera are part of the entomofaunal colonization of a dead body. The use of Hymenoptera parasitoids in forensic entomology can be relevant to evaluate the time of death. Hymenoptera parasitoids of the larvae and pupae of flies may play an important role in the estimation of the post-mortem period because their time of attack is often restricted to a small, well-defined window of time in the development of the host insect. However, these parasitoids can interfere with the developmental times of colonizing Diptera, and therefore a better understanding of their ecology is needed. The work reported here monitored the presence of adult Hymenoptera parasitoids on decaying pig carcasses in an urban biotope during the summer season (from May to September). Six families and six species of parasitoids were recorded in the field: Aspilota fuscicornis Haliday (Braconidae), Alysia manducator Panzer, Nasonia vitripennis Walker (Pteromalidae), Tachinaephagus zealandicus Ashmead (Encyrtidae), Trichopria sp. (Diapriidae), and Figites sp. (Figitidae). In the laboratory, five species emerged from pupae collected in the field: Trichopria sp., Figites sp., A. manducator, N. vitripennis, and T. zealandicus. These five species colonize a broad spectrum of Diptera hosts, including those species associated with decomposing carcasses, namely those from the families Calliphoridae, Muscidae, Fanniidae, and Sarcophagidae.


Temporally specific miRNA expression patterns in the dorsal and ventral striatum of addiction-prone rats.
MicroRNAs (miRNAs) within the ventral and dorsal striatum have been shown to regulate addiction-relevant behaviours. However, it is unclear how cocaine experience alone can alter the expression of addiction-relevant miRNAs within striatal subregions. Further, it is not known whether differential expression of miRNAs in the striatum contributes to individual differences in addiction vulnerability. We first examined the effect of cocaine self-administration on the expression of miR-101b, miR-137, miR-212 and miR-132 in nucleus accumbens core and nucleus accumbens shell (NAcSh), as well as dorsomedial striatum and dorsolateral striatum (DLS). We then examined the expression of these same miRNAs in striatal subregions of animals identified as being 'addiction-prone', either immediately following self-administration training or following extinction and relapse testing. Cocaine self-administration was associated with changes in miRNA expression in a regionally discrete manner within the striatum, with the most marked changes occurring in the nucleus accumbens core. When we examined the miRNA profile of addiction-prone rats following self-administration, we observed increased levels of miR-212 in the dorsomedial striatum. After extinction and relapse testing, addiction-prone rats showed significant increases in the expression of miR-101b, miR-137, miR-212 and miR-132 in NAcSh, and miR-137 in the DLS. This study identifies temporally specific changes in miRNA expression consistent with the engagement of distinct striatal subregions across the course of the addiction cycle. Increased dysregulation of miRNA expression in NAcSh and DLS at late stages of the addiction cycle may underlie habitual drug seeking, and may therefore aid in the identification of targets designed to treat addiction.


Sounds emitted by the bottlenose dolphin.
The sonic emissions of the bottlenose dolphin are remarkably complex. Three classes of these sounds are discussed and presented graphically. The sine-type wave whistles range in frequency from about 4000 to 18,000 cycles per second. The clicks contain components of this same frequency range plus some components of higher frequencies. Complex waves of high amplitude and of many frequencies are also emitted in water or in air. Situations in which sounds of one or more of these classes can be elicited simultaneously from one and from two restrained animals are described. The necessity for, and occurrence of, creakings for purpose of navigation, ranging, and recognition (sonar) have been eliminated in the experiments under discussion.


Carotid stent-assisted angioplasty.
We present the results of the first 33 patients who underwent carotid stent-assisted angioplasty at the Heart Unit of Panorama Medi-Clinic between March 1995 and June 1996. Intravascular stents (48 Palmaz-Schatz and 1 Wall stent) were deployed in the common carotid arteries (5) and internal carotid arteries (38) of both symptomatic (28 patients) and asymptomatic patients (5 patients) with > 60% stenosis (35 with > 70% and 6 with 60% stenosis). Thirteen patients underwent bilateral stent implantation, and had percutaneous transluminal coronary angioplasty or a peripheral and/or coronary stent implanted. Mean admission time was 2 days. Follow-up for 15 months (mean 9 months) employed clinical evaluation, duplex scanning at 6 and 12 months, and cerebral magnetic resonance imaging before, 48 hours and 6 months after the procedure. Angiographic success, defined as maximal residual stenosis < 10%, was achieved in 100%. Clinical success, defined as maximal residual stenosis < 10% and absence of death or recurrent transient ischaemic attack or stroke in hospital, was achieved in 97.7% of treated lesions. Complications included one procedure-related ipsilateral stroke and two angiography-related cerebellar infarcts. No transient ischaemic attacks or deaths occurred. No early or late restenoses have been observed to date. This experience with carotid stent-assisted angioplasty indicates that interventional neurovascular therapies may provide a useful alternative for selected patients requiring endoluminal reconstruction of carotid stenoses.


Sexual functioning in military personnel: preliminary estimates and predictors.
Although the military is a young and vigorous force, service members and veterans may experience sexual functioning problems (SFPs) as a result of military service. Sexual functioning can be impaired by physical, psychological, and social factors and can impact quality of life (QOL) and happiness. This study aims to estimate rates and correlates of SFPs in male military personnel across demographic and psychosocial characteristics, to examine the QOL concomitants, and to evaluate barriers for treatment seeking. This exploratory cross-sectional study was conducted using data from a larger nationwide study conducted between October 2013 and November 2013. This sample consists of 367 male active duty service members and recent veterans (military personnel) age 40 or younger. Erectile dysfunction (ED) was determined using the five-item International Index of Erectile Function, sexual dysfunction (SD) was determined using the Arizona Sexual Experiences Scale, Male, and QOL was determined using the World Health Organization Quality of Life, Brief. SFPs were associated with various demographic, physical, and psychosocial risk factors. The rates of SD and ED were 8.45% and 33.24%, respectively, for male military personnel aged 21-40. Those who were 36-40, nonmarried, nonwhite, and of lower educational attainment reported the highest rates of SFPs. Male military personnel with poor physical and psychosocial health presented the greatest risk for ED and SD. SFPs were associated with reduced QOL and lower happiness, and barriers for treatment were generally related to social barriers. SFPs in young male military personnel are an important public health concern that can severely impact QOL and happiness.


Country of birth and risk of hospitalization due to heart failure: a Swedish population-based cohort study.
To explore the relation between country of birth and risk of hospitalization due to heart failure (HF). All 40-89 year-old inhabitants in the city of Malmö, Sweden (n = 114,917, of whom 15.2% were born outside Sweden) were followed from November 1st, 1990 until December 31st, 2007. During a mean follow-up of 13.5 ± 5.3 years, a total of 7,640 individuals (47.4% men) were discharged from hospital with first-ever HF as primary diagnosis. Of them, 1,243 individuals had myocardial infarction (MI) before or concurrent with the HF hospitalization. The risk of HF was compared between immigrants from selected countries and Swedish natives. The overall analysis showed substantial differences among immigrant groups (P < 0.001). Compared to Swedish natives, significantly increased HF risk was found among immigrants from Finland (HR (hazard ratio): 1.40; 95% CI, 1.10-1.81), Former Yugoslavia (1.45: 1.23-1.72) and Hungary (1.48: 1.16-1.89), taking age, sex, marital status, annual income and housing condition into account. Analysis results were similar when cases with MI before or concurrent with the HF hospitalization were included in the analysis. In general, the risk of HF was significantly higher among immigrants from high-income and middle-income countries. Marital status, annual income and housing condition were also significant independent risk factors for HF in this population. There are substantial differences in risk of hospitalization due to HF among immigrants from different countries that can not be explained by socioeconomic factors. To what extent these differences could be explained by biological risk factors remains to be explored.


Cannabinoid receptors in human astroglial tumors.
In animal models, cannabinoids are reported to inhibit the growth of tumors, including gliomas. These effects have been claimed to be mediated via cannabinoid receptors 1 and 2 (CB1, CB2). To elucidate a possible relevance for treatment of human gliomas, we investigated receptor subtype expression in surgical material of solid human astrocytomas, gliomas and cultivated glioma cells by quantitative reverse transcriptase polymerase chain reaction, western blot and immunohistochemistry and assayed their functionality. In normal brain, cultivated glioma cells and solid tumors, CB1 mRNA was expressed to a much greater extent than CB2, which in some samples was even undetectable. Expression of both receptor subtypes was unrelated to malignancy, varied between patients, and was not significantly increased in relation to normal brain tissues. In normal brain, CB1 protein was localized on astroglial and other cell types; in gliomas, it was found on astroglial/glioma cells. CB2 protein was detected on microglial cells/macrophages but rarely on astroglial cells. Functionally, CB1 receptor agonists reduced elevated cyclic AMP levels and slightly reduced proliferation of glioma cells in vitro, but did not induce apoptosis. We conclude that cannabinoid therapy of human gliomas targets not only receptors on tumor, but also on other cell types. Therefore, complex and potential side-effects should be considered carefully.


Recognizing misfolded and distorted protein structures by the assumption-based similarity score.
A new similarity score (sigma-score) is proposed which is able to find the correct protein structure among the very close alternatives and to distinguish between correct and deliberately misfolded structures. This score is based on the general principle 'similar likes similar', and it favors hydrophobic and hydrophilic contacts, and disfavors hydrophobic-to-hydrophilic contacts in proteins. The values of sigma-scores calculated for the high-resolution protein structures from the representative set are compared with those of alternatives: (i) very close alternatives which are only slightly distorted by conformational energy minimization in vacuo; (ii) alternatives with subsequently growing distortions, generated by molecular dynamics simulations in vacuo; (iii) structures derived by molecular dynamics simulation in solvent at 300 K; (iv) deliberately misfolded protein models. In nearly all tested cases the similarity score can successfully distinguish between experimental structure and its alternatives, even if the root mean square displacement of all heavy atoms is less than 1 A. The confidence interval of the similarity score was estimated using the high-resolution X-ray structures of domain pairs related by non-crystallographic symmetry. The similarity score can be used for the evaluation of the general quality of the protein models, choosing the correct structures among the very close alternatives, characterization of models simulating folding/unfolding, etc.


Management of travelers' diarrhea by local physicians in tropical and subtropical countries--a questionnaire survey.
There is an ongoing debate as to whether patients with travelers' diarrhea (TD) should self-medicate with a travel kit in developing countries or whether they should consult local doctors. Thus, we have analyzed TD management conducted by local health professionals. Practicing physicians recommended to tourists in Goa (India), Mombasa (Kenya), and Phuket (Thailand) were invited to participate in a cross-sectional questionnaire survey. Three TD case descriptions were presented, and suggested diagnostic and therapeutic procedures were analyzed. In each of the three locations, approximately 20 physicians (59 in total, response rate 95%) completed the questionnaires. Oral rehydration was proposed by more than 80% of the physicians for mild cases of TD and for TD with vomiting, while 73% of them would have treated febrile TD patients orally and 17% would have used intravenous (IV) fluids. Antimicrobials, primarily fluoroquinolones, would have been prescribed for 61, 73, and 95%, respectively, of these three cases. Cephalosporins, aminoglycosides (usually IV gentamicin), IV amoxicillin, and once co-trimoxazole were recommended. Many medical doctors added nitroimidazole to the antibiotic therapy. Multiple symptomatic drugs would have been prescribed. The rate of invasive procedures (infusions, injections, and diagnostic venipuncture) would have ranged from 20% to 86% in the scenarios of the different patients. Mainly practitioners who owned a clinic would have hospitalized patients with TD. Many physicians in destination countries treat TD patients similarly to the treatments prescribed in the "Western world." A minority uses obsolete antimicrobials. Polypharmacy and the high rate of invasive procedures with a theoretical risk of nosocomial infection are of concern. Training initiatives for both local physicians and travelers might be beneficial, and the guidelines should be based on internationally accepted expert advice.


Detection of plasmid-mediated AmpC beta-lactamase genes in clinical isolates by using multiplex PCR.
Therapeutic options for infections caused by gram-negative organisms expressing plasmid-mediated AmpC beta-lactamases are limited because these organisms are usually resistant to all the beta-lactam antibiotics, except for cefepime, cefpirome, and the carbapenems. These organisms are a major concern in nosocomial infections and should therefore be monitored in surveillance studies. Six families of plasmid-mediated AmpC beta-lactamases have been identified, but no phenotypic test can differentiate among them, a fact which creates problems for surveillance and epidemiology studies. This report describes the development of a multiplex PCR for the purpose of identifying family-specific AmpC beta-lactamase genes within gram-negative pathogens. The PCR uses six sets of ampC-specific primers resulting in amplicons that range from 190 bp to 520 bp and that are easily distinguished by gel electrophoresis. ampC multiplex PCR differentiated the six plasmid-mediated ampC-specific families in organisms such as Klebsiella pneumoniae, Escherichia coli, Proteus mirabilis, and Salmonella enterica serovar Typhimurium. Family-specific primers did not amplify genes from the other families of ampC genes. Furthermore, this PCR-based assay differentiated multiple genes within one reaction. In addition, WAVE technology, a high-pressure liquid chromatography-based separation system, was used as a way of decreasing analysis time and increasing the sensitivity of multiple-gene assays. In conclusion, a multiplex PCR technique was developed for identifying family-specific ampC genes responsible for AmpC beta-lactamase expression in organisms with or without a chromosomal AmpC beta-lactamase gene.


Retention strategies and factors associated with missed visits among low income women at increased risk of HIV acquisition in the US (HPTN 064).
Women at high-risk for HIV acquisition often face challenges that hinder their retention in HIV prevention trials. These same challenges may contribute to missed clinical care visits among HIV-infected women. This article, informed by the Gelberg-Andersen Behavioral Model for Vulnerable Populations, identifies factors associated with missed study visits and describes the multifaceted retention strategies used by study sites. HPTN 064 was a multisite, longitudinal HIV seroincidence study in 10 US communities. Eligible women were aged 18-44 years, resided in a census tract/zipcode with high poverty and HIV prevalence, and self-reported ≥1 personal or sex partner behavior related to HIV acquisition. Multivariate analyses of predisposing (e.g., substance use) and enabling (e.g., unmet health care needs) characteristics, and study attributes (i.e., recruitment venue, time of enrollment) identified factors associated with missed study visits. Retention strategies included: community engagement; interpersonal relationship building; reduction of external barriers; staff capacity building; and external tracing. Visit completion was 93% and 94% at 6 and 12 months. Unstable housing and later date of enrollment were associated with increased likelihood of missed study visits. Black race, recruitment from an outdoor venue, and financial responsibility for children were associated with greater likelihood of attendance. Multifaceted retention strategies may reduce missed study visits. Knowledge of factors associated with missed visits may help to focus efforts.


Association of nerve growth factor and vascular endothelial growth factor A with psychometric measurements of opiate dependence: results of a pilot study in patients participating in a structured diamorphine maintenance program.
Preclinical study results suggest that neurotrophic peptides like nerve growth factor (NGF) and vascular endothelial growth factor A (VEGF-A) may be associated with symptoms of addictive behavior like withdrawal symptoms and rewarding effects. We investigated alterations in NGF and VEGF-A serum levels in opiate-dependent patients (25 male patients), who received diamorphine (DAM, heroin) treatment within a structured opiate maintenance program, and compared the results with the NGF and VEGF-A serum levels of healthy controls (23 male controls). NGF and VEGF-A serum levels were assessed before and after DAM administration twice a day (in the morning (16 h after last application--t1) and in the afternoon (7 h after last application--t3)) in order to detect a possible immediate or summative (in the afternoon) heroin effect on these two neuropeptides. Moreover, we investigated possible associations between the serum levels of these neurotrophic growth factors and psychometric dimensions of addictive behavior, e.g. craving, withdrawal, depression. Whereas there was no direct effect of DAM application on the serum levels of both neurotrophic growth factors neither in the morning nor in the afternoon, the NGF serum levels of the patient group were found to be significantly increased at all four time points of investigation compared with the healthy controls. In contrast, VEGF-A serum levels did not differ significantly in the patient and control groups. We found a significant positive association between the NGF serum levels and several items of the short opiate withdrawal scale as well as a negative association between self-reported mood (measured by visual analogue scale) and mood before heroin application (in the morning as in the afternoon). Moreover, we found a significant positive association between the NGF serum levels (t1 and t3) and the self-reported craving for methadone. In contrast, we found a negative association between the VEGF-A serum levels and avoidance, anxiety, suicide intentions of the SCL-90 as well as a positive association between the VEGF-A serum levels and the subscales of the heroin craving questionnaire measuring the rewarding effects of heroin. In conclusion, the results of this pilot study show that there might be an association between symptoms of opiate dependence and withdrawal and serum levels of VEGF-A and NGF.


PCSK9 inhibitors in the prevention of cardiovascular disease.
Reducing plasma levels of low-density lipoprotein cholesterol (LDL-C) remains the cornerstone in the primary and secondary prevention of cardiovascular disease. However, lack of efficacy and adverse effects mean that a substantial proportion of patients fail to achieve acceptable LDL-C levels with currently available lipid-lowering drugs. Over the last decade, inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a promising therapeutic strategy to reduce residual cardiovascular disease risk. Binding of PCSK9 to the LDL receptor targets the receptor for lysosomal degradation. The recognition that inhibition of PCSK9 increases LDL receptor activity has led to the development of a number of approaches to directly target PCSK9. Numerous monoclonal antibodies against PCSK9 are currently being evaluated in phase 3 trials, involving various patient categories on different background lipid-lowering therapies. Current evidence shows reductions in LDL-C levels of up to 70 % may be achieved with PCSK9 inhibition, independent of background statin therapy. This review examines the most recent evidence and future prospects for the use of PCSK9 inhibitors in the prevention of cardiovascular disease.


Tumor targeting using affibody molecules: interplay of affinity, target expression level, and binding site composition.
Radionuclide imaging of cancer-associated molecular alterations may contribute to patient stratification for targeting therapy. Scaffold high-affinity proteins, such as Affibody molecules, are a new, promising class of probes for in vivo imaging. The effects of human epidermal growth factor receptor 2 (HER2) affinity and binding site composition of HER2-binding Affibody molecules, and of the HER2 density on the tumor targeting, were studied in vivo. The tumor uptake and tumor-to-organ ratios of Affibody molecules with moderate (dissociation constant [K(D)] = 10(-9) M) or high (K(D) = 10(-10) M) affinity were compared between tumor xenografts with a high (SKOV-3) and low (LS174T) HER2 expression level in BALB/C nu/nu mice. Two Affibody molecules with similar affinity (K(D) = 10(-10) M) but having alternative amino acids in the binding site were compared. In SKOV-3 xenografts, uptake was independent of affinity at 4 h after injection, but high-affinity binders provided 2-fold-higher tumor radioactivity retention at 24 h. In LS174T xenografts, uptake of high-affinity probes was already severalfold higher at 4 h after injection, and the difference was increased at 24 h. The clearance rate and tumor-to-organ ratios were influenced by the amino acid composition of the binding surface of the tracer protein. The optimal affinity of HER2-binding Affibody molecules depends on the expression of a molecular target. At a high expression level (>10(6) receptors per cell), an affinity in the low-nanomolar range is sufficient. At moderate expression, subnanomolar affinity is desirable. The binding site composition can influence the imaging contrast. This information may be useful for development of imaging agents based on scaffold affinity proteins.


Implementation of the European Union's Bathing Water Directive in Turkey.
The European Union (EU) Bathing Water Directive (2006/7/EC) sets out standards for designated bathing waters which should be complied with by all Member States. Turkey, being a candidate country to the EU, requires heavy-cost investments in achieving approximation with the EU Environmental Acquis. This paper provides a description of the technical measures and investment and operational cost assessment related to the implementation of the Bathing Water Directive in Turkey. Bathing waters are defined as "all running or still freshwaters or parts thereof and seawater, in which bathing is explicitly authorized by the competent authorities, or bathing is not prohibited and is traditionally practiced by a large number of bathers". Since there is no complete registration of bathing waters in Turkey, this study has targeted all coastal agglomerations and designated these as in proximity to "highly-touristic" and "other" agglomerations including the agglomerations in the proximity of six lakes that are popularly used as bathing waters. For each of these agglomerations an assessment of the existing infrastructure has been made. In defining the infrastructural need, two scenarios have been developed. According to Scenario 1, only highly-touristic and touristic places are to receive investment. The suggested further treatment was "disinfection+sea outfall" and "sea-outfall", for highly-touristic and touristic agglomerations, respectively. In Scenario 2, other coastal agglomerations and all freshwater lakes were also included and disinfection has been proposed for these settlements. It appears that the total investment is at around 12.6 million Euros for Scenario 1 and increases to 21.8 million Euros for Scenario 2; whereas the annual operational and maintenance costs are about 0.5 and 0.8 million Euros for Scenarios 1 and 2, respectively.


Etiology of Ibrutinib Therapy Discontinuation and Outcomes in Patients With Chronic Lymphocytic Leukemia.
The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is effective in patients with chronic lymphocytic leukemia (CLL). Reasons for discontinuing therapy with this drug and outcomes following discontinuation have not been evaluated outside of clinical trials with relatively short follow-up. To determine features associated with discontinuation of ibrutinib therapy and outcomes. A total of 308 patients participating in 4 sequential trials of ibrutinib at The Ohio State University Comprehensive Cancer Center were included. These clinical trials accrued patients included in this analysis from May 2010 until April 2014, and data were locked in June 2014. Patients were evaluated for time to therapy discontinuation, reasons for discontinuation, and survival following discontinuation. For patients who discontinued therapy because of disease progression, targeted deep sequencing was performed in samples at baseline and time of relapse. With a median follow-up of 20 months, 232 patients remained on therapy, 31 had discontinued because of disease progression, and 45 had discontinued for other reasons. Disease progression includes Richter's transformation (RT) or progressive CLL. Richter's transformation appeared to occur early and CLL progressions later (cumulative incidence at 12 months, 4.5% [95% CI, 2.0%-7.0%] and 0.3% [95% CI, 0%-1.0%], respectively). Median survival following RT was 3.5 months (95% CI, 0.3-6.0 months) and 17.6 months (95% CI, 4.7 months-"not reached") following CLL progression. Sequencing on peripheral blood from 8 patients with RT revealed 2 with mutations in BTK, and a lymph node sample showed no mutations in BTK or PLCG2. Deep sequencing on 11 patients with CLL progression revealed BTK or PLCG2 mutations in all. These mutations were not identified before treatment in any patient. This single-institution experience with ibrutinib confirms it to be an effective therapy and identifies, for the first time, baseline factors associated with ibrutinib therapy discontinuation. Outcomes data show poor prognosis after discontinuation, especially for those patients with RT. Finally, sequencing data confirm initial reports associating mutations in BTK and PLCG2 with progression and clearly show that CLL progressions are associated with these mutations, while RT is likely not. clinicaltrials.gov Identifiers:NCT01105247, NCT01217749, NCT01589302, and NCT01578707.


Calcaneocuboid distraction arthrodesis for posterior tibial tendon dysfunction and flatfoot: a cadaveric study.
Nine fresh-frozen foot specimens were studied to determine the mechanical behavior of the foot using calcaneocuboid distraction arthrodesis, an operation designed for treatment of posterior tibial tendon dysfunction with flatfoot deformity. Flatfoot deformity was created in cadaveric specimens, and to simulate toe-off phase of gait, loads were applied to the plantar surface of the foot and six tendons. Three-dimensional tarsal bone positions were determined with a magnetic tracking system. With ligament sectioning, flatfoot deformity was observed and average arch height decreased 53 +/- 3.5 mm. Height arch increased after calcaneocuboid distraction arthrodesis an average of 3.2 +/- 3.6 mm and was less than normal arch at an average of 2.1 +/- 2.4 mm. Metatarsotalar alignment compared with flatfoot improved after calcaneocuboid distraction arthrodesis in adduction and inversion to the extent that these were not significantly different from intact foot positions. Calcaneotalar position improved after calcaneocuboid distraction arthrodesis in adduction and inversion. Calcaneocuboid alignment compared with flatfoot improved after calcaneocuboid distraction arthrodesis in adduction, plantar flexion, and eversion, but compared with an intact foot was overcorrected in all three planes of motion. Arch alignment in simulated toe-off phase of gait in cadaveric feet was improved significantly with calcaneocuboid distraction arthrodesis but was not reduced anatomically.


Heavy metal in the intensive care unit: a review of current literature on trace element supplementation in critically ill patients.
Trace elements are essential for many physiologic processes. In recent years, supplementation has been studied for a variety of indications, including glycemic control, wound healing, antioxidant effect, and anemia. Critical illness, especially states such as burns, traumas, and septic shock, is associated with inflammatory and oxidative stress, immune dysfunction, and malnutrition. In these patients, enteral and parenteral nutrition or pharmaceutical supplementation is used to provide essential macronutrients, including trace elements. The purpose of this review is to describe trace element supplementation, including iron, copper, chromium, manganese, selenium, and zinc, and highlight their mechanism, pharmacology, outcome data, and adverse effects.


GAPDH--a recruits a plant virus movement protein to cortical virus replication complexes to facilitate viral cell-to-cell movement.
The formation of virus movement protein (MP)-containing punctate structures on the cortical endoplasmic reticulum is required for efficient intercellular movement of Red clover necrotic mosaic virus (RCNMV), a bipartite positive-strand RNA plant virus. We found that these cortical punctate structures constitute a viral replication complex (VRC) in addition to the previously reported aggregate structures that formed adjacent to the nucleus. We identified host proteins that interacted with RCNMV MP in virus-infected Nicotiana benthamiana leaves using a tandem affinity purification method followed by mass spectrometry. One of these host proteins was glyceraldehyde 3-phosphate dehydrogenase-A (NbGAPDH-A), which is a component of the Calvin-Benson cycle in chloroplasts. Virus-induced gene silencing of NbGAPDH-A reduced RCNMV multiplication in the inoculated leaves, but not in the single cells, thereby suggesting that GAPDH-A plays a positive role in cell-to-cell movement of RCNMV. The fusion protein of NbGAPDH-A and green fluorescent protein localized exclusively to the chloroplasts. In the presence of RCNMV RNA1, however, the protein localized to the cortical VRC as well as the chloroplasts. Bimolecular fluorescence complementation assay and GST pulldown assay confirmed in vivo and in vitro interactions, respectively, between the MP and NbGAPDH-A. Furthermore, gene silencing of NbGAPDH-A inhibited MP localization to the cortical VRC. We discuss the possible roles of NbGAPDH-A in the RCNMV movement process.


Mitochondrial DNA phylogeography and mating compatibility reveal marked genetic structuring and speciation in the NE Atlantic bryozoan Celleporella hyalina.
The marine bryozoan Celleporella hyalina is a species complex composed of many highly divergent and mostly allopatric genetic lineages that are reproductively isolated but share a remarkably similar morphology. One such lineage commonly encrusts macroalgae throughout the NE Atlantic coast. To explore the processes leading to geographical diversification, reproductive isolation and speciation in this taxon, we (i) investigated NE Atlantic C. hyalina mitochondrial DNA phylogeography, and (ii) used breeding trials between geographical isolates to ascertain reproductive isolation. We find that haplotype diversity is geographically variable and there is a strong population structure, with significant isolation by distance. NE Atlantic C. hyalina is structured into two main parapatric lineages that appear to have had independent Pleistocene histories. Range expansions have resulted in two contact zones in Spain and W Ireland. Lineage 1 is found from Ireland to Spain and has low haplotype diversity, with closely related haplotypes, suggesting a recent population expansion into the Irish Sea, S Ireland, S England and Spain. Lineage 2 is found from Iceland to Spain and has high haplotype diversity. Complete reproductive isolation was found between some geographical isolates representing both lineages, whereas it was incomplete or asymmetric between others, suggesting these latter phylogeographical groups probably represent incipient species. The phylogeographical distribution of NE Atlantic C. hyalina does not fall easily into a pattern of southern refugia, and we discuss likely differences between terrestrial and marine system responses to Pleistocene glacial cycles.


Childhood behavior problems and age at first sexual intercourse: a prospective birth cohort study.
Early first sexual intercourse (FSI) is a risk factor for unplanned teenage pregnancy, sexually transmitted infection, and adverse social, emotional, and physical health outcomes in adolescence and into adulthood. The aim of this study was to examine relationships between internalizing (eg, anxious/depressed, withdrawn) and externalizing (eg, delinquent, aggressive) behavior problems in childhood and age at FSI. We used a large, population-based birth cohort (The Western Australian Pregnancy Cohort [Raine] Study) to address this question. Child behavior was measured by using the Child Behavior Checklist collected from parents at ages 2, 5, 8, 10, and 14 and scores calculated for total, internalizing, and externalizing behavior problems. At age 17, 1200 participants reported sexual behavior. Participants with clinically significant Child Behavior Checklist scores (T ≥ 60) were at increased risk for earlier first sexual intercourse (FSI) (<16 years). Adjusted odds ratios revealed that total and externalizing behavior problems from age 5 years onward significantly increased the risk of earlier FSI for boys. In girls, externalizing problems from age 10 years increased the risk for earlier FSI. Internalizing problems at ages 8 and 10 were significantly associated with early FSI for boys but not girls. Externalizing behavior from as early as 5 in boys and 10 in girls is a significant risk factor for earlier age at FSI. Adolescent sexual health promotion should consider early intervention in children with behavior problems, particularly boys.


Potent, p53-independent induction of NOXA sensitizes MLL-rearranged B-cell acute lymphoblastic leukemia cells to venetoclax.
The prognosis for B-cell precursor acute lymphoblastic leukemia patients with Mixed-Lineage Leukemia (MLL) gene rearrangements (MLLr BCP-ALL) is still extremely poor. Inhibition of anti-apoptotic protein BCL-2 with venetoclax emerged as a promising strategy for this subtype of BCP-ALL, however, lack of sufficient responses in preclinical models and the possibility of developing resistance exclude using venetoclax as monotherapy. Herein, we aimed to uncover potential mechanisms responsible for limited venetoclax activity in MLLr BCP-ALL and to identify drugs that could be used in combination therapy. Using RNA-seq, we observed that long-term exposure to venetoclax in vivo in a patient-derived xenograft model leads to downregulation of several tumor protein 53 (TP53)-related genes. Interestingly, auranofin, a thioredoxin reductase inhibitor, sensitized MLLr BCP-ALL to venetoclax in various in vitro and in vivo models, independently of the p53 pathway functionality. Synergistic activity of these drugs resulted from auranofin-mediated upregulation of NOXA pro-apoptotic protein and potent induction of apoptotic cell death. More specifically, we observed that auranofin orchestrates upregulation of the NOXA-encoding gene Phorbol-12-Myristate-13-Acetate-Induced Protein 1 (PMAIP1) associated with chromatin remodeling and increased transcriptional accessibility. Altogether, these results present an efficacious drug combination that could be considered for the treatment of MLLr BCP-ALL patients, including those with TP53 mutations.


Prognostic Role of Blood NETosis in the Progression of Head and Neck Cancer.
Neutrophil extracellular traps (NETs) represent web-like structures consisting of externalized DNA decorated with granule proteins that are responsible for trapping and killing bacteria. However, undesirable effects of NET formation during carcinogenesis, such as metastasis support, have been described. In the present study, we evaluated the correlation between NETosis and disease progression in head and neck cancer (HNC) patients in order to establish a valid biomarker for an early detection and monitoring of HNC progression. Moreover, factors influencing NET release in HNC patients were revealed. We showed a significantly elevated vital NETosis in neutrophils isolated from early T1-T2 and N0-N2 stage patients, as compared to healthy controls. Additionally, in our experimental setting, we confirmed the involvement of tumor cells in the stimulation of NET formation. Interestingly, in advanced cancer stages (T3-4, N3) NETosis was reduced. This also correlated with the levels of granulocyte colony-stimulating factor (G-CSF) in plasma and tumor tissue. Altogether, we suggest that the elevated NETosis in blood can be used as a biomarker to detect early HNC and to predict patients at risk to develop tumor metastasis. Therapeutic disruption of NET formation may offer new roads for successful treatment of HNC patients in order to prevent metastasis.


Modelling determinants of extinction across two Mesozoic hyperthermal events.
The Late Triassic and Early Toarcian extinction events are both associated with greenhouse warming events triggered by massive volcanism. These Mesozoic hyperthermals were responsible for the mass extinction of marine organisms and resulted in significant ecological upheaval. It has, however, been suggested that these events merely involved intensification of background extinction rates rather than significant shifts in the macroevolutionary regime and extinction selectivity. Here, we apply a multivariate modelling approach to a vast global database of marine organisms to test whether extinction selectivity varied through the Late Triassic and Early Jurassic. We show that these hyperthermals do represent shifts in the macroevolutionary regime and record different extinction selectivity compared to background intervals of the Late Triassic and Early Jurassic. The Late Triassic mass extinction represents a more profound change in selectivity than the Early Toarcian extinction but both events show a common pattern of selecting against pelagic predators and benthic photosymbiotic and suspension-feeding organisms, suggesting that these groups of organisms may be particularly vulnerable during episodes of global warming. In particular, the Late Triassic extinction represents a macroevolutionary regime change that is characterized by (i) the change in extinction selectivity between Triassic background intervals and the extinction event itself; and (ii) the differences in extinction selectivity between the Late Triassic and Early Jurassic as a whole.


Metastatic endometrial stromal sarcoma of the lung: importance of immunohistochemical staining, clinical history and imaging studies.
Proper evaluation of lung nodules is a difficult issue for clinical management of patients. Discriminating metastatic endometrial stromal sarcoma (ESS) from other primary spindle cell neoplasms of the lung using histological analysis can be challenging. This is particularly true when an adequate clinical history is lacking, because ESS metastasis can be delayed by a couple of decades. To emphasize the importance of the correlation of pathological findings with clinical history and imaging studies, we investigated 11 cases of ESS (seven low grade and four high grade) metastatic to the lung. All cases presented with one to multiple unilateral or bilateral lung nodules that were detected by chest computed tomography. Primary ESS was diagnosed from hysterectomy specimens except for one by endometrial biopsy, 0.5 to 23 years prior to metastasis. Immunohistochemical studies showed that all ESS cases were moderately to strongly positive for Bcl-2 and CD10 with >50% of tumor cells stained, except for one high grade ESS that was negative for CD10. Eight (72.7%) and seven (63.6) of the 11 cases showed positive estrogen and progesterone receptors, respectively, with a majority of positive cases showing diffuse and moderate to strong staining. Strong but patchy staining for CD34 was detected in one (9.1%) case with smooth muscle differentiation. CK7 and TTF-1 were negative in all cases. Two (18.2%) cases exhibited patchy and strong positivity for caldesmon. Two (18.2%) low grade ESS cases showed moderate to strong AE1/AE3 positivity in >50% of tumor cells, one of which also showed moderate CK19 and Cam 5.2 staining in >30% of tumor cells. One should be cautious when assessing spindle cell neoplasms of the lung in women with a history of hysterectomy. Correlation of clinical history and imaging studies with histological and immunohistochemical findings is essential to diagnosis of metastatic ESS to the lung.


Cardioprotective Effects of HSP72 Administration on Ischemia-Reperfusion Injury.
Although early reperfusion is the most desirable intervention after ischemic myocardial insult, it may add to damage through oxidative stress. This study investigated the cardioprotective effects of a single intravenous dose of heat shock protein-72 (HSP72) coupled to a single-chain variable fragment (Fv) of monoclonal antibody 3E10 (3E10Fv) in a rabbit ischemia-reperfusion model. The Fv facilitates rapid transport of HSP72 into cells, even with intact membranes. A left coronary artery occlusion (40 min) reperfusion (3 h) model was used in 31 rabbits. Of these, 12 rabbits received the fusion protein (Fv-HSP72) intravenously. The remaining 19 control rabbits received a molar equivalent of 3E10Fv alone (n = 6), HSP72 alone (n = 6), or phosphate-buffered saline (n = 7). Serial echocardiographic examinations were performed to assess left ventricular function before and after reperfusion. Micro-single-photon emission computed tomography imaging of 99mTc-labeled annexin-V was performed with micro-computed tomography scanning to characterize apoptotic damage in vivo, followed by gamma counting of the excised myocardial specimens to quantify cell death. Histopathological characterization of the myocardial tissue and sequential cardiac troponin I measurements were also undertaken. Myocardial annexin-V uptake was 43% lower in the area at risk (p = 0.0003) in Fv-HSP72-treated rabbits compared with control animals receiving HSP72 or 3E10Fv alone. During reperfusion, troponin I release was 42% lower and the echocardiographic left ventricular ejection fraction 27% higher in the Fv-HSP72-treated group compared with control animals. Histopathological analyses confirmed penetration of 3E10Fv-containing molecules into cardiomyocytes in vivo, and treatment with Fv-HSP72 showed fewer apoptotic nuclei compared with control rabbits. Single-dose administration of Fv-HSP72 fusion protein at the time of reperfusion reduced myocardial apoptosis by almost one-half and improved left ventricular functional recovery after myocardial ischemia-reperfusion injury in rabbits. It might have potential to serve as an adjunct to early reperfusion in the management of myocardial infarction.


Functional Analysis of the Adrenomedullin Pathway in Malignant Pleural Mesothelioma.
Malignant pleural mesothelioma (MPM) grows aggressively within the thoracic cavity and has a very low cure rate, thus highlighting the need for identification of new therapeutic targets. Adrenomedullin (AM) is a multifunctional peptide that is highly expressed in several tumors and plays an important role in angiogenesis and tumor growth after binding to its receptors, calcitonin receptor-like receptor/receptor activity-modifying protein 2 (CLR/RAMP2) and calcitonin receptor-like receptor/receptor activity-modifying protein 3 (CLR/RAMP3). Real time quantitative reverse transcriptase polymerase chain reaction (RT-PCR) was used to assess the steady-state levels of AM, CLR, RAMP2 and RAMP3 messenger RNA (mRNA) transcripts in normal pleural tissue (n=5) and MPM (n=24). The expression of these candidates at protein level was revealed by immunohistochemistry. We also characterized the expression and regulation by hypoxia of AM system in MPM cell lines and MeT-5A cells. In vitro and in vivo studies were performed to determine the functional role of AM system in MPM. In this study, real-time quantitative reverse transcriptase polymerase chain reaction showed twofold to 10-fold higher levels of AM messenger RNA in MPM tissue than in normal pleural tissue. The MPM cell lines H2452, H2052, and human mesothelioma cell line MSTO-211H showed a significant increase in expression of AM messenger RNA under hypoxic conditions. Our results also show that AM stimulates cell proliferation in vitro through the Raf1 proto-oncogene, serine/threonine kinase (CRAF)/ Mitogen-activated protein kinase kinase 1 (MEK)/Extracellular regulated MAPKinase (ERK) pathway. Furthermore, the proliferation, migration, and invasion of MPM cells were decreased after treatment with anti-AM (αAM) and anti-AM receptor antibodies, thus indicating that MPM cells are regulated by AM. The action of AM was specific and mediated by CLR/RAMP2 and CLR/RAMP3 receptors. In vivo, αAM and AM22-52 antagonist therapies blocked angiogenesis and induced apoptosis in MSTO-211H xenografts, thereby resulting in tumor regression. Histologic examination of tumors treated with AM22-52 and αAM antibody showed evidence of disruption of tumor vasculature with depletion of vascular endothelial cells and a significant decrease in lymphatic endothelial cells. Our findings highlight the importance of the AM pathway in growth of MPM and in neovascularization by supplying and amplifying signals that are essential for pathologic neoangiogenesis and lymphangiogenesis.


Bioavailability and efficacy of levofloxacin against Francisella tularensis in the common marmoset (Callithrix jacchus).
Pharmacokinetic and efficacy studies with levofloxacin were performed in the common marmoset (Callithrix jacchus) model of inhalational tularemia. Plasma levofloxacin pharmacokinetics were determined in six animals in separate single-dose and multidose studies. Plasma drug concentrations were analyzed using liquid chromatography-tandem mass spectrometry-electrospray ionization. On day 7 of a twice-daily dosing regimen of 40 mg/kg, the levofloxacin half-life, maximum concentration, and area under the curve in marmoset plasma were 2.3 h, 20.9 microg/ml, and 81.4 microg/liter/h, respectively. An efficacy study was undertaken using eight treated and two untreated control animals. Marmosets were challenged with a mean of 1.5 x 10(2) CFU of Francisella tularensis by the airborne route. Treated animals were administered 16.5 mg/kg levofloxacin by mouth twice daily, based on the pharmacokinetic parameters, beginning 24 h after challenge. Control animals had a raised core body temperature by 57 h postchallenge and died from infection by day 5. All of the other animals survived, remained afebrile, and lacked overt clinical signs. No bacteria were recovered from the organs of these animals at postmortem after culling at day 24 postchallenge. In conclusion, postexposure prophylaxis with orally administered levofloxacin was efficacious against acute inhalational tularemia in the common marmoset. The marmoset appears to be an appropriate animal model for the evaluation of postexposure therapies.


Development of collagen-hydroxyapatite scaffolds incorporating PLGA and alginate microparticles for the controlled delivery of rhBMP-2 for bone tissue engineering.
The spatiotemporally controlled delivery of the pro-osteogenic factor rhBMP-2 would overcome most of the severe secondary effects linked to the products delivering this protein for bone regeneration. With this in mind, the aim of the present work was to develop a controlled rhBMP-2 release system using collagen-hydroxyapatite (CHA) scaffolds, which had been previously optimized for bone regeneration, as delivery platforms to produce a device with enhanced capacity for bone repair. Spray-drying and emulsion techniques were used to encapsulate bioactive rhBMP-2 in alginate and PLGA microparticles, with a high encapsulation efficiency. After incorporation of these microparticles into the scaffolds, rhBMP-2 was delivered in a sustained fashion for up to 28days. When tested in vitro with osteoblasts, these eluting materials showed an enhanced pro-osteogenic effect. From these results, an optimal rhBMP-2 eluting scaffold composition was selected and implanted in critical-sized calvarial defects in a rat model, where it demonstrated an excellent healing capacity in vivo. These platforms have an immense potential in the field of tissue regeneration; by tuning the specific therapeutic molecule to the tissue of interest and by utilizing different collagen-based scaffolds, similar systems can be developed for enhancing the healing of a diverse range of tissues and organs.


Hormonal contraception and the risks of STI acquisition: results of a feasibility study to plan a future randomized trial.
Because of limitations in observational studies, a randomized controlled trial (RCT) would help clarify whether hormonal contraception increases the risks of acquiring a sexually transmitted infection (STI). However, the feasibility of such a trial is uncertain. We conducted a study to assess the feasibility of conducting a RCT that would compare the acquisition risk for Chlamydia trachomatis and Neisseria gonorrhoeae in women randomized to an intrauterine device (IUD) or depot medroxyprogesterone acetate (DMPA). In our cross-sectional survey conducted at three clinics, we gave information on a potential RCT to clients, asked them questions to assess comprehensibility and finally asked respondents whether they would consider enrolling in such a trial. In addition, the 190 participants provided urine or endocervical swab specimens so we could estimate the prevalence of STIs. Overall, 70% of participants stated that they would take part in a future trial and accept randomization to either the IUD or DMPA. Participant understanding of the trial requirements was high. Twenty-nine percent of the participants were infected with either N. gonorrhoeae or C. trachomatis. With a high prevalence of STI in this population and the apparent willingness of appropriate candidates to participate, an RCT to measure risks of incident STI infection from hormonal contraception appears feasible.


The female adolescent breast: disorders of development.
This article will provide an overview on female breast development and focus on common abnormalities of growth, the emerging role of breast self-awareness, and discuss trends in the evaluation and treatment of the breast masses and disorders most often encountered in the female adolescent population. Although the embryology of breast development is unchanged, data are emerging on the role of environmental factors on the timing of puberty and thelarche. As breast development occurs, the role of breast self-awareness is also a new trend that allows teens to be cognizant of changes in their own breast and to become more comfortable with their own anatomy. Finally, when breast treatments are needed or desired, the timing of breast treatments is a subject that must be individualized. There are numerous conditions that can result from disruption of normal breast development. These resultant breast disorders are generally benign but can still cause emotional distress to both the patient and family. It is thus imperative that healthcare providers be educated on breast development, the common breast masses that occur in the adolescent population and be prepared to discuss breast self-awareness and shared decision-making in this population.


Alternative splicing of Nav1.5: an electrophysiological comparison of 'neonatal' and 'adult' isoforms and critical involvement of a lysine residue.
In developmentally regulated D1:S3 splicing of Nav1.5, there are 31 nucleotide differences between the 5'-exon ('neonatal') and the 3'-exon ('adult') forms, resulting in 7 amino acid differences in D1:S3-S3/S4 linker. In particular, splicing replaces a conserved negative aspartate residue in the 'adult' with a positive lysine. Here, 'neonatal' and 'adult' Nav1.5 alpha-subunit splice variants were stably transfected into EBNA-293 cells and their electrophysiological properties investigated by whole-cell patch-clamp recording. Compared with the 'adult' isoform, the 'neonatal' channel exhibited (1) a depolarized threshold of activation and voltage at which the current peaked; (2) much slower kinetics of activation and inactivation; (3) 50% greater transient charge (Na(+)) influx; (4) a stronger voltage dependence of time to peak; and (5) a slower recovery from inactivation. Tetrodotoxin sensitivity and VGSCbeta1-4 mRNA expression levels did not change. The significance of the charge-reversing aspartate to lysine substitution was investigated by mutating the lysine in the 'neonatal' channel back to aspartate. In this 'neonatal K211D' mutant, the electrophysiological parameters studied strongly shifted back towards the 'adult', that is the lysine residue was primarily responsible for the electrophysiological effects of Nav1.5 D1:S3 splicing. Taken together, these data suggest that the charge reversal in 'neonatal' Nav1.5 would (1) modify the channel kinetics and (2) prolong the resultant current, allowing greater intracellular Na(+) influx. Developmental and pathophysiological consequences of such differences are discussed.


Human and canine echinococcosis infection in informal, unlicensed abattoirs in Lima, Peru.
Echinococcus granulosus infections are a major public health problem in livestock-raising regions around the world. The life cycle of this tapeworm is sustained between dogs (definitive host, canine echinococcosis), and herbivores (intermediary host, cystic hydatid disease). Humans may also develop cystic hydatid disease. Echinococcosis is endemic in rural areas of Peru; nevertheless, its presence or the extension of the problem in urban areas is basically unknown. Migration into Lima, an 8-million habitant's metropolis, creates peripheral areas where animals brought from endemic areas are slaughtered without veterinary supervision. We identified eight informal, unlicensed abattoirs in a peripheral district of Lima and performed a cross-sectional study in to assess the prevalence of canine echinococcosis, evaluated by coproELISA followed by PCR evaluation and arecoline purge. Eight of 22 dogs (36%) were positive to coproELISA, and four (18%) were confirmed to be infected with E. granulosus tapeworms either by PCR or direct observation (purge). Later evaluation of the human population living in these abattoirs using abdominal ultrasound, chest X-rays and serology, found 3 out of 32 (9.3%) subjects with echinococcal cysts in the liver (two viable, one calcified), one of whom had also lung involvement and a strongly positive antibody response. Autochthonous transmission of E. granulosus is present in Lima. Informal, unlicensed abattoirs may be sources of infection to neighbouring people in this urban environment.


Dermoscopy in general dermatology: practical tips for the clinician.
In addition to its well-documented value in improving the diagnosis of skin tumours, dermoscopy is continually gaining appreciation in the field of general dermatology. Dermoscopy has been shown to facilitate the clinical recognition of several inflammatory and infectious diseases, as well as their discrimination from skin tumours. Moreover, recent data indicate that it might also be profitable in assessing the outcome and adverse effects of various treatments. Application of dermoscopy should follow the standard procedure of acquiring information from patient history and clinically evaluating the number, location and morphology of the lesion(s). Four parameters should be assessed when applying dermoscopy in the realm of inflammatory and infectious diseases: (i) morphological vascular patterns; (ii) arrangement of vascular structures; (iii) colours; and (iv) follicular abnormalities, while the presence of other specific features (clues) should also be evaluated. It must be underlined that dermoscopic findings should always be interpreted within the overall clinical context of the patient, integrated with information from the history and the macroscopic examination. With new evidence continuously being gathered, the dermatoscope gradually acquires a role similar to the stethoscope of general practitioners, becoming an irreplaceable clinical tool for dermatologists. In this article, we provide a succinct summary of existing data on dermoscopy in general dermatology. Practical tips are suggested, which can assist clinicians in profitably utilizing and applying the available knowledge in their everyday practice.


Concomitant prediction of environmental fate and toxicity of chemical compounds.
The environmental fate of many functional molecules that are produced on a large scale as precursors or as additives to specialty goods (plastics, fibers, construction materials, etc.), let alone those synthesized by the pharmaceutical industry, is generally unknown. Assessing their environmental fate is crucial when taking decisions on the manufacturing, handling, usage, and release of these substances, as is the evaluation of their toxicity in humans and other higher organisms. While this data are often hard to come by, the experimental data already available on the biodegradability and toxicity of many unusual compounds (including genuinely xenobiotic molecules) make it possible to develop machine learning systems to predict these features. As such, we have created a predictor of the "risk" associated with the use and release of any chemical. This new system merges computational methods to predict biodegradability with others that assess biological toxicity. The combined platform, named BiodegPred (https://sysbiol.cnb.csic.es/BiodegPred/), provides an informed prognosis of the chance a given molecule can eventually be catabolized in the biosphere, as well as of its eventual toxicity, all available through a simple web interface. While the platform described does not give much information about specific degradation kinetics or particular biodegradation pathways, BiodegPred has been instrumental in anticipating the probable behavior of a large number of new molecules (e.g. antiviral compounds) for which no biodegradation data previously existed.


Compact optical curvature sensor with a flexible microdisk laser on a polymer substrate.
We demonstrate a chip-scale compact optical curvature sensor. It consists of a low threshold InGaAsP microdisk laser on a flexible polydimethylsiloxane polymer substrate. The curvature dependence of lasing wavelength was characterized by bending the cavity at different bending radii. The measurements showed that the lasing wavelength decreases monotonously with an increasing bending curvature. A good agreement between experiment and three-dimensional finite-difference time-domain simulation was also obtained. The sensitivity of the compact device to the bending curvature is -23.7 nm/mm from the experiment.