PD-1/PD-L1 expression and interaction by automated quantitative immunofluorescent analysis show adverse prognostic impact in patients with diffuse large B-cell lymphoma having T-cell infiltration: a study from the International DLBCL Consortium Program.
Programmed cell death protein 1/programmed cell death protein ligand1 (PD-1/PD-L1) interaction is an important immune checkpoint targeted by anti-PD-1/PD-L1 immunotherapies. However, the observed prognostic significance of PD-1/PD-L1 expression in diffuse large B-cell lymphoma treated with the standard of care has been inconsistent and even contradictory. To clarify the prognostic role of PD-1/PD-L1 expression and interaction in diffuse large B-cell lymphoma, in this study we used 3-marker fluorescent multiplex immunohistochemistry and Automated Quantitative Analysis Technology to assess the CD3+, PD-L1+, and PD-1+CD3+ expression in diagnostic samples and PD-1/PD-L1 interaction as indicated by presence of PD-1+CD3+ cells in the vicinity of PD-L1+ cells, analyzed their prognostic effects in 414 patients with de novo diffuse large B-cell lymphoma, and examined whether PD-1/PD-L1 interaction is required for the prognostic role of PD-1+/PD-L1+ expression. We found that low T-cell tissue cellularity, tissue PD-L1+ expression (irrespective of cell types), PD-1+CD3+ expression, and PD-1/PD-L1 interaction showed hierarchical adverse prognostic effects in the study cohort. PD-1/PD-L1 interaction showed higher sensitivity and specificity than PD-1+ and PD-L1+ expression in predicting inferior prognosis in patients with high CD3+ tissue cellularity ("hot"/inflammatory tumors). However, both PD-1+ and PD-L1+ expression showed adverse prognostic effects independent of PD-1/PD-L1 interaction, and PD-1/PD-L1 interaction showed favorable prognostic effect in PD-L1+ patients without high CD3+ tissue cellularity. Macrophage function and tumor-cell MYC expression may contribute to the PD-1-independent adverse prognostic effect of PD-L1+ expression. In summary, low T-cell tissue cellularity has unfavorable prognostic impact in diffuse large B-cell lymphoma, and tissue PD-L1+ expression and T-cell-derived PD-1+ expression have significant adverse impact only in patients with high T-cell infiltration. PD-1/PD-L1 interaction in tissue is essential but not always responsible for the inhibitory effect of PD-L1+/PD-1+ expression. These results suggest the benefit of PD-1/PD-L1 blockade therapies only in patients with sufficient T-cell infiltration, and the potential of immunofluorescent assays and Automated Quantitative Analysis in the clinical assessment of PD-1/PD-L1 expression and interaction.


Discerning Bulk and Interfacial Polarons in a Dual Electron Donor/Acceptor Polymer.
The active layer of organic solar cells typically possesses a complex morphology, with amorphous donor/acceptor mixed domains present in addition to purer, more crystalline domains. These crystalline domains may represent an energy sink for free charges that aids charge separation and suppresses bimolecular recombination. The first step in exploiting this behavior is the identification and characterization of charges located in these different domains. Herein, the generation and recombination of both bulk and interfacial polarons are demonstrated in the dual electron donor/acceptor polymer XIND using transient absorption spectroscopy. The absorption spectra of XIND bulk polarons, present in pristine polymer domains, are clearly distinguishable from those of polarons present at the donor/acceptor interface. Furthermore, it is shown that photogenerated polarons are transferred from the interface to the bulk. These findings support the energy sink hypothesis and offer a way to maximize morphology relationships to enhance charge generation and suppress recombination.


The Role of Simulation in the Design of a Semi-Enclosed Tubular Embolus Retrieval.
A numerical analysis of a semi-enclosed tubular mechanical embolus retrieval device (MERD) for the treatment of acute ischemic stroke (AIS) is presented. In this research, the finite element analysis (FEA) methodology is used to evaluate mechanical performance and provide suggestions for optimizing the geometric design. A MERD fabricated from nickel-titanium alloy (Nitinol) tubing is simulated and analyzed under complex in vivo loading conditions involving shape-setting, crimping, deployment, and embolus retrieval. As a result, the peak strain of the shape-setting procedure is proved to be safe for the device pattern. However, the MERD shows poor mechanical behavior after crimping into a catheter, because the peak crimping strain obtains a value of 12.1%. The delivery and deployment step demonstrates that the artery wall has little risk of serious injuries or rupture. In addition, the process of simulation of embolus retrieval and device system migration inside the cerebral artery lumen provides useful information during the design process.


Aurora-A promotes chemoresistance in hepatocelluar carcinoma by targeting NF-kappaB/microRNA-21/PTEN signaling pathway.
Hepatocellular carcinoma (HCC) is highly resistant to chemotherapy. Previously, we have shown that Aurora-A mRNA is upregulated in HCC cells or tissues and silencing of Aurora-A using small interfering RNA (siRNA) decreases growth and enhances apoptosis in HCC cells. However, the clinical significance of Aurora-A protein expression in HCC and association between Aurora-A expression and HCC chemoresistance is unclear. Here, we showed that Aurora-A protein is upregulated in HCC tissues and significantly correlated with recurrence-free and overall survival of patients and multivariate analysis indicated that immunostaining of Aurora-A will be an independent prognostic factor for patients. Silencing of Aurora-A significantly increased the chemosensitivity of HCC cells both in vitro and in vivo, while overexpression of Aurora-A induced the opposite effects. Furthermore, overexpression of Aurora-A reduces chemotherapy-induced apoptosis by promoting microRNA-21 expression, which negatively regulates PTEN and then inhibits caspase-3-mediated apoptosis induction. Mechanically, we demonstrated that Aurora-A promotes expression of nuclear Ikappaβ-alpha (Iκβα) protein and enhances NF-kappa B (NF-κB) activity, thus promotes the transcription of miR-21. This study first reported the involvement of Aurora-A/NF-κB/miR-21/PTEN/Akt signaling axis in chemoresistance of HCC cells, suggesting that targeting this signaling pathway would be helpful as a therapeutic strategy for the reversal of chemoresistance in HCC.


Steroid Alkaloids from Holarrhena africana with Strong Activity against Trypanosoma brucei rhodesiense.
In our continued search for natural compounds with activity against Trypanosoma brucei, causative agent of human African trypanosomiasis (HAT, "sleeping sickness"), we have investigated extracts from the leaves and bark of the West African Holarrhenaafricana (syn. Holarrhena floribunda; Apocynaceae). The extracts and their alkaloid-enriched fractions displayed promising in vitro activity against bloodstream forms of T. brucei rhodesiense (Tbr; East African HAT). Bioactivity-guided chromatographic fractionation of the alkaloid-rich fractions resulted in the isolation of 17 steroid alkaloids, one nitrogen-free steroid and one alkaloid-like non-steroid. Impressive activities (IC50 in µM) against Tbr were recorded for 3β-holaphyllamine (0.40 ± 0.28), 3α-holaphyllamine (0.37 ± 0.16), 3β-dihydroholaphyllamine (0.67 ± 0.03), N-methylholaphyllamine (0.08 ± 0.01), conessimine (0.17 ± 0.08), conessine (0.42 ± 0.09), isoconessimine (0.17 ± 0.11) and holarrhesine (0.12 ± 0.08) with selectivity indices ranging from 13 to 302. Based on comparison of the structures of this congeneric series of steroid alkaloids and their activities, structure-activity relationships (SARs) could be established. It was found that a basic amino group at position C-3 of the pregnane or pregn-5-ene steroid nucleus is required for a significant anti-trypanosomal activity. The mono-methylated amino group at C-3 represents an optimum for activity. ∆5,6 unsaturation slightly increased the activity while hydrolysis of C-12β ester derivatives led to a loss of activity. An additional amino group at C-20 engaged in a pyrrolidine ring closed towards C-18 significantly increased the selectivity index of the compounds. Our findings provide useful empirical data for further development of steroid alkaloids as a novel class of anti-trypanosomal compounds which represent a promising starting point towards new drugs to combat human African trypanosomiasis.


Ocular dominance predicts neither strength nor class of disparity selectivity with random-dot stimuli in primate V1.
We address two unresolved issues concerning the coding of binocular disparity in primary visual cortex. Experimental studies and theoretical models have suggested a relationship between a cell's ocular dominance, assessed with monocular stimuli, and its tuning to binocular disparity. First, the disparity energy model of disparity selectivity suggests that there should be a correlation between ocular dominance and the strength of disparity tuning. Second, several studies have reported a relationship between ocular dominance and the shape of the disparity tuning curve, with cells dominated by one eye more likely to have disparity tuning of the tuned-inhibitory type. We investigated both of these relationships in single neurons recorded from the primary visual cortex of awake fixating macaques, using dynamic random-dot patterns as a stimulus. To classify disparity tuning curves quantitatively, we develop a new measure of symmetry, which can be applied to any function. We find no evidence for any correlation between ocular dominance and the nature of disparity tuning. This places constraints on the circuitry underlying disparity tuning.


The use of endoscopic ultrasonography in the diagnosis and staging of carcinoma of the papilla of Vater.
Endoscopic ultrasonography (EUS) was evaluated in the diagnosis of carcinoma of the papilla of Vater. Thirteen cases of carcinoma of the papilla examined by EUS were investigated with the aim of assessing the detection capability of EUS in comparison with other diagnostic tools, and its usefulness in diagnosing the extent of the tumor. The EUS image of the normal papilla of Vater presents as a round protruded region with the layered structure of the duodenal papilla along with images of periampullary organs. All but one of 13 tumors of the duodenal papilla presented as a hypoechoic solid mass at EUS. On the basis of an analysis of the layered structure of the papilla of Vater and/or the duodenal wall, EUS images of 12 cases of ampullary carcinoma confirmed histologically were analysed. The EUS images of the tumors of the duodenal papilla corresponded well with the histological findings. When the extent of carcinoma was classified in 4 stages by EUS, the accuracy rate was 83%. EUS is one of the most promising procedures for determining the extent of tumors of the duodenal papilla.


Optical Fiber Sensors Based on Microstructured Optical Fibers to Detect Gases and Volatile Organic Compounds-A Review.
Since the first publications related to microstructured optical fibers (MOFs), the development of optical fiber sensors (OFS) based on them has attracted the interest of many research groups because of the market niches that can take advantage of their specific features. Due to their unique structure based on a certain distribution of air holes, MOFs are especially useful for sensing applications: on one hand, the increased coupling of guided modes into the cladding or the holes enhances significantly the interaction with sensing films deposited there; on the other hand, MOF air holes enhance the direct interaction between the light and the analytes that get into in these cavities. Consequently, the sensitivity when detecting liquids, gasses or volatile organic compounds (VOCs) is significantly improved. This paper is focused on the reported sensors that have been developed with MOFs which are applied to detection of gases and VOCs, highlighting the advantages that this type of fiber offers.


MODELING THE GENETIC BASIS OF HETEROSIS: TESTS OF ALTERNATIVE HYPOTHESES.
Houle (1994) showed that marker-associated heterosis due to general inbreeding depression could not be distinguished from direct overdominance at the marker locus by examining mean genotypic fitnesses, in the one-locus case. Indeed, both hypotheses equally fit the same regression model, referred to as the "adaptive distance model" (Smouse 1986). I here extend the analysis to several loci and to the relationship between marker genotype and variance in fitness. Several predictions differ between the overdominance and inbreeding hypotheses: (1) all locus-specific effects are equal under inbreeding, whereas they are not under overdominance; (2) the adaptive distance model has an increasingly low fit when the number of loci increases, under inbreeding, whereas it always explains the whole variance in fitness under overdominance; (3) a negative relationship is predicted between mean fitness and the variance in fitness, under inbreeding, which is not predicted under overdominance. Some statistical tests are derived from these predictions, that help to identify the genetic basis of heterosis. Simulations show that the power of these tests allows their application to real datasets.


On the use of absorbing discs to sample mucosal surface liquids.
A common technique to sample airway mucosal 'surface' liquids is with absorbing discs of filter paper. The present study examined the efficacy of this technique by analysing tracheal liquids of control and capsaicin (0.1 nmol)-exposed guinea-pig airways. Mucosal fluids, obtained by topically applied discs or by a specific lavage procedure, and tracheal tissue were sampled. The animals had received FITC-dextran (MW 70 kDa) intravenously and this specific plasma tracer was analysed in the sampled material. Under control conditions significantly more FITC-dextran was found in the discs than in the tracheal lavage fluids (P less than 0.001) despite the fact that the lavaged mucosal surface was much larger than that covered by the discs. Capsaicin significantly increased the content of FITC-dextran in all fluids sampled as well as in the airway tissue. In all cases concentrations of FITC-dextran in the disc fluids did not differ much from that in the tissue samples. These data suggest that absorbing discs severely disturb the epithelial-barrier function and sample subepithelial fluid and solutes including macromolecules. As demonstrated in this study by the elevated content of a plasma tracer molecule an inflammatory process may, nevertheless, be traced in the mixture of surface and tissue fluids that is sampled by the discs.


Electrocardiographic criteria in tako-tsubo cardiomyopathy-is there added certainty in a diagnosis per exclusionem?
Tako-Tsubo cardiomypathy (TTC), also known as transient left ventricular apical ballooning syndrome, is a stress-induced cardiomyopathy that predominantly affects post-menopausal, elderly women during emotional or physical stress. Apical left ventricular dysfunction in the absence of significant coronary artery disease is the hallmark of this condition. Because the electrocardiogram (ECG) classically depicts precordial ST-segment elevations and cardiac biomarkers can often be raised, it can be a challenge to differentiate TTC from an acute myocardial infarction (AMI). Indeed, several recent studies have proposed ECG criteria to differentiate TTC from an AMI. We present a case series of consecutive patients in whom we had employed such ECG criteria but were unable to conclusively differentiate TTC from an AMI. In each case, TTC remained a diagnosis per exclusionem, where coronary angiography was necessary to rule out myocardial infarction. We review and discuss the commonly used ECG criteria and highlight the evolutionary ECG changes commonly noted with TTC to help better prepare clinicians when dealing with patients with similar clinical scenarios.


Bidirectional plasticity at developing climbing fiber-Purkinje neuron synapses.
Climbing fibers provide one of the two major excitatory inputs to the cerebellar cortex. In an immature animal, several climbing fibers form synapses with one Purkinje neuron. During postnatal development most climbing fiber innervations with a Purkinje neuron are eliminated and only one strong fiber remains. Previous studies suggested that this pruning of surplus climbing fiber innervations depends on the neuronal activity. We hypothesized that synaptic plasticity might play a role in the maturation and refinement of such a climbing fiber projection pattern, and examined the plasticity properties of synapses between postnatal days 5 and 9 in mice. We found that a 5 Hz conditioning stimulation of climbing fibers forming relatively strong synapses with a Purkinje neuron induced long-term potentiation of the transmission accompanied by a decrease in the paired-pulse ratio of excitatory postsynaptic current amplitudes. This was suggestive of an increased probability of presynaptic release. However, the conditioning stimulation of climbing fibers forming relatively weak synapses induced long-term depression and tended to increase the paired-pulse ratio. Thus, the direction of plasticity appears to be determined by the strength of synaptic connection. Long-term depression occurred only in the conditioned climbing fiber, whereas long-term potentiation spread to unconditioned climbing fibers. A postsynaptic increase in the intracellular Ca(2+) concentration was required for long-term potentiation but not for long-term depression. These results reveal the existence of novel presynaptic plasticity at immature climbing fiber-Purkinje cell synapses, which may contribute to the maturation and refinement of the climbing fiber projection pattern.


Implicit and explicit memory in individuals with mental retardation.
Students with and without mental retardation from three age groups were compared on implicit and explicit memory tasks. Consistent with previous research on intelligence-related differences in controlled and automatic processes, students without mental retardation performed better than those with mental retardation on the explicit memory task, but there was no difference between groups on the implicit memory task. For both groups implicit and explicit memory increased from age 6 to 8 to age 10 to 12, but did not significantly increase to age 15 to 17. Because implicit memory appears to be a relative strength for students with mental retardation, we suggest further exploration into broader types of implicit processes that may be useful in training situations.


Tarsometatarsal joint arthrodesis with trephine joint resection and dowel calcaneal bone graft.
Arthritis of the tarsometatarsal joints is a challenging problem to treat. It can cause chronic foot pain and functional disability. We present a surgical technique for tarsometatarsal joint arthrodesis using a trephine to resect the articular surfaces and a dowel plug of an autogenous calcaneal graft with locking plate fixation. The procedure has been shown to result in osseous fusion, and it is technically relatively simple to complete.


Detection of radical species in mixtures of some retinoids with hematin by using the ESR spin-trapping technique.
Radical species were detected in mixtures of some retinoids with hematin by using the ESR spin-trapping technique. The rates of radical formation were approximately proportional to the oxygen consumption during the incubation of the retinoids with hematin. HPLC analyses of the incubation mixtures of the retinoids with hematin showed that 5,6-epoxides of the retinoids were formed. The amounts of the epoxides formed were proportional to both oxygen consumption and the amounts of radicals formed. These results suggest that the 5,6-epoxidations proceed via radical intermediates.


5-Methylcytosine and 5-hydroxymethylcytosine spatiotemporal profiles in the mouse zygote.
In the mouse zygote, DNA methylation patterns are heavily modified, and differ between the maternal and paternal pronucleus. Demethylation of the paternal genome has been described as an active and replication-independent process, although the mechanisms responsible for it remain elusive. Recently, 5-hydroxymethylcytosine has been suggested as an intermediate in this demethylation. In this study, we quantified DNA methylation and hydroxymethylation in both pronuclei of the mouse zygote during the replication period and we examined their patterns on the pericentric heterochromatin using 3D immuno-FISH. Our results demonstrate that 5-methylcytosine and 5-hydroxymethylcytosine localizations on the pericentric sequences are not complementary; indeed we observe no enrichment of either marks on some regions and an enrichment of both on others. In addition, we show that DNA demethylation continues during DNA replication, and is inhibited by aphidicolin. Finally, we observe notable differences in the kinetics of demethylation and hydroxymethylation; in particular, a peak of 5-hydroxymethylcytosine, unrelated to any change in 5-methylcytosine level, is observed after completion of replication. Together our results support the already proposed hypothesis that 5-hydroxymethylcytosine is not a simple intermediate in an active demethylation process and could play a role of its own during early development.


Novel Chemotherapy Modalities for Different Cancers.
Even though many of the approved drugs still have high systemic toxicity due to a lack of tumor selectivity and present pharmacokinetic drawbacks, like low water solubility, that negatively influence the drug circulation time and bioavailability, the anti-cancer study has produced commendable results in recent years. The stability tests carried out under stressful exposure to high temperatures, hydrolytic media, or light sources during their development or under moderate settings have shown the vulnerability of anti-cancer medications to various factors. Because of this, the development of degradation products is considered hospital waste in pharmaceutical formulations and the environment. Until now, various formulations have been created for attaining tissue-specific therapeutic targeting, lowering harmful side effects, and enhancing drug stability. To boost the specificity, efficiency, and durability of active molecules that are targeted in cancer therapy the invention of prodrugs is the potential approach. The latest study illustrates that the solubility, pharmacokinetics, cellular uptake, and stability of chemotherapy drugs can be improved through the incorporation of them into vesicular systems, such as polymeric micelles or cyclodextrins, or via nanocarriers containing chemotherapeutics linked to monoclonal antibodies. In this review article, we provide an overview of the most recent advances in the field of designing very stable prodrugs or nanosystems that are powerful anti-cancer medications and their actions on the body.


Protracted Morphological Changes in the Corticospinal Tract Within the Cervical Spinal Cord After Intracerebral Hemorrhage in the Right Striatum of Mice.
Intracerebral hemorrhage (ICH) is associated with high morbidity and mortality rates. Currently, there is no promising treatment that improves prognosis significantly. While a thorough investigation of the pathological process within the primary site of injury in the brain has been conducted by the research field, the focus was mainly on gray matter injury, which partly accounted for the failure of discovery of clinically efficacious treatments. It is not until recent years that white matter (WM) injury in the brain after subcortical ICH was examined. As WM tracts form networks between different regions, damage to fibers should impair brain connectivity, resulting in functional impairment. Although WM changes have been demonstrated in the brain after ICH, alterations distant from the initial injury site down in the spinal cord are unclear. This longitudinal study, for the first time, revealed prolonged morphological changes of the contralesional dorsal corticospinal tract (CST) in the spinal cord 5 weeks after experimental ICH in mice by confocal microscopy and transmission electron microscopy, implying that the structural integrity of the CST was compromised extensively after ICH. Given the important role of CST in motor function, future translational studies targeting motor recovery should delineate the treatment effects on CST integrity.


Dianthraceno[a,e]pentalenes: synthesis, crystallographic structures and applications in organic field-effect transistors.
Two soluble and stable dianthraceno[a,e]pentalenes with two (DAP1) and six (DAP2) phenyl substituents were synthesized. Both compounds possess a small energy band gap and show amphoteric redox behaviour due to intramolecular donor-accepter interactions. X-ray crystallographic analysis revealed that DAP2 has a closely packed structure with multi-dimensional [C-H···π] interactions although there are no π-π interactions between the dianthraceno[a,e]pentalene cores. As a result, solution-processed field effect transistors based on DAP2 exhibited an average hole mobility of 0.65 cm(2) V(-1) s(-1). Under similar conditions, DAP1 showed an average field effect hole mobility of 0.001 cm(2) V(-1) s(-1).


PKCβII-induced upregulation of PGP9.5 and VEGF in postoperative persistent pain in rats.
Postoperative pain is a common clinical problem. In this study, we aimed to investigate the role of protein kinase C βII (PKCβII) in the progression of postoperative pain following skin/muscle incision and retraction (SMIR) surgery. SMIR postoperative pain model was established in rats, akin to a clinical procedure. The expression level and location of p-PKCβII were observed in dorsal root ganglion (DRG) or spinal cord from SMIR-operated rats by Western blotting and immunofluorescence. In addition, the effects of PKCβII on the expression of protein gene product 9.5 (PGP9.5) or vascular endothelial growth factor (VEGF) were assessed by using pharmacological activator and inhibitor of PKCβII. Moreover, mechanical withdrawal threshold (MWT) was assessed before or after SMIR-operated rats were treated with inhibitor or activator of PKCβII. The expression of PKCβII in DRG and spinal cord was significantly increased after SMIR surgery (P < 0.001, P < 0.01) and expression of PKCβII was located in the neurons of the spinal cord, and magnocellular neurons, non-peptide neurons, and peptide neurons in DRG. Besides, compared with skin/muscle incision group, retraction caused a marked increase in the expression of PKCβII and a significant decrease of MWT (P < 0.001, P < 0.05). The activator of PKCβII greatly increased the expression of PGP9.5 and VEGF (P < 0.05, P < 0.01) and enhanced MWT (P < 0.001), while inhibitor of PKCβII decreased the expression of PGP9.5 and VEGF and attenuated MWT (P < 0.05, P < 0.01, P < 0.001). Activation of PKCβII signaling pathways might be an important mechanism in the progression of postoperative pain.


Differential biosynthesis and intracellular transport of follistatin isoforms and follistatin-like-3.
Follistatin (FST) and FST-like-3 (FSTL3) are structurally related proteins that bind and neutralize activin and closely related members of the TGFbeta superfamily. Three FST isoforms (FST288, FST303, and FST315) are produced from the Fst gene that are primarily secreted proteins. FSTL3 is secreted, but is also observed within the nucleus of most cells. We used pulse-chase (35)S labeling to examine the biosynthetic and intracellular transport patterns that lead to differential secretion and intracellular retention of these proteins. Among the FST isoforms, FST315 was secreted fastest and FST288 was secreted more slowly, with some remaining intracellular. In contrast, FSTL3 was secreted the slowest, with newly synthesized proteins being both secreted and trafficked to the nucleus. This nuclear FSTL3 was N-glycosylated, although not to the same degree as secreted FSTL3. Both FST and FSTL3 have two Mets in their signal sequence. Mutation of the first Met in FST288 eliminated protein translation, whereas FSTL3 could be translated from either Met. However, although FSTL3 translated from the second Met, which had no signal sequence, was confined to the nucleus, it was not glycosylated. Interestingly, this FSTL3 retained activin-antagonizing activity. Thus, although bioactive, nuclear FSTL3 can be translated from the second Met when the first Met is mutated, the glycosylated nuclear FSTL3 produced endogenously indicates that a different mechanism must be used under natural conditions that apparently includes N-glycosylation. Moreover, the differential biosynthetic and intracellular transport patterns for FST288 and FSTL3 suggest that these two activin-binding proteins may have distinct intracellular roles.


Thermodynamics of the decomposition processes of donor-acceptor complexes MX3 x en x MX3 and MX3 x en.
The structural and thermodynamic properties of the donor-acceptor (DA) complexes of Group 13 metal halides (MX3) with ethylenediamine and their decomposition products have been studied theoretically at the B3LYP/LANL2DZ(d,p) level of theory. Gas-phase dissociation into various components and HX elimination reactions are considered. Both processes are endothermic but favored by entropy. Complexes of 2:1 composition are predicted to be stable in the gas phase up to 640-1000 K. It is found that complexation with the second acceptor molecule lowers the HX elimination enthalpy; in turn, HX elimination increases DA bonding with a second MX3 molecule. Exceptionally high values of the dissociation enthalpies (310-390 kJ mol(-1)) and HX elimination reactions (360-420 kJ mol(-1)) of the amido compounds MX2NHC2H4NH2 and MX2NHC2H4NHMX2 make them important intermediates in the decomposition processes. Dissociation reactions of the complexes are more favorable than HX elimination reactions; however, the subsequent oligomerization and cyclization processes of coordinationally unsaturated amido and imido compounds may facilitate HX elimination. Since HI elimination reactions are predicted to be the least endothermic, and aluminum-containing compounds have the strongest M-N dissociation enthalpies, it is expected that compounds based on aluminum iodide are promising objects for experimental studies.


Hamartomatous polyps - a clinical and molecular genetic study.
Hamartomatous polyps (HPs) in the gastrointestinal (GI) tract are rare compared to other types of GI polyps, yet they are the most common type of polyp in children. The symptoms are usually rectal bleeding, abdominal pain, obstipation, anaemia, and/or small bowel obstruction. The polyps are typically removed concurrently with endoscopy when located in the colon, rectum, or stomach, whereas polyps in the small bowel are removed during push-enteroscopy, device-assisted enteroscopy, or by surgery. HPs can be classified as juvenile polyps or Peutz-Jeghers polyps based on their histopathological appearance. Patients with one or a few juvenile polyps are usually not offered clinical follow-up as the polyp(s) are considered not to harbour any malignant potential. Nevertheless, it is important to note that juvenile polyps and HPs are also found in patients with hereditary hamartomatous polyposis syndromes (HPS). Patients with HPS have an increased risk of cancer, recurrences of polyps, and extraintestinal complications. The syndromes are important to diagnose, as patients should be offered surveillance from childhood or early adolescence. The syndromes include juvenile polyposis syndrome, Peutz-Jeghers syndrome, and the PTEN hamartoma tumour syndrome. Currently, the HPS diagnoses are based on clinical criteria and are often assisted with genetic testing as candidate genes have been described for each syndrome. This thesis is based on six scientific papers. The overall aim of the studies was to expand the knowledge on clinical course and molecular genetics in patients with HPs and HPS, and to investigate research participants' attitude towards the results of extensive genetic testing. Paper I: In the first paper we investigated the occurrence, anatomic distribution, and other demographics of juvenile polyps in the colon and rectum in Denmark in 1995-2014. Based on the Danish Pathology Data Bank we found that 1772 patients had 2108 JPs examined in the period, and we calculated the incidence of juvenile polyps to be between 1:45,000 and 1:65,000. The majority of patients with juvenile polyps were adults and 1% fulfilled to diagnostic criteria of JPS. The majority of patients had a single juvenile polyp. Paper II: In this paper we conducted a review of the HPS based on the current literature. Paper III: We investigated the hypothesis that patients with one or few HPs may have a HPS based on genetic screening. We de-signed a panel of 26 genes associated with HPS and used targeted next generation sequencing in 77 patients with mainly one juvenile polyp. We detected several germ line variants, among them three in ENG, two in BMPR1A, one in PTEN, and one in SMAD4. Although some of the detected variants have been reported previously none could be classified as definitely pathogenic or likely pathogenic according to our variant classification scheme and thus we concluded that genetic screening of patients with one or few JPs are not indicated. Paper IV: In Paper IV we investigated one of the ethical aspects of next generation sequencing: the issue whether research participants in NGS studies should be offered the possibility of not re-ceiving information on incidental genetic findings (the "opting out possibility"). We conducted semi-structures interviews in 127 research participants, and found that the majority (61%) wanted information on all incidentals findings, while 36% wanted information on actionable incidental findings. Only 3% did not want information on incidental findings at all. Paper V: In this paper we wanted to gather information on all Danish patients with Peutz-Jeghers syndrome in order to investigate the phenotype and genotype. Through Danish registers we detected 43 patients of which 14 had deceased. We calculated the prevalence of Peutz-Jeghers syndrome to be approximately one in 195,000 individuals. The median age at diagnosis was 29 years with obstruction of the small bowel as the most frequent presenting symptom. We noted 18 cancer occurrences in the population in both the GI tract and at extraintestinal sites, demonstrating that these patients are predisposed to cancer at various anatomical sites. The study also underlined the wide phenotypic expression of the syndrome. Paper VI: In the last paper we identified patients with juvenile polyposis syndrome, who carry a SMAD4 mutation, and described their genotype and phenotype. We especially investigated whether these patients have symptoms of both juvenile polyposis syndrome and hereditary hemorrhagic telangiectasia. We identified 14 Danish patients. Most of these had symptoms of both conditions and one had aortic root dilatation. Thus, this group of patients requires a multidisciplinary follow-up program.


Larval ecology, geographic range, and species survivorship in Cretaceous mollusks: organismic versus species-level explanations.
The observation that geographic range size in Cretaceous mollusks is correlated with species survivorship and is heritable at the species level has figured repeatedly in discussions of species selection over the past two decades. However, some authors have suggested that the relationship between mode of larval development and geographic range supports the reduction of this example to selection on organismic properties. Our reanalysis of Jablonski's work on heritability at the species level finds that geographic range is significantly heritable (using a randomization test) in both bivalves and gastropods, even within a single larval mode. Further, generalized linear models show that geographic range size is more important than larval mode in predicting extinction probability in both gastropods and bivalves. These results reaffirm the role and heritability of geographic range as a species-level property that can promote species selection; the model-based approach applied here may help to operationalize "screening off " and related approaches to evaluating hierarchical explanations in evolution.


Comparison of conventional versus three-dimensional ultrasound in fetal renal pelvis measurement and their potential prediction of neonatal uropathies.
To establish a threshold value for fetal renal pelvis dilatation measured by automatic volume calculation (SonoAVC) in the third trimester of pregnancy to predict neonatal uropathies, and to compare these results with conventional antero-posterior (AP) measurement, fetal kidney 3D volume and renal parenchymal thickness. In a prospective cohort study, 125 fetuses with renal pelvis AP diameter of ≥5 mm both at 20 weeks of gestation and in the third trimester, underwent an additional 3D volume measurement of the fetal kidney in the third trimester. Receiver operating characteristic (ROC) curves for establishing threshold values for fetal renal pelvis volume, AP measurement, fetal kidney volume and renal parenchymal thickness to predict neonatal uropathies were analyzed. Also, sensitivity, specificity, area under the curve (AUC) and likelihood ratios were calculated. A cut-off point of 1.58 cm³ was identified in the third trimester of pregnancy (AUC 0.865 (95% CI 0.789-0.940), sensitivity 76.3%, specificity 87.4%, LR+ 6.06, LR- 0.27) for measurements with SonoAVC. A cut-off value of 11.5 mm was established in the third trimester of pregnancy (AUC 0.828 (95% CI 0.737-0.918), sensitivity 71.1%, specificity 85.1%, LR+ 4.77, LR- 0.34) for the conventional AP measurement. A cut-off point for fetal kidney volume was calculated at 13.29 cm³ (AUC 0.769 (95% CI 0.657-0.881), sensitivity 71%, specificity 66%, LR+ 2.09, LR- 0.44). For renal parenchymal thickness, a cut-off point of 8.4 mm was established (AUC 0.216 (95% CI 0.117-0.315), sensitivity 31.6%, specificity 32.6%, LR+ 0.47, LR- 2.10). This study demonstrates that 3D fetal renal pelvis volume measurements and AP measurements both have a good and comparable diagnostic performance, fetal renal volume a fair accuracy and renal parenchymal thickness a poor accuracy in predicting postnatal renal outcome.


Disorder-related risk factors for revision total hip arthroplasty after hip hemiarthroplasty in displaced femoral neck fracture patients: a nationwide population-based cohort study.
The choice of primary hip hemiarthroplasty or total hip arthroplasty for displaced femoral neck fracture is still controversial. Revision hip arthroplasty not only increases risk and cost but also could result in worse outcome. Determining the risk factors for revision can help inform medical decision-making and aid in risk stratification of publicly reported outcomes. Therefore, we conducted a nationwide population-based study to identify the disease-related risk factors and construct a risk score nomogram to predict revision surgery. Records of all 68,030 femoral neck fracture patients receiving partial hemiarthroplasty (HA) in 2000-2010, with no total hip arthroplasty (THA) or revision HA history, were collected from the National Health Insurance Research Database. Cox proportional hazard regression was used to estimate the risk of revision hip replacement (RHA). The score of each risk factor was the quotient of the regression coefficient of the variable by the regression coefficient for a 10-year increase in age. The predictive accuracy was tested using the area under the receiver operating characteristic curve (AUROC). The revision risk for hemiarthroplasty increased in male, those with schizophrenia and end-stage renal disease patients had 1.58-, 1.88-, and 1.74-fold revision HA risk (95 % confidence interval (CI) = 1.40-1.78, 1.26-2.79, and 1.29-2.34, respectively). In a predictive model, the cumulative risk score ranged from 0 to 13 with a 5.08 to 91.82 % 10-year predicted RHA risk. The percentage of AUROC for 10-year RHA risk in nomogram was 61.9 (95 % CI = 60.0-63.4). Males, schizophrenia and end-stage renal disease patients have higher risk of revision surgery after hemiarthroplasty for femoral neck fracture.


Comparative evaluation of single fixed dosing and weight-based dosing of rasburicase for tumor lysis syndrome.
To evaluate single fixed dosing versus weight-based dosing strategies for rasburicase to determine the minimum dose required to mitigate hyperuricemia in the treatment or prevention of tumor lysis syndrome. Retrospective medical record review Academic medical center A total of 373 patients with a diagnosis of a hematologic malignancy or solid tumor and who received at least one dose of rasburicase over a 6-year period between January 1, 2005, and February 18, 2011; 180 patients received single doses of 3 mg (38 patients), 6 mg (99 patients), or 7.5 mg (43 patients), and 193 patients received weight-based dosing. Tumor lysis syndrome laboratory data were recorded at baseline and monitored up to 72 hours after initial rasburicase administration. Median baseline plasma uric acid levels were 6.85 mg/dl, 8.80 mg/dl, 8.00 mg/dl, and 9.20 mg/dl, respectively, in the 3-mg, 6-mg, 7.5-mg, and weight-based dosing groups. Treatment success was defined as a normalized plasma uric acid level (< 7.5 mg/dl) within 24 hours after receiving rasburicase. The mean weight-based dose was 0.16 mg/kg. Six rasburicase treatment failures occurred; two were in the 3-mg group, one was in the 6-mg group, and three were in the weight-based dosing group. At 24 hours after rasburicase administration, no statistically significant differences in treatment success were noted among groups (92.9% vs 97.6% vs 100.0% vs 98.0% in the 3-mg, 6-mg, 7.5-mg, and weight-based dosing groups, respectively, p=0.1238). The efficacy of all single fixed doses and weight-based dosing strategies evaluated in this study appear to be comparable in normalizing plasma uric acid levels within 24 hours of rasburicase administration. Although use of a 3-mg rasburicase dose may be the most cost-effective treatment strategy in managing hyperuricemia secondary to tumor lysis syndrome, the 6-mg dose resulted in lower sustained uric acid levels after rasburicase administration. Further analysis of patient specific factors contributing to the need for repeat rasburicase administration should be conducted in larger, prospective clinical trials.


Positive immunostaining with MLuC1 of bone marrow aspirate predicts poor outcome in patients with small-cell lung cancer.
Immunocytochemistry has been proven able to identify tumor cells in bone marrow aspirate (BMA) of patients with SCLC. However, few data exist about the clinical significance of the procedure. 108 BMA taken from 60 patients were incubated with the MoAb MLuC1 (cluster 6) and stained by the APAAP (alkaline phosphatase-antialkaline phosphatase) method. The serum levels of LDH, TPA, NSE and CEA were also studied in relation to bone marrow involvement by means of discriminant analysis. Immunocytochemistry of the aspirate with MLuC1 detected positive cells in 23 patients (38%) (38 of 108 samples) vs. 13% of the conventional biopsies studied without MLuC1 (P < 0.001). With respect to bone marrow positivity, three groups of patients were identified: those with no positive cells in the aspirate and negative biopsy (group A); those with less than 10 positive cells in the aspirate and negative biopsy (group B); and those with more than 10 positive cells or clumps in the aspirate or positive biopsy (group C). Group C patients had poorer median survivals than those in the other two groups (5.5 vs. 11 months, respectively, P = 0.01). Discriminant analysis showed that the four serum markers were poor discriminators of the degree of bone marrow involvement, with only 55% of grouped cases being correctly classified. These results show that detection of bone marrow involvement i) can be improved by the use of MLuC1 ii) is not predictable by conventional tumor markers, and iii) is related to poor outcome.


Nonlinear alignment of chromatograms by means of moving window fast Fourier transfrom cross-correlation.
The preprocessing of chromatograms is essential to modern chromatography for further qualitative and quantitative analysis, especially when chromatographic instruments are used for herb products analysis involving large number of samples. To accurately compare and analyze the obtained chromatograms, it is necessary to preprocess, especially align retention time shifts. Here moving window fast Fourier transform (FFT) cross-correlation is introduced to perform nonlinear alignment of high-throughput chromatograms. Since elution characteristics of chromatograms will produce local similarity in retention time shifts, moving window procedure seems to be a better substitute of segmentation steps. The retention time shifts can be calculated and accelerated by FFT cross-correlation. The artifacts can be detected and eliminated from the retention time shifts profile since the continuity of moving window procedure. The proposed method is demonstrated in comparison with recursive alignment by FFT on chromatographic datasets from herb products analysis. It is shown that the proposed method can address nonlinear retention time shift problem in chromatograms with the simple moving window procedure, which will not introduce segments size optimization problem. In additional, the parameters are intuitive and easy to adjust, which makes it off-the-shelf toolbox for alignment of chromatograms.


Epigenetic Modification Drives Acute Kidney Injury-to-Chronic Kidney Disease Progression.
Acute kidney injury (AKI) is a common clinical critical disease. Due to its high morbidity, increasing risk of complications, high mortality rate, and high medical costs, it has become a global concern for human health problems. Initially, researchers believed that kidneys have a strong ability to regenerate and repair, but studies over the past 20 years have found that kidneys damaged by AKI are often incomplete or even unable to repair. Even when serum creatinine returns to baseline levels, renal structural damage persists for a long time, leading to the development of chronic kidney disease (CKD). The mechanism of AKI-to-CKD transition has not been fully elucidated. As an important regulator of gene expression, epigenetic modifications, such as histone modification, DNA methylation, and noncoding RNAs, may play an important role in this process. Alterations in epigenetic modification are induced by hypoxia, thus promoting the expression of inflammatory factor-related genes and collagen secretion. This review elaborated the role of epigenetic modifications in AKI-to-CKD progression, the diagnostic value of epigenetic modifications biomarkers in AKI chronic outcome, and the potential role of targeting epigenetic modifications in the prevention and treatment of AKI to CKD, in order to provide ideas for the subsequent establishment of targeted therapeutic strategies to prevent the progression of renal tubular-interstitial fibrosis.


Expression of the fibroblast growth factor-2 gene during chick development.
In this report, we have carried out mRNA in situ hybridization analysis to study the pattern of expression of the fibroblast growth factor-2 (FGF-2) gene during chick development. The expression pattern of FGF-2 was compared to that of the fibroblast growth factor-1 (FGF-1) gene to further assess a possible role of the FGF-2 during chick embryogenesis. The whole embryos of various stages were examined with 35S-labeled riboprobes transcribed from the coding regions of chick FGF-2 and FGF-1 cDNAs. We show that the distribution pattern of FGF-2 mRNA was highly specific. The FGF-2 transcripts were localized to limb mesenchymes, pharyngeal regions, and embryonic kidneys in day 3 to day 6 chick embryos. However, no FGF-1 mRNA was detected in these structures indicating a unique role of FGF-2 in chick development. These results support the hypothesis that FGF-2 may be a crucial signaling molecule during chick embryogenesis.


Physical activity across the life-span: Does feeling physically younger help you to plan physical activities?
We tested whether the relationship between subjective physical age and physical activity is mediated by planning. Participants came from a broad age range (25-78 years, M = 39.57, standard deviation = 10.75) and reported relatively good health ( M = 3.36, standard deviation = 0.90). The model supported the suggested mediation ( β = -.01, standard error = .01, p = .042). Feeling physically younger is associated with higher planning to adopt higher levels of physical activity and more planning is associated with more subsequent physical activity. Results open avenues for interventions that help people to become more active by focusing on subjective age. One way to do so might be tailoring approaches for interventions.


Ayurvedic hospital wastewater degradation using electrochemical treatment.
The goal of this research was to remove COD, oil and grease (O&G) and color from raw ayurvedic hospital wastewater (AHWW) using a novel electrochemical coagulation (ECC) process. Cell voltage was initially optimized using iron electrodes in bipolar mode for both raw AHWW and ayurvedic hospital therapy room wastewater (AH-TRWW) for a pre-optimized electrolysis time (ET) of 60 min. O&G, COD and color removals for AHWW at 8 V optimized cell voltage were 96, 61 and 96% respectively. Different electrode materials, copper, aluminum, graphite, were used to evaluate relative performances at 8 V. Iron electrodes showed maximum pollutant removal from raw AHWW. The sludge obtained after the ECC process showed good settling and filterability properties compared to graphite and aluminum electrodes. The low SVI value of 146 mL/g was obtained exercising absolute control on sludge volume. Solids flux values showed assurances of compact settling tank design with least spatial footprint. EDX analysis for ECC sludge of AHWW using iron showed gross elements 40.19% C, 48.63% O and 7.92% Fe redefining the fate of sludge. The XRD pattern of the ECC sludge showed an amorphous nature. Post-ECC filtration effluent showed clear water reclamation of 80-82%, proving the effectiveness of the novel ECC treatment process.


Heart failure in women: a special approach?
Heart failure causes significant morbidity and mortality in women, especially elderly women. Risk factors for the development of heart failure in women differ from those in men, with hypertension and diabetes playing a greater role in women and ischemic heart disease a greater role in men. However, the risk of developing heart failure after symptomatic myocardial infarction is higher in women than in men. Data from the Studies of Left Ventricular Dysfunction Registry suggest that event rates after the diagnosis of heart failure are greater in women than in men. Only 13% of the patients included in the major heart failure mortality trails were women, and data for the women in these trials have not been reported separately. The survival of women who have undergone heart transplantation is similar to that of men; however, women have more rejection and are more likely to require maintenance corticosteroid therapy. Data are critically needed to determine whether the treatment of heart failure in women, whether medically or by heart transplantation, requires a special approach.


The effect of MDR1 C3435T polymorphism on the eradication rate of H. pylori infection in PPI-based triple therapy: A meta-analysis.
Several studies have reported that multidrug resistance gene 1 (MDR1) C3435T polymorphism was associated with the rate of Helicobacter pylori (H. pylori) eradication in proton pump inhibitor (PPI)-based triple therapy. However, the conclusions were inconsistent. Therefore, this meta-analysis was conducted to evaluate the impact of MDR1 C3435T polymorphism on H. pylori eradication by PPI-based triple therapy. Seven eligible studies published up to August 2016 and including 1019 patients were identified by searching the Chinese Biomedical Literature database, Wan fang, PubMed, and the Web of Science electronic databases. Consequently, a meta-analysis was conducted with STATA software, using summary odds ratios (OR) and a 95% confidence interval (CI). Overall, there was no significant difference between MDR1 C3435T polymorphism and the eradication rate of H. pylori in the entire genetic model, irrespective of the PPI used. Furthermore, in Asian populations, the TT genotype decreased H. pylori eradication (TT vs CT+CC: OR=0.411, 95% CI = 0.280-0.602, P = 0.000). In addition, a significantly low eradication rate was observed in a recessive model, in which either lansoprazole (TT vs CT+CC: OR = 0.305, 95% CI = 0.184-0.504, P = 0.000) or omeprazole (TT vs CT+CC: OR = 0.229, 95% CI = 0.069-0.763, P = 0.016) was taken, in a subanalysis of individual PPIs. In the analyses that were stratified by disease type, no significant difference was observed in the peptic ulcer group and the combined diseases subgroup. This meta-analysis indicated that the TT genotype of the MDR1 C3435T polymorphism decreased H. pylori eradication in Asian populations and was also associated with a low cure rate of H. pylori in patients taking lansoprazole- and omeprazole-based triple therapies. However, future studies using larger sample sizes are required.


Association between human papilloma virus-type infections with micronuclei frequencies.
To determine the association between Human papillomavirus (HPV)-type infections with the frequency of Micronucleus (MN), a hospital-based, unmatched case-control study was carried out. We evaluated and compared the average number of MN/1,000 cells among three groups of Mexican females. Twenty one women ranging in age from 31-56 years and divided into three groups were studied. Group I comprised seven control women without cervical lesions and with HPV-negative, Group II was composed of seven women with Squamous intraepithelial lesions (SIL) infected with low-risk HPV low-risk, and Group III was made up of seven women with SIL infected with high-risk HPV infection. Analysis of variance (ANOVA) test revealed differences among Groups I (5.14+/-3.02), II (13.43+/-3.41), and III (25.43+/-3.41) (F=67.46; P=0.0001). We demonstrated an association between HPV type infection and higher MN frequencies. However, a larger controlled study with sufficient follow-up will be required to further evaluate the usefulness of this test in the clinical management of women with HPV infection.


Impairment of the brachial plexus after harvest of the latissimus dorsi muscle for reanimation of a paralysed face.
The one-stage neurovascular pedicled latissimus dorsi muscle transfer with a long thoracodorsal nerve for dynamic reanimation of long-standing facial paralysis offers several advantages over other options. However, extensive dissection of the thoracodorsal nerve risks injury to the brachial plexus. We reviewed 264 consecutive cases to assess the extent of the risk of impairment of the brachial plexus and to elicit factors that could possibly induce complications. Six patients had impairment of brachial plexus, but both sensory and motor disturbance disappeared about 11 months postoperatively. All symptoms had completely vanished by 18.5 months. The complications were thought to have resulted from positioning and excessive retraction in four cases. Direct invasion of the brachial cord may not be the main cause. Proper knowledge of the anatomy and optimum attention minimise the risk of severe complications associated with harvesting of the latissimus dorsi muscle.


When Sexual Trauma Survivors with Severe Psychiatric Disabilities Experience Institutional Care.
Individuals with severe psychiatric disabilities face many challenges from their experience of mental health problems, but also from disenfranchisement, marginalization, and stigmatization from a sociocultural experience. Those who are sexual trauma survivors also have unique challenges and intersecting experiences, which are not historically well understood, acknowledged, or treated in U.S. systems of care. Both in historic and modern mental health systems there have been methods thought of as interventions that have been or are currently reported as traumatizing to those who experience them. This article highlights the specific challenges, needs, and organizational shifts that U.S. systems of care need to be aware of and embark upon in order to provide treatment that is more efficacious with and cognizant of the experiences of those who are sexual trauma survivors. Furthermore, new paradigms for providing mental health treatment are offered in the context of providing trauma-informed as well as trauma treatment to those who are sexual trauma survivors and experience severe psychiatric disabilities.


Dual Channel S-Band Frequency Modulated Continuous Wave Through-Wall Radar Imaging.
This article deals with the development of a dual channel S-Band frequency-modulated continuous wave (FMCW) system for a through-the-wall imaging (TWRI) system. Most existing TWRI systems using FMCW were developed for synthetic aperture radar (SAR) which has many drawbacks such as the need for several antenna elements and movement of the system. Our implemented TWRI system comprises a transmitting antenna and two receiving antennas, resulting in a significant reduction of the number of antenna elements. Moreover, a proposed algorithm for range-angle-Doppler 3D estimation based on a 3D shift invariant structure is utilized in our implemented dual channel S-band FMCW TWRI system. Indoor and outdoor experiments were conducted to image the scene beyond a wall for water targets and person targets, respectively. The experimental results demonstrate that high-quality imaging can be achieved under both experimental scenarios.


Re-thinking technology and its growing role in enabling patient empowerment.
The presence and increase of challenges to eHealth in today's society have begun to generate doubts about the capability of technology in patient empowerment, especially within the frameworks supporting empowerment. Through the review of existing frameworks and articulation of patient demands, weaknesses in the current application of technology to support empowerment are explored, and key constituents of a technology-driven framework for patient empowerment are determined. This article argues that existing usage of technology in the design, development and implementation of patient empowerment in the healthcare system, although well intentioned, is insufficiently constituted, primarily as a result of fragmentation. Systems theory concepts such as holism and iteration are considered vital in improving the role of technology in enabling patient empowerment.


Interleukin-1β activates focal adhesion kinase and Src to induce matrix metalloproteinase-9 production and invasion of MCF-7 breast cancer cells.
Interleukin-1β (IL-1b) is a pleiotropic cytokine that is important in tumor progression and invasion. Matrix metalloproteinase-9 (MMP-9), which is a secreted matrix-degrading enzyme, is one of the key regulators of tumor invasion and metastasis. The current report indicated that IL-1b promotes MMP-9 production and cell invasion in non-metastatic MCF-7 breast cancer cells. IL-1b activated focal adhesion kinase (FAK) and proto-oncogene tyrosine-protein kinase Src (Src). Moreover, inhibiting the Src/FAK pathway reduced the IL-1b-induced production of MMP-9 and cell invasion. To investigate the functional role of FAK in MMP-9 production cell lines expressing mutant FAK in FAK knock-out mouse fibroblasts were generated. In wild-type FAK-expressing cells, MMP-9 production was induced by IL-1b stimulation. By contrast, IL-1b-induced MMP-9 production was abrogated in FAK knock-out, FAK Y397F, FAK Y925F, and kinase dead mutant-expressing cells. Therefore the results of the current study indicate that FAK and Src kinases are activated by IL-1b and play a critical role in MMP-9 production and tumor cell invasion.


Directionality of polypeptide transfer in the mitochondrial pathway of chaperone-mediated protein folding.
Protein folding in mitochondria depends on the functional cooperation of the Hsp70 and Hsp60 chaperone systems, at least for a subset of mitochondrial polypeptides. As suggested previously, Hsp70 and Hsp60 act sequentially. However, recent proposals that the chaperonin Hsp60 functions by releasing substrate protein in an unfolded state would predict a lateral partitioning of folding intermediates between chaperone systems. Firefly luciferase, carrying a mitochondrial targeting signal, was used as a model protein to analyze the degree of coupling and the directionality of substrate transfer between the Hsp70 and Hsp60 chaperones. In vitro, Hsp60 binds unfolded luciferase with high affinity but is unable to promote its folding, whereas the Hsp70 system assists the folding of luciferase efficiently. Upon import into yeast mitochondria, luciferase interacted first with Hsp70. Surprisingly, most of the protein subsequently accumulated in a complex with Hsp60 and never reached the native state. Import into mitochondria that lack a functional Hsp60 did not result in increased folding, but in the aggregation of luciferase. Thus, in intact organelles the two chaperone systems do not function independently in de novo folding of aggregation-sensitive proteins but rather act in an ordered pathway with substrate transfer predominantly in the direction from Hsp70 to Hsp60.


Metaphors for development: how important are experiences early in life?
The many students of development have held rather diverse views on the importance of early experience. Some gave early experiences great prominence (e.g., Freud and his followers, Kuo, 1967), while others largely rejected the pivotal importance of particular early events (e.g., Thorndike), and yet others took a more eclectic tack: Some events in certain species but not all events or in all cases (e.g., Hinde, 1974, Lehrman, 1970). The extremes among the prevailing views are often characterized metaphorically. I propose to do this, then to examine the kinds of situations the metaphors describe, and inquire into their generality and usefulness. Clearly this runs the risk of undue simplification, but there is, I believe merit in occasionally ignoring some of the subtleties that usually must concern us.


Somatomedin peptide distribution and somatomedin-binding protein content in cord plasma: comparison to normal and hypopituitary plasma.
To characterize the macromolecular forms of somatomedin (SM) in human newborn plasma, we have studied the molecular weight distribution of endogenous SM peptides as well as the content and distribution of the acid-stable and the unsaturated SM-binding proteins (SMBP) in cord blood from 13 normal term infants. The radioreceptor assayable SM peptide content was significantly reduced in newborns compared with that in normal adults. Furthermore, 50% of the SM content of newborns circulated as part of a 50,000 mol wt complex, in contrast to adult plasma where the majority of SM peptide content is found in the 150,000 mol wt range. Unsaturated SMBP was strikingly elevated in newborns (mean +/- SRM, 2.75 +/- 1.73 U/ml) compared to adult values of 0.63 +/- 0.24. Sephacryl-200 chromatography demonstrated that the unsaturated SMBP is found in the 40,000-50,000 mol wt region in newborns, adults, and GH-deficient children, although adults appear to have a secondary peak of unsaturated SMBP in the 150,000 mol wt region. Assay of the acid-stable SMBP indicated similar levels in newborns (1.15 +/- 0.26 U/ml) and adults (1.18 +/- 0.47) and strikingly lower values in GH-deficient subjects. The molecular weight of the acid-stable SMBP of newborns, adults, and hypopituitary dwarfs appeared to be similar, measuring approximately 60,000. We conclude that despite low levels of SM peptides, human cord plasma contains normal levels of the acid-stable SMBP and elevated of the unsaturated SMBP. The role of these binding proteins in cord plasma remains uncertain, but suggests that other SM peptides may be important in fetal growth.


Spatial organization of inner hair cell synapses and cochlear spiral ganglion neurons.
The morphological organization of the central projections of the cat cochlear spiral ganglion into the cochlear nucleus was previously investigated by creating restricted lesions in the anteroventral cochlear nucleus (AVCN) to ablate selectively either the lateral or the medial aspect of isofrequency projection laminae. Such lesions resulted in highly selective retrograde degeneration of spiral ganglion cells. Ablation of the lateral part of the AVCN caused degeneration of cells within the scala tympani part of the ganglion, whereas medial ablations within the AVCN induced degeneration of the scala vestibuli aspect of the ganglion. The peripheral axons also degenerated and this fiber loss exhibited selective topographies that paralleled the cell loss within the spiral ganglion, although this phenomenon was more prominent in the proximal part of the osseous spiral lamina near the ganglion and less obvious more distally near the habenula perforata. In this investigation, inner hair cells (IHCs) from these selective lesion cases were evaluated by electron microscopy of serial sections through the basal synaptic regions. Results demonstrated differential degeneration of afferent synapses, with greater (but not completely selective) loss of pillar synapses after lateral AVCN lesions and greater loss of modiolar synapses after medial lesions. Because auditory nerve fibers of different spontaneous discharge rates (SRs) have different spatial distributions on the IHC (Liberman, Science 216:1239, 1982), our results suggest that this SR-based organization is maintained in a topographic organization across the vertical (scala tympani-to-scala vestibuli) dimension of the spiral ganglion cell cluster and carried into the ventral cochlear nuclei (VCN). Thus, in addition to the spiral frequency organization represented by the dorsal-to-ventral frequency map in the VCN, there is also an orderly organization of inputs from high- and low-SR fibers across the lateral-to-medial dimension of the VCN such that the lateral isofrequency laminae receive a proportionately greater input from high-SR fibers, whereas medial isofrequency laminae receive preferential input from low- and medium-SR fibers.


Early and concurrent home stimulation: Unique and indirect links with fine motor skills among 4-year-old children in rural Pakistan.
Fine motor skills enable children to make precise and coordinated movements with their hands and support their ability to engage in everyday activities and learning experiences. In a longitudinal study of 1,058 4-year-old children in rural Pakistan (n = 488 girls), we examined how prior and concurrent levels of home stimulation relate to change in fine motor skills from ages 2 to 4 while controlling for family wealth, maternal education, number of siblings at birth, prior and concurrent measures of children's physical growth and food insecurity, and prior motor skills at age 2. Moreover, we tested whether the association between early home stimulation and subsequent fine motor skills was mediated by physical growth, food insecurity, motor skills at age 2, and concurrent home stimulation. Results revealed that home stimulation at 18 months was positively associated with change in fine motor skills from ages 2 to 4, over and above family socioeconomic resources. This association was mediated by physical growth, food insecurity and motor skills at age 2. In contrast to home stimulation at 18 months, home stimulation at age 4 was positively associated with concurrent motor skills at age 4 when controlling for all antecedent family factors, as well as prior and concurrent measures of physical growth and food insecurity, and prior motor skills at age 2. Findings suggest that the preschool period may be an important window of time when physically and cognitively stimulating experiences at home uniquely relate to variability in fine motor development. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Rous-Whipple Award Lecture. Contributions to the physiology and pathology of the Golgi apparatus.
The importance of the Golgi apparatus in the transport, processing, and targeting of proteins destined for secretion, plasma membranes, and lysosomes has emerged from numerous studies. In this paper we review studies from our laboratory dealing with 1) the Golgi apparatus during mitosis and the role of microtubules in maintaining the structure of the organelle, 2) the endocytosis of antibodies, exogenous lectins, and toxins into the Golgi apparatus of several cells including neurons in vivo and in vitro, 3) the traffic of MG-160, a membrane sialoglycoprotein of the medial cisternae of the Golgi apparatus, from the trans-Golgi network to the Golgi cisternae, and 4) the involvement of the Golgi apparatus of motor neurons in the pathogenesis of amyotrophic lateral sclerosis. We conclude with a summary of ongoing work on the primary structure of MG-160 and introduce evidence suggesting that this intrinsic membrane protein of the Golgi apparatus may be involved in the regulation of endogenous, autocrine, basic fibroblast growth factor. We hope that this review will stimulate studies on the Golgi apparatus of neurons, which may lead to the discovery of neuron-specific properties of this important organelle and its involvement in the pathogenesis of neurodegenerative disorders.


Ivermectin susceptibility and sporontocidal effect in Greater Mekong Subregion Anopheles.
Novel vector control methods that can directly target outdoor malaria transmission are urgently needed in the Greater Mekong Subregion (GMS) to accelerate malaria elimination and artemisinin resistance containment efforts. Ivermectin mass drug administration (MDA) to humans has been shown to effectively kill wild Anopheles and suppress malaria transmission in West Africa. Preliminary laboratory investigations were performed to determine ivermectin susceptibility and sporontocidal effect in GMS Anopheles malaria vectors coupled with pharmacokinetic models of ivermectin at escalating doses. A population-based pharmacokinetic model of ivermectin was developed using pre-existing data from a clinical trial conducted in Thai volunteers at the 200 µg/kg dose. To assess ivermectin susceptibility, various concentrations of ivermectin compound were mixed in human blood meals and blood-fed to Anopheles dirus, Anopheles minimus, Anopheles sawadwongporni, and Anopheles campestris. Mosquito survival was monitored daily for 7 days and a non-linear mixed effects model with probit analyses was used to calculate concentrations of ivermectin that killed 50% (LC50) of mosquitoes for each species. Blood samples were collected from Plasmodium vivax positive patients and offered to mosquitoes with or without ivermectin at the ivermectin LC25 or LC5 for An. dirus and An. minimus. The GMS Anopheles displayed a range of susceptibility to ivermectin with species listed from most to least susceptible being An. minimus (LC50 = 16.3 ng/ml) > An. campestris (LC50 = 26.4 ng/ml) = An. sawadwongporni (LC50 = 26.9 ng/ml) > An. dirus (LC50 = 55.6 ng/ml). Mosquito survivorship results, the pharmacokinetic model, and extensive safety data indicated that ivermectin 400 µg/kg is the ideal minimal dose for MDA in the GMS for malaria parasite transmission control. Ivermectin compound was sporontocidal to P. vivax in both An. dirus and An. minimus at the LC25 and LC5 concentrations. Ivermectin is lethal to dominant GMS Anopheles malaria vectors and inhibits sporogony of P. vivax at safe human relevant concentrations. The data suggest that ivermectin MDA has potential in the GMS as a vector and transmission blocking control tool to aid malaria elimination efforts.


Association of Chronotype and Shiftwork with COVID-19 Infection.
This study assesses whether chronotype is related to COVID-19 infection and whether there is an interaction with shift work. Cross-sectional survey of 19,821 U.S. adults. COVID-19 infection occurred in 40% of participants, 32.6% morning and 17.2% evening chronotypes. After adjusting for demographic and socioeconomic factors, shift work, sleep duration and comorbidities, morning chronotype was associated with a higher (aOR: 1.15, 95% CI 1.10-1.21) and evening chronotype with a lower (aOR: 0.82, 95% CI: 0.78-0.87) prevalence of COVID-19 infection in comparison to an intermediate chronotype. Working exclusively night shifts was not associated with higher prevalence of COVID-19. Morning chronotype and working some evening shifts was associated with the highest prevalence of previous COVID-19 infection (aOR: 1.87, 95% CI: 1.28-2.74). Morning chronotype and working a mixture of shifts increase risk of COVID-19 infection.


Six3 in a small population of progenitors at E8.5 is required for neuroretinal specification via regulating cell signaling and survival in mice.
Neuroretina and retinal pigment epithelium (RPE) are differentiated from the progenitors in optic vesicles, but it is unclear when and how the two lineages are segregated. Manipulation of chick embryos reveals that the early anteroventral optic vesicle is crucial for neuroretinal development, but the molecular mechanism is unclear. Homeodomain transcription factor Six3 is required for neuroretinal specification and is dispensable for RPE formation, but the cell fates of Six3-deficient progenitors and the origins of remnant RPE are unknown. Here, we performed lineage tracing of Six3-Cre positive cells in wild-type and Six3-deficient mouse embryos. Six3-Cre positive progenies were found in a population of progenitors in the anteroventral optic pits/vesicles starting at E8.5, and were found in neuroretina, optic stalk, ventral forebrain, but not RPE, at E10.5. Six3-deletion in the small population of progenitors at E8.5 was sufficient to cause rostral expansion of Wnt8b and drastic reduction of Fgf8/MAPK signaling, ablating neuroretinal specification without affecting RPE. Lineage tracing revealed Six3-deficient progenitors at E8.5 were eventually lost and the remnant RPE was derived from Six3-Cre negative cells. Thus, Six3 in a small population of progenitors expressing Six3-Cre at E8.5 is required for neuroretinal specification via regulating cell signaling and survival in mice.


Assessment of Olea europaea L. fruit extracts: Phytochemical characterization and anticancer pathway investigation.
Olea europaea L. has been widely used as an advantageous rich source of bioactive compounds of high economic value leading to its use in pharmaceutical, cosmetic, and agriculture industries. Ethanolic extracts of olive fruits from three different cultivars (OFE) were studied for their phytochemical contents and were investigated for antioxidant activities and anticancer potential. Major polyphenols detected in these extracts were tyrosol, hydroxytyrosol, oleuropein, rutin, quercetin and glucoside forms of luteolin and apigenin. All these compounds have shown to significantly contribute to the antioxidant activity of OFE, which was evaluated by DPPH and ABTS assays. Proliferation of hepatic and colon cancer cells, HepG2 and Caco-2, were shown to be sensitive to OFE with IC50 less than 1.6mg/ml for all tested extracts. Moreover, flow cytometry analysis showed that OFE induced cell cycle arrest in the S-phase within both HepG2 and Caco-2 cells. This has triggered a cell death mechanism as shown by DNA fragmentation, expression of p53 and phosphorylation level of Akt and Erk proteins. Interestingly, these extracts could be further used as a potential source of natural compounds with both antioxidant and anticancer effects.


Principal component analysis yields results comparable to those of an elaborate Boolean strategy: simplifying the assessment of measurable residual disease in chronic lymphocytic leukemia patients.
Measurable residual disease (MRD) is becoming increasingly important in the chronic lymphocytic leukemia (CLL) context. It is of independent prognostic significance in terms of favorable progression-free and overall survival. The standardized methods used to assess CLL MRD are based on flow cytometry and real-time quantitative PCR. We here present a nine-color assay for CLL MRD with the ROR-1 marker antigen as recommended by the European Research Initiative (ERIC) on CLL; the sensitivity is at least 10-5. We used 54 samples to develop a new principal component analysis (PCA) method based on the Kaluza© "radar" presentation mode. We used a Navios flow cytometer (Beckman Coulter©). We confirmed the linearity of our method over more than five dilutions. The specificity limit was 1.3×10-6 and the lower limit of detection was 3.6×10-6. Compared to the Boolean method, the sensitivity, specificity, and positive and negative predictive values of our PCA method were 100%. When MRD was detectable, PCA and Boolean assays were in agreement (linear regression, R2 = 0.99). We developed a new PCA-based method for detection of CLL MRD. Our method is comparable to that of the consensus method in terms of sensitivity, and it is also much easier and faster.


Refractory Adult-onset Still's Disease Treated with a Combination of Methotrexate and Etanercept.
Adult-onset Still's disease (AOSD) is a challenging diagnosis because of the variability in clinical presentation and lack of gold-standard diagnostic investigations. Even after diagnosis, the treatment is challenging, especially when the disease is refractory to first-line therapy. Multiple pharmacotherapeutic options exist for refractory AOSD, but treatment failures still occur. Etanercept, a Tumor necrosis factor (TNF)-alpha inhibitor, is one of the options that has been rarely used for refractory AOSD, with various outcomes ranging from no response to complete remission. In this case, we highlight how a previously healthy lady had refractory AOSD to glucocorticoids, methotrexate, and hydroxychloroquine combination therapy. There was no response to interleukin (IL)-1 therapy, which necessitated a switch to a combination of etanercept, low-dose methotrexate, and low-dose glucocorticoids with complete remission for a total of three- -year follow-up. The combination of methotrexate and Etanercept can maintain remission in patients with refractory AOSD.


The window period between hepatitis B e antigen and antibody in chronic type hepatitis.
To examine the period between disappearance of hepatitis B e antigen (HBeAg) and appearance of anti-HBe, 48 patients with clinicopathologically verified chronic B hepatitis were followed every 1 to 3 months after HBeAg clearance. Sera were tested by radioimmunoassay for HBeAg and anti-HBe. Anti-HBe appeared in days to years, mostly (78.7%) within 1 year, after disappearance of HBeAg. Only 40.5% of patients had an "e-window" shorter than 1 month. Clinical and histological exacerbation preceding HBeAg clearance precipitated or accelerated appearance of anti-HBe. Since the patients in the "e-window" period were positive for DNA polymerase, it is suggested that the "e-window" reflects relative insensitivity of the radioimmunoassay rather than absence of HBeAg/anti-HBe. Therefore, HBeAg can reappear and clinical activity can relapse particularly during immunosuppressive therapy.


Effects of four different cooking methods on anthocyanins, total phenolics and antioxidant activity of black rice.
Two cultivars of black rice were investigated for the effects of different cooking methods on anthocyanins, total phenolic compounds and antioxidant activities. There was a significant loss of anthocyanins during cooking: roasting resulted in the greatest decrease (94%), followed by steaming (88%), pan-frying (86%) and boiling (77%). Contents of phenolic compounds decreased drastically after cooking, with significantly lower retention in the black rice cultivar that had higher amylose content. DPPH radical-scavenging activity of black rice decreased after cooking. In contrast, metal-chelating activity increased significantly after cooking. Anthocyanins showed a high positive correlation with total phenolic compounds (r2 = 0.936) but a significant negative correlation with metal-chelating activity (r2 = 0.6107). The results indicate that cooking degraded anthocyanins and other phenolic compounds, but with a concomitant increase in phenolics from possible degradation of anthocyanins, which resulted in the enhancement of metal-chelating activity.


Development and use of behavior and social interaction software installed on Palm handheld for observation of a child's social interactions with the environment.
In settings in developing countries, children often socialize with multiple socializing agents (peers, siblings, neighbors) apart from their parents, and thus, a measurement of a child's social interactions should be expanded beyond parental interactions. Since the environment plays a role in shaping a child's development, the measurement of child-socializing agents' interactions is important. We developed and used a computerized observational software Behavior and Social Interaction Software (BASIS) with a preloaded coding scheme installed on a handheld Palm device to record complex observations of interactions between children and socializing agents. Using BASIS, social interaction assessments were conducted on 573 preschool children for 1 h in their natural settings. Multiple screens with a set of choices in each screen were designed that included the child's location, broad activity, state, and interactions with child-socializing agents. Data were downloaded onto a computer and systematically analyzed. BASIS, installed on Palm OS (M-125), enabled the recording of the complex interactions of child-socializing agents that could not be recorded with manual forms. Thus, this tool provides an innovative and relatively accurate method for the systematic recording of social interactions in an unrestricted environment.


[Aberration of the spliceosome in amyotrophic lateral sclerosis].
TDP-43 is a nuclear protein that plays a role in RNA metabolism, and its dysfunction has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), a typical adult-onset motor neuron disease. We investigated RNA metabolism in relation to TDP-43 function in neuronal tissues affected by ALS, and found a decrease in the number of nuclear GEM bodies, as well as reduced expression of minor spliceosomes, which are functional RNA-protein complexes. Similar features have been reported in spinal muscular atrophy (SMA), a motor neuron disease affecting infants. These findings, together with those reported in SMA, strongly suggest that reduction of minor spliceosomes has an important role in the pathomechanism underlying the selective degeneration of motor neurons characteristic of both ALS and SMA.


Sorption of acid red 57 from aqueous solution onto sepiolite.
Sepiolite, a highly porous mineral, is becoming widely used as an alternative material in areas where sorptive, catalytic and rheological applications are required. High ion exchange capacity and high surface area and more importantly its relatively cheap price make it an attractive adsorbent. In this study, the adsorption of acid red 57 by natural mesoporous sepiolite has been examined in order to measure the ability of this mineral to remove coloured textile dyes from wastewater. For this purpose, a series of batch adsorption tests of acid red 57 from aqueous sepiolite solutions have been systematically investigated as a function of parameters such as pH, ionic strength and temperature. Adsorption equilibrium was reached within 1h. The removal of acid red 57 decreases with pH from 3 to 9 and temperature from 25 to 55 degrees C, whereas it increases with ionic strength from 0 to 0.5 mol L(-1). Adsorption isotherms of acid red on sepiolite were determined and correlated with common isotherm equations such as Langmuir and Freundlich models. It was found that the Langmuir model appears to fit the isotherm data better than the Freundlich model. The physical properties of this adsorbent were consistent with the parameters obtained from the isotherm equations. Approximately, 21.49% weight loss was observed. The surface area value of sepiolite was 342 m2 g(-1) at 105 degrees C, and it increased to 357 m2 g(-1) at 200 degrees C. Further increase in temperature caused channel plugging and crystal structure deformation, as a result the surface area values showed a decrease with temperature. The data obtained from adsorption isotherms at different temperatures have been used to calculate some thermodynamic quantities such as the Gibbs energy, heat and entropy of adsorption. The thermodynamic data indicate that acid red 57 adsorption onto sepiolite is characterized by physical adsorption. The dimensionless separation factor (RL) have shown that sepiolite can be used for removal of acid red 57 from aqueous solutions. The sorption capacity of the sepiolite is comparable to the other available adsorbents, and it is quite cheaper.


Scaling law for the partitioning of energy in fragmenting multicharged carbon clusters.
The complete fragmentation of highly excited and multicharged C(n)(q+) clusters (n=5-10; q=2-4), produced in high velocity collisions of C(n)(+) with atoms, has been measured. Multiplicity distributions are presented and used to deduce, within a statistical framework, the partitioning of energy between the fragments' production and fragments' kinetic energy. This partitioning is found to scale as the charge over mass ratio of the cluster.


The E. coli sirtuin CobB shows no preference for enzymatic and nonenzymatic lysine acetylation substrate sites.
N(ε) -lysine acetylation is an abundant posttranslational modification of thousands of proteins involved in diverse cellular processes. In the model bacterium Escherichia coli, the ε-amino group of a lysine residue can be acetylated either catalytically by acetyl-coenzyme A (acCoA) and lysine acetyltransferases, or nonenzymatically by acetyl phosphate (acP). It is well known that catalytic acCoA-dependent N(ε) -lysine acetylation can be reversed by deacetylases. Here, we provide genetic, mass spectrometric, structural and immunological evidence that CobB, a deacetylase of the sirtuin family of NAD(+) -dependent deacetylases, can reverse acetylation regardless of acetyl donor or acetylation mechanism. We analyzed 69 lysines on 51 proteins that we had previously detected as robustly, reproducibly, and significantly more acetylated in a cobB mutant than in its wild-type parent. Functional and pathway enrichment analyses supported the hypothesis that CobB regulates protein function in diverse and often essential cellular processes, most notably translation. Combined mass spectrometry, bioinformatics, and protein structural data provided evidence that the accessibility and three-dimensional microenvironment of the target acetyllysine help determine CobB specificity. Finally, we provide evidence that CobB is the predominate deacetylase in E. coli.


Testing the performance of a cryogenic visualization system on thermal counterflow by using hydrogen and deuterium solid tracers.
An experimental apparatus has been designed to analyze by visualization cryogenic flows of liquid (4)He and consequently address unresolved problems of quantum turbulence. The newly implemented flow visualization setup is described and its specific features discussed. Thermal counterflow experiments have been performed and the motion of solid hydrogen and deuterium tracers studied by using the particle tracking velocimetry technique in order to probe the system capabilities. It is shown that the obtained results are consistent with the two-fluid model describing the behavior of superfluid (4)He. A number of technical and fundamental issues, such as particles' aggregation, role of rotating particles in counterflow and evidence of non-Gaussian distribution of tracers' velocities, are also discussed. The apparatus appears to be well-suited to the task of analyzing cryogenic flows and potentially capable of obtaining new results stimulating further understanding of the underlying physics.


Criteria for an increased specificity of MRI interpretation in elderly subjects with suspected multiple sclerosis.
We reviewed the MRIs of 49 asymptomatic volunteers (age range, 31 to 77 years) and of 50 MS patients (age range, 14 to 63) for areas of increased signal (AIS) and features discriminating MS lesions from lesions seen with normal aging. We obtained optimal specificity of MRI interpretation (100%) if we required at least two of the following three AIS features--size greater than or equal to 6 mm, abutting ventricular bodies, infratentorial location--for a positive MRI diagnosis of MS. Applying these criteria to the MRIs of elderly patients with suspected MS should significantly improve specificity (p less than 0.001) over current quantitative criteria (at least three AIS greater than or equal to 3 mm) without significantly decreasing sensitivity.


[Fungal infections after renal transplantation (author's transl)].
21 of 41 patients developed clinically manifest or systemic Candida albicans infection 1-36 months after renal transplantation. Asymptomatic candiduria was diagnosed in all patients even before the onset of clinical symptoms. Fungal stomatitis was the most frequent clinical sign, followed by mycotic changes in the respiratory, genito-urinary (vaginitis) and gastro-intestinal tract. In five cases intrahepatic biliary stasis was diagnosed in the course of a Candida albicans septicaemia. In 12 patients with renal transplants it was possible, by treatment with nystatin, clotrimazole, flucytosine, miconazole and amphotericine B to control a generalized or clinically manifest Candida albicans infection. Three died of the septicaemia or meningoencephalitis, six as the result of bacterial superinfections. Inspection of the mouth is an important means of early diagnosing fungal infections. Antimycotic treatment should be started if fungal cultures from urine are repeatedly positive even if the clinical findings are still negative.


[Repeating DNA sequences of closely related species of mosquitoes].
Repeated DNA sequences of mosquitoes were studied by using of reassociation kinetics, molecular hybridization, restriction analysis and Southern blot-hybridization. Mosquitoes of two genera, the species of one of them being sibling species, were investigated. The content of all repeated families is the same both in sibling species and in species of different genera DNA. The percent of homologous sequences is low as compared to the high thermal stability of heterologous duplexes both in sibling species DNA and in different genera DNA. Restriction analysis of DNA and blot-hybridization with 35S repeated fraction revealed certain specific families of repeated sequences in the DNA of sibling species and of different genera of mosquitoes.


Inhibitory effects on the production of inflammatory mediators and reactive oxygen species by Mori folium in lipopolysaccharide-stimulated macrophages and zebrafish.
Mori folium, the leaf of Morus alba L. (Moraceae), has been traditionally used for various medicinal purposes from ancient times to the present. In this study, we examined the effects of water extract of Mori folium (WEMF) on the production of inflammatory mediators, such as nitric oxide (NO) and prostaglandin E2 (PGE2), and reactive oxygen species (ROS) in lipopolysaccharide (LPS)-stimulated murine RAW 264.7 macrophages. Our data indicated that WEMF significantly suppressed the secretion of NO and PGE2 in RAW 264.7 macrophages without any significant cytotoxicity. The protective effects were accompanied by a marked reduction in their regulatory gene expression at the transcription level. WEMF attenuated LPS-induced intracellular ROS production in RAW 264.7 macrophages. It inhibited the nuclear translocation of the nuclear factor-kappa B p65 subunit and the activation of mitogen-activated protein kinases in LPS-treated RAW 264.7 macrophages. Furthermore, WEMF reduced LPS-induced NO production and ROS accumulation in zebrafish. Although more efforts are needed to fully understand the critical role of WEMF in the inhibition of inflammation, the findings of the present study may provide insights into the approaches for Mori folium as a potential therapeutic agent for inflammatory and antioxidant disorders.


Consequences of Decreased Light Harvesting Capability on Photosystem II Function in Synechocystis sp. PCC 6803.
Cyanobacteria use large pigment-protein complexes called phycobilisomes to harvest light energy primarily for photosystem II (PSII). We used a series of mutants with partial to complete reduction of phycobilisomes to examine the effects of antenna truncation on photosystem function in Synechocystis sp. PCC 6803. The antenna mutants CB, CK, and PAL expressed increasing levels of functional PSII centers to compensate for the loss of phycobilisomes, with a concomitant decrease in photosystem I (PSI). This increased PSII titer led to progressively higher oxygen evolution rates on a per chlorophyll basis. The mutants also exhibited impaired S-state transition profiles for oxygen evolution. Additionally, P700+ re-reduction rates were impacted by antenna reduction. Thus, a decrease in antenna size resulted in overall physiological changes in light harvesting and delivery to PSII as well as changes in downstream electron transfer to PSI.


The Birmingham Urban Climate Laboratory-A high density, urban meteorological dataset, from 2012-2014.
There is a paucity of urban meteorological observations worldwide, hindering progress in understanding and mitigating urban meteorological hazards and extremes. High quality urban datasets are required to monitor the impacts of climatological events, whilst providing data for evaluation of numerical models. The Birmingham Urban Climate Laboratory was established as an exemplar network to meet this demand for urban canopy layer observations. It comprises of an array of 84 wireless air temperature sensors nested within a coarser array of 24 automatic weather stations, with observations available between June 2012 and December 2014. data routinely underwent quality control, follows the ISO 8601 naming format and benefits from extensive site metadata. The data have been used to investigate the structure of the urban heat island in Birmingham and its associated societal and infrastructural impacts. The network is now being repurposed into a testbed for the assessment of crowd-sourced and satellite data, but the original dataset is now available for further analysis, and an open invitation is extended for its academic use.


Translation of the international outcome inventory for hearing aids into Portuguese from Portugal.
To translate the International Outcome Inventory for Hearing Aids (IOI-HA) Questionnaire from English to Portuguese (from Portugal) and to validate this instrument of study on the Portuguese population. In this prospective study, a translation from English into Portuguese of the IOI-HA was performed, and linguistic adaptation and counter translation were also accomplished. The data were analysed for internal consistency testing for correlations between each individual item and the total score of the IOI-HA, assessing the Cronbach α and performing test-retest analysis. 80 hearing aid users aged 18 years or older were recruited from an ear, nose and throat (ENT) appointment in Coimbra's hospital, Portugal. 84% of the participants were unilateral hearing aid users, whereas 16% were bilateral users. The patients volunteered to answer the questionnaire during an ENT appointment. All of the patients had been using the hearing aids for more than 3 years.After the first application of the questionnaire, a new appointment was planned for retesting, within at least 7 days to no more than 60 days. 29 participants answered the questionnaire again according to the same procedure. The mean IOI-HA total score in the study population was 27.33±4.93 (9-35). The mean values obtained for each item of the questionnaire ranged from 3.19 to 4.54. The Cronbach α was 0.838 and the Cronbach α values when the item was removed, were also significantly strong. The test-retest analysis revealed no differences between the paired groups. In the present study a valid and reliable translation and adaptation of the IOI-HA into Portuguese from Portugal is proposed. This tool will be available for clinical assessment of hearing aid users.


In vivo optical coherence tomography detection of differences in regional large airway smoke inhalation induced injury in a rabbit model.
Smoke inhalation injury causes acute airway injury that may result in airway compromise with significant morbidity and mortality. We investigate the ability of high resolution endobronchial optical coherence tomography (OCT) to obtain real-time images for quantitatively assessing regional differences between upper tracheal versus lower tracheal and bronchial airway injury responses to smoke inhalation in vivo using a prototype spectral domain (SLD)-OCT system we constructed, and flexible fiber optic probes. 33 New Zealand White rabbits are intubated and mechanically ventilated. The treatment groups are exposed to inhaled smoke. The OCT probe is introduced through the endotracheal tube and maintained in place for 5 to 6 h. Images of airway mucosa and submucosa are obtained at baseline and at specified intervals postexposure. Starting within less than 15 min after smoke inhalation, there is significant airway thickening in the smoke-exposed animals. This is maintained over 5 h of imaging studies. The lower tracheal airway changes, correlating closely with carboxyhemoglobin levels, are much greater than upper tracheal changes. Significant differences are seen in lower trachea and bronchi after acute smoke inhalation compared to upper trachea as measured in vivo by minimally invasive OCT. OCT is capable of quantitatively detecting regional changes in airway swelling following inhalation injury.