Expression of leucine-rich repeats and immunoglobulin-like domains (LRIG) proteins in human ependymoma relates to tumor location, WHO grade, and patient age.
Three human leucine-rich repeats and immunoglobulin-like domains (LRIG1-3) genes and proteins have recently been characterized. LRIG1 has been shown to be a suppressor of tumor growth by counteracting the signaling of epidermal growth factor receptor (EGFR) family members, including EGFR (ERBB1). Expression of LRIG proteins seems to be of importance in the pathogenesis of astrocytic tumors. In this study, the expression of LRIG1-3 was evaluated in 51 human ependymomas by immunohistochemistry. LRIG proteins were detected in all ependymomas analyzed, however, with a pronounced heterogeneity in expression and subcellular localization. Higher cytoplasmic immunoreactivity of LRIG1 correlated with older patient age and higher LRIG1 nuclear immunoreactivity with lower WHO Grade. LRIG1 displayed a stronger immunoreactivity in the cytoplasm and nuclei in spinal ependymomas than in the posterior fossa or supratentorial ependymomas, while perinuclear LRIG3 was more highly expressed in supratentorial than in infratentorial ependymomas. The indications that expression and subcellular localization of LRIG proteins could be pathogenetically associated with specific clinicopathological features of ependymoma tumors might be of importance in the carcinogeneses and tumor progression of human ependymomas.


Plasticity of ovarian cancer cell SKOV3ip and vasculogenic mimicry in vivo.
The aim of this study is to investigate the plasticity of human epithelial ovarian cancer cell SKOV3ip and formation of vasculogenic mimicry (VM) in vivo. SKOV3ip was transfected with lentiviral vector carrying green fluorescence protein (GFP). Female nude mice were implanted intraperitoneally with GFP-labled SKOV3ip. When the transplanted tumor reached a volume of approximately 1 cm(3), paraffin-embedded, formaldehyde-fixed tissue was prepared and stained with hematoxylin and eosin (H & E). Tumor tissues were also studied by electron microscopy and fluorescence microscopy. The results of H & E staining, electron microscopy, and fluorescence microscopy indicated SKOV3ip formed patterned networks with erythrocytes in them, in the absence of vascular epithelial cells, which was a sign that SKOV3ip engaged in VM in vivo. Expression of vascular epithelium marker CD31 was investigated by immunohistochemical staining, immunofluorescence assay, semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR), and flow cytometric analysis (FACS). Factor VIII and vascular endothelial growth factor (VEGF) were also analyzed by FACS. Weak and focal CD31 immunohistochemical staining was found along the channels of tumor cells. Immunofluorescence assay and RT-PCR demonstrated that CD31 was expressed in primary-cultured SKOV3ip. CD31 and Factor VIII, but not VEGF were detected in primary-cultured SKOV3ip by FACS. The present study has shown that human ovarian cancer cell line SKOV3ip may be able to express some specific markers of vascular epithelial cells and has plasticity to form VM in vivo. In the following study, we indicated that hypoxia-inducible factor (HIF)-1alpha inhibitor, rapamycin, could possibly prevent VM and phenotype transformation of SKOV3ip, reflected by down-regulating expression of CD31 and Factor VIII. HIF-1alpha protein expression correlated with CD31 and Factor VIII protein expression in SKOV3ip. These results indicated that VM might be associated with HIF-1alpha.


The magnitude of the somatosensory cortical activity is related to the mobility and strength impairments seen in children with cerebral palsy.
The noted disruption of thalamocortical connections and abnormalities in tactile sensory function has resulted in a new definition of cerebral palsy (CP) that recognizes the sensorimotor integration process as central to the motor impairments seen in these children. Despite this updated definition, the connection between a child's motor impairments and somatosensory processing remains almost entirely unknown. In this investigation, we explored the relationship between the magnitude of neural activity within the somatosensory cortices, the strength of the ankle plantarflexors, and the gait spatiotemporal kinematics of a group of children with CP and a typically developing matched cohort. Our results revealed that the magnitude of somatosensory cortical activity in children with CP had a strong positive relationship with the ankle strength, step length, and walking speed. These results suggest that stronger activity within the somatosensory cortices in response to foot somatosensations was related to enhanced ankle plantarflexor strength and improved mobility in the children with CP. These results provide further support for the notion that children with CP exhibit, not only musculoskeletal deficits, but also somatosensory deficits that potentially contribute to their overall functional mobility and strength limitations.


Dosing and efficacy of glutamine supplementation in human exercise and sport training.
Some athletes can have high intakes of l-glutamine because of their high energy and protein intakes and also because they consume protein supplements, protein hydrolysates, and free amino acids. Prolonged exercise and periods of heavy training are associated with a decrease in the plasma glutamine concentration and this has been suggested to be a potential cause of the exercise-induced immune impairment and increased susceptibility to infection in athletes. However, several recent glutamine feeding intervention studies indicate that although the plasma glutamine concentration can be kept constant during and after prolonged strenuous exercise, the glutamine supplementation does not prevent the postexercise changes in several aspects of immune function. Although glutamine is essential for lymphocyte proliferation, the plasma glutamine concentration does not fall sufficiently low after exercise to compromise the rate of proliferation. Acute intakes of glutamine of approximately 20-30 g seem to be without ill effect in healthy adult humans and no harm was reported in 1 study in which athletes consumed 28 g glutamine every day for 14 d. Doses of up to 0.65 g/kg body mass of glutamine (in solution or as a suspension) have been reported to be tolerated by patients and did not result in abnormal plasma ammonia levels. However, the suggested reasons for taking glutamine supplements (support for immune system, increased glycogen synthesis, anticatabolic effect) have received little support from well-controlled scientific studies in healthy, well-nourished humans.


Attenuation of blood pressure in spontaneously hypertensive rats by acupuncture was associated with reduction oxidative stress and improvement from endothelial dysfunction.
Hypertension can be treated effectively by acupuncture; however, the association between acupuncture and endothelial function remains unknown. This study aimed to investigate the effects of acupuncture on endothelial dysfunction and oxidative stress-related parameters in spontaneously hypertensive animals. Eighteen-week-old Wistar-Kyoto rats (WKYs) and spontaneously hypertensive rats (SHRs) were arbitrarily divided into four groups: WKY control (n = 8), SHR control (n = 8), SHR sham-acupuncture (n = 8) and SHR acupuncture (n = 8). The SHR acupuncture group had electroacupuncture for 6 consecutive weeks on acupoints ST36 and LR3. Blood pressure was monitored during the treatment period, and animals were euthanized at the 6th week. Aortas were harvested for determination of angiotensin II levels, NADPH oxidase activity and nitrate/nitrite levels. The level of reactive oxygen species (ROS) was determined by dihydroethidium (DHE) imaging, and functional studies were performed to assess vascular reactivity. Endothelial nitric oxide synthase was measured by Western blot assay. Blood pressure at the end of treatment was significantly lower in the SHR acupuncture group (185.0 ± 5.6 mmHg) compared with the SHR sham-acupuncture and the SHR control groups (201.0 ± 5.4 and 197.4 ± 5.9 mmHg, respectively; P < 0.001). Serum angiotensin II level in the SHR control group was significantly higher than in the WKY control group (P < 0.001), while it was significantly attenuated by acupuncture treatment (P = 0.023). DHE staining showed that ROS level was reduced in the aortas (P = 0.0017) and carotid arteries (P = 0.039) of acupuncture-treated SHRs. Biochemical assays showed that acupuncture inhibited the NADPH oxidase activity (P = 0.022) and enhanced antioxidant capacity (P = 0.0039). In functional studies, endothelium-dependent relaxation of aortic rings (P = 0.018) and carotid arteries (P = 0.022) in response to acetylcholine was improved in the SHR acupuncture group. Aortas of SHRs receiving acupuncture also expressed an elevated level of eNOS (P > 0.001) and p-eNOS (P = 0.012) and a reduced nitrotyrosine level (P = 0.0012). The nitrate/nitrite level in aortic tissue was also attenuated after acupuncture (P = 0.0018). The effects of acupuncture in treating hypertension were associated with reduced oxidative stress, increased nitric oxide bioavailability and endothelial function in SHRs.


Substance use disorders in the U.S. Armed Forces, 2000-2011.
Drug misuse is associated with serious health consequences and has detrimental effects on military readiness. During 2000 to 2011, 70,104 service members received an incident diagnosis of a substance use disorder (SUD) (excluding alcohol and tobacco-related disorders). Incidence rates declined with increasing age, time in service, rank, and number of combat deployments. Service members in a combat occupation had 1.2 times the rate of individuals in a health care or administation/supply occupation. The median time to discharge after an SUD diagnosis was longest in the Air Force (327 days) and shortest in the Navy (133 days). The substances with the highest incidence rates were cannabis (160 per 100,000 person-years [p-yrs]), "mixed/unspecified/other" (125 per 100,000 p-yrs), and cocaine (61 per 100,000 p-yrs). Incidence rates of cannabis and cocaine use diagnoses generally declined while rates of mixed/unspecified/other and opioid use increased over the surveillance period. The increasing trend in opioid-related diagnoses since 2002 may reflect an increase in prescription drug misuse. The Department of Defense recently expanded its drug testing program to screen for hydrocodone and benzodiazepines.


Using the Web to reduce postoperative pain following ambulatory surgery.
To test the hypothesis that educational information provided via the web would not only be accessed by our patients, but could also reduce postoperative pain following ambulatory surgery, we enrolled 195 patients into a randomized controlled study. Fifty-two percent of our ambulatory surgery patients already knew how to use and had access to the Internet. Eighty-five percent of our study patients accessed the resources made available to them on the web site. Patients who had access to the pain management information on the ambulatory surgery web site reported significantly less postoperative pain on arrival to their home after surgery (p < 0.016) and into the night after surgery (p < 0.013). These patients also reported significantly less postoperative pain for the day immediately following surgery (p < 0.037). We conclude that using the Internet to provide just-in-time patient education can significantly effect the clinical outcome of care.


Comprehensive proteomic analysis reveals omega-3 fatty acids to counteract endotoxin-stimulated metabolic dysregulation in porcine enterocytes.
Omega-3 polyunsaturated fatty acids (n-3 PUFA), such as the eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are reported to beneficially affect the intestinal immunity. The biological pathways modulated by n-3 PUFA during an infection, at the level of intestinal epithelial barrier remain elusive. To address this gap, we investigated the proteomic changes induced by n-3 PUFA in porcine enterocyte cell line (IPEC-J2), in the presence and absence of lipopolysaccharide (LPS) stress conditions using shotgun proteomics analysis integrated with RNA-sequencing technology. A total of 33, 85, and 88 differentially abundant proteins (DAPs) were identified in cells exposed to n-3 PUFA (DHA:EPA), LPS, and n-3 PUFA treatment followed by LPS stimulation, respectively. Functional annotation and pathway analysis of DAPs revealed the modulation of central carbon metabolism, including the glycolysis/gluconeogenesis, pentose phosphate pathway, and oxidative phosphorylation processes. Specifically, LPS caused metabolic dysregulation in enterocytes, which was abated upon prior treatment with n-3 PUFA. Besides, n-3 PUFA supplementation facilitated enterocyte development and lipid homeostasis. Altogether, this work for the first time comprehensively described the biological pathways regulated by n-3 PUFA in enterocytes, particularly during endotoxin-stimulated metabolic dysregulation. Additionally, this study may provide nutritional biomarkers in monitoring the intestinal health of human and animals on n-3 PUFA-based diets.


Adverse drug effects across patients with heart failure: a systematic review.
To summarize published literature on the incidence of adverse drug effects (ADEs) associated with guideline-directed medical therapy (GDMT) for patients with heart failure with reduced ejection fraction (HFrEF). Systematic literature review. A systematic literature review was conducted in PubMed, Ovid MEDLINE, and Clinical Key covering January 1990 to December 2018. Key search terms were ADEs for β-blockers (BBs), ACE inhibitors (ACEis), angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists (MRAs), and/or angiotensin receptor-neprilysin inhibitors (ARNis) in adult patients (≥ 18 years) with HFrEF. A total of 279 eligible articles were identified, of which 29 reported drug-related adverse effects and were included in this review. Of the 29 studies, 11 examined BBs; 9, MRAs; 6, ARNis; 2, ACEis; and 1, ARBs. The most common reported ADEs across these therapeutic classes included bradycardia, dizziness, hypotension, hyperkalemia, cough, and renal impairment. The incidence of BB-induced bradycardia was 1% to 52% based on 9 studies, and 6 studies described dizziness as a result of BBs and ARNis (15%-43%). Fourteen studies reported induced hypotension (1.4%-63%); 13 studies, hyperkalemia (0.6%-30.2%); 3 studies, cough (37%-50%); and 4 studies, renal impairment (0.6%-7.6%). Findings show that drug-related adverse effects are commonly reported in clinical trials and highlight the sizable burden of ADEs with medical therapy across patients with HFrEF. Additional real-world evidence and studies aiming to improve the tolerability of GDMT for patients with HFrEF are warranted.


Lewis acid-induced change from four- to two-electron reduction of dioxygen catalyzed by copper complexes using scandium triflate.
Mononuclear copper complexes, [(tmpa)Cu(II)(CH3CN)](ClO4)2 (1, tmpa = tris(2-pyridylmethyl)amine) and [(BzQ)Cu(II)(H2O)2](ClO4)2 (2, BzQ = bis(2-quinolinylmethyl)benzylamine)], act as efficient catalysts for the selective two-electron reduction of O2 by ferrocene derivatives in the presence of scandium triflate (Sc(OTf)3) in acetone, whereas 1 catalyzes the four-electron reduction of O2 by the same reductant in the presence of Brønsted acids such as triflic acid. Following formation of the peroxo-bridged dicopper(II) complex [(tmpa)Cu(II)(O2)Cu(II)(tmpa)](2+), the two-electron reduced product of O2 with Sc(3+) is observed to be scandium peroxide ([Sc(III)(O2(2-))](+)). In the presence of 3 equiv of hexamethylphosphoric triamide (HMPA), [Sc(III)(O2(2-))](+) was oxidized by [Fe(bpy)3](3+) (bpy = 2,2-bipyridine) to the known superoxide species [(HMPA)3Sc(III)(O2(•-))](2+) as detected by EPR spectroscopy. A kinetic study revealed that the rate-determining step of the catalytic cycle for the two-electron reduction of O2 with 1 is electron transfer from Fc* to 1 to give a cuprous complex which is highly reactive toward O2, whereas the rate-determining step with 2 is changed to the reaction of the cuprous complex with O2 following electron transfer from ferrocene derivatives to 2. The explanation for the change in catalytic O2-reaction stoichiometry from four-electron with Brønsted acids to two-electron reduction in the presence of Sc(3+) and also for the change in the rate-determining step is clarified based on a kinetics interrogation of the overall catalytic cycle as well as each step of the catalytic cycle with study of the observed effects of Sc(3+) on copper-oxygen intermediates.


PopulusPtERF85 Balances Xylem Cell Expansion and Secondary Cell Wall Formation in Hybrid Aspen.
Secondary growth relies on precise and specialized transcriptional networks that determine cell division, differentiation, and maturation of xylem cells. We identified a novel role for the ethylene-induced Populus Ethylene Response Factor PtERF85 (Potri.015G023200) in balancing xylem cell expansion and secondary cell wall (SCW) formation in hybrid aspen (Populus tremula x tremuloides). Expression of PtERF85 is high in phloem and cambium cells and during the expansion of xylem cells, while it is low in maturing xylem tissue. Extending PtERF85 expression into SCW forming zones of woody tissues through ectopic expression reduced wood density and SCW thickness of xylem fibers but increased fiber diameter. Xylem transcriptomes from the transgenic trees revealed transcriptional induction of genes involved in cell expansion, translation, and growth. The expression of genes associated with plant vascular development and the biosynthesis of SCW chemical components such as xylan and lignin, was down-regulated in the transgenic trees. Our results suggest that PtERF85 activates genes related to xylem cell expansion, while preventing transcriptional activation of genes related to SCW formation. The importance of precise spatial expression of PtERF85 during wood development together with the observed phenotypes in response to ectopic PtERF85 expression suggests that PtERF85 contributes to the transition of fiber cells from elongation to secondary cell wall deposition.


Biologically active 4-thiazolidinones: a review of QSAR studies and QSAR modeling of antitumor activity.
4-Thiazolidinone is a promising scaffold for the search of new potential antibacterial, antiviral, antidiabetic and anticancer agents etc. SAR analysis of the most potent compounds and different activities evaluation provide a solid background for de novo design of novel drugs. Current review summarizes recent QSAR studies on the 4-thiazolidinones making the emphasis on both technical and interpretative sides of reported models. Several papers among them are devoted to the anticancer activity of 4-thiazolidinone derivatives and are reporting QSAR models that were obtained via multiple linear regressions (MLR). Additionally, a non-linear approach, namely Gaussian processes, has been applied to identify the relationships between 4-thiazolidinones structure and tumor cell growth inhibition. The interpretation of the reported model highlights the core template for the design of new highly-potent anticancer agents and proposes a hypothesis about key role of Hydrogen at the N-atom three bonds away from thiazolidine in the interaction with biotarget.


Imaging of athletic wrist and hand injuries.
Sports-related injuries of the wrist and hand are commonly encountered in clinical practice. Athletic injuries create special challenges for the orthopedic surgeon and radiologist, as these patients expect to recover quickly and return to the same athletic endeavors that caused their original injuries. A thorough understanding of the mechanism of injury and imaging findings are necessary for accurate diagnosis and effective therapy. This knowledge allows the clinician to effectively educate the athlete concerning the risks, complications, and prognosis of the injury and its treatment. This article will review mechanisms of injury, imaging findings, and some therapeutic options of common sports-related injuries to the wrist and hand.


[Group and group interaction in nurses' activities: a needed knowledge].
This study aimed at verifying the knowledge of nurses about groups and group functioning, as well as knowing which premises found their activities as coordinators of their working teams. The research was outlined by the descriptive-exploratory approach, carried out in a university hospital in Porto Alegre, Brazil. The results show that 97% of the participants like group work while 77.7% of the nurses use both empirical and theoretical knowledge as the basis for their activities. However, most of them were unaware of the meaning of operative group and basic assumptions. By using the empiric and theoretical knowledge, the nurse can have tools to work with group emotions and support actions regarding the client's care.


Micromachined filter-chamber array with passive valves for biochemical assays on beads.
The filter-chamber array presented here enables a real-time parallel analysis of three different samples on beads in a volume of 3 nL, on a 1 cm2 chip. The filter-chamber array is a system containing three filter-chambers, three passive valves at the inlet channels and a common outlet. The design enables parallel sample handling and time-controlled analysis. The device is microfabricated in silicon and sealed with a Pyrex lid to enable real-time analysis. Single nucleotide polymorphism analysis by using pyrosequencing has successfully been performed in single filter-chamber devices. The passive valves consist of plasma-deposited octafluorocyclobutane and show a much higher resistance towards water and surface-active solutions than previous hydrophobic patches. The device is not sensitive to gas bubbles, clogging is rare and reversible, and the filter-chamber array is reusable. More complex (bio)chemical reactions on beads can be performed in the devices with passive valves than in the devices without valves.


Gaps and Opportunities for Faculty Workload Policies in Pharmacy and Health Professions Education.
Faculty workload is difficult to delineate and quantify equitably because of the various factors and diverse roles that define faculty positions. This is especially true in health professions education, including pharmacy. Nonetheless, ensuring fair and transparent distribution of faculty workload is necessary for equity and engagement of the faculty workforce. While it is impossible to develop a uniform policy for all faculty, there can be a guide for how workload is developed and measured, especially for promotion or awarding of tenure, focusing on equity and transparency. Developing clear definitions of workload, setting mutually agreed expectations, and sharing transparent workload assignments and distribution within the institution may be needed. It is imperative to discuss an optimal policy for equitable and transparent workload in each institution and in academic pharmacy as a whole; a lack of this effort can create undue hardship for faculty, decrease productivity, potentially worsen faculty morale, and ultimately impair faculty retention.


Antihypertensive and Renoprotective Effects of Dietary Flaxseed and its Mechanism of Action in Deoxycorticosterone Acetate-Salt Hypertensive Rats.
Flaxseed contains alpha-linolenic acid (ALA), lignans, and dietary fiber, and its intake lowers blood pressure in hypertensive patients. Here, we examined the effects of flaxseed powder, which includes all flaxseed components, flaxseed oil, composed mainly of ALA, flaxseed lignan, and flaxseed fiber, on hypertension and renal damage induced by deoxycorticosterone acetate (DOCA)-salt. Then, we investigated the mechanisms of action associated with the effects of flaxseed. Flaxseed powder, oil, lignan, or fiber was administered to DOCA-salt rats. Systolic blood pressure (SBP), urinary protein excretion, renal angiotensin converting enzyme (ACE) activity, sympathetic nerve activity, and gene expression of inflammatory mediators in the kidney and hypothalamus were measured. Flaxseed powder and oil reduced the increases in SBP and urinary protein excretion induced by DOCA-salt treatment, whereas lignan and fiber had no effects. Flaxseed oil suppressed the increase in renal ACE activity, sympathetic nerve activity, and gene expression of renal and hypothalamic inflammatory mediators. Flaxseed has antihypertensive and renoprotective effects in DOCA-salt rats. These effects are likely principally exerted by ALA. Furthermore, the suppression of renal ACE activity, sympathetic nerve activity, and inflammation is partly involved in the effects of flaxseed.


The large conductance Ca2+-activated potassium channel (pSlo) of the cockroach Periplaneta americana: structure, localization in neurons and electrophysiology.
Voltage-activated, Ca2+-sensitive K+ channels (BK or maxi K,Ca channels) play a major role in the control of neuronal excitability. We have cloned pSlo, the BK channel alpha subunit of the cockroach Periplaneta americana. The amino acid sequence of pSlo shows 88% identity to dSlo from Drosophila. There are five alternatively spliced positions in pSlo showing differential expression in various tissues. A pSlo-specific antibody prominently stained the octopaminergic dorsal unpaired median (DUM) neurons and peptidergic midline neurons in Periplaneta abdominal ganglia. HEK293 cells expressing pSlo exhibit K+ channels of 170 pS conductance. They have a tendency for brief closures, exhibit subconductance states and show slight inward rectification. Activation kinetics and voltage dependence are controlled by cytoplasmic [Ca2+]. In contrast to dSlo, pSlo channels are sensitive to charybdotoxin and iberiotoxin. Mutagenesis at two positions (E254 and Q285) changed blocking efficacy of charybdotoxin. In contrast to pSlo expressed in HEK293 cells, native IbTx-sensitive K,Ca currents in DUM and in peptidergic neurons, exhibited rapid, partial inactivation. The fast component of the K,Ca current partly accounts for the repolarization and the early after-hyperpolarization of the action potential. By means of Ca2+-induced repolarization, BK channels may reduce the risk of Ca2+ overload in cockroach neurons. Interestingly, the neurons expressing pSlo were also found to express taurine, a messenger that is likely to limit overexcitation by an autocrine mechanism in mammalian central neurons.


Genome-wide investigation of aromatic acid transporters in Corynebacterium glutamicum.
Genome-wide data mining indicated that six genes (ncgl1031, ncgl2302, ncgl2325, ncgl2326, ncgl2922 and ncgl2953) encoding putative transport proteins are involved in uptake of various aromatic compounds that are further degraded through the beta-ketoadipate, gentisate and resorcinol pathways in Corynebacterium glutamicum. The gentisate (GenK/NCgl2922) and vanillate (VanK/NCgl2302) transporters have been identified previously. In this study, physiological functions of the remaining four putative transporters as well as the vanillate transporter (VanK/NCgl2302) were examined by genetic disruption/complementation and uptake assays. Results indicated that ncgl1031 encodes PcaK for 4-hydroxybenzoate and protocatechuate transport, and ncgl2302 encodes VanK for vanillate transport. Genetic studies and uptake assays indicated that both ncgl2325/benK and ncgl2326/benE are involved in benzoate transport in C. glutamicum. When growth rates were compared for two benzoate transporter mutants, benK and benE, a high growth rate was observed for the benE mutant. Sequence alignments revealed that PcaK, VanK, BenK and GenK belong to the major facilitator superfamily (MFS). Modelling of secondary structures based on previously characterized MFS members revealed that NCgl1031, NCgl2302, NCgl2325 and NCgl2922 are typical 12 helix transmembrane proteins but NCgl2326 contains only 11 alpha-helices. Thus the functionally identified NCgl2326 belongs to a novel type of benzoate transporters. Attempts to identify the phenotype of a hydK/ncgl2953 mutant failed, so the function of ncgl2953 remains unclear.


Molecular characterization of inflammatory myofibroblastic tumors with frequent ALK and ROS1 gene fusions and rare novel RET rearrangement.
Approximately 50% of conventional inflammatory myofibroblastic tumors (IMTs) harbor ALK gene rearrangement and overexpress ALK. Recently, gene fusions involving other kinases have been implicated in the pathogenesis of IMT, including ROS1 and in 1 patient PDGFRB. However, it remains uncertain whether the emerging genotypes correlate with clinicopathologic characteristics of IMT. In this study, we expand the molecular investigation of IMT in a large cohort of different clinical presentations and analyze for potential genotype-phenotype associations. Criteria for inclusion in the study were typical morphology and tissue availability for molecular studies. The lack of ALK immunoreactivity was not an excluding factor. As overlapping gene fusions involving actionable kinases are emerging in both IMT and lung cancer, we set out to evaluate abnormalities in ALK, ROS1, PDGFRB, NTRK1, and RET by fluorescence in situ hybridization. In addition, next-generation paired-end RNA sequencing and FusionSeq algorithm was applied in 4 cases, which identified EML4-ALK fusions in 2 cases. Of the 62 IMTs (25 children and 37 adults), 35 (56%) showed ALK gene rearrangement. Of note, EML4-ALK inversion was noted in 7 (20%) cases, seen mainly in the lung and soft tissue of young children including 2 lesions from newborns. There were 6 (10%) ROS1-rearranged IMTs, all except 1 presenting in children, mainly in the lung and intra-abdominally and showed a distinctive fascicular growth of spindle cells with long cell processes, often positive for ROS1 immunohistochemistry. Two of the cases showed TFG-ROS1 fusions. Interestingly, 1 adult IMT revealed a RET gene rearrangement, a previously unreported finding. Our results show that 42/62 (68%) IMTs are characterized by kinase fusions, offering a rationale for targeted therapeutic strategies. Interestingly, 90% of fusion-negative IMTs were seen in adults, whereas >90% of pediatric IMT showed gene rearrangements. EML4-ALK inversion and ROS1 fusions emerge as common fusion abnormalities in IMT, closely recapitulating the pattern seen in lung cancer.


Molar tooth development in caspase-3 deficient mice.
Tooth morphogenesis is accompanied by apoptotic events which show restricted temporospatial patterns suggesting multiple roles in odontogenesis. Dental apoptosis seems to be caspase dependent and caspase-3 has been shown to be activated during dental apoptosis.Caspase-3 mutant mice on different genetic backgrounds were used to investigate alterations in dental apoptosis and molar tooth morphogenesis. Mouse embryos at E15.5 were analyzed to reveal any changes in enamel knots, which are transient structures eliminated by apoptosis. In caspase-3(-/-) mice on the B57BL/6 background, disorganization of the epithelium was found in the original primary enamel knot area and confirmed by altered expression of Shh. Despite this early defect in molar tooth development, these mutants showed correct formation of secondary enamel knots as indicated by Fgf-4 expression. Analyses of adult molar teeth did not reveal any major alterations in tooth shape, enamel structure or pattern when compared to heterozygote littermates. In caspase-3(-/-) mice on the 129X1/SvJ background, no defects in tooth development were found except the position of the upper molars which developed more posteriorly in the oral cavity. This is likely, however, to be a secondary defect caused by a physical squashing of the face by the malformed brain. The results suggest that although caspase-3 becomes activated and may be essential for dental apoptosis, it does not seem fundamental for formation of normal mineralised molar teeth.


Near-infrared noninvasive blood glucose prediction without using multivariate analyses: introduction of imaginary spectra due to scattering change in the skin.
A noninvasive measurement method is proposed and examined to continuously predict blood glucose contents using near-infrared diffuse reflection difference spectra measured at the skin tissue without using multivariate analyses. Using the modified Beer's law, the difference spectra are assumed to be synthesized from four major components in the human skin (water, protein, glucose, and fat) and a scattering equivalent component called baseline. As a result, one of the origins of the errors in blood glucose prediction using near-infrared is found to be the similarity of the shapes of the absorption spectrum between glucose and baseline. After separating the glucose contributions from the difference spectra at the characteristic wavelengths of baseline and fat, an imaginary component combining baseline and fat is introduced by considering that both the change in the fat contribution and the generation of baseline originate from the change in scattering in the skin. The imaginary component enables us to reduce the errors in blood glucose prediction. In contrast to the methods using multivariate analyses, the calculation process of the blood glucose contents from the measured reflection spectra is clear in this method, thus, it is easy to estimate the origins of the changes and contributions of the components in the measured difference spectra. The proposed method may become a useful tool for realization of noninvasive blood glucose prediction using near-infrared spectroscopy.


Bronchial glomus tumor with right upper lobe atelectasis.
Glomus tumors are uncommon benign soft tissue neoplasms. We report the case of a 32-year-old male who presented with right upper lobe atelectasis due to an endobronchial tumor. The patient underwent right upper lobectomy and wedge bronchoplasty. The pathological diagnosis was bronchial glomus tumor. To our knowledge, this presentation (with right upper lobe atelectasis) has never before been reported. Glomus tumor should be considered in the differential diagnosis of endobronchial lesions causing lobar atelectasis.


Review and management of clozapine side effects.
Clozapine has demonstrated superior efficacy in relieving positive and negative symptoms in treatment-resistant schizophrenic patients; unlike other antipsychotics, it causes minimal extrapyramidal side effects (EPS) and has little effect on serum prolactin. Despite these benefits, the use of clozapine has been limited because of infrequent but serious side effects, the most notable being agranulocytosis. In recent years, however, mandatory blood monitoring has significantly reduced both the incidence of agranulocytosis and its associated mortality. The occurrence of seizures appears to be dose-related and can generally be managed by reduction in clozapine dosage. Less serious and more common side effects of clozapine including sedation, hypersalivation, tachycardia, hypotension, hypertension, weight gain, constipation, urinary incontinence, and fever can often be managed medically and are generally tolerated by the patient. Appropriate management of clozapine side effects facilitates a maximization of the benefits of clozapine treatment, and physicians and patients alike should be aware that there is a range of benefits to clozapine use that is wider than its risks.


Does attention affect visual feature integration?
Two questions are investigated in this work: first, whether the integration of color and shape information is affected by attending to the stimulus location, and second, whether attending to a stimulus location enhances the perceptual representation of the stimulus or merely affects decision processes. In three experiments, subjects were briefly presented with colored letters. On most trials, subjects were precued to the stimulus location (valid cue); on some trials, a nonstimulus location was cued (invalid cue). Subjects were less likely to incorrectly combine colors and letter shapes following a valid cue. The attentional facilitation afforded by the cue was not limited to feature integration but also affected the registration of features. However, when the amount of feature information was strictly controlled, attention still affected feature integration. The results indicate that orienting attention to the location of the cue affects the quality of the perceptual representation for features and their integration.


The Integration of the Metabolome and Transcriptome for Dendrobium nobile Lindl. in Response to Methyl Jasmonate.
Dendrobium nobile Lindl., as an endangered medicinal plant within the genus Dendrobium, is widely distributed in southwestern China and has important ecological and economic value. There are a variety of metabolites with pharmacological activity in D. nobile. The alkaloids and polysaccharides contained within D. nobile are very important active components, which mainly have antiviral, anti-tumor, and immunity improvement effects. However, the changes in the compounds and functional genes of D. nobile induced by methyl jasmonate (MeJA) are not clearly understood. In this study, the metabolome and transcriptome of D. nobile were analyzed after exposure to MeJA. A total of 377 differential metabolites were obtained through data analysis, of which 15 were related to polysaccharide pathways and 35 were related to terpenoids and alkaloids pathways. Additionally, the transcriptome sequencing results identified 3256 differentially expressed genes that were discovered in 11 groups. Compared with the control group, 1346 unigenes were differentially expressed in the samples treated with MeJA for 14 days (TF14). Moreover, the expression levels of differentially expressed genes were also significant at different growth and development stages. According to GO and KEGG annotations, 189 and 99 candidate genes were identified as being involved in terpenoid biosynthesis and polysaccharide biosynthesis, respectively. In addition, the co-expression analysis indicated that 238 and 313 transcription factors (TFs) may contribute to the regulation of terpenoid and polysaccharide biosynthesis, respectively. Through a heat map analysis, fourteen terpenoid synthetase genes, twenty-three cytochrome P450 oxidase genes, eight methyltransferase genes, and six aminotransferase genes were identified that may be related to dendrobine biosynthesis. Among them, one sesquiterpene synthase gene was found to be highly expressed after the treatment with MeJA and was positively correlated with the content of dendrobine. This study provides important and valuable metabolomics and transcriptomic information for the further understanding of D. nobile at the metabolic and molecular levels and provides candidate genes and possible intermediate compounds for the dendrobine biosynthesis pathway, which lays a certain foundation for further research on and application of Dendrobium.


Improving the performance of perovskite solar cells using a dual-hole transport layer.
The energy loss (Eloss) caused by inefficient charge transfer and large energy level offset at the buried interface can easily restrict the performance of p-i-n perovskite solar cells (PVSCs). In this study, the utilization of poly-TPD and P3CT-N as a dual-hole transporting layer (HTLs) was implemented in a sequential manner. This approach aimed to improve the charge transfer efficiency of the HTL and mitigate charge recombination at the interface between the HTL and PVK. The results showed that this strategy also could achieve more suitable energy levels, improve the quality of the perovskite film layer, and ultimately enhance the device's stability. IPVSCs employing the dual-HTLs approach exhibited the highest power conversion efficiency of 19.85%, and the open-circuit voltage increased to 1.09 V from 1.00 V. This study offers a straightforward and efficient approach to boost the device performance by minimizing Eloss and reducing the buried interfacial defects. The findings underscore the potential of employing a dual-HTL strategy as a promising pathway for further advancements in PVSCs.


A new serotonin 5-HT6 receptor antagonist with procognitive activity - Importance of a halogen bond interaction to stabilize the binding.
Serotonin 5-HT6 receptor has been proposed as a promising therapeutic target for cognition enhancement though the development of new antagonists is still needed to validate these molecules as a drug class for the treatment of Alzheimer's disease and other pathologies associated with memory deficiency. As part of our efforts to target the 5-HT6 receptor, new benzimidazole-based compounds have been designed and synthesized. Site-directed mutagenesis and homology models show the importance of a halogen bond interaction between a chlorine atom of the new class of 5-HT6 receptor antagonists identified herein and a backbone carbonyl group in transmembrane domain 4. In vitro pharmacological characterization of 5-HT6 receptor antagonist 7 indicates high affinity and selectivity over a panel of receptors including 5-HT2B subtype and hERG channel, which suggests no major cardiac issues. Compound 7 exhibited in vivo procognitive activity (1 mg/kg, ip) in the novel object recognition task as a model of memory deficit.


[An influence of mexidol on the restoration of neurological deficit, increase of social adaptation and removal of neglect and push syndromes in stroke patients].
To evaluate efficacy of mexidol in the rehabilitative treatment of patients with stroke, treatment results of 440 patients were analyzed. The functional rehabilitation and adaptation level were followed up using Barthel, Lindmark, Scandinavian and Merton and Sutton scales. The inclusion of mexidol in the scheme of complex rehabilitative study significantly improves the results of rehabilitation facilitating the increase in the restoration of neurological functions and social adaptation level. The effect of neglect and push syndromes on the results of rehabilitation in stroke patients and efficacy of mexidol in their removal were studied as well. We examined 630 stroke patients. Mexidol efficacy was evaluated by the absence of these syndromes and by the results of balance testing. Neglect and push syndromes significantly reduce the effectiveness of rehabilitation. At the same time, the better regression of syndrome presentations was seen in patients treated with mexidol.


Short Assessment of Health Literacy-Spanish and English: a comparable test of health literacy for Spanish and English speakers.
The intent of the study was to develop and validate a comparable health literacy test for Spanish-speaking and English-speaking populations. The design of the instrument, named the Short Assessment of Health Literacy-Spanish and English (SAHL-S&E), combined a word recognition test, as appearing in the Rapid Estimate of Adult Literacy in Medicine (REALM), and a comprehension test using multiple-choice questions designed by an expert panel. We used the item response theory (IRT) in developing and validating the instrument. Validation of SAHL-S&E involved testing and comparing the instrument with other health literacy instruments in a sample of 201 Spanish-speaking and 202 English-speaking subjects recruited from the Ambulatory Care Center at the University of North Carolina Healthcare System. Based on IRT analysis, 18 items were retained in the comparable test. The Spanish version of the test, SAHL-S, was highly correlated with other Spanish health literacy instruments, Short Assessment of Health Literacy for Spanish-Speaking Adults (r=0.88, p<.05) and the Spanish Test of Functional Health Literacy in Adults (TOFHLA) (r=0.62, p<.05). The English version, SAHL-E, had high correlations with REALM (r=0.94, p<.05) and the English TOFHLA (r=0.68, p<.05). Significant correlations were found between SAHL-S&E and years of schooling in both Spanish- and English-speaking samples (r=0.15 and 0.39, respectively). SAHL-S&E displayed satisfactory reliability of 0.80 and 0.89 in the Spanish- and English-speaking samples, respectively. IRT analysis indicated that the SAHL-S&E score was highly reliable for individuals with a low level of health literacy. The new instrument, SAHL-S&E, has good reliability and validity. It is particularly useful for identifying individuals with low health literacy and could be used to screen for low health literacy among Spanish and English speakers.


TGF-β and αvβ6 integrin act in a common pathway to suppress pancreatic cancer progression.
The TGF-β pathway is under active consideration as a cancer drug target based on its capacity to promote cancer cell invasion and to create a protumorigenic microenvironment. However, the clinical application of TGF-β inhibitors remains uncertain as genetic studies show a tumor suppressor function of TGF-β in pancreatic cancer and other epithelial malignancies. Here, we used genetically engineered mouse models to investigate the therapeutic impact of global TGF-β inhibition in pancreatic cancer in relation to tumor stage, genetic profile, and concurrent chemotherapy. We found that αvβ6 integrin acted as a key upstream activator of TGF-β in evolving pancreatic cancers. In addition, TGF-β or αvβ6 blockade increased tumor cell proliferation and accelerated both early and later disease stages. These effects were dependent on the presence of Smad4, a central mediator of TGF-β signaling. Therefore, our findings indicate that αvβ6 and TGF-β act in a common tumor suppressor pathway whose pharmacologic inactivation promotes pancreatic cancer progression.


Oligonucleotides complementary to c-myb messenger RNA inhibit growth and induce apoptosis in human Burkitt lymphoma cells.
A 24-mer (antisense) phosphorothioate oligonucleotide (ODN) corresponding to the codons 2-9 of the c-myb gene was evaluated for its effects on the growth of a human Burkitt lymphoma cell line (Raji) in vitro. Raji cells incubated with different concentrations of c-myb antisense ODN (5-15 mu g/ml) for 24-72 h showed a significant dose-dependent decrease in growth. The same concentrations of control (sense) or scrambled c-myb phosphorothioate ODNs did not inhibit Raji cell growth. The c-myb antisense ODN, but not the control ODNs, significantly decreased c-myb mRNA levels in treated cells as determined by RT-PCR. Additionally, the c-myb antisense ODN induced apoptosis of Raji cells as demonstrated by i) flow cytometry to enumerate the A(o) (apoptotic cell population) population of propidium iodide stained cells; ii) electron microscopy to evaluate the cell morphology; and iii) DNA fragmentation pattern. Thus, an antisense c-myb ODN causes significant growth inhibition of Burkitt lymphoma cells, and one mechanism of growth inhibition is the induction of apoptosis of the lymphoma cells. In addition, antisense c-myb ODN did not reduce CFU-GM or BFU-e colony-forming ability of normal hematopoietic stem/progenitor cells. Because the inhibition is sequence-specific and Burkitt lymphoma cell selective, evaluation of the therapeutic effects of c-myb antisense ODN against Burkitt lymphoma is warranted.


Ergonomics and musculoskeletal symptoms in surgeons performing endoscopic procedures for benign prostatic hyperplasia.
Benign prostatic hyperplasia (BPH) is the most common urologic disorder affecting older men, necessitating medical or surgical intervention. Limited data exists regarding the effect these surgeries have on the endourologist's musculoskeletal system following the surgery because of the required difficult posture, prolonged procedures, repetitive movements, and the settings of an adjustable visual display terminal workstation. The aim of our study was to survey the prevalence and possible causes of musculoskeletal disorders among endourologists performing transurethral resection of the prostate (TURP) or laser prostatectomy using either holmium laser enucleation or thulium laser enucleation. An email inviting all members of the Endourological Society to participate in the survey was sent. The questionnaire included different demographic and practice characteristics, with concern regarding performing either TURP or laser prostatectomy and the incidence and type of musculoskeletal incidents following these surgeries. All responses were collected by a commercially available internet based survey host (www.surveymonkey.com) over a period of 6 weeks. Of the 121 complete responses, 84 (69%) of endourologists complained of a musculoskeletal disorder following TURP or laser prostatectomy. The most frequent complaint was for neck (64%), followed by back (57%), shoulder (48%), hand (40%), and elbow (18%). The average prostate volume turned out to be the most compelling predictor for musculoskeletal disorder occurrence with an average prostate volume of 76 g operated on by the complaining group compared with 59 g in the noncomplaining group. Those with more severe symptoms were linked to a mean prostate size of 80 g (60-146) and constantly complained of shoulder, neck, or back trouble compared with the less-severely complaining group. A high prevalence of musculoskeletal complaints among urologists performing endourologic prostatectomy was confirmed and was found to be proportionally related to the size of the prostate. The integration of an ergonomic specialist inside the operation room to watch and correct the surgeon's position during endourologic procedures may reduce the endourologist's exposure to these occupational hazards.


The Effectiveness of Empowerment Program on Increasing Self-Esteem, Learned Resourcefulness, and Coping Ways in Women Exposed to Domestic Violence.
This study was conducted to assess the effectiveness of empowerment program on increasing self-esteem, learned resourcefulness, and coping ways in women exposed to domestic violence. This experimental study was conducted between October 2012 and June 2014 in the obstetrics and gynaecology departments of the Giresun Maternity Hospital, and at the Family Counseling Center (FCC) in Turkey. Sixty women who agreed to participate in the study were randomly assigned into two groups. Data were collected by the Coopersmith Self-Esteem Inventory (SEI), The Rosenbaum's Learned Resourcefulness Scale (RLRS), and the Ways of Coping Inventory (WCI). The assessment of the women before and after the empowerment program showed that women in the intervention group showed significant improvements in the SEI, RLRS, and WCI scores compared with controls. These results suggest that the empowerment program is an effective practice for increasing the levels of self-esteem, learned resourcefulness, and coping ways of women exposed to domestic violence.


Characterization of dynamic 3-D PET imaging for functional brain mapping.
Methods for optimizing the acquisition, reconstruction and analysis of positron emission tomography (PET) images for functional brain mapping have been investigated. The scatter fraction and noise-equivalent count rate characteristics were measured for the ECAT 951/31R PET scanner operating in septa-extended two-dimensional (2-D) and septa-retracted three-dimensional (3-D) modes. The 3-D mode is shown to provide higher signal-to-noise images than the 2-D mode at specific activities less than 30 kBq/ml. To enable increased temporal resolution in dynamic 3-D PET activation studies, a parallel version of the 3-D reconstruction algorithm was developed. Implementation of the reprojection algorithm on an 88 processor 1860 supercomputer resulted in a more than tenfold increase in reconstruction speed compared to a single 1860 processor system. An investigation of the optimal duration for imaging brain activations was undertaken in 12 normal subjects using repeated H2(15)O slow infusions and a visually presented lexical decision task. The significance of change in regional cerebral blood flow (CBF) was determined using statistical parametric maps for images acquired during stimulation, immediately after stimulation, and commencing 1 min after cessation of the stimulus. Regions of CBF change were detected in all three images. Dynamic 3-D, or four-dimensional (4-D), PET activation scanning is shown to be practical and likely to further improve the sensitivity of PET for detection of subtle regional CBF changes in functional brain mapping research.


Paeoniflorin diminishes ConA-induced IL-8 production in primary human hepatic sinusoidal endothelial cells in the involvement of ERK1/2 and Akt phosphorylation.
Liver diseases are closely associated with elevated levels of interleukin-8 (IL-8), suggesting the ability to inhibit IL-8 production could enhance the treatment of liver diseases. Paeoniflorin is a major active constituent of dried Paeoniae Radix Alba root (Baishao in Chinese) which is widely used in China to treat liver diseases. We examined the effects and underlying mechanisms of paeoniflorin on IL-8 production in primary human hepatic sinusoidal endothelial cells (HHSECs). Concanavalin A (ConA) at 20 μg/mL produced a 5.2-fold increase in IL-8 mRNA by 8h, and a 14.2-fold rise in IL-8 levels by 16 h. Inhibition of MEK (ERK kinase) and extracellular signal-regulated kinase (ERK) by PD98059 and U0126, or inhibition of phosphatidylinositol 3-kinase (PI3K) by LY294002 blocked both ConA-induced IL-8 mRNA expression and IL-8 secretion. Paeoniflorin reduced ConA-induced IL-8 mRNA expression and IL-8 release by 57.9% and 52.8%, respectively, and also decreased ConA-stimulated phosphorylation of ERK1/2 and Akt, suggesting paeoniflorin inhibits IL-8 expression and release by inhibiting the ERK1/2 and Akt pathways. Combining paeoniflorin with U0126 or LY294002 at low doses showed supra-additive inhibition of not only phospho-ERK1/2 and phospho-Akt by 46.4% and 35.0%, but also IL-8 release by 42.4% and 36.1% and IL-8 mRNA expression by 43.5% and 31.8%, respectively. In conclusion, paeoniflorin most likely contributes to the therapy for liver disease by exerting anti-inflammatory effects on HHSECs through blocking IL-8 secretion via downregulation of ERK1/2 and Akt phosphorylation.


In vivo quantum dot labeling of mammalian stem and progenitor cells.
Fluorescent semiconductor nanocrystal quantum dots (QDs) are a class of multifunctional inorganic fluorophores that hold great promise for clinical applications and biomedical research. Because no methods currently exist for directed QD-labeling of mammalian cells in the nervous system in vivo, we developed novel in utero electroporation and ultrasound-guided in vivo delivery techniques to efficiently and directly label neural stem and progenitor cells (NSPCs) of the developing mammalian central nervous system with QDs. Our initial safety and proof of concept studies of one and two-cell QD-labeled mouse embryos reveal that QDs are compatible with early mammalian embryonic development. Our in vivo experiments further show that in utero labeled NSPCs continue to develop in an apparent normal manner. These studies reveal that QDs can be effectively used to label mammalian NSPCs in vivo and will be useful for studies of in vivo fate mapping, cellular migration, and NSPC differentiation during mammalian development.


Interindividual, repositioning, and time-of-day effects on single voxel proton MR spectroscopy of the anterior cingulate cortex.
To measure interindividual, repositioning, and time-of-day effects of single voxel PRESS (Point RESolved Spectroscopy) proton magnetic resonance spectroscopy ((1)H-MRS) acquisition of the anterior cingulate cortex (AC) in healthy human subjects. AC (1)H-MRS measurements were performed in 15 healthy adult volunteers using a short echo PRESS sequence (GE Healthcare 3 Tesla, TE/TR = 30/2500 ms, 192 acquisitions, 6 cm(3) voxels). For each individual, a total of eight spectra were obtained during two identical scanning sessions separated by 3.5 h. In each, two consecutive AC spectra were acquired. After the first two scans, the subject left the scanner, then immediately returned for repositioning and acquisition of two more consecutive spectra. The subject then left the imaging centre to return 3.5 h later for a repeated procedure. Spectroscopic postprocessing was done using LCmodel. Interindividual, repositioning and time-of-day effects were measured using restricted maximum likelihood (REML) models of variance components analysis, where response variables were levels of creatine/phosphocreatine (Cr), N-acetyl-aspartate (NAA), myo-inositol (mI), choline (Cho), and the glutamate-glutamine complex (Glx). Interindividual effects were markedly higher than time-of-day and repositioning effects for all metabolites. Our findings show that (1)H-MRS measurements of the AC are sensitive to interindividual differences, while time of day and repositioning are markedly less important.


Accumulation and potential health effects of organohalogenated compounds in the arctic fox (Vulpes lagopus)--a review.
This review addresses biological effects of anthropogenic organohalogenated compounds in the arctic fox (Vulpes lagopus). When considering the current levels, spatial and tissue distributions of selected organic pollutants in arctic fox subpopulations, especially the Svalbard based populations accumulate high levels. The dominating contaminant groups are the polychlorinated biphenyls (PCBs) and chlordanes (CHLs), which reach high levels in adipose tissues, adrenals and liver. Recent controlled exposure studies on domesticated arctic fox and Greenland sledge dogs, show adverse health effects associated with OC concentrations lower than those measured in free-ranging populations. This indicates that especially populations at Svalbard may be at risk of experiencing OC related effects. The arctic fox as such may be an overlooked species in the Arctic Monitoring and Assessment Programs and it would add further information about pollution in the Arctic to include this species in the monitoring program.


Neonatal sevoflurane exposure induces long-term changes in dendritic morphology in juvenile rats and mice.
General anesthetics are potent neurotoxins when given during early development, causing apoptotic deletion of substantial number of neurons and persistent neurocognitive and behavioral deficits in animals and humans. The period of intense synaptogenesis coincides with the peak of susceptibility to deleterious effects of anesthetics, a phenomenon particularly pronounced in vulnerable brain regions such as subiculum. With steadily accumulating evidence confirming that clinical doses and durations of anesthetics may permanently alter the physiological trajectory of brain development, we set out to investigate the long-term consequences on dendritic morphology of subicular pyramidal neurons and expression on genes regulating the complex neural processes such as neuronal connectivity, learning, and memory. Using a well-established model of anesthetic neurotoxicity in rats and mice neonatally exposed to sevoflurane, a volatile general anesthetic commonly used in pediatric anesthesia, we report that a single 6 h of continuous anesthesia administered at postnatal day (PND) 7 resulted in lasting dysregulation in subicular mRNA levels of cAMP responsive element modulator (Crem), cAMP responsive element-binding protein 1 (Creb1), and Protein phosphatase 3 catalytic subunit alpha, a subunit of calcineurin (Ppp3ca) (calcineurin) when examined during juvenile period at PND28. Given the critical role of these genes in synaptic development and neuronal plasticity, we deployed a set of histological measurements to investigate the implications of anesthesia-induced dysregulation of gene expression on morphology and complexity of surviving subicular pyramidal neurons. Our results indicate that neonatal exposure to sevoflurane induced lasting rearrangement of subicular dendrites, resulting in higher orders of complexity and increased branching with no significant effects on the soma of pyramidal neurons. Correspondingly, changes in dendritic complexity were paralleled by the increased spine density on apical dendrites, further highlighting the scope of anesthesia-induced dysregulation of synaptic development. We conclude that neonatal sevoflurane induced persistent genetic and morphological dysregulation in juvenile rodents, which could indicate heightened susceptibility toward cognitive and behavioral disorders we are beginning to recognize as sequelae of early-in-life anesthesia.


Appropriateness of tumor marker request: a case of study.
Appropriateness is crucial to provide efficient and high-quality health services at affordable costs. Laboratory medicine is a sector of special interest for the investigation of inappropriateness, due to the high rate of technological innovation and its pivotal role in many diseases and clinical settings. Some subjective aspects related to either the patient or physician seem to have a major role on inappropriateness rates. Given the psychological impact of cancer on both patients and physicians, tumor markers represent a case of study for appropriateness. The assessment of inappropriateness of laboratory tests has been focused mainly on ordering patterns. Appropriateness can barely be appraised by matching the requested test with the clinical problem because clinical information on the test requisition form is usually inadequate. Monitoring inappropriateness through individual clinical information may be feasible in inpatient (clinical data are available), while an indirect approach should be used for outpatients. To estimate inappropriateness in outpatients our group developed innovative models based on comparison between the actually ordered and expected requests of tumor marker, calculated according to recommendations of clinical practice guidelines (CPGs) applied to figures of cancer prevalence. The implementation of the model at national scale in Italy led to recognize a very high rate of overordering of tumor markers. The model was further focused by a dedicated algorithm to be adapted to different clinical conditions or organizational settings by applying performance indicators to cohort-wide structured information in electronic health records (EHRs). With this novel approach, we showed that inappropriateness is multifaceted even within the specific category of tumour markers. The model was effective in identifying both over- and underordering. Implementation of evidence based information and monitoring their impact on the clinical practice are parts of the same, multistage, process aimed at the progressive improvement of health care.


Hyperbaric oxygen preconditioning induces tolerance against spinal cord ischemia by upregulation of antioxidant enzymes in rabbits.
The present study examined the hypothesis that spinal cord ischemic tolerance induced by hyperbaric oxygen (HBO) preconditioning is triggered by an initial oxidative stress and is associated with an increase of antioxidant enzyme activities as one effector of the neuroprotection. New Zealand White rabbits were subjected to HBO preconditioning, hyperbaric air (HBA) preconditioning, or sham pretreatment once daily for five consecutive days before spinal cord ischemia. Activities of catalase (CAT) and superoxide dismutase were increased in spinal cord tissue in the HBO group 24 h after the last pretreatment and reached a higher level after spinal cord ischemia for 20 mins followed by reperfusion for 24 or 48 h, in comparison with those in control and HBA groups. The spinal cord ischemic tolerance induced by HBO preconditioning was attenuated when a CAT inhibitor, 3-amino-1,2,4-triazole,1 g/kg, was administered intraperitoneally 1 h before ischemia. In addition, administration of a free radical scavenger, dimethylthiourea, 500 mg/kg, intravenous, 1 h before each day's preconditioning, reversed the increase of the activities of both enzymes in spinal cord tissue. The results indicate that an initial oxidative stress, as a trigger to upregulate the antioxidant enzyme activities, plays an important role in the formation of the tolerance against spinal cord ischemia by HBO preconditioning.


The evolutionary theories of aging revisited--a mini-review.
This short review portrays the evolutionary theories of aging in the light of the existing discoveries from genomic and molecular genetic studies on aging and longevity. At the outset, an historical background for the development of the evolutionary theories of aging is presented through the works of August Weismann (programmed death and the germ plasm theories) including his exceptional theoretical postulation, later experimentally validated by the existence of cell division limits. Afterwards, the theory of mutation accumulation of Peter Medawar and the theory modification by Charlesworth (late-life mortality plateau) are presented as well as the antagonistic pleiotropy hypothesis of George Williams, and the disposable soma theory of Kirkwood and Holliday. These theories are discussed in the light of the different research studies, which include studies on insulin signaling and longevity, the possibility that nuclear factor kappa B may be a major mediator of aging, studies of anti-aging Sirtuins and studies on heat shock proteins and longevity and on gene sets as biomarkers of aging. Finally, the proposals for future research in biogerontology, such as studies on the control of protein synthesis, validation of biomarkers of aging, understanding the biochemistry of longevity and research in the field of gerontologic pathology are presented. Likewise, further attention is suggested regarding the work on telomere shortening, stem cells and studies on understanding the biochemical and molecular basis for longevity in centenarians.


Use and safety perception of herbal remedies in patients with liver/biliary tract disorders: an Italian study.
Use of herbal remedies (HR) has increased in the general population, particularly among patients with chronic diseases. Marketing of HR is usually regulated by imperfect standards, and the reporting of HR-related adverse reactions has increased. Studies assessing prevalence of HR use among patients with liver/biliary tract disorders are limited and no data are available in Italy. Aims of this study were to assess the prevalence of HR use, the clinical and demographic variables of HR users, and to evaluate their safety perception about HR. From October 1, 2007 to April 30, 2008, 231 consecutive patients attending the Liver Disease Unit clinic at Sant'Andrea Hospital, II Faculty of Medicine "La Sapienza" Rome, were interviewed using an ad hoc developed questionnaire. The questionnaire addressed the following items: demographic and clinical characteristics, use of conventional therapy, use of HR and safety perception. Data were expressed as mean (+/-SD) or number/total, and evaluated by student t and chi2 tests; univariate analysis and multivariate logistic regression (MLR) were conducted. Prevalence of HR use was 35.5%. HR use was more common among women (P=0.01), and in patients attending sports activity (P=0.03). 72% of patients using HR had never considered potentially harmful HR-side effects or interactions. Sixty-seven percent used HR in addition to conventional therapy. More than a third of patients attending Liver/Biliary Disorders Clinic uses HR. Misconceptions about HR safety is common.


Brain chemiluminescence and oxidative stress in hyperthyroid rats.
Newborn Wistar rats were made hyperthyroid by injection of tri-iodothyronine and assayed for survival, brain oxygen uptake, brain chemiluminescence and activity of antioxidant enzymes. Brain chemiluminescence was measured (1) by removing the parietal bones or (2) through the translucid parietal bones. Control animals showed a brain chemiluminescence of 130 +/- 12 c.p.s./cm2 and 99 +/- 10 c.p.s./cm2 for procedures (1) and (2) respectively. Hyperthyroid rats showed increases in the spontaneous brain photoemission of 46 and 70% compared with controls, measured by procedures 1 and 2 respectively. The hyperthyroid state did not modify the oxygen-dependent chemiluminescence of brain homogenates. The hyperthyroid animals showed a 30% increase in the oxygen uptake of brain slices and a dramatic shortening of life-span to about 16 weeks. Superoxide dismutase (the Cu-Zn enzyme), catalase and Se-dependent glutathione peroxidase activities of brain homogenates were increased by 18, 36 and 30% respectively in the hyperthyroid animals. Isolated brain mitochondria produced 0.18-0.20 nmol of H2O2/min per mg of protein in state 4 in the presence of succinate as substrate. No difference was observed between control and hyperthyroid animals. It is concluded that hyperthyroidism leads to hypermetabolism and oxidative stress in the brain. The increased levels of oxygen and peroxyl radicals may contribute to premature ageing in these animals.


PhoP-PhoQ-regulated loci are required for enhanced bile resistance in Salmonella spp.
As enteric pathogens, Salmonella spp. are resistant to the actions of bile. Salmonella typhimurium and Salmonella typhi strains were examined to better define the bile resistance phenotype. The MICs of bile for wild-type S. typhimurium and S. typhi were 18 and 12%, respectively, and pretreatment of log-phase S. typhimurium with 15% bile dramatically increased bile resistance. Mutant strains of S. typhimurium and S. typhi lacking the virulence regulator PhoP-PhoQ were killed at significantly lower bile concentrations than wild-type strains, while strains with constitutively active PhoP were able to survive prolonged incubation with bile at concentrations of >60%. PhoP-PhoQ was shown to mediate resistance specifically to the bile components deoxycholate and conjugated forms of chenodeoxycholate, and the protective effect was not generalized to other membrane-active agents. Growth of both S. typhimurium and S. typhi in bile and in deoxycholate resulted in the induction or repression of a number of proteins, many of which appeared identical to PhoP-PhoQ-activated or -repressed products. The PhoP-PhoQ regulon was not induced by bile, nor did any of the 21 PhoP-activated or -repressed genes tested play a role in bile resistance. However, of the PhoP-activated or -repressed genes tested, two (prgC and prgH) were transcriptionally repressed by bile in the medium independent of PhoP-PhoQ. These data suggest that salmonellae can sense and respond to bile to increase resistance and that this response likely includes proteins that are members of the PhoP regulon. These bile- and PhoP-PhoQ-regulated products may play an important role in the survival of Salmonella spp. in the intestine or gallbladder.


Impact of the Respiratory Microbiome on Host Responses to Respiratory Viral Infection.
Viruses are responsible for most of both upper and lower acute respiratory infections (ARIs). The microbiome-the ecological community of microorganisms sharing the body space, which has gained considerable interest over the last decade-is modified in health and disease states. Even if most of these disturbances have been previously described in relation to chronic disorders of the gastrointestinal microbiome, after a short reminder of microbiome characteristics and methods of characterization, this review will describe the impact of the microbiome (mainly respiratory) on host responses to viral ARIs. The microbiome has a direct environmental impact on the host cells but also an indirect impact on the immune system, by enhancing innate or adaptive immune responses. In microbial infections, especially in viral infections, these dramatic modifications could lead to a dramatic impact responsible for severe clinical outcomes. Studies focusing on the microbiome associated with transcriptomic analyses of the host response and deep characterization of the pathogen would lead to a better understanding of viral pathogenesis and open avenues for biomarker development and innovative therapeutics.


Getting the Message Out: Social Media and Word-of-Mouth as Effective Communication Methods during Emergencies.
Effective communication is a critical part of managing an emergency. During an emergency, the ways in which health agencies normally communicate warnings may not reach all of the intended audience. Not all communities are the same, and households within communities are diverse. Because different communities prefer different communication methods, community leaders and emergency planners need to know their communities' preferred methods for seeking information about an emergency. This descriptive report explores findings from previous community assessments that have collected information on communication preferences, including television (TV), social media, and word-of-mouth (WoM) delivery methods. Data were analyzed from 12 Community Assessments for Public Health Emergency Response (CASPERs) conducted from 2014-2017 that included questions regarding primary and trusted communication sources. A CASPER is a rapid needs assessment designed to gather household-based information from a community. In 75.0% of the CASPERs, households reported TV as their primary source of information for specific emergency events (range = 24.0%-83.1%). Households reporting social media as their primary source of information differed widely across CASPERs (3.2%-41.8%). In five of the CASPERs, nearly one-half of households reported WoM as their primary source of information. These CASPERs were conducted in response to a specific emergency (ie, chemical spill, harmful algal bloom, hurricane, and flood). The CASPERs conducted as part of a preparedness activity had lower percentages of households reporting WoM as their primary source of information (8.3%-10.4%). The findings in this report demonstrate the need for emergency plans to include hybrid communication models, combining traditional methods with newer technologies to reach the broadest audience. Although TV was the most commonly reported preferred source of information, segments of the population relied on social media and WoM messaging. By using multiple methods for risk communication, emergency planners are more likely to reach the whole community and engage vulnerable populations that might not have access to, trust in, or understanding of traditional news sources. Multiple communication channels that include user-generated content, such as social media and WoM, can increase the timeliness of messaging and provide community members with message confirmation from sources they trust encouraging them to take protective public health actions.WolkinAF, SchnallAH, NakataNK, EllisEM. Getting the message out: social media and word-of-mouth as effective communication methods during emergencies. Prehosp Disaster Med. 2019;34(1):89-94.


Delays in medical malpractice litigation in civil law jurisdictions: some evidence from the Italian Court of Cassation.
Medical malpractice law and tort reform are contentious issues. In this paper, we focus on Italy as an example of a civil law jurisdiction. Italian medical malpractice law is essentially judge-made law. However, its effectiveness is likely to be curtailed by excessive delays in litigation. Several reforms have been enacted since the late 1980s to correct this situation. By making use of the decisions of the Italian Court of Cassation (which have shaped medical malpractice law) from 1970 to 2009, we show that these reforms had no general statistically significant impact on delays. Recent reduction of delays does not seem to be related to legal reforms but rather explained by other factors.


Effectiveness of Adding Antiplatelets to Oral Anticoagulants in Patients with Acute Ischemic Stroke with Atrial Fibrillation and Concomitant Large Artery Steno-Occlusion.
We investigated the effectiveness of adding antiplatelet (AP) to oral anticoagulant (OAC) treatment versus OAC treatment alone in patients with AIS with atrial fibrillation (AF) and significant large artery steno-occlusion (LASO). This study is a retrospective analysis of a nationwide, prospective, multicenter stroke registry between April 2008 and November 2017. Patients with acute (within 48 h of onset) and mild-to-moderate (NIHSS score ≤ 15) stroke with AF and concomitant LASO were identified. Antithrombotic regimens at discharge were categorized into OAC alone or OAC + AP. The primary outcome event was a composite of recurrent stroke, myocardial infarction, and all-cause mortality within 3 months of stroke. Among the 2553 patients (age, 73 ± 10 years; men, 50.4%), 78.8% were treated with OAC alone, and 21.2% were treated with OAC + AP. The primary outcome events were significantly more common in the OAC + AP group (6.7%) than the OAC alone group (4.3%) (p = 0.02). Weighted Cox proportional hazard analysis showed that OAC + AP increased the risk of 3-month primary outcome events compared with OAC alone (HR, 1.62 [1.06 to 2.46]). A potential interaction between the type of LASO and discharge antithrombotics was suggested (Pinteraction = 0.04); unlike in patients with complete occlusion (OAC + AP; HR, 2.00 [1.27-3.15]), OAC + AP was comparable with OAC alone for 3-month primary outcome in patients with moderate-to-severe stenosis (HR, 0.54 [0.17-1.70]). In conclusion, OAC + AP might increase the risk of 3-month outcome events compared with OAC alone in patients with AIS with AF and concomitant LASO. However, the effect of additional AP to OAC might differ according to LASO type.


Esterified dendritic TAM radicals with very high stability and enhanced oxygen sensitivity.
In this work, we have developed a new class of dendritic TAM radicals (TG, TdG, and dTdG) through a convergent method based on the TAM core CT-03 or its deuterated analogue dCT-03 and trifurcated Newkome-type monomer. Among these radicals, dTdG exhibits the best EPR properties with sharpest EPR singlet and highest O(2) sensitivity due to deuteration of both the ester linker groups and the TAM core CT-03. Like the previous dendritic TAM radicals, these new compounds also show extremely high stability toward various reactive species owing to the dendritic encapsulation. The highly charged nature of these molecules resulting from nine carboxylate groups prevents concentration-dependent EPR line broadening at physiological pH. Furthermore, we demonstrate that these TAM radicals can be easily derivatized (e.g., PEGylation) at the nine carboxylate groups and the resulting PEGylated analogue dTdG-PEG completely inhibits the albumin binding, thereby enhancing suitability for in vivo applications. These new dendritic TAM radicals show great potential for in vivo EPR oximetric applications and provide insights on approaches to develop improved and targeted EPR oximetric probes for biomedical applications.


GABA(A) receptor modulation by terpenoids from Sideritis extracts.
GABAA receptors are modulated by Sideritis extracts. The aim of this study was to identify single substances from Sideritis extracts responsible for GABAA receptor modulation. Single volatile substances identified by GC have been tested in two expression systems, Xenopus oocytes and human embryonic kidney cells. Some of these substances, especially carvacrol, were highly potent on GABAA receptors composed of α1β2 and α1β2γ2 subunits. All effects measured were independent from the presence of the γ2 subunit. As Sideritis extracts contain a high amount of terpenes, 13 terpenes with similar structure elements were tested in the same way. Following a prescreening on α1β2 GABAA receptors, a high-throughput method was used for identification of the most effective terpenoid substances on GABA-affinity of α1β2γ2 receptors expressed in transfected cell lines. Isopulegol, pinocarveol, verbenol, and myrtenol were the most potent modifiers of GABAA receptor function. Comparing the chemical structures, the action of terpenes on GABAA receptors is most probably due to the presence of hydroxyl groups and a bicyclic character of the substances tested. We propose an allosteric modulation independent from the γ2 subunit and similar to the action of alcohols and anesthetics.


Role of immunohistochemistry for hepatitis D and hepatitis B virus in hepatitis delta.
Immunohistochemical assessment of liver tissue in chronic delta hepatitis (CDH) is underinvestigated. Aim of the study was (i) to assess variables associated with hepatitis D antigen (HDAg), hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg) staining in the liver. Demographic, biochemical and virologic data collected from the HIDIT 1 study were used. HBsAg, HBcAg and HDAg immunohistochemical (IHC) staining was semiquantitatively assessed. Hepatitis D antigen immunohistochemical staining displayed positive correlations with age and alanine aminotransferase (ALT) and negative correlations with serum HBsAg (P = 0.01 for all). HBsAg IHC displayed a negative correlation with gamma glutamyl transferase and positive correlations with serum HBV DNA, serum HBsAg levels and HBeAg serology (P < 0.001, P = 0.02 and P = 0.007 respectively). HBcAg staining was mainly nuclear and displayed negative correlations with serum HBsAg and histologic activity (P = 0.002 and P = 0.02 respectively). Pegylated IFN based treatment led to a decline of all IHC markers, however, these markers had no impact on treatment outcome. These data suggest an association of liver injury with HDAg expression in CDH whereas the negative correlation between HBcAg expression and liver injury and the overall nuclear localization of HBcAg suggest that HBcAg does not contribute to liver injury in CDH. HDV cases with high level of HBV replication, high serum HBsAg levels, HBeAg positivity, that are probably in the earlier stages of disease (low gamma-glutamyl transferase), had a more intense HBsAg staining profile. Overall, the data enforce the importance of HDAg and HBsAg in different phases of CDH infection.


A novel mutation in the steroidogenic acute regulatory protein gene promoter leading to reduced promoter activity.
We have identified a novel cytosine/thymidine polymorphism of the human steroidogenic acute regulatory (StAR) gene promoter located 3 bp downstream of the steroidogenic factor-1 (SF-1)-binding site and 9 bp upstream of the TATA box (ATTTAAG). Carriers of this mutation have a high prevalence of primary aldosteronism. In transfection experiments, basal StAR promoter activity was unaltered by the mutation in murine Y-1 cells and human H295R cells. In Y-1 cells, forskolin (25 microM, 6 h) significantly increased wild-type promoter activity to 230+/-33% (P<0.05, n=4). In contrast, forskolin increased mutated promoter activity only to 150+/-27%, with a significant 35% reduction compared to wild type (P<0.05, n=3). In H295R cells, angiotensin II (AngII; 10 nM) increased wild-type StAR promoter activity to 265+/-22% (P<0.01, n=3), while mutated StAR promoter activity in response to AngII only reached 180+/-29% of controls (P< 0.01, n=3). Gel mobility shift assays show the formation of two additional complexes with the mutated promoter: one with the transcription repressor DAX-1 and another with a yet unidentified factor, which strongly binds the SF-1 response element. Thus, this novel mutation in the human StAR promoter is critically involved in the regulation of StAR gene expression and is associated with reduced promoter activity, a finding relevant for adrenal steroid response to physiological stimulators.


Echocardiographic predictors of clinical outcome in patients with left ventricular dysfunction enrolled in the SOLVD registry and trials: significance of left ventricular hypertrophy. Studies of Left Ventricular Dysfunction.
To assess the relation of left ventricular (LV) and left atrial (LA) dimensions, ejection fraction (EF) and LV mass to subsequent clinical outcome of patients with LV dysfunction enrolled in the Studies of Left Ventricular Dysfunction (SOLVD) Registry and Trials. Data are lacking on the relation of LV mass to prognosis in patients with LV dysfunction and on the interaction of LV mass with other measurements of LV size and function as they relate to clinical outcome. A cohort of 1,172 patients enrolled in the SOLVD Trials (n = 577) and Registry (n = 595) had baseline echocardiographic measurements and follow-up for 1 year. After adjusting for age, New York Heart Association (NYHA) functional class, Trial vs. Registry and ischemic etiology, a 1-SD difference in EF was inversely associated with an increased risk of death (risk ratio, 1.62; p = 0.0008) and cardiovascular (CV) hospitalization (risk ratio, 1.59; p = 0.0001). Consequently, the other echo parameters were adjusted for EF in addition to age, NYHA functional class, Trial vs. Registry and ischemic etiology. A 1-SD difference in LV mass was associated with increased risk of death (risk ratio of 1.3, p = 0.012) and CV hospitalization (risk ratio of 1.17, p = 0.018). Similar results were observed with the LA dimension (mortality risk ratio, 1.32; p < 0.02; CV hospitalizations risk ratio, 1.18; p < 0.04). Likewise, LV mass > or =298 g and LA dimension > or =4.17 cm were associated with increased risk of death and CV hospitalization. An end-systolic dimension >5.0 cm was associated with increased mortality only. A protective effect of EF was noted in patients with LV mass > or =298 g (those in the group with EF >35% had lower mortality) but not in the group with LV mass <298 g. In patients with LV dysfunction enrolled in the SOLVD Registry and Trials, increasing levels of hypertrophy are associated with adverse events. A protective effect of EF was noted in patients with LV mass > or =298 g (those in the group with EF >35% fared better) but not in the group with LV mass <298 g. These data support the development and use of drugs that can inhibit hypertrophy or alter its characteristics.


Electrodermal recording and fMRI to inform sensorimotor recovery in stroke patients.
Functional magnetic resonance imaging (fMRI) appears to be useful for investigating motor recovery after stroke. Some of the potential confounders of brain activation studies, however, could be mitigated through complementary physiological monitoring. To investigate a sensorimotor fMRI battery that included simultaneous measurement of electrodermal activity in subjects with hemiparetic stroke to provide a measure related to the sense of effort during motor performance. Bilateral hand and ankle tasks were performed by 6 patients with stroke (2 subacute, 4 chronic) during imaging with blood oxygen level-dependent (BOLD) fMRI using an event-related design. BOLD percent changes, peak activation, and laterality index values were calculated in the sensorimotor cortex. Electrodermal recordings were made concurrently and used as a regressor. Sensorimotor BOLD time series and percent change values provided evidence of an intact motor network in each of these well-recovered patients. During tasks involving the hemiparetic limb, electrodermal activity changes were variable in amplitude, and electrodermal activity time-series data showed significant correlations with fMRI in 3 of 6 patients. No such correlations were observed for control tasks involving the unaffected lower limb. Electrodermal activity activation maps implicated the contralesional over the ipsilesional hemisphere, supporting the notion that stroke patients may require higher order motor processing to perform simple tasks. Electrodermal activity recordings may be useful as a physiological marker of differences in effort required during movements of a subject's hemiparetic compared with the unaffected limb during fMRI studies.


Variability in Dispersal Syndromes Is a Key Driver of Metapopulation Dynamics in Experimental Microcosms.
Evolutionary ecology studies have increasingly focused on the impact of intraspecific variability on population processes. However, the role such variation plays in the dynamics of spatially structured populations and how it interacts with environmental changes remains unclear. Here we experimentally quantify the relative importance of intraspecific variability in dispersal-related traits and spatiotemporal variability of environmental conditions for the dynamics of two-patch metapopulations using clonal genotypes of a ciliate in connected microcosms. We demonstrate that in our simple two-patch microcosms, differences among genotypes are at least as important as spatiotemporal variability of resources for metapopulation dynamics. Furthermore, we show that an important proportion of this effect results from variability of dispersal syndromes. These syndromes can therefore be as important for metapopulation dynamics as spatiotemporal variability of environmental conditions. This study demonstrates that intraspecific variability in dispersal syndromes can be key in the functioning of metapopulations facing environmental changes.


VTD-melphalan is well tolerated and results in very high rates of stringent CR and MRD-negative status in multiple myeloma.
The addition of cytotoxic drugs to high-dose melphalan as a preparative regimen for autologous stem cell transplantation in multiple myeloma has not resulted in superior activity. Although novel agents have significantly improved outcome in multiple myeloma, their role in preparative regimens remains largely unknown. We have evaluated the toxicity and efficacy of combining bortezomib, thalidomide, and dexamethasone with high-dose melphalan. An institutional review board-approved retrospective analysis was performed on 100 consecutive patients receiving 153 transplants; 53 had tandem transplants; 64 patients received early transplants; and 36 had salvage transplantation. Endpoints were treatment-related toxicity and mortality, and quality of response post-transplantation with assessment of stringent complete remission (sCR) and minimal residual disease (MRD) status. Median age was 61 years, and median follow-up was 16.2 months. At 6 months, sCR was attained in 56% of patients and CR in 20%. An MRD status, assessed by sensitive (10-4) multiparameter flow cytometry, was achieved in 85%. The 100-day mortality rate was 2.6% (4/153); 1.8% for early transplants and 4.5% for salvage transplants. Grade 3-5 non-hematologic toxicities were mainly related to metabolism/nutrition; gastrointestinal and infectious problems. Median time to absolute neutrophil count of >500/µL was 12 days for both early and salvage transplantations. No significant differences in quality of response were observed between early and salvage transplantation or between single and tandem autologous stem cell transplantation. Since both sCR and MRD are excellent early surrogate markers for progression-free and overall survival, this regimen will likely be superior to melphalan alone, but it needs to be formally assessed in a randomized study.


Expression of the duodenal iron transporters divalent-metal transporter 1 and ferroportin 1 in iron deficiency and iron overload.
Imbalances of iron homeostasis are accompanied by alterations of intestinal iron absorption. The identification of divalent-metal transporter 1 (DMT1) and ferroportin 1 (FP1) has improved our understanding of transmembrane iron trafficking. To gain insight into the regulatory properties of these transporters in the duodenum, we studied their expression in patients with hereditary hemochromatosis (HFE-associated and non-HFE-associated), secondary iron overload, and iron deficiency. DMT1, FP1 messenger RNA (mRNA), and protein expression were analyzed in duodenal biopsy specimens from patients by means of TaqMan real-time polymerase chain reaction, Western blotting technique, and immunohistochemistry. DMT1 and FP1 mRNA levels are positively correlated with each other in all patient groups (P < 0.001). Moreover, DMT1 and FP1 mRNA levels were significantly increased in patients with iron deficiency, HFE and non-HFE hemochromatosis, whereas they were unchanged in patients with secondary iron overload. Alterations in DMT1 and FP1 mRNA levels were paralleled by comparable changes in the duodenal expression of these proteins. In patients with normal iron status or iron deficiency, significant negative correlations between DMT1, FP1 mRNA, and serum iron parameters were found, which were absent in subjects with primary hemochromatosis. DMT1 and FP1 are centrally involved in iron uptake/transfer in the duodenum and in the adaptive changes of iron homeostasis to iron deficiency and overload.


All-optical XOR logic gate using intersubband transition in III-V quantum well materials.
A monolithically integrated all-optical exclusive-OR (XOR) logic gate is experimentally demonstrated based on a Michelson interferometer (MI) gating device in InGaAs/AlAsSb coupled double quantum wells (CDQWs). The MI arms can convert the pump data with return-to-zero ON-OFF keying (RZ OOK) to binary phase-shift keying (BPSK) format, then two BPSK signals can interfere with each other for realizing a desired logical operation. All-optical format conversion from the RZ OOK to BPSK is based on the cross-phase modulation to the transverse electric (TE) probe wave, which is caused by the intersubband transition excited by the transverse magnetic (TM) pump light. Bit error rate measurements show that error free operation for both BPSK format conversion and XOR logical operation can be achieved.


Stability of penicillin-susceptible and nonsusceptible clones of Streptococcus pneumoniae in southern Sweden.
Understanding what determines the stability and global spread of pneumococcal clones is important for future public health interventions. This requires better knowledge about the stability and distribution of existing clones. In this study we characterized and compared penicillin nonsusceptible (PNSP) and susceptible pneumococci (PSP) from southern Sweden. A total of 166 isolates of Streptococcus pneumoniae, recovered in Malmohus County between 1982 and 1997, were analyzed with molecular and microbiological techniques; 107 PNSP isolates of serogroup 15, collected between 1992 and 1995, and 15 PNSP isolates of serogroup 9, isolated in 1996 and 1997, were studied. In addition, PSP of serogroups 9 and 15, isolated approximately 10 years apart, were studied; 23 of serogroup 9 and 21 of serogroup 15, isolated in 1982-1983 and 1992-1993. As expected, a high degree of homogeneity was found in the PNSP isolates, where all the isolates of serogroup 9 belonged to the same clone, Spain(9V)-3, and the majority of the serogroup 15 isolates belonged to the Sweden(15A)-25 clone. The remaining PNSP isolates of serogroup 15 belonged to a clone found in The Netherlands and Greece. An unexpectedly high degree of clonality and stability of the PSP isolates was observed. Isolates representing clones that remained stable for over 10 years were found among both serogroups. These results indicate that factors, other than antimicrobial resistance, play an important part in establishing successful clones of S. pneumoniae, and these factors may be instrumental in determining the success or failure of clones after they acquire resistance.


Generation of Bessel beam arrays through Dammann gratings.
In this work we apply the Dammann grating concept to generate an equal-intensity square array of Bessel quasi-free diffraction beams that diverge from a common center. We generate a binary phase mask that combines the axicon phase with the phase of a Dammann grating. The procedure can be extended to include vortex spiral phases that generate an array of optical pipes. Experimental results are provided by means of a twisted nematic liquid crystal display operating as a binary π phase spatial light modulator.


Assessing the role of color cues and people's beliefs about color-flavor associations on the discrimination of the flavor of sugar-coated chocolates.
We report 2 experiments designed to investigate the effect of people's prior beliefs concerning specific color-flavor associations on their ability to discriminate the flavor of colored sugar-coated chocolate sweets. The participants in our study judged whether pairs of Smarties had the same flavor or not. In our first experiment, the participants either performed the task with their eyes open or else while wearing a blindfold to eliminate any visual cues. We used pairs of Smarties that either did or did not differ in flavor. In making a sighted comparison between red and green Smarties, the participants were more likely to judge them as tasting the same if they believed all non-orange Smarties to be identical in flavor and as different in flavor if they did not hold such a belief. The ability of our participants to discriminate orange Smarties from the red and green Smarties was unaffected by their prior belief that orange Smarties taste different. In a second experiment, participants' ratings of their certainty of there being a difference in flavor between a red and an orange Smartie that either tasted the same or different were affected by their prior beliefs-those participants who expected a difference were more likely to report a difference than those without any such prior expectation. Taken together, these results demonstrate that people's expectations concerning color-flavor associations can modulate their flavor discrimination responses, even for a familiar food product such as Smarties.


Reduced expression of DNMT3B in the germ cells of patients with bilateral spermatogenic arrest does not lead to changes in the global methylation status.
DNA methylation events during spermatogenesis have important implications for gamete integrity and transmission of epigenetic information to the next generation. However, the role of DNA methyltransferases in the disorders of human spermatogenesis has not been elucidated. The aim of the present study was to evaluate the expression of DNMT3B, crucial for full germ cell methylation, in testicular germ cells of patients with spermatogenic arrest and to determine whether or not there is an association with the global methylation status. In order to determine the DNMTs expression status at various stages of spermatogenesis, immunohistochemical localization was performed on 16 fertile controls having normal spermatogenesis and 11 patients with bilateral spermatogenic arrest. DNMT3B was expressed in most of the germ cell types in both controls and patients with bilateral spermatogenic arrest. The number of DNMT3B positive preleptotene/zygotene cells and pachytene spermatocytes was significantly lower in patients with bilateral arrest. However, evaluation of 5-methylcytosine, a global methylation marker, in the few matured germ cells of these patients did not reveal altered methylation. In conclusion, the global methylation status of germ cells is not affected by spermatogenic defects in spite of aberrant DNMT3B expression indicating the necessity of proper methylation for full spermatogenesis.