Treatment of unresectable and metastatic cutaneous squamous cell carcinoma.
Cutaneous squamous cell carcinoma (SCC) is an already common disorder with a rapidly increasing incidence. Treatment of early disease depends primarily on surgery or destructive techniques. In contrast to the frequency of early SCC, unresectable or metastatic SCC is relatively rare, but potentially life-threatening without clearly proven treatment options. Few rigorous studies of the treatment of advanced SCC have been undertaken. In the past, various agents have been explored in a limited fashion, including chemotherapy (cisplatin, fluoropyrimidines, bleomycin, doxorubicin), 13-cis-retinoic acid, and interferon-α2a. Clinical activity has been suggested by these trials, but their small sizes, heterogeneous patient populations, and lack of randomization have hindered the use of their results in defining treatment paradigms. Only one rigorous randomized trial has focused on cutaneous SCC. Enrolling 66 patients, that trial randomized patients at high recurrence risk to either observation or postoperative interferon-α2a and 13-cis-retinoic acid. This treatment did not improve time to recurrence or prevent secondary cutaneous SCC from developing. Though not in the metastatic setting, this study casts doubt on the ability of this regimen to control metastatic disease. Recently, agents targeting the human epidermal growth factor receptor (erlotinib, gefitinib, cetuximab) have displayed preliminary evidence of activity in phase II clinical trials and case series reports. Expression of this receptor is frequent in cutaneous SCC and appears to be prognostically adverse. Only the conduct of rigorous trials, with well-defined endpoints, adequate patient numbers, and preferably randomization, can prove the clinical efficacy of this promising treatment approach and define better therapy for this vexing clinical problem.


Limited role of lipopolysaccharide Lewis antigens in adherence of Helicobacter pylori to the human gastric epithelium.
In vitro and in vivo studies from various groups have suggested that Helicobacter pylori lipopolysaccharide (LPS) Lewis x (Le(x)) antigens mediate bacterial adhesion. We have now reevaluated this hypothesis by studying the adherence in situ of H. pylori strain 11637 and its corresponding Le(x)-negative rfbM mutant to human gastric mucosa from patients (n = 22) with various gastric pathologies. Significant binding of the parent strain was observed in only 8 out of 22 sections; in four out of eight patients, the Le(x)-negative mutant bound less well. One of these four patients displayed no gastric abnormalities, and the other three showed dysplasia, metaplasia, and adenocarcinoma, respectively; hence, we are unable to define the circumstances under which LPS-mediated adhesion takes place. We conclude that H. pylori LPS plays a distinct but minor role in adhesion.


The therapeutic effect of decitabine combined with HAG in acute myeloid leukemia: a retrospective case-control analysis.
Explore the efficacy of decitabine combined with homoharringtonine + cytarabine + granulocyte colony-stimulating factor (HAG) in the treatment of acute myeloid leukemia (AML). A retrospective analysis of clinical data of 125 patients with AML was done. Of them, 61 patients received a simple HAG treatment (HAG group), and 64 received decitabine combined with an HAG regimen (combined group). Treatment efficacy, immune function before and after the treatment, levels of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and incidence of adverse reactions in the two groups were compared. The total response rate of the combined group (84.38%) was higher than that of the HAG group (65.63%) (p < 0.05). After the treatment, levels of CD4+ and CD4+/CD8+ in both groups increased and were significantly higher in the combined group compared to the HAG group. Levels of CD8+, bFGF and VEGF decreased compared to pre-treatment levels and were significantly lower in the combined group than in the HAG group (p < 0.05). There was no significant difference in the rate of adverse reactions between the two groups (p > 0.05). Compared to HAG treatment alone, the combination of decitabine and HAG in the treatment of AML is safe, can significantly improve the immune function of the patients, regulate bFGF and VEGF levels, and improve overall treatment efficacy.


A qualitative study of mental health problems among children displaced by war in northern Uganda.
While multiple studies have found that children affected by war are at increased risk for a range of mental health problems, little research has investigated how mental health problems are perceived locally. In this study we used a previously developed rapid ethnographic assessment method to explore local perceptions of mental health problems among children and adults from the Acholi ethnic group displaced by the war in northern Uganda. We conducted 45 free list interviews and 57 key informant interviews. The rapid assessment approach appears to have worked well for interviewing caretakers and children aged 10-17 years. We describe several locally defined syndromes: two tam/par/kumu (depression and dysthymia-like syndromes), ma lwor (a mixed anxiety and depression-like syndrome), and a category of conduct problems referred to as kwo maraco/gin lugero. The descriptions of these local syndromes were similar to western mood, anxiety and conduct disorders, but included culture-specific elements.


Predictive values of the in vivo diffusion chamber for cyclophosphamide treatment of L1210 murine leukemia.
In vivo culture of tumor cells using the Millipore diffusion chamber implanted i.p. into female C57BL X DBA/2 F1 (hereafter called BD2F1) mice provides a means for direct examination of drug effect on tumor cells. The effect of various doses and schedules of i.p. cyclophosphamide (CY) on murine L1210 leukemia cell count in the chambers was compared to survival of leukemia-bearing animals treated similarly. Tumor cell viability was assessed by transfer of chamber contents to recipient animals who were then observed for survival. Unless perturbed by CY, L1210 cells grew in log phase within chambers to 10(8) cells/cu mm. The effect of CY on chamber cell count was dose related, quantifiable, reproducible, and predictive of survival of leukemia-bearing animals treated similarly. Single doses proved to be more effective than were equally divided doses in decreasing chamber cell number and prolonged leukemic animal survival. Reinjection of L1210 cells rescued from chambers after hosts had been treated with CY revealed that many could not produce tumors. Results suggest that this technique provides reproducible information on drug effects and may be a valuable tool for designing clinically useful dose schedules.


Platelet-activating factor acetylhydrolases: broad substrate specificity and lipoprotein binding does not modulate the catalytic properties of the plasma enzyme.
Platelet-activating factor acetylhydrolases (PAF-AHs) are a group of enzymes that hydrolyze the sn-2 acetyl ester of PAF (phospholipase A(2) activity) but not phospholipids with two long fatty acyl groups. Our previous studies showed that membrane-bound human plasma PAF-AH (pPAF-AH) accesses its substrate only from the aqueous phase, which raises the possibility that this enzyme can hydrolyze a variety of lipid esters that are partially soluble in the aqueous phase. Here we show that pPAF-AH has broad substrate specificity in that it hydrolyzes short-chain diacylglycerols, triacylglycerols, and acetylated alkanols, and displays phospholipase A(1) activity. On the basis of all of the substrate specificity results, it appears that the minimal structural requirement for a good pPAF-AH substrate is the portion of a glyceride derivative that includes an sn-2 ester and a reasonably hydrophobic chain in the position occupied by the sn-1 chain. In vivo, pPAF-AH is bound to high and low density lipoproteins, and we show that the apparent maximal velocity for this enzyme is not influenced by lipoprotein binding and that the enzyme hydrolyzes tributyroylglycerol as well as the recombinant pPAF-AH does. Broad substrate specificity is also observed for the structurally homologous PAF-AH which occurs intracellularly [PAF-AH(II)] as well as for the PAF-AH from the lower eukaryote Physarum polycephalum although pPAF-AH and PAF-AH(II) tolerate the removal of the sn-3 headgroup better than the PAF-AH from P. polycephalum does. In contrast, the intracellular PAF-AH found in mammalian brain [PAF-AH(Ib) alpha 1/alpha 1 and alpha 2/alpha 2 homodimers] is more selectively operative on compounds with a short acetyl chain although this enzyme also displays significant phospholipase A(1) activity.


Is there nursing phenomenology after Paley? Essay on rigorous reading.
At the bedside, nurses are expected to be precise when they read indications on screens and on the bodies of patients and decide on the meaning of words framed by the context of acute care. In academia, although there is no incident report to fill when we misread or misrepresent complex philosophical ideas, the consequences of inaccurate reading include misplaced epistemological claims and poor scholarship. A long and broad convention of nursing phenomenological research, in its various forms, claims a philosophical grounding in the ideas of Husserl, Heidegger, and other thinkers. But for nearly two decades, nurse phenomenologists' knowledge claims have been challenged by well-informed criticisms, most notably by John Paley. At the heart of criticism lies an observation that Continental phenomenological thought is misrepresented in many nursing sources and that nursing phenomenology, both descriptive and interpretive, cannot appeal to the authority of either Husserl or Heidegger. Taking these criticisms seriously, I am asking, Is phenomenology after Paley possible? If misreading seems to be an issue, how can - or should - we read rigorously? My thinking through these questions is influenced by the ideas of Jacques Derrida. Under a condition of a play of language, of Derridian différance, when meaning is never self-identical and never fully arrives, I suggest that one has to negotiate meanings through reading for differences. I develop this idea in relation to the methodological conventions of phenomenological nursing research and argue for a careful rereading of the whole field of phenomenological nursing research. Such rereading presupposes and necessitates interdisciplinary engagement between nursing and the humanities and interpretive social sciences. Greater familiarity with research practices of those disciplines that stress theoretical and writing rigour might make visible the limits of nursing research approaches and their quality criteria. An understanding of philosophical and theoretical works - a condition of quality scholarship - depends on our reading of both originary texts and contemporary literature from the humanities and the social sciences. This understanding, far from obliging researchers to always trace (often erroneously) their work to its philosophical roots, opens other, often more sound, methodological possibilities.


Chromosomes tell half of the story: the correlation between karyotype rearrangements and genetic diversity in sedges, a group with holocentric chromosomes.
Chromosome rearrangements may affect the rate and patterns of gene flow within species, through reduced fitness of structural heterozygotes or by reducing recombination rates in rearranged areas of the genome. While the effects of chromosome rearrangements on gene flow have been studied in a wide range of organisms with monocentric chromosomes, the effects of rearrangements in holocentric chromosomes--chromosomes in which centromeric activity is distributed along the length of the chromosome--have not. We collected chromosome number and molecular genetic data in Carex scoparia, an eastern North American plant species with holocentric chromosomes and highly variable karyotype (2n = 56-70). There are no deep genetic breaks within C. scoparia that would suggest cryptic species differentiation. However, genetic distance between individuals is positively correlated with chromosome number difference and geographic distance. A positive correlation is also found between chromosome number and genetic distance in the western North American C. pachystachya (2n = 74-81). These findings suggest that geographic distance and the number of karyotype rearrangements separating populations affect the rate of gene flow between those populations. This is the first study to quantify the effects of holocentric chromosome rearrangements on the partitioning of intraspecific genetic variance.


Retention of HIV-infected and HIV-exposed children in a comprehensive HIV clinical care programme in Western Kenya.
To describe incidence rates (IR) and risk factors for loss-to-follow-up (LTFU) among HIV-infected and HIV-exposed children in a large HIV treatment programme in Western Kenya. The USAID-AMPATH Partnership has enrolled >100,000 patients (20% children) at 23 clinic sites throughout western Kenya. LTFU is defined as being absent from the clinic for >3 months if on combination antiretroviral treatment (cART) and >6 months if not. Included in this analysis were children aged <14 years, HIV exposed or infected at enrollment, and enrolled between April 2002 and March 2009. The IR for LTFU are presented per 100 child-years (CY) of follow-up. Proportional hazards models with time-independent and time-dependent covariates were used to model factors associated with LTFU. Weight for height Z-scores were calculated using EpiInfo, with severe malnutrition being defined as a Z-score <or=-3.0. Immune suppression was defined as per WHO age-specific categories. There were 13,510 children eligible for analysis, comprising 3106 children who at enrollment were HIV infected and 10,404 children who were HIV exposed. The overall IR of LTFU was 18.4 (17.8-18.9) per 100 CY. Among HIV-infected children, 15.2 (13.8-16.7) and 14.1 (13.1-15.8) per 100 CY became LTFU, pre- and post-cART initiation, respectively. The only independent risk factor for becoming LTFU among the HIV-infected children was severe immune suppression (AHR: 2.17, 95% CI: 1.51-3.12). Among the HIV-exposed children, 20.1 per 100 (19.4-20.7) became LTFU. Independent risk factors for LTFU among them were being severely low weight for height (AHR: 1.69, 95% CI: 1.25-2.28), being orphaned at enrollment (AHR: 1.57, 95% CI: 1.23-1.64), being CDC Class B or C (AHR: 1.41, 95% CI: 1.14-1.74), and having received cART (AHR: 1.56, 95% CI: 1.23-1.99). Protective against becoming LTFU among the HIV exposed were testing HIV positive (AHR: 0.26, 95% CI: 0.21-0.32), older age (AHR: 0.90, 95% CI: 0.85-0.96), enrolling in later time periods, and receiving food supplementation (AHR: 0.58, 95% CI: 0.32-1.04). There is a high rate of LTFU among these highly vulnerable children, particularly among the HIV exposed. These data suggest that HIV-infected and HIV-exposed children are at especially high risk for LTFU if they are sick or malnourished.


New Repeat Polymorphism in the AKT1 Gene Predicts Striatal Dopamine D2/D3 Receptor Availability and Stimulant-Induced Dopamine Release in the Healthy Human Brain.
The role of the protein kinase Akt1 in dopamine neurotransmission is well recognized and has been implicated in schizophrenia and psychosis. However, the extent to which variants in the AKT1 gene influence dopamine neurotransmission is not well understood. Here we investigated the effect of a newly characterized variant number tandem repeat (VNTR) polymorphism in AKT1 [major alleles: L- (eight repeats) and H- (nine repeats)] on striatal dopamine D2/D3 receptor (DRD2) availability and on dopamine release in healthy volunteers. We used PET and [11C]raclopride to assess baseline DRD2 availability in 91 participants. In 54 of these participants, we also measured intravenous methylphenidate-induced dopamine release to measure dopamine release. Dopamine release was quantified as the difference in specific binding of [11C]raclopride (nondisplaceable binding potential) between baseline values and values following methylphenidate injection. There was an effect of AKT1 genotype on DRD2 availability at baseline for the caudate (F(2,90) = 8.2, p = 0.001) and putamen (F(2,90) = 6.6, p = 0.002), but not the ventral striatum (p = 0.3). For the caudate and putamen, LL showed higher DRD2 availability than HH; HL were in between. There was also a significant effect of AKT1 genotype on dopamine increases in the ventral striatum (F(2,53) = 5.3, p = 0.009), with increases being stronger in HH > HL > LL. However, no dopamine increases were observed in the caudate (p = 0.1) or putamen (p = 0.8) following methylphenidate injection. Our results provide evidence that the AKT1 gene modulates both striatal DRD2 availability and dopamine release in the human brain, which could account for its association with schizophrenia and psychosis. The clinical relevance of the newly characterized AKT1 VNTR merits investigation.SIGNIFICANCE STATEMENT The AKT1 gene has been implicated in schizophrenia and psychosis. This association is likely to reflect modulation of dopamine signaling by Akt1 kinase since striatal dopamine hyperstimulation is associated with psychosis and schizophrenia. Here, using PET with [11C]raclopride, we identified in the AKT1 gene a new variable number tandem repeat (VNTR) marker associated with baseline striatal dopamine D2/D3 receptor availability and with methylphenidate-induced striatal dopamine increases in healthy volunteers. Our results confirm the involvement of the AKT1 gene in modulating striatal dopamine signaling in the human brain. Future studies are needed to assess the association of this new VNTR AKT1 variant in schizophrenia and drug-induced psychoses.


Tailoring flavin-based photosensitizers for efficient photooxidative coupling of benzylic amines.
Photooxidative coupling of benzylic amines using naturally abundant O2 as an oxidant under visible light irradiation is an alternative green approach to synthesis imines and is of both fundamental and practical significance. We investigated the photophysical properties of flavin (FL) that is a naturally available sensitizer and its derivatives, i.e. 9-bromoflavin (MB-FL), 7,8-dibromoflavin (DB-FL) and 10-phenylflavin (Ph-FL), as well as the performance of these FL-based sensitizers (FLPSs) in the photooxidative coupling of benzylic amines to imines combining experimental and theoretical efforts. We showed that chemical functionalization with Br and phenyl effectively improves the photophysical properties of these FLPSs, in terms of absorption in the visible light range, singlet oxygen quantum yields, triplet lifetime, etc. Apart from nearly quantitative selectivity for the production of imines, the performance of DB-FL is superior to those of other FLPSs, and it is among the best photocatalysts for imine synthesis. Specifically, 0.5 mol% DB-FL is capable of converting 91% of 0.2 mmol benzylamine and more than 80% of 0.2 mmol fluorobenzylic amine derivatives into their corresponding imines in 5 h batch runs. Mechanistic investigation finely explained the observed photophysical properties of FLPSs and highlighted the dominant role of electron transfer in FLPS sensitized coupling of benzylic amines to imines. This work not only helps to understand the pathways for photocatalysis with FLPSs but also paves the way for the design of novel and efficient PSs to promote organic synthesis.


Bacteriological profile of pancreatic juice in patients with chronic pancreatitis.
Information regarding the association of bacteria in the pancreatic fluid in patients with chronic pancreatitis is limited. This study was designed to analyze the prevalence of bacteria in pancreatic juice in patients with chronic pancreatitis and the association of positive pancreatic fluid culture with pre-operative and post-operative parameters. All patients with chronic pancreatitis who underwent operation from November 2011 to October 2013 were prospectively included in the study. Intra-operatively pancreatic duct fluid was collected and sent for culture sensitivity in all patients. The bacteriology of the fluid was analyzed and was correlated with preoperative, intraoperative and postoperative parameters. A total of 26 patients were analyzed. Two patients underwent endoscopic retrograde cholangio-pancreatography (ERCP) preoperatively. Bacteria was present in pancreatic duct fluid in 11 (42%) patients. Both patients who underwent ERCP had positive cultures. Most common organism observed was Escherichia coli (6/11, 55%) followed by Klebsiella pneumonia (3/11, 27%). Five patients with positive culture developed wound infection. Bacteria isolated from the wound were similar to pancreatic fluid. Bacteria is commonly present in the pancreatic juice in patients with chronic pancreatitis and its presence may have an effect on the post-operative infections following operations. Based on the pancreatic fluid culture results appropriate antibiotic can be given to the patients who will develop septic complications following surgery. Role of bacteria in the pathogenesis of the chronic calcific pancreatitis needs to be investigated in future studies.


Nature Bank and the Queensland Compound Library: unique international resources at the Eskitis Institute for Drug Discovery.
The Eskitis Institute for Drug Discovery is home to two unique resources, Nature Bank and the Queensland Compound Library (QCL), that differentiate it from many other academic institutes pursuing chemical biology or early phase drug discovery. Nature Bank is a comprehensive collection of plants and marine invertebrates that have been subjected to a process which aligns downstream extracts and fractions with lead- and drug-like physicochemical properties. Considerable expertise in screening natural product extracts/fractions was developed at Eskitis over the last two decades. Importantly, biodiscovery activities have been conducted from the beginning in accordance with the UN Convention on Biological Diversity (CBD) to ensure compliance with all international and national legislative requirements. The QCL is a compound management and logistics facility that was established from public funds to augment previous investments in high throughput and phenotypic screening in the region. A unique intellectual property (IP) model has been developed in the case of the QCL to stimulate applied, basic and translational research in the chemical and life sciences by industry, non-profit, and academic organizations.


Non-NMDAR neuronal Ca(2+)-permeable channels in delayed neuronal death and as potential therapeutic targets for ischemic brain damage.
Transient cerebral ischemia represents the most common cause of complex chronic disability in adults due to delayed neuronal death as a result of aberrant post-ischemic increases in the [Ca(2+)]c and [Zn(2+)]c. A number of Ca(2+)-permeable channels are engaged in transient ischemia-induced neuronal death. In this review, the authors discuss the GluA2-lacking AMPARs, acid-sensing ion channel 1a, melastatin-related transient receptor potential 2 (TRPM2), TRPM7 and store-operated Ca(2+) channels expressed in ischemia-vulnerable neurons, and focus on the studies using in vitro and in vivo models of transient ischemia that supports a significant role for these channels in inducing increases in the [Ca(2+)]c and/or [Zn(2+)]c and delayed neuronal death, and their potential as therapeutic targets. Non-NMDAR Ca(2+)-permeable channels are important mechanisms mediating delayed neuronal death and cognitive dysfunctions after transient ischemia. Identification of such Ca(2+)-permeable channels significantly improves our understanding of the molecular events leading to ischemic brain damage and provides promising novel targets for post-ischemic therapeutics treating ischemic brain damage.


Identification of tumor-initiating cells derived from two canine rhabdomyosarcoma cell lines.
Cancer stem cells or tumor-initiating cells (TICs) are a small subpopulation of cells that have the capacity to self-renew, differentiate and initiate tumors. These cells may function in tumor initiation, aggression and recurrence. Whether spheres derived from canine rhabdomyosarcoma cells have stem cell-like properties is unclear. We induced sphere formation in the canine rhabdomyosarcoma cell lines, CMS-C and CMS-J, and characterized the spheres in vitro and in vivo. Sphere-forming cells were more resistant to vincristine, mitoxantrone and doxorubicin than adherent cells. Xenograft transplantation demonstrated that 1 × 103 sphere-forming cells derived from CMS-C were sufficient for tumor formation. The sphere assay showed that the sphere-forming cells were present in these tumors. These results suggest that the spheres derived from canine rhabdomyosarcoma cells may possess characteristics of TICs. This study provides the foundation for elucidating the contribution of TICs to rhabdomyosarcoma tumorigenesis.


Sequencing of a 65 kb region of the Bacillus subtilis genome containing the lic and cel loci, and creation of a 177 kb contig covering the gnt-sacXY region.
Within the framework of an international project for the sequencing of the entire Bacillus subtilis genome, this paper communicates the sequencing of a chromosome region containing the lic and cel loci (65 kb), which creates a 177 kb contig covering the region from gnt to sacXY. This 65 kb region contains 64 ORFs (62 complete and two partial genes). The 14th, 15th and 17th genes correspond to licT, licS and katE, encoding the antiterminator for licS transcription, beta-glucanase (lichenase) and catalase 2, respectively. The 11th, 30th, 36th, 39th, 41st, 45th-48th, 51st and 58th genes are designated deaD, pepT, galE, aldY, msmX, cydABCD, sigY and katX because their products probably encode ATP-dependent RNA helicase, tripeptidase, UDP-glucose 4-epimerase, aldehyde dehydrogenase, multiple sugar-binding transport ATP-binding protein, the respective components of cytochrome d ubiquinol oxidase and ATP-binding cassette transporter, sigma-factor of RNA polymerase and catalase, respectively. The 60th-64th genes are celRABCD, which are probably involved in cellobiose utilization. Gene organization and gene features in the gnt-sacXY region are discussed.


[Role of the determinance factor in formation of systemic connections during ontogenesis].
Behaviour of differentiating neuroblasts was studied in the nervous tissue culture of the newborn rats cortex and medulla oblongata of the rabbit embryo. The phasic-contrast microscopy and study of fixated preparations revealed that distribution of the neuroblasts over the substrate, their mutual orientation, the character of their branches growth and formation of contacts occur in vitro involving certain stages of morphological forming of the brain systemic organization. The clear trend of the neuroblasts behaviour to formation of certain connections suggests their genetic determinance. The distribution of neuroblasts over the substrate from different brain areas has its own phenotypic features.


Metagenomic analysis of rumen microbial population in dairy heifers fed a high grain diet supplemented with dicarboxylic acids or polyphenols.
The aim of this study was to investigate the effects of two feed supplements on rumen bacterial communities of heifers fed a high grain diet. Six Holstein-Friesian heifers received one of the following dietary treatments according to a Latin square design: no supplement (control, C), 60 g/day of fumarate-malate (organic acid, O) and 100 g/day of polyphenol-essential oil (P). Rumen fluid was analyzed to assess the microbial population using Illumina sequencing and quantitative real time PCR. The P treatment had the highest number of observed species (P < 0.10), Chao1 index (P < 0.05), abundance based coverage estimated (ACE) (P < 0.05), and Fisher's alpha diversity (P < 0.10). The O treatment had intermediate values between C and P treatments with the exception of the Chao1 index. The PCoA with unweighted Unifrac distance showed a separation among dietary treatments (P = 0.09), above all between the C and P (P = 0.05). The O and P treatments showed a significant increase of the family Christenenellaceae and a decline of Prevotella brevis compared to C. Additionally, the P treatment enhanced the abundance of many taxa belonging to Bacteroidetes, Firmicutes and Tenericutes phyla due to a potential antimicrobial activity of flavonoids that increased competition among bacteria. Organic acid and polyphenols significantly modified rumen bacterial populations during high-grain feeding in dairy heifers. In particular the polyphenol treatment increased the richness and diversity of rumen microbiota, which are usually high in conditions of physiological rumen pH and rumen function.


Sweat Sensor Based on Wearable Janus Textiles for Sweat Collection and Microstructured Optical Fiber for Surface-Enhanced Raman Scattering Analysis.
Wearable sweat sensors provide real-time monitoring of biomarkers, enabling individuals to gain real-time insight into their health status. Current sensors primarily rely on electrochemical mechanisms, limiting their capacity for the concurrent detection of multiple analytes. Surface-enhanced Raman scattering spectroscopy offers an alternative approach by providing molecular fingerprint information to facilitate the identification of intricate analytes. In this study, we combine a wearable Janus fabric for efficient sweat collection and a grapefruit optical fiber embedded with Ag nanoparticles as a sensitive SERS probe. The Janus fabric features a superhydrophobic side in contact with the skin and patterned superhydrophilic regions on the opposite surface, facilitating the unidirectional flow of sweat toward these hydrophilic zones. Grapefruit optical fibers feature sharp tips with the ability to penetrate transparent dressings. Its microchannels extract sweat through capillary force, and nanoliter-scale volumes of sweat are sufficient to completely fill them. The Raman signal of sweat components is greatly enhanced by the plasmonic hot spots and accumulates along the fiber length. We demonstrate sensitive detection of sodium lactate and urea in sweat with a detection limit much lower than the physiological concentration levels. Moreover, the platform shows its capability for multicomponent detection and extends to the analysis of real human sweat.


Microbial Inoculum Composition and Pre-weaned Dairy Calf Age Alter the Developing Rumen Microbial Environment.
The objective of this experiment was to determine if dosing pre-weaned calves with enriched ruminal microbiota alters the rumen microbial environment and growth performance. Twenty Holstein bull calves were removed from their dam at birth, fed 3.8 L colostrum within 4 h after birth, and housed individually. Calves were fed pasteurized milk 3×/d from 0 to 7 weeks of age and offered a texturized calf starter ad libitum at 6 days of age. A randomized complete block design with repeated measures and a 2 × 2 factorial arrangement of treatments was used to evaluate responses. Treatments were administered by stomach intubation once per week from 3 to 6 weeks of age and included: 50 mL autoclaved rumen fluid (RF), 50 mL bacterial-enriched RF (BE), 50 mL protozoal-enriched RF (PE); or 50 mL of each BE and PE inoculum. A rumen content composite was collected from 4 rumen fistulated, lactating cows and used to create the inocula. BE inocula were microscopically confirmed to be free of ciliate protozoa before inoculation, while PE contained 2.9 ± 2.2 × 105 protozoa/mL. RF was collected from the calves once per week before 50 mL of the inoculum was administered. Animal performance (e.g., weight gain and dry matter intake) was not altered by inocula type. All calves were microscopically free of rumen ciliates before inoculum administration and calves that did not receive PE remained ciliate-free. Ciliate protozoa were observed in RF from 6, 8, and 6 PE treated calves (n = 10) at weeks 4, 5, and 6, respectively. Ruminal NH3 was lower in PE treated calves (3.3 vs. 6.8 ± 1.0 mM), while ruminal butyrate molar percent was greater in BE treated calves (10.8 vs. 8.3 ± 0.8). Rumen bacterial diversity measures did not differ by treatment at 3-6 weeks. Individual calf bacterial communities from treated calves became temporarily similar to the inocula at 4 weeks of age, but these communities diverged from the inocula at 5 weeks. This study provides new information about two types of rumen-derived inocula and insight into the challenges of directing the rumen microbial environment in the pre-weaned calf.


Quantitative X-ray phase-contrast computed tomography at 82 keV.
Potential applications of grating-based X-ray phase-contrast imaging are investigated in various fields due to its compatibility with laboratory X-ray sources. So far the method was mainly restricted to X-ray energies below 40 keV, which is too low to examine dense or thick objects, but a routine operation at higher energies is on the brink of realisation. In this study, imaging results obtained at 82 keV are presented. These comprise a test object consisting of well-defined materials for a quantitative analysis and a tooth to translate the findings to a biomedical sample. Measured linear attenuation coefficients ? and electron densities ?e are in good agreement with theoretical values. Improved contrast-to-noise ratios were found in phase contrast compared to attenuation contrast. The combination of both contrast modalities further enables to simultaneously assess information on density and composition of materials with effective atomic numbers Z? > 8. In our biomedical example, we demonstrate the possibility to detect differences in mass density and calcium concentration within teeth.


Molecular biological methods for studying the gut microbiota: the EU human gut flora project.
Seven European laboratories co-operated in a joint project (FAIR CT97-3035) to develop, refine and apply molecular methods towards facilitating elucidation of the complex composition of the human intestinal microflora and to devise robust methodologies for monitoring the gut flora in response to diet. An extensive database of 16S rRNA sequences for tracking intestinal bacteria was generated by sequencing the 16S rRNA genes of new faecal isolates and of clones obtained by amplification with polymerase chain reaction (PCR) on faecal DNA from subjects belonging to different age groups. The analyses indicated that the number of different species (diversity) present in the human gut increased with age. The sequence information generated, provided the basis for design of 16S rRNA-directed oligonucleotide probes to specifically detect bacteria at various levels of phylogenetic hierarchy. The probes were tested for their specificity and used in whole-cell and dot-blot hybridisations. The applicability of the developed methods was demonstrated in several studies and the major outcomes are described.


A tailored approach to refractory severe Mepolizumab-associated headache: a case study.
Introduction. Biologic drugs have been shown to reduce asthma exacerbations, improve lung function and quality of life, reduce oral corticosteroid use in appropriately selected patients. Mepolizumab has been demonstrated to have a safety profile that is similar to placebo, however, when present side effects may lead to treatment discontinuation. Among these, headache is one of the most common.Case study. We hereby describe the case of a never-smoking male patient with an eosinophilic corticosteroid-dependent severe asthma. He displayed well controlled comorbidities and good adherence to the inhaled therapy. Mepolizumab was started in 2017 with an initial remarkable clinical improvement. After three doses of biologic therapy, he reported a severe orthostatic headache associated with vomiting, unresponsive to analgesic drugs, that required hospitalization. No other cause than treatment with Mepolizumab was found to be plausibly associated with this new-onset headache. The therapeutic regimen was modified by administering Mepolizumab for two consecutive months alternated with a one-month break.Results. The patient did not experience any further episodes of headache, while maintaining a good and stable control of his asthma. We were able to taper oral corticosteroids, and no flares-ups occurred in the following 5 years.Conclusion. Our experience indicates that a tailored strategy for managing severe asthmatic patients, who have experienced side effects from biologic drugs, can be effective in maintaining drug efficacy while minimizing side effects. Further studies on a larger number of patients are required to demonstrate whether the positive outcomes here described are replicable on a larger scale.


Cardiac vagal regulation and early peer status.
A sample of 341 5 (1/2) -year-old children participating in an ongoing longitudinal study was the focus of a study on the relation between cardiac vagal regulation and peer status. To assess cardiac vagal regulation, resting measures of respiratory sinus arrhythmia (RSA) and RSA change (suppression) to 3 cognitively and emotionally challenging tasks were derived. Results indicated that vagal regulation was positively associated with peer status. In addition, mediational analyses revealed that the relation between vagal regulation and peer status was mediated through better social skills for girls and better social skills and fewer behavior problems for boys. These findings are discussed in terms of the role of vagal regulation in the facilitation of children's positive social behavior.


Male Breast Cancer: Epidemiology and Risk Factors.
Male breast cancer is a rare malignancy that accounts for less than 1% of all cancers in men and less than 1% of all breast cancers. But the incidence is rising and in some patient groups reaching 15% over the course of their lives. The major risk factors for the development of male breast cancer include advancing age, hormonal imbalance, radiation exposure, and a family history of breast cancer. Regarding the latter, incidence can be linked to mutations in high- or low-penetrance genes. The most relevant risk factor for the development of male breast cancer is a mutation in the BRCA2 gene. Most cases present late because of a lack of awareness of the existence of such a malignancy in males and ignorance of the related risk factors. Additionally, males with breast cancer are at special risk for developing a second cancer. This in depth review highlights the epidemiology and risk factors for the development of male breast cancer.


Understanding the intramolecular vibrational energy transfer and structural dynamics of anionic ligands in a photo-catalytic CO2 reduction catalyst.
The knowledge of intramolecular vibrational energy redistribution (IVR) and structural dynamics of rhenium photo-catalysts is essential for understanding the mechanism of the photo-catalytic process of CO2 reduction. In this study, the rhenium compound Re(dcbyp)(CO)3NCS (Re-NCS), which served as a model CO2 reduction catalyst, was investigated using two dimensional infrared (2D IR) spectroscopy. The vibrational relaxation dynamics and rotational dynamics of Re-NCS were measured by monitoring both the CO and NCS vibrational modes. The rotational dynamics measurement of the CO vibrational stretch shows a single exponential decay with a time constant of 140 ± 10 ps. In contrast, a bi-exponential decay is needed to describe the rotational dynamics of the NCS stretching mode with time constants of 1.5 ± 0.3 ps and 189 ± 15 ps. The 2D IR experiment indicated that the carbonyl CO vibrational modes in Re-NCS are strongly coupled. Furthermore, the intramolecular vibrational energy transfer between CO and NCS stretching modes was observed and analyzed based on an energy exchange model. The energy down flowing transfer from CN to CO stretching mode was determined using time constants of 50 ps. The relatively slow intramolecular vibrational energy transfer rate suggests that there is a weak coupling between CO and NCS ligands. Further theoretical calculation showed that the coupling strength between CO and CN is relatively weak and is about 5-6 times smaller than the coupling strength between the CO vibrational modes in Re-NCS. The distinct structural dynamics of the NCS ligand in Re-NCS presented in this study should provide a fundamental understanding of the role of an anionic ligand in rhenium photo-catalysts, which is believed to play an important role in the photo-catalytic reduction of CO2.


Diameters of the main excretory ducts of the adult human submandibular and parotid gland: a histologic study.
In assessing new minimally invasive diagnostic techniques (duct endoscopy) and therapy (lithotripsy), it is of importance to know the true dimensions of the excretory ducts. Twenty-five ducts of the parotid gland and 20 ducts of the submandibular gland were examined histologically at different points of their anatomic course, and their in vivo diameters were evaluated with the use of a previously determined formalin-induced shrinking-factor. The mean diameter of Stensen's duct at four different points along its length ranged between 1.4 mm and 0.5 mm, with a maximum of 2.3 mm and a minimum of 0.1 mm, depending on the site. A narrowing at the middle of the duct was striking. In all preparations examined, the minimum width of the excretory duct was located at the ostium. In Wharton's duct the narrowest duct diameter was also identified at the ostium. The mean values for the duct diameters ranged between 1.5 mm and 0.5 mm. The largest duct diameter reached 2.2 mm; the smallest one, 0.2 mm. For diagnostic and therapeutic purposes, endoscopes, balloon catheters, and stone-extraction-baskets probably should, despite the extensibility of the duct, conform as much as possible to the physiologic duct widths. A diameter of 1.2 mm should be aimed at as an upper limit for these instruments. Our findings also suggest that, in the case of salivary stone lithotripsy, the best results will be achieved when the maximum size of stone fragments does not exceed 1.2 mm.


Heart of newt: a recipe for regeneration.
The field of regenerative medicine holds tremendous promise for the treatment of chronic diseases. While the adult mammalian heart has limited regenerative capacity, previous studies have focused on cellular therapeutic strategies in an attempt to modulate cardiac regeneration. An alternative strategy relies on the modulation of endogenous stem/progenitor cells or signaling pathways to promote cardiac regeneration. Several organisms, including the newt, have an incomparable capacity for the regeneration of differentiated tissues. An enhanced understanding of the signals, pathways, and factors that mediate the regenerative response in these organisms may be useful in modulating the regenerative response of mammalian organs including the injured adult heart.


Guidelines for Sanger sequencing and molecular assay monitoring.
Genetic sequencing, or DNA sequencing, using the Sanger technique has become widely used in the veterinary diagnostic community. This technology plays a role in verification of PCR results and is used to provide the genetic sequence data needed for phylogenetic analysis, epidemiologic studies, and forensic investigations. The Laboratory Technology Committee of the American Association of Veterinary Laboratory Diagnosticians has prepared guidelines for sample preparation, submission to sequencing facilities or instrumentation, quality assessment of nucleic acid sequence data performed, and for generating basic sequencing data and phylogenetic analysis for diagnostic applications. This guidance is aimed at assisting laboratories in providing consistent, high-quality, and reliable sequence data when using Sanger-based genetic sequencing as a component of their laboratory services.


inv(16) and NPM1mut AMLs engraft human cytokine knock-in mice.
Favorable-risk human acute myeloid leukemia (AML) engrafts poorly in currently used immunodeficient mice, possibly because of insufficient environmental support of these leukemic entities. To address this limitation, we here transplanted primary human AML with isolated nucleophosmin (NPM1) mutation and AML with inv(16) in mice in which human versions of genes encoding cytokines important for myelopoiesis (macrophage colony-stimulating factor [M-CSF], interleukin-3, granulocyte-macrophage colony-stimulating factor, and thrombopoietin) were knocked into their respective mouse loci. NPM1mut AML engrafted with higher efficacy in cytokine knock-in (KI) mice and showed a trend toward higher bone marrow engraftment levels in comparison with NSG mice. inv(16) AML engrafted with high efficacy and was serially transplantable in cytokine KI mice but, in contrast, exhibited virtually no engraftment in NSG mice. Selected use of cytokine KI mice revealed that human M-CSF was required for inv(16) AML engraftment. Subsequent transcriptome profiling in an independent AML patient study cohort demonstrated high expression of M-CSF receptor and enrichment of M-CSF inducible genes in inv(16) AML cases. This study thus provides a first xenotransplantation mouse model for and informs on the disease biology of inv(16) AML.


[Characteristics of the ultrastructural organization of Actinomyces rimosus and Actinomyces violocinereus in monocultures and in an association producing extracellular proteases].
The ultrastructural organization of Actinomyces rimosus and Actinomyces violocinereus was compared in monocultures and in associations. The cells of the two species can be discriminated by certain cytological characteristics. A rimosus predominated under the studied conditions and periods of growth. This organism had growth processes disordered (intrahyphal growth). A. violocinereus was characterized by the following processes in the association: peptidoglycan hypersynthesis, formation of calloses of the cell wall which occurred in parallel to hypertrophy of mesosomes, a loss of the capability to form capsules, and delayed spore formation. The reduced synthesis of granular and fibrillar material indicated that these products were not associated with exoprotease. The enzymatic activity was higher and could be detected in earlier in the association than in the monoculture of A. rimosus.


Nestin-Cre mice are affected by hypopituitarism, which is not due to significant activity of the transgene in the pituitary gland.
Nestin-Cre mice express Cre recombinase under control of the rat nestin promoter and central nervous system (CNS) enhancer. While endogenous Nestin is expressed in some other tissues including the pituitary gland, Nestin-Cre mice induce recombination predominantly in the CNS. For this reason, they have been widely used to explore gene function or cell fate in the latter. Pituitary hormonal deficiencies, or hypopituitarism, are associated with a wide range of symptoms and with a significant morbidity. These can have a neural and/or a pituitary origin as the gland's secretions are controlled by the hypothalamus. We report here that Nestin-Cre mice themselves are affected by mild hypopituitarism. Hence, physiological consequences are expected, especially in combination with defects resulting from Cre mediated deletion of any gene under investigation. To further investigate the origin of this phenotype, we re-examined the activity of the transgene. We compared it with expression of Nestin itself in the context of the hypothalamo-pituitary axis, especially in the light of a recent report showing pituitary Nestin-Cre activity, which contrasts with previous data. Our results disagree with those of this recent study and do not support the claim that Nestin positive cells are present in the pituitary anlagen, the Rathke's pouch (RP). Moreover we did not observe any significant activity in the post-natal pituitary, in agreement with the initial report.


Finite element analysis of a knee joint replacement during a gait cycle.
A three-dimensional (3-D) computer model was developed to predict, simultaneously, the knee joint replacement motions and the stresses occurring within the tibial insert under complex loading conditions. Friction contacts, polyethylene elastic- plastic behavior and soft tissue restraints were considered. Finite element analysis of the entire gait cycle was performed applying the displacement and loading conditions reported in the draft ISO 14243-1. The 3-D model was used to predict contact stresses and areas occurring within the polyethylene insert, when static loads of single instants on the gait cycle were applied. Results at 13% and 46% of the gait cycle were calculated with both entire cycle sim-ulation and single instant simulations. The predicted peak contact stress and contact area values were greater for single in-stant analyzes (respectively, 21% and 9%) if compared with those of the entire cycle simulation. In addition, single instant simulations were unable to predict accurately the contact region location, which was displaced in the anterior direction. Two different configurations of soft tissue restraints were compared; the first adopted from the draft ISO 14243-1 and the second from literature data. There were no significant differences observed between the two configurations. In particular, peak contact stresses followed the same trend, although the restraints of the literature data provided lower values in the last phase of the gait cycle. A preliminary verification of model reliability was performed comparing the tibial insert motions with data reported in the literature, under simplified loading conditions applied to the femoral component. (Journal of Applied Biomaterials & Biomechanics 2004; 2: 45-54).


Exploring calixarene-based clusters for efficient functional presentation of Streptococcus pneumoniae saccharides.
Calixarenes are promising scaffolds for an efficient clustered exposition of multiple saccharide antigenic units. Herein we report the synthesis and biological evaluation of a calix[6]arene functionalized with six copies of the trisaccharide repeating unit of Streptococcus pneumoniae (SP) serotype 19F. This system has demonstrated its ability to efficiently inhibit the binding between the native 19F capsular polysaccharide and anti-19F antibodies, despite a low number of exposed saccharide antigens, well mimicking the epitope presentations in the polysaccharide. The calix[6]arene mobile scaffold has been selected for functionalization with SP 19F repeating unit after a preliminary screening of four model glycocalixarenes, functionalized with N-acetyl mannosamine, and differing in the valency and/or conformational properties. This work is a step forward towards the development of new fully synthetic calixarenes comprising small carbohydrate antigens as potential carbohydrate-based vaccine scaffolds.


Differential interactions of sex pheromone and plant odour in the olfactory pathway of a male moth.
Most animals rely on olfaction to find sexual partners, food or a habitat. The olfactory system faces the challenge of extracting meaningful information from a noisy odorous environment. In most moth species, males respond to sex pheromone emitted by females in an environment with abundant plant volatiles. Plant odours could either facilitate the localization of females (females calling on host plants), mask the female pheromone or they could be neutral without any effect on the pheromone. Here we studied how mixtures of a behaviourally-attractive floral odour, heptanal, and the sex pheromone are encoded at different levels of the olfactory pathway in males of the noctuid moth Agrotis ipsilon. In addition, we asked how interactions between the two odorants change as a function of the males' mating status. We investigated mixture detection in both the pheromone-specific and in the general odorant pathway. We used a) recordings from individual sensilla to study responses of olfactory receptor neurons, b) in vivo calcium imaging with a bath-applied dye to characterize the global input response in the primary olfactory centre, the antennal lobe and c) intracellular recordings of antennal lobe output neurons, projection neurons, in virgin and newly-mated males. Our results show that heptanal reduces pheromone sensitivity at the peripheral and central olfactory level independently of the mating status. Contrarily, heptanal-responding olfactory receptor neurons are not influenced by pheromone in a mixture, although some post-mating modulation occurs at the input of the sexually isomorphic ordinary glomeruli, where general odours are processed within the antennal lobe. The results are discussed in the context of mate localization.


The cost of cerebral ischaemia.
Cerebral ischaemia is a major cause of disability and death globally and has a profoundly negative impact on the individuals it affects, those that care for them and society as a whole. The most common and familiar manifestation is stroke, 85% of which are ischaemic and which is the second leading cause of death and most common cause of complex chronic disability worldwide. Stroke survivors often suffer from long-term neurological disabilities significantly reducing their ability to integrate effectively in society with all the financial and social consequences that this implies. These difficulties cascade to their next of kin who often become caregivers and are thus indirectly burdened. A more insidious consequence of cerebral ischaemia is progressive cognitive impairment causing dementia which although less abrupt is also associated with a significant long-term disability. Globally cerebrovascular diseases are responsible for 5.4 million deaths every year (1 in 10 of total). Approximately 3% of total healthcare expenditure is attributable to cerebral ischaemia with cerebrovascular diseases costing EU healthcare systems 21 billion euro in 2003. The cost to the wider economy (including informal care and lost productivity) is even greater with stroke costing the UK 7-8 billion pound in 2005 and the US $62.7 billion in 2007. Cerebrovascular disease cost the EU 34 billion euro in 2003. From 2005 to 2050 the anticipated cost of stroke to the US economy is estimated at $2.2 trillion. Given the global scale of the problem and the enormous associated costs it is clear that there is an urgent need for advances in the prevention of cerebral ischaemia and its consequences. Such developments would result in profound benefits for both individuals and their wider societies and address one of the world's most pre-eminent public health issues.


Fish and long-chain omega-3 fatty acid intake and risk of coronary heart disease and total mortality in diabetic women.
Although several prospective cohort studies have found an inverse association between fish consumption and risk of coronary heart disease (CHD) or sudden cardiac death in the general population, limited data are available among diabetic patients. We examined prospectively the association between intake of fish and omega-3 fatty acids and risk of CHD and total mortality among 5103 female nurses with diagnosed type 2 diabetes but free of cardiovascular disease or cancer at baseline. Between 1980 and 1996 (45 845 person-years of follow-up), we documented 362 incident cases of CHD (141 CHD deaths and 221 nonfatal myocardial infarctions) and 468 deaths from all causes. Compared with women who seldom consumed fish (<1 serving/mo), the relative risks (RRs) (95% CI) of CHD adjusted for age, smoking, and other established coronary risk factors were 0.70 (0.48 to 1.03) for fish consumption 1 to 3 times per month, 0.60 (0.42 to 0.85) for once per week, 0.64 (0.42 to 0.99) for 2 to 4 times per week, and 0.36 (0.20 to 0.66) for 5 or more times per week (P for trend=0.002). Higher consumption of fish was also associated with a significantly lower total mortality (multivariate RR=0.48 [0.29 to 0.80] for > or =5 times per week [P for trend=0.005]). Higher consumption of long-chain omega-3 fatty acids was associated with a trend toward lower incidence of CHD (RR=0.69 [95% CI 0.47 to 1.03], P for trend=0.10) and total mortality (RR=0.63 [95% CI, 0.45 to 0.88], P for trend=0.02). A higher consumption of fish and long-chain omega-3 fatty acids was associated with a lower CHD incidence and total mortality among diabetic women.


Efficacy of an incentive-based community smoking cessation program.
Although the number of smokers has declined in recent years, many people remain resistant to traditional smoking cessation programs. Therefore, new and innovative approaches have been attempted. This study describes the application and effects of a community-wide smoking cessation program over three successive years. Smoking cessation rates ranged from 10.6% (CO verified) to 30.1% (self-report) at 1 month, and 17.3% to 24.5% at 1 year follow-up. Analyses revealed that successful quitters were more likely to have heart about the program at work and to have used materials contained in the self-help kit; and were more likely to be married and have a higher average income than either people who attempted to quit or made no attempt. Twelve-month follow-up data were used to classify participants into four new, distinct groups: maintainers, new quitters, relapsers, and nonquitters. Maintainers were more likely to have heard about the program at work and less likely to have become involved at Octoberfest. These programs do reach representative samples of the community. Their results compare favorably to other minimal contact intervention and physician-mediated efforts.


Increased beta I-adrenoceptor density after 6-hydroxydopamine pretreatment in rat colon and lung.
Estimation of beta-adrenoceptor-binding sites with 125I-(-)-pindolol in rat colon show a proportion of 30% beta I-adrenoceptors and 70% beta 2-adrenoceptors. Studies on the isolated colon strip have revealed a neuronal beta-adrenoceptor involved in the inhibitory response of colon motility to beta-adrenoceptor stimulation. In order to further characterize the beta-adrenoceptors in the colon, acute and chronic treatments with 6-hydroxydopamine were made. Both acute pretreatment of rats with 6-hydroxydopamine for 8 and 24 h (one intravenous injection) and chronic treatment for 3 days (implanted osmotic mini-pumps), reduced the noradrenaline tissue content by 90%, and successively increased the beta-adrenoceptor-binding sites from 14.2 to 21.7 fmol mg-I P-I in colon and from 158 to 240 fmol mg-I P-I in lung membranes. Displacement of the radiolabelled ligand by the selective beta-adrenoceptor antagonists, pafenolol and ICI 118.551 showed that the density of beta I-adrenoceptor binding sites was more than doubled, whereas the density of beta 2-adrenoceptor-binding sites was only marginally increased by chronic treatment with 6-hydroxydopamine. Thus sympathetic denervation by 6-hydroxydopamine treatment produced a selective increase in beta I-adrenoceptors in the rat colon. These results may indicate that stimulation of beta I-adrenoceptors in both colon and lung have a neuronal linkage.


[Effect of intermittent catheterization on urinary tract infections and incontinence in children with spina bifida].
Although the primary objective of clean intermittent (self) catheterization (CIC) was to regain continence in (older) children with myelomeningocele (MMC), we used the method also in the very young with detrusor-sphincter dyssynergia, to prevent future damage from the combined effects of obstruction and urinary tract infection (UTI). The results, in terms of incidence of UTI and degree of incontinence before and during CIC, were assessed in 61 children with MMC who had started CIC between 1985 and 1988. Mean follow up was 45.3 +/- 27.3 months, mean age at the start of CIC was 6.9 +/- 4.6 years. The incidence of UTI during CIC proved significantly lower than before CIC (chi 2 = 20.92, p less than 0.001), and the improvement in incontinence was also statistically significant (chi 2 = 45.16, p less than 0.001). In children with MMC, CIC seems ideally suited to prevent damage to the kidneys from the life-long problem of recurrent UTI's. It will also help in preventing bladder wall fibrosis--an important cause of loss of detrusor compliance--secondary to repeated UTIs.


Acute Alcohol Drinking Promotes Piecemeal Percepts during Binocular Rivalry.
Binocular rivalry refers to perceptual alternation when two eyes view different images. One of the potential percepts during binocular rivalry is a spatial mosaic of left- and right-eye images, known as piecemeal percepts, which may result from localized rivalries between small regions in the left- and right-eye images. It is known that alcohol increases inhibitory neurotransmission, which may reduce the number of alternations during binocular rivalry. However, it is unclear whether alcohol affects rivalry dynamics in the same manner for both coherent percepts (i.e., percepts of complete left or right images) and piecemeal percepts. To address this question, the present study measured the dynamics of binocular rivalry before and after 15 moderate-to-heavy social drinkers consumed an intoxicating dose of alcohol versus a placebo beverage. Both simple rivalrous stimuli consisting of gratings with different orientations, and complex stimuli consisting of a face or a house were tested to examine alcohol effects on rivalry as a function of stimulus complexity. Results showed that for both simple and complex stimuli, alcohol affects coherent and piecemeal percepts differently. More specifically, alcohol reduced the number of coherent percepts but not the mean dominance duration of coherent percepts. In contrast, for piecemeal percepts, alcohol increased the mean dominance duration but not the number of piecemeal percepts. These results suggested that alcohol drinking may selectively affect the dynamics of transitional period of binocular rivalry by increasing the duration of piecemeal percepts, leading to a reduction in the number of coherent percepts. The differential effect of alcohol on the dynamics of coherent and piecemeal percepts cannot be accounted for by alcohol's effect on a common inhibitory mechanism. Other mechanisms, such as increasing neural noise, are needed to explain alcohol's effect on the dynamics of binocular rivalry.


Perchlorate binding to cytochrome c: a magnetic and optical study.
1. The effects of perchlorate on cytochrome c have been investigated by 1H and 35Cl NMR, electron paramagnetic resonance and optical spectroscopy. 2. The pK values for the formation and disappearance of the major alkaline conformation were found to be displaced from 9.3 to 8.3 and from 10.4 to 10.9, respectively. The displacement was dependent on the ClO4(-) concentration below 0.1 M. 3. Competition experiments between perchlorate and chloride show that ClO4(-) binds both to the neutral and alkaline forms but with a higher affinity for the latter. The appearance of a new binding site in the alkaline form accounts for the markedly enhanced relaxation rate of 35ClO4(-) in this pH range. Complex formation between cyanide and the alkaline species results in the loss of this binding site, which probably is located close to or within the heme crevice. 4. The neutral form of ferricytochrome c also binds perchlorate strongly as evidence by the unique appearance of a high-spin signal dependent on pH and perchlorate concentration. This signal disappears with the same pK value as the neutral form. The effects of perchlorate on cytochrome c are due to specific binding of this ion.


Prognostic value of baseline absolute lymphocyte concentration and neutrophil/lymphocyte ratio in dogs with newly diagnosed multi-centric lymphoma.
Canine multi-centric B-cell lymphoma shares similarities with diffuse large B-cell (Non-Hodgkin's) lymphoma (NHL) in people. In people with NHL, lymphopenia at diagnosis and first relapse and neutrophil/lymphocyte ratio (N:L) > 3.5 are negative prognostic factors for survival. The objective of this study was to determine if lymphocyte concentration at diagnosis and first relapse and N:L were prognostic for survival in dogs with newly diagnosed multi-centric lymphoma. Medical records of 77 dogs with multi-centric lymphoma treated with a CHOP-based chemotherapy protocol were retrospectively evaluated. Absolute lymphocyte concentration and N:L ratio at presentation of dogs pre-treated with steroids was not significantly different from dogs who had not received steroids. On multivariate analysis, only immunophenotype remained significant for progression-free survival (PFS), whereas no variables remained significant for ST. A prospective study of these haematologic variables is warranted to assess their true significance.


Probiotics added to maternal nutrition affect ınfantile colic symptoms and fecal microbiota profile: a single-blind randomized controlled study.
Infantile colic has a multifactorial etiology; although various treatments have been attempted to manage and alleviate its symptoms, a solution is lacking, adversely affecting mothers and their babies. Recent studies have suggested that dysbiosis may play a role in the pathogenesis of infantile colic and that modulating the gut microbiota, including the use of probiotics, may aid its management. This single-blind randomized controlled study evaluated the effect of probiotics (Actiregularis, 5×106) added to the diet of mothers on infantile colic symptoms and neonatal gut microbiota content. A probiotic drink containing the Actiregularis (5× 106) strain was added to the diet of mothers in the experimental group once daily for 15 consecutive days. Stool samples were collected from each infant twice, on days 0 and 15, and fecal 16s rRNA gene sequencing and compositional-based metabolomic analyses were performed. The mothers recorded the babies' crying frequency and severity for 15 days using a daily form created by the researchers. This study was registered at ClinicalTrials.gov (ID: NCT04374955). Infants whose mothers were supplemented with Actiregularis for 15 days showed a decreased frequency (P= 0.00) and intensity (P<0.001) of crying as well as a significantly increased bacterial diversity in the stools (P=0.017). This variety was substantially affected by the addition of probiotic products. The greatest species diversity was observed in the group treated with probiotics, while the least diversity was observed in the control group (Shannon, P=0.0043; Simpson, P=0.017). Babies treated with Actiregularis added to their mother's diet for 15 days showed decreased crying frequency and intensity and increased bacterial diversity and density.


Hormone replacement therapy and breast cancer.
The concern that postmenopausal hormone replacement therapy (HRT) may cause cancer of the breast has lead to an enormous volume of research in epidemiology, endocrinology and tumour cell biology. The epidemiology has become extremely sophisticated because the anticipated effect is small and there are several confounding factors. The consensus today is that long-term HRT (>10 years) is associated with an increase in the risk of breast cancer which, on average, is equivalent to delaying menopause for the same period of time that the patient is on treatment. The risk is related to endogenous and exogenous oestrogen levels. Studies that have investigated individual susceptibility are reviewed, as are environmental factors such as the interaction of HRT with alcohol intake. The clinical implication of these data is that the dosage of HRT should be the smallest that is efficacious. Subcutaneous implants of oestrogen typically cause very high oestrogen levels and, in the opinion of this reviewer, should be restricted to women unable to take or absorb oestrogen by mouth or percutaneously. Finally, the issue of HRT for women with a history of breast cancer is considered. The potential is discussed for treatment of women with severe symptoms of oestrogen deficiency with a low dose of oestrogen, together with a selective oestrogen receptor modulator to protect the breast.


The Effect of Concomitant Rib Deformity in Congenital Scoliosis on Spinal Curve Correction After Segmental Pedicle Screw Instrumentation.
A single-center, prospective study. To investigate the effect of rib anomaly on surgical curve correction outcome in congenital scoliosis. The presence of rib anomalies may complicate surgical correction of congenital scoliosis. The outcome of surgical correction, however, has not been documented in scoliotic patients with and without rib deformity. Percent Cobb angle decrease (CAD) after operation was calculated in 94 patients with congenital scoliosis. Posterior segmental pedicle screw instrumentation (posterior approach) with or without previous anterior spinal release and fusion (anterior approach) was the method of correction. The impact of vertebral anomaly and rib deformity on CAD was examined. Although the type of vertebral anomaly had no significant effect on the mean CAD, it was significantly lower in 56 patients with rib deformity compared with that in the remaining patients without rib deformity (35.14%±15.83% vs. 51.54%±17.82%, P<0.001); particularly in those with complex, unilateral rib abnormalities, and in those with same-level vertebral and rib deformities. Patients' sex and age at the time of operation, rib number abnormality, and the type of operation (ie, posterior-only approach vs. anterior and posterior approach) did not contribute significantly to Cobb angle change after operation. Concomitant rib deformities, particularly of complex and unilateral types, significantly compromise operative curve correction outcome in congenital scoliosis.


Effects of a prostate awareness pilot on GP consultations and PSA requests.
A Department of Health prostate awareness initiative, piloted in Coventry in 2006, promoted reporting of symptoms of benign prostatic hyperplasia, prostatitis and prostate cancer to GPs without causing sudden increases in workload. Qualitative evaluation showed a wide distribution of materials. Evaluation of effects of the pilot on rates of GP urological consultations, prescriptions and prostate-specific antigen (PSA) requests in general practice in Coventry and three control areas. Data on GP consultations provided by the General Practice Research Database for three to five practices per area covered the periods 1 October 2005 to 31 March 2006 and 1 October 2006 to 31 March 2007. Pathology laboratory data on PSA requests covered 18 months from 1 December 2005 in consenting practices: 44/55 (80%) in Coventry and 102/159 (64%) in control areas. The rates of GP consultations for urological symptoms and of prescriptions issued for urological conditions per 100 person-years in men with no prior diagnosis of benign or malignant prostate disease and rates of PSA tests per 100 men were analysed. There was no significant change in consultation rates for urological symptoms over time in Coventry. The rate of prescriptions and of PSA testing increased in Coventry before the pilot began (P < 0.001) but there was no sudden increase after the pilot launch with similar trends in the control areas. There was no increase in GP workload following the start of the pilot. Routine data can be used in evaluation but should be linked to surveys of awareness, health-seeking behaviour and delivery of campaign materials.


Bax/bcl-2: cellular modulator of apoptosis in feline skin and basal cell tumours.
Bcl-2 and bax are two members of the BCL-2 gene family that play a prominent role in the regulation of apoptosis. Bax and bcl-2 expression were examined immunohistochemically in normal (healthy) feline skin and in 24 benign feline cutaneous basal cell tumours. The tumours were also examined for cellular proliferation by measurement of reactivity for the proliferation marker Ki-67, and for apoptosis by in-situ labelling for fragmented DNA. Bcl-2 was detected in normal basal epithelium and in 23 of 24 basal cell tumours. Bax was detected in both basal and suprabasal epithelium, but in only seven of 24 tumours. For tumours that expressed both bax and bcl-2, the bax:bcl-2 ratio was low. Neither bax nor bcl-2 expression was detected in 14 feline cutaneous squamous cell carcinomas. Basal cell tumours showed modest cellular proliferation (median, 17.5% Ki-67- reactive cells), but few (less than 1%) apoptotic cells. The slow, indolent growth of feline cutaneous basal cells in these benign skin tumours may be a response, at least in part, to opposing regulatory expressions of bcl-2 and bax.


Sampling considerations for multilevel crossing analysis.
This paper examines the amplitude fluctuations of band-limited functions with bounded zeroth absolute moments, and the problems associated with estimating the level crossing profiles of these functions. Level crossings have received increased attention as features for pattern recognition because of their capability to provide information related to both amplitude and frequency behavior. A detailed analysis of the average rate of change of band-limited functions is presented, including a derivation of the least upper bound on functions for which the zeroth absolute moments of the functions are bounded. The average rate of change of a function over an interval in which one endpoint of the interval is an extremum of the function is similarly bounded and used to establish a sampling rate which guarantees that between successive samples of a band-limited function with bounded zeroth absolute moment the function itself does not deviate from the amplitude interval defined by the samples by more than some predefined amplitude change. Based on these results, a theorem is developed which defines the sampling rate required to ensure that, in the estimation of level crossing profiles, no more than 2m (m >> 1) level crossings of m levels are missed per extremum of the sampled function. It is shown that the sampling rate defined by this theorem reduces to the well-known Nyquist rate for the special case of zero crossing analysis.


Strength and Deformation Behavior of Graphene Aerogel of Different Morphologies.
Graphene aerogels are of high interest nowadays since they have ultralow density, rich porosity, high deformability, and good adsorption. In the present work, three different morphologies of graphene aerogels with a honeycomb-like structure are considered. The strength and deformation behavior of these graphene honeycomb structures are studied by molecular dynamics simulation. The effect of structural morphology on the stability of graphene aerogel is discussed. It is shown that structural changes significantly depend on the structural morphology and the loading direction. The deformation of the re-entrant honeycomb is similar to the deformation of a conventional honeycomb due to the opening of the honeycomb cells. At the first deformation stage, no stress increase is observed due to the structural transformation. Further, stress concentration on the junctions of the honeycomb structure and over the walls occurs. The addition of carbon nanotubes and graphene flakes into the cells of graphene aerogel does not result in a strength increase. The mechanisms of weakening are analyzed in detail. The obtained results further contribute to the understanding of the microscopic deformation mechanisms of graphene aerogels and their design for various applications.


Genetic Predisposition to Type 2 Diabetes and Risk of Subclinical Atherosclerosis and Cardiovascular Diseases Among 160,000 Chinese Adults.
In observational studies, type 2 diabetes is associated with two- to fourfold higher risk of cardiovascular diseases (CVD). Using data from the China Kadoorie Biobank (CKB), we examined associations of genetically predicted type 2 diabetes with CVD among ∼160,000 participants to assess whether these relationships are causal. A type 2 diabetes genetic risk score (comprising 48 established risk variants) was associated with the presence of carotid plaque (odds ratio 1.17 [95% CI 1.05, 1.29] per 1 unit higher log-odds of type 2 diabetes; n = 6,819) and elevated risk of ischemic stroke (IS) (1.08 [1.02, 1.14]; n = 17,097), nonlacunar IS (1.09 [1.03, 1.16]; n = 13,924), and major coronary event (1.12 [1.02, 1.23]; n = 5,081). There was no significant association with lacunar IS (1.03 [0.91, 1.16], n = 3,173) or intracerebral hemorrhage (ICH) (1.01 [0.94, 1.10], n = 6,973), although effect estimates were imprecise. These associations were consistent with observational associations of type 2 diabetes with CVD in CKB (P for heterogeneity >0.3) and with the associations of type 2 diabetes with IS, ICH, and coronary heart disease in two-sample Mendelian randomization analyses based on summary statistics from European population genome-wide association studies (P for heterogeneity >0.2). In conclusion, among Chinese adults, genetic predisposition to type 2 diabetes was associated with atherosclerotic CVD, consistent with a causal association.


[Prognostic value of arterial lactate combined with central venous-to-arterial carbon dioxide difference to arterial-to-central venous oxygen content difference ratio in septic shock patients].
To evaluate the prognostic value of arterial lactate (Lac) combined with central venous-to-arterial carbon dioxide difference to arterial-to-central venous oxygen content difference ratio (Pcv-aCO2/Ca-cvO2) in patients with septic shock following early fluid resuscitation. A total of 97 patients with septic shock admitted to intensive care unit (ICU) of Lanzhou University Second Hospital from January 2017 to December 2019 were enrolled. The Pcv-aCO2/Ca-cvO2 ratio was calculated from blood gas analysis of radial artery and superior vena cava which was performed before resuscitation and at 6 hours of resuscitation at the same time. The patients were divided into death group and survival group according to the 28-day prognosis. The baseline data, acute physiology and chronic health evaluation II (APACHE II) score, sequential organ failure score (SOFA), clinical therapy, lactate clearance rate (LCR) at 6 hours, the length of ICU stay, hemodynamics and oxygen metabolism parameters before and after resuscitation were compared between the two groups. Risk factors were analyzed by multivariate Cox regression for 28-day mortality of patients with septic shock. The receiver operating characteristic (ROC) curve was plotted to assess the prognostic values of these factors for 28-day mortality. (1) Compared with the survival group, the patients in the death group showed significantly higher levels of APACHE II score (23.96±4.31 vs. 17.70±3.92) and SOFA score (12.74±2.80 vs. 9.23±2.43, both P < 0.01), significantly higher proportions of mechanical ventilation [85.2% (23/27) vs. 50.0% (35/70)] and continuous renal replacement therapy [CRRT; 51.9% (14/27) vs. 25.7% (18/70), both P < 0.05], a significantly more fluid replacement at 6 hours (L: 2.92±0.24 vs. 2.63±0.25, P < 0.01), a significantly lower level of LCR at 6 hours [(11.61±7.76)% vs. (27.67±13.71)%, P < 0.01], and a shorter length of ICU stay (days: 6.37±2.70 vs. 7.67±2.31, P < 0.05). (2) Compared with the survival group, the patients before resuscitation in the death group showed a significantly lower level of mean arterial pressure [MAP (mmHg, 1 mmHg = 0.133 kPa): 52.63±4.35 vs. 55.74±3.01, P < 0.01], significantly higher levels of Lac and Pcv-aCO2/Ca-cvO2 ratio [Lac (mmol/L): 7.13±1.75 vs. 5.22±1.36, Pcv-aCO2/Ca-cvO2 ratio: 1.67±0.29 vs. 1.48±0.22, both P < 0.01]; and the patients at 6 hours of resuscitation in the death group showed a significantly lower level of MAP (mmHg: 62.59±4.80 vs. 66.71±3.91, P < 0.01), significantly higher levels of central venous pressure (CVP), Lac, Pcv-aCO2 and Pcv-aCO2/Ca-cvO2 ratio [CVP (mmHg): 10.74±1.40 vs. 8.80±0.75, Lac (mmol/L): 6.36±1.86 vs. 3.90±1.95, Pcv-aCO2 (mmHg): 7.59±2.02 vs. 4.34±1.37, Pcv-aCO2/Ca-cvO2 ratio: 1.87±0.51 vs. 1.03±0.27, all P < 0.01]. (3) Multivariate Cox regression analysis showed that the independent risk factors for 28-day mortality in patients with septic shock were Lac and Pcv-aCO2/Ca-cvO2 ratio whether before or at 6 hours of resuscitation [Lac before resuscitation: relative risk (RR) = 1.434, 95% confidence interval (95%CI) was 1.070-1.922, P = 0.016; Lac at 6 hours of resuscitation: RR = 1.564, 95%CI was 1.202-2.035, P = 0.001; Pcv-aCO2/Ca-cvO2 ratio before resuscitation: RR = 2.828, 95%CI was 1.108-4.207, P = 0.038; Pcv-aCO2/Ca-cvO2 ratio at 6 hours of resuscitation: RR = 4.386, 95%CI was 2.842-5.730, P = 0.000]. (4) ROC curve analysis showed that Lac and Pcv-aCO2/Ca-cvO2 ratio at 6 hours of resuscitation had predictive value for the prognosis of patients with septic shock, the area under ROC curve (AUC) was 0.849 (95%CI was 0.762-0.914) and 0.905 (95%CI was 0.828-0.955), respectively. However, the predictive value of Lac combined with Pcv-aCO2/Ca-cvO2 ratio in patients with septic shock was significantly higher than Lac [AUC (95%CI): 0.976 (0.923-0.996) vs. 0.849 (0.762-0.914), Z = 3.354, P = 0.001], the sensitivity was 97.14%, and the specificity was 88.89%. Lac and Pcv-aCO2/Ca-cvO2 ratio are independent risk factors for predicting 28-day mortality in patients with septic shock. Lac combined with Pcv-aCO2/Ca-cvO2 ratio can assess the prognosis of patients with septic shock more accurately.


Interpretation, accuracy and management implications of FDG PET/CT in cutaneous malignant melanoma.
To investigate the accuracy of different interpretative approaches and to evaluate the management implications of fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) in cutaneous malignant melanoma. We retrospectively identified 60 consecutive patients who underwent 76 PET/CT scans for cutaneous malignant melanoma. PET/CT reports were classified as positive, negative, or equivocal for regional and distant disease. Scan indication (staging, restaging, surveillance, or therapeutic monitoring), tumour stage, presence or absence of regional or distant disease, and post-scan management changes were determined by review of all available medical records. Maximum standardized uptake values (SUV(max)) of all findings were noted. Diagnostic accuracy of PET/CT was compared using either a high or low threshold interpretation (i.e. subtle, but indeterminate findings coded negative or positive, respectively). The frequency of management changes was compared between patient subgroups (stratified by tumour stage or indication). Using a high threshold interpretative approach, the overall accuracy of PET/CT for disease was 72.4% (55/76), which was significantly (P<0.05) greater than the accuracy of 53.9% (41/76) seen when using a low threshold approach. Per scan accuracy by staging site was 92.1% (70/76) for regional and 76.3% (58/76) for distant disease. PET/CT changed management in 21 of 76 studies (27.6%). When stratified by stage and indication, management changes occurred in all patient subgroups, except for stage I patients (0 of 5). When interpreted with a high threshold approach, PET/CT demonstrates high accuracy for the diagnosis of both regional and distant disease in cutaneous malignant melanoma and frequently changes management in patients with stage II-IV disease referred for a variety of indications.


Effect of Angiotensin converting enzyme inhibitors and Angiotensin receptor blockers on patients following ablation of atrial fibrillation.
It is known that angiotensin converting enzyme inhibitors and angiotensin II type 1 receptor blockers (ACEIs and ARBs, respectively) are effective in preventing atrial fibrillation (AF) in high-risk patients. However, it is not known whether ACEIs and ARBs are effective in preventing the recurrence of AF after catheter ablation. One hundred fifty-two patients (mean age, 57+/-10 years; M : F=94 : 58) who underwent catheter ablation due to drug-refractory paroxysmal (mean age, 57+/-10 years; M : F=58 : 43) or persistent AF (mean age, 56+/-10 years; M : F=36 : 15) were enrolled. We compared the recurrence rates between the groups with and without ACEIs or ARBs use in paroxysmal and persistent AF. The mean duration of follow-up was 18+/-14 months. The overall recurrence rate after ablation therapy was 26% (n=39). The recurrence rate was significantly decreased in the patients with persistent AF with the use of ACEIs or ARBs (12.1% vs. 61.1%, p<0.01), but this difference was not observed in the patients with paroxysmal AF (24.2% vs. 22.9%, p=0.87). In patients with persistent AF with and without recurrence, the size of the left atrium (44.2+/-8.4 mm vs. 44.3+/-5.8 mm, respectively, p=0.45) and the ejection fraction (62+/-6.5% vs. 61.5+/-6.2%, respectively, p=0.28) were not significantly different. In multivariate analysis, the use of ACEIs or ARBs was independently associated with recurrence after adjusting for the size of the left atrium and the ejection fraction {odds ratio (OR)=0.078, 95% confidence interval (CI)=0.02-0.35, p<0.01}. ACEIs and ARBs were shown to be effective in preventing AF recurrence after catheter ablation in patients with persistent AF.


Severe Acute Hemolytic Transfusion Reaction Treated with Ruxolitinib and Plasma Exchange.
Acute hemolytic transfusion reaction is a rare but extremely mortal condition. Even small quantities of ABO-incompatible erythrocytes, as much as 50 mL, can lead to fatality. Since there is no successful standard therapy, preventive measures are very important. In this case report, we presented a 29-year-old woman who was transfused with 2 units of AB Rh-positive instead of 0 Rh-positive red blood cells following a cesarean section. As far as we know, this is the first patient in the literature for whom ruxolitinib was used as a part of therapy. The patient was referred to our center 22 h after the ABO-mismatched transfusion. On admission, she had severe hemolysis, acute renal failure, and disseminated intravascular coagulation. Massive plasma exchange, hemodialysis, and pulse steroid therapy were commenced. The patient was refractory to first-line therapies. She was intubated on day 2 due to hypoxia, respiratory failure and changes in consciousness. Ruxolitinib, 2 × 10 mg/day, was started on day 3. The patient's clinical status improved on day 6. Ruxolitinib was withdrawn on day 15, and the patient was discharged without any complications or sequels on day 26. Ruxolitinib may be life-saving in patients with ABO-incompatible transfusion reaction which follows a severe and catastrophic course.


The change of gravity vector induces short-term phosphoproteomic alterations in Arabidopsis.
Plants can sense the gravitational force. When plants perceive a change in this natural force, they tend to reorient their organs with respect to the direction of the gravity vector, i.e., the shoot stem curves up. In the present study, we performed a 4C quantitative phosphoproteomics to identify those altered protein phosphosites resulting from 150 s of reorientation of Arabidopsis plants on earth. A total of 5556 phosphopeptides were identified from the gravistimulated Arabidopsis. Quantification based on the 15N-stable isotope labeling in Arabidopsis (SILIA) and computational analysis of the extracted ion chromatogram (XIC) of phosphopeptides showed eight and five unique PTM peptide arrays (UPAs) being up- and down-regulated, respectively, by gravistimulation. Among the 13 plant reorientation-responsive protein groups, many are related to the cytoskeleton dynamic and plastid movement. Interestingly, the most gravistimulation-responsive phosphosites are three serine residues, S350, S376, and S410, of a blue light receptor Phototropin 1 (PHOT1). The immunoblots experiment confirmed that the change of gravity vector indeed affected the phosphorylation level of S410 in PHOT1. The functional role of PHOT1 in gravitropic response was further validated with gravicurvature measurement in the darkness of both the loss-of-function double mutant phot1phot2 and its complementary transgenic plant PHOT1/phot1phot2. SIGNIFICANCE: The organs of sessile organisms, plants, are able to move in response to environmental stimuli, such as gravity vector, touch, light, water, or nutrients, which is termed tropism. For instance, the bending of plant shoots to the light source is called phototropism. Since all plants growing on earth are continuously exposed to the gravitational field, plants receive the mechanical signal elicited by the gravity vector change and convert it into plant morphogenesis, growth, and development. Past studies have resulted in various hypotheses for gravisensing, but our knowledge about how the signal of gravity force is transduced in plant cells is still minimal. In the present study, we performed a SILIA-based 4C quantitative phosphoproteomics on 150-s gravistimulated Arabidopsis seedlings to explore the phosphoproteins involved in the gravitropic response. Our data demonstrated that such a short-term reorientation of Arabidopsis caused changes in phosphorylation of cytoskeleton structural proteins like Chloroplast Unusual Positioning1 (CHUP1), Patellin3 (PATL3), and Plastid Movement Impaired2 (PMI2), as well as the blue light receptor Phototropin1 (PHOT1). These results suggested that protein phosphorylation plays a crucial role in gravisignaling, and two primary tropic responses of plants, gravitropism and phototropism, may share some common components and signaling pathways. We expect that the phosphoproteins detected from this study will facilitate the subsequent molecular and cellular studies on the mechanism underlying the signal transduction in plant gravitropic response.


Extended Nucleic Acid (exNA): A Novel, Biologically Compatible Backbone that Significantly Enhances Oligonucleotide Efficacy in vivo.
Metabolic stabilization of therapeutic oligonucleotides requires both sugar and backbone modifications, where phosphorothioate (PS) is the only backbone chemistry used in the clinic. Here, we describe the discovery, synthesis, and characterization of a novel biologically compatible backbone, extended nucleic acid (exNA). Upon exNA precursor scale up, exNA incorporation is fully compatible with common nucleic acid synthetic protocols. The novel backbone is orthogonal to PS and shows profound stabilization against 3'- and 5'-exonucleases. Using small interfering RNAs (siRNAs) as an example, we show exNA is tolerated at most nucleotide positions and profoundly improves in vivo efficacy. A combined exNA-PS backbone enhances siRNA resistance to serum 3'-exonuclease by ~32-fold over PS backbone and >1000-fold over the natural phosphodiester backbone, thereby enhancing tissue exposure (~6-fold), tissues accumulation (4- to 20-fold), and potency both systemically and in brain. The improved potency and durability imparted by exNA opens more tissues and indications to oligonucleotide-driven therapeutic interventions.


Functional analysis of the gibbon foot during terrestrial bipedal walking: plantar pressure distributions and three-dimensional ground reaction forces.
This paper gives a detailed analysis of bipedal walking in the white-handed gibbon, based on collected pressure and force data. These data were obtained from four gibbons in the Wild Animal Park, Planckendael, Belgium, by using a walkway with integrated force plate and pressure mat. This is the first study that collects and describes dynamic plantar pressure data of bipedally walking gibbons, and combines these with force plate data. The combination of these data with previously described roll-off patterns of gibbons, based on general observations, video images, force plates, and EMG data, gives us a detailed description of foot function during gibbon bipedalism. In addition, we compare the observed characteristics of hylobatid bipedalism with the main characteristics of bonobo and human bipedalism. We found that gibbons are midfoot/heel plantigrade, and lack the typical heel-strike of other hominoids. The hallux is widely abducted and touches down at the onset of the stance phase, which results in an L-shaped course of the center of pressure. The vertical force curve is trapezoid to triangular in shape, with high peak values compared to humans. The braking component is shorter than the accelerating component, and shortens further at higher walking velocities. Speed has a significant influence on the forefoot peak pressures and on most of the defined gait parameters (e.g., vertical force peak), and it alters the foot contact pattern as well. The investigation of existing form-function relationships in nonhuman primates is essential for the interpretation of fossil remains, and might help us understand the evolution of habitual bipedal walking in hominids.


What is found positive in healthcare information and communication technology implementation?-the results of a nationwide survey in Finland.
Considerable expectations have been placed on information and communication technology (ICT) in improving the processes and quality of healthcare. Our purpose was to find out which element is found positive in healthcare ICT implementation. An online questionnaire on e-Health implementation submitted to all Finnish public health service providers and a sample from the private sector included an open question about which the electronic working methods, systems, or applications have most positively influenced the fluency or quality of service processes. The electronic health record was mentioned as an item that has positive influence by 52% of the respondents from the hospital districts, 27% of those from the primary healthcare centers, and 38% of those from the private providers. Digital radiology systems (including teleradiology) were mentioned by 52% of the hospital districts and 27% of the primary healthcare centers. The figures for digital laboratory systems (including telelaboratory) were 5% and 11%, respectively. The figures for teleradiology itself were 5% for the hospital districts and 15% for the primary healthcare centers; the figures for telelaboratory systems were 5% and 9%, respectively. The specialized healthcare seem to experience intraorganizational electronic services integrated to the electronic health record, such as digital radiology and laboratory services as exerting a positive influence, whereas the primary healthcare find such influence from different functions such as interorganizational data exchange and telemedicine services. These might indicate where the efforts should be focused when implementing ICT in healthcare.


Accounting for respiration is necessary to reliably infer Granger causality from cardiovascular variability series.
This study was designed to demonstrate the need of accounting for respiration (R) when causality between heart period (HP) and systolic arterial pressure (SAP) is under scrutiny. Simulations generated according to a bivariate autoregressive closed-loop model were utilized to assess how causality changes as a function of the model parameters. An exogenous (X) signal was added to the bivariate autoregressive closed-loop model to evaluate the bias on causality induced when the X source was disregarded. Causality was assessed in the time domain according to a predictability improvement approach (i.e., Granger causality). HP and SAP variability series were recorded with R in 19 healthy subjects during spontaneous and controlled breathing at 10, 15, and 20 breaths/min. Simulations proved the importance of accounting for X signals. During spontaneous breathing, assessing causality without taking into consideration R leads to a significantly larger percentage of closed-loop interactions and a smaller fraction of unidirectional causality from HP to SAP. This finding was confirmed during paced breathing and it was independent of the breathing rate. These results suggest that the role of baroreflex cannot be correctly assessed without accounting for R.


Longest held occupation in a lifetime and risk of disability in activities of daily living.
To examine the association between the longest held occupation in a lifetime and risk of disability in activities of daily living (ADL) among elderly people (65 years and older) in northern Taiwan. A case-control design was used nested within two cohorts of a total of 2198 elderly people who had been followed up either between 1993 and 1997 or between 1996 and 1997. Cases were 360 elderly people with ADL disability within the study period. For each case, two sex matched controls were randomly sampled from the pool of elderly people free from ADL disability. Occupational data were collected through interviews conducted in 1997. Performed job contents were classified into occupational categories and occupation based social classes. Unconditional logistic regression techniques were used to estimate relative risk and 95% confidence intervals (95% CIs) of ADL disability. Compared with people who were former legislators, government administrators, or business executives and managers, workers in agriculture, animal husbandry, forestry, or fishing (odds ratio (OR) 1.9, 95% CI 1.1 to 3.5) and workers in craft and related trades (OR 1.9, 95% CI 1.1 to 3.4) had significantly increased risks of subsequent ADL disability. Differential risks of ADL disability were found across social classes, with a significant dose-response trend in which unskilled blue collar workers had an 1.8 times higher risk of ADL disability than higher social classes of white collar workers. After adjustment for education, there was still an inverse relation between risk of ADL disability and social class. Although total control for all the known risk factors for ADL disability among elderly people was impossible, the results tend to suggest a potential for an effect of longest held occupation in a lifetime on risk of ADL disability.